Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH2:9][C:10]1[O:11][CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:14]=1)C1C=CC=CC=1.B(Br)(Br)[Br:23].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:23][CH2:9][C:10]1[O:11][CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:14]=1
Reactant: Clc1ccc(-c2coc(COCc3ccccc3)n2)cc1
Reactant: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1ccc(-c2coc(CBr)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
A solution of 2-Benzyloxymethyl-4-(4-chloro-phenyl)-oxazole (1.10 g, 3.6 mmol) in 10 ml of DCM was cooled to −78° C. followed by addition of BBr3 (1.76 ml, 18.0 mmol). The reaction mixture was stirred at 25° C. for 2 h. After the completion of the reaction mixture (TLC monitoring), solution of NaHCO3 (20 mL) was added at 0° C. and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated to get the desired product (0.5 g, 49%, crude).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:39])[N:4]([C:19]2[CH:20]=[C:21]([CH:36]=[CH:37][CH:38]=2)[CH2:22][NH:23][C:24](=O)[O:25]C2C=CC([N+]([O-])=O)=CC=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[CH3:40][NH:41][CH3:42]>ClCCl>[Br:1][C:2]1[C:3](=[O:39])[N:4]([C:19]2[CH:20]=[C:21]([CH:36]=[CH:37][CH:38]=2)[CH2:22][NH:23][C:24](=[O:25])[N:41]([CH3:42])[CH3:40])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CNC
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cccc(CNC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Solvent: ClCCl
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cccc(CNC(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
To a reaction vessel (borosilicate culture tube) was added 4-nitrophenyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzylcarbamate (from step 1) (0.150 g, 0.250 mmol) and dichloromethane (2.5 mL). The parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 15 minutes. A stock solution of N,N-dimethylamine in tetrahydrorfuran (0.15 mL, 2.0 M) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature overnight. The reaction mixture was concentrated and subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) which afforded an off white solid (0.065 g, 51%). 1H NMR (400 MHz, DMF-d6) δ 7.58 (app q, J=7.79 Hz, 1H), 7.42 (app t, J=7.65 Hz, 1H), 7.37 (app d, J=7.79 Hz, 1H), 7.08 (s, 1H), 7.03 (app dt, J=1.58, 5.37 Hz, 1H), 6.96 (app dt, J=2.55, 8.39 Hz, 1H), 6.88-6.83 (m, 1H), 6.06 (s, 1H), 5.24 (s, 2H), 4.95 (app t, J=5.57 Hz, 1H), 4.42 (app dddd, J=5.10, 5.71, 10.20, 15.17 Hz, 2H), 2.90 (s, 6H), 1.96 (s, 3H). ES-HRMS m/z 506.0848 (M+H C23H22BrF2N3O3 requires 506.0885).
Reaction SMILES: [C:1]([C:3]1[C:4]([N:9]=[CH:10][N:11](C)C)=[N:5][CH:6]=[N:7][CH:8]=1)#[N:2].N[C:15]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=2)[CH:18]=[CH:17][C:16]=1[S:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1.NC1C=C(C)C=CC=1SC1C=CC(O)=CC=1.C(C1C(N=CN(C)C)=NC(SCC)=NC=1)#N>>[Br:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[CH2:22][O:21][C:19]1[CH:20]=[CH:15][C:16]([S:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)=[C:17]([NH:2][C:1]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][CH:8]=3)[N:9]=[CH:10][N:11]=2)[CH:18]=1
Reactant: Nc1cc(OCc2cccc(Br)c2)ccc1Sc1ccc(O)cc1
Reactant: CN(C)C=Nc1ncncc1C#N
Agent: CCSc1ncc(C#N)c(N=CN(C)C)n1
Agent: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Product: Oc1ccc(Sc2ccc(OCc3cccc(Br)c3)cc2Nc2ncnc3ncncc23)cc1

Procedure:
The product from Example 194A was reacted with the product from Example 15A according to the procedure from Example 156C substituting the product from Example 15A for the product from Example 6c and substituting the product from Example 194A for the product from Example 156B to provide the crude product which was purified by HPLC with NH4OAc to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm: 5.12 (s, 2H), 6.64 (d, J=8.82 Hz, 2H), 6.93-7.04 (m, 1H), 7.10 (d, J=8.82 Hz, 2H), 7.14-7.23 (m, 2H), 7.36 (t, J=7.72 Hz, 1H), 7.43-7.49 (m, 1H), 7.54 (dt, J=7.81, 1.61 Hz, 1H), 7.65 (d, J=1.47 Hz, 1H), 9.04 (m, 1H), 9.63 (s, 1H), 10.29 (m, 1H); MS (ESI−) m/z 531 (M−H)−.
Reaction SMILES: NC1NC=NC=1C(N)=O.[N+:10](=[C:12]1[NH:16][CH2:15][N:14]=[C:13]1[C:17]([NH2:19])=[O:18])=[N-:11].[CH3:20][N:21]=[C:22]=[O:23]>ClCCl>[CH3:20][N:21]1[N:11]=[N:10][C:12]2[N:16]([CH:15]=[N:14][C:13]=2[C:17]([NH2:19])=[O:18])[C:22]1=[O:23]
Reactant: [N-]=[N+]=C1NCN=C1C(N)=O
Reactant: CN=C=O
Agent: NC(=O)c1nc[nH]c1N
Solvent: ClCCl
Product: Cn1nnc2c(C(N)=O)ncn2c1=O

Procedure:
Med. Chem. 1984, 27, 196-201 describes a process wherein 5-amino-1H-imidazole-4-carboxamide is converted into 5-diazo-1H-imidazole-4-carboxamide, which is then cyclised with methylisocyanate in dichloromethane to provide a high yield of temozolomide.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[N:20]([CH2:21][CH2:22][O:23][CH2:24][CH:25]=[CH2:26])[C:19]3[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH2:24]([O:23][CH2:22][CH2:21][N:20]1[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[N:17]=[C:16]1[C:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15])[CH:25]=[CH2:26]
Reactant: C=CCOCCn1c(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: C=CCOCCn1c(C(=O)C2CCNCC2)nc2ccccc21
Reaction time: 0.5 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1-(2-allyloxy-ethyl)-1H-benzoimidazole-2-carbonyl)-piperidine (1.0 mmol) and dioxane (3 mL). Add a solution of hydrochloric acid in dioxane (4 mL, 4 M, 16 mmol). After 30 minutes, partition the residue between ethyl acetate and saturated aqueous sodium bicarbonate solution. Separate the organic layer and extract with saturated aqueous sodium chloride solution. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: IC.[Br:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[C:8]([F:18])[C:7]([OH:19])=[C:6]([CH:20]=[O:21])[CH:5]=1.[C:22](=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[C:8]([F:18])[C:7]([O:19][CH3:22])=[C:6]([CH:20]=[O:21])[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(Br)c(-c2ccc(F)cc2F)c(F)c1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C=O)cc(Br)c(-c2ccc(F)cc2F)c1F
Yield: 93.2 %

Procedure:
Iodomethane (0.907 g) was added at room temperature to a mixture of 6-bromo-2,2′,4′-trifluoro-3-hydroxybiphenyl-4-carbaldehyde (1.41 g), potassium carbonate (1.18 g), and DMF (20 mL), and the resultant mixture was stirred at 60° C. for 3 hours in a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.37 g).
Reaction SMILES: NCC(C1NC2C(C=1)=CC=CN=2)OC1CCCCO1.[Cl:20][C:21]1[CH:29]=[CH:28][N:27]=[C:26]2[C:22]=1[CH:23]=[C:24]([CH:30]([O:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][O:45]1)[CH2:31][N:32]1C(=O)C3=CC=CC=C3C1=O)[NH:25]2.NN.O>CCO>[NH2:32][CH2:31][CH:30]([C:24]1[NH:25][C:26]2[C:22]([CH:23]=1)=[C:21]([Cl:20])[CH:29]=[CH:28][N:27]=2)[O:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][O:45]1
Reactant: O=C1c2ccccc2C(=O)N1CC(OC1CCCCO1)c1cc2c(Cl)ccnc2[nH]1
Agent: NCC(OC1CCCCO1)c1cc2cccnc2[nH]1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCC(OC1CCCCO1)c1cc2c(Cl)ccnc2[nH]1
Yield: 98.4 %

Procedure:
Following the same procedure as for 9a, from 4-Chloro-2-[2-phthalimido-1-(2,3,5,6-tetrahydropyran-2-yl)oxyethyl]-7-azaindole (950 mg, 2.2 mmol) in EtOH (50 ml) and NH2NH2.H2O (250 μl, 4.4 mmol). After a reaction time of 3 h. a diastereomeric mixture (1:1) of 9c (640 mg, 97%/o) was obtained.
Reaction SMILES: C(OOC(C)(C)C)(C)(C)C.[Br:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1Br>>[Br:11][CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCCc1ccccc1Br
Agent: CC(C)(C)OOC(C)(C)C
Product: BrC=Cc1ccccc1
Temperature: 360 °C

Procedure:
2 g of di-tert-butyl peroxide were dissolved in 100 g of β-bromoethyl bromobenzene and fed into the reactor described in Example 1 at a rate of 70 g/h together with superheated steam (20 g/h). The temperature of the reaction was maintained at 360°C. The products yielded bromostyrene at a conversion of 90%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Cl[C:28]1[N:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[N:37]=[CH:36][C:35]6[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=6)[N:29]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Clc1ncc2ccccc2n1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ncc6ccccc6n5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-chloro-quinazoline following a procedure analogous to that described for Intermediate 12; K2CO3 and acetonitrile are used as base and solvent, respectively, at 50° C. LC (method 3): tR=0.53 min; Mass spectrum (ESI+): m/z=487 [M+H]+.
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:17][CH3:18])[CH2:5][CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)[CH3:3].S(Cl)([Cl:21])=O>C(Cl)Cl>[ClH:21].[CH2:2]([N:4]([CH2:17][CH3:18])[CH2:5][CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([Cl:1])=[O:13])=[CH:10][CH:9]=1)[CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CCN(CC)CCOc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc(C(=O)Cl)cc1

Procedure:
4-(2-Diethylaminoethoxy)benzoic acid hydrochloride is suspended in methylene chloride and a five-fold excess of thionyl chloride is added. The mixture is refluxed until the solid dissolves, then concentrated under reduced pressure to give 4-(2-diethylaminoethoxy)benzoyl chloride hydrochloride.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[NH:28]1[CH:32]([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[C:31](=[O:41])[NH:30][C:29]1=[O:42]>>[NH:28]1[CH:32]([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH:38]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:36][CH:35]=2)[C:31](=[O:41])[NH:30][C:29]1=[O:42]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: Nc1ccc(CC2NC(=O)NC2=O)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CC2NC(=O)NC2=O)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-((imidazolidin-2,4-dion-5-yl)-methyl)-aniline Rf value: 0.6 (silica gel, methylene chloride/methanol=5:1) C27H22N4O5
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=O)[CH:12]=[CH:13][CH:14]=1.C1(C)C=CC(S([CH2:32][N+:33]#[C-])(=O)=O)=CC=1.C(OCC)C>C(O)(C)(C)C.COCCOC.COCCOC.O>[C:32]([CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH3:7])[CH:10]=1)#[N:33]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1cccc(CC2CCCCC2=O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CC(C)(C)O
Product: COc1cccc(CC2CCCCC2C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
A solution of potassium tert-butoxide (4.10 g) in tert-butanol-1,2-dimethoxyethane (1:1, 38 ml) was added dropwise to a stirred solution of 2-[(3-methoxyphenyl)-methyl]cyclohexanone (4.10 g) and (p-tolylsulfonyl)methyl isocyanide (4.10 g) in 1,2-dimethoxyethane under ice cooling over 30 minutes. The resulting mixture was stirred at the same temperature for 1 hour and at room temperature for 2 hours and 30 minutes, and then a mixture of diethyl ether and water was added thereto. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was chromatographed over silica gel using n-hexane--ethyl acetate as an eluent to afford 1-cyano-2-[(3-methoxyphenyl)methyl]cyclohexane (3.73 g) as an oil.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7](C(OCC3C4C=CC=CC=4C4C3=CC=CC=4)=O)[CH2:8][C@H:9]([S:10][CH3:11])[C@H:5]2[O:4][CH2:3]1.Cl.O[C@@H]1[C@H]2N(C(OC(C)(C)C)=O)C[C@H](SC)[C@H]2OC1>O1CCOCC1>[CH3:11][S:10][C@H:9]1[CH2:8][NH:7][C@@H:6]2[C@@H:2]([OH:1])[CH2:3][O:4][C@H:5]12
Reactant: CS[C@H]1CN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@H]2[C@@H]1OC[C@@H]2O
Agent: CS[C@H]1CN(C(=O)OC(C)(C)C)[C@H]2[C@@H]1OC[C@@H]2O
Agent: Cl
Solvent: C1COCCO1
Product: CS[C@H]1CN[C@H]2[C@@H]1OC[C@@H]2O
Reaction time: 1 h

Procedure:
Preparation of (3R,3aR,6S,6aS)(9H-fluoren-9-yl)methyl 3-hydroxy-6-(methylthio)tetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (55) A solution of HCl in 1,4-dioxane (4M, 5.5 mL) was added to thiomethylether (54) (152 mg, 0.55 mmol). The mixture stirred for 1 hour then the solvents removed in vacuo. The residue was azeotroped with CH3CN (5 mL) to obtain (3R,3aR,6S,6aS)-6-(methylthio)hexahydro-2H-furo[3,2-b]pyrrol-3-ol which was used without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([OH:3])=O.[PH2:12]([OH:14])=[O:13]>C1(C)C=CC=CC=1>[O:7]=[C:6]1[C:5]2[C:4](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:1]([P:12]([CH:6]2[C:5]3[C:4](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:1](=[O:3])[O:7]2)(=[O:14])[OH:13])[O:3]1
Reactant: O=Cc1ccccc1C(=O)O
Reactant: O=[PH2]O
Solvent: Cc1ccccc1
Product: O=C1OC(P(=O)(O)C2OC(=O)c3ccccc32)c2ccccc21
Yield: 91.5 %

Procedure:
Into a suspension of 30.1 grams (0.2 moles) of 2-carboxybenzaldehyde in 220 mL of toluene is added 10.4 mL (0.1 moles) of 50% aqueous hypophosphorous acid. The resultant mixture is heated to reflux and 9 mL of water is collected by azeotropic distillation using a Dean-Stark receiver. Upon cooling the reaction mixture, the precipitated white solid is collected by filtration and dried to give 30.2 grams (91% yield) of bis-(3-oxo-1,3-dihydro-isobenzofuran-1-yl)-phosphinic acid as a white powder, mp 280-285° C.
Reaction SMILES: Br[C:2]1[CH:16]=[C:15]2[C:5]([C:6](=[O:18])[C:7](=[O:17])[C:8]3[S:13][CH2:12][CH:11]([CH3:14])[O:10][C:9]=32)=[CH:4][CH:3]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:14][CH:11]1[O:10][C:9]2[C:15]3[C:5]([C:6](=[O:18])[C:7](=[O:17])[C:8]=2[S:13][CH2:12]1)=[CH:4][CH:3]=[C:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:16]=3
Reactant: CC1CSC2=C(O1)c1cc(Br)ccc1C(=O)C2=O
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC1CSC2=C(O1)c1cc(-c3ccccc3)ccc1C(=O)C2=O
Temperature: 90 °C
Yield: 24 %

Procedure:
To a solution of 9-bromo-2-methyl-2,3-dihydronaphtho[1,2-b][1,4]oxathiine-5,6-dione (0.1 g, 0.31 mmol) in 1,4-dioxane (1.0 mL) was added phenylboronic acid (0.056 g, 0.459 mmol), potassium carbonate (0.118 g, 0.857 mmol) and 1,1′-bis[di(t-butylphosphine)ferrocene]PdCl (0.02 g, 0.031 mmol). The reaction mixture was heated at 90° C. for 6 hours. The resulting mixture was filtered and solvent removed under reduced pressure. The crude mixture was purified by flash column chromatography (SiO2, 16% EtOAc in hexanes) to give the product as a purple solid (0.024 g, 20%). M.p.=190-192° C.; 400 MHz 1H NMR (CDCl3) δ: 8.11 (d, J=7.6, 1H), 7.93 (d, J=1.6, 1H), 7.66 (m, 3H), 7.45 (m, 3H), 4.70 (m, 1H), 3.11 (d, J=13.2, 1H), 2.94 (m, 1H), 1.65 (m, 3H); LCMS: 323 [M+H].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][CH3:25])[CH:19]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1>>[CH2:24]([C:20]1[CH:19]=[C:18]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:32]4[C:27]([F:26])=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:3]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:23]=[CH:22][N:21]=1)[CH3:25]
Reactant: OB(O)c1cccnc1F
Reactant: CCc1cc(C2(c3cccc(Br)c3)N=C(N)c3ccccc32)ccn1
Product: CCc1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)c3ccccc32)ccn1
Yield: 61 %

Procedure:
The title compound was synthesized from 1-(3-bromophenyl)-1-(2-ethylpyridin-4-yl)-1H-isoindol-3-amine (Example 110) as described in Example 67 Scheme #10, D in 61% yield using 2-fluoropyridine-3-boronic acid. 1H NMR (DMSO-d6) δ 8.28 (d, J=5.31 Hz, 1 H), 8.20-8.11 (m, 1 H), 7.98-7.89 (m, 1 H), 7.79-7.71 (m, 2 H), 7.47-7.28 (m, 7 H), 7.15-7.10 (m, 1 H), 7.06 (dd, J=5.18, 1.64 Hz, 1 H), 6.83 (br s, 2 H), 2.60 (q, J=7.58 Hz, 2 H), 1.08 (t, J=7.58 Hz, 3 H); MS (ESI) m/z 409 [M+1]+.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[F:59][C:60]([F:71])([F:70])C1C=CC=CC=1C(Cl)=O>>[CH3:32][CH:31]([CH3:33])[C@H:26]([N:21]1[CH2:20][C:19]2[C:23](=[CH:24][C:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=4[C:60]([F:71])([F:70])[F:59])=[CH:15][CH:14]=3)=[CH:17][CH:18]=2)[C:22]1=[O:25])[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4C(F)(F)F)cc3)cc2C1=O
Yield: 73 %

Procedure:
The compound of example 199 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 2-trifluoromethyl benzoyl chloride.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1)=[O:32]>C(Cl)Cl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([N:17]2[CH2:18][CH2:19][CH:20]([O:23][C:31]([O:33][C:34]3[CH:35]=[CH:36][C:37]([N+:40]([O-:42])=[O:41])=[CH:38][CH:39]=3)=[O:32])[CH2:21][CH2:22]2)=[O:16])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Oc1ccc(Oc2ccccc2)cc1)N1CCC(O)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCN(C(=O)Oc2ccc(Oc3ccccc3)cc2)CC1
Reaction time: 2 h
Yield: 97.4 %

Procedure:
A solution of the alcohol (25 g, 80 mmol) produced in Example 2 and pyridine (6.4 mL, 80 mmol) in 300 mL of methylene chloride was added under nitrogen dropwise over one hour to a solution of 4-nitrophenyl chloroformate (16.1 g, 80 mmol) in 200 mL of methylene chloride at ice bath temperature. The reaction was stirred at ice bath temperature for two hours and then overnight at room temperature. The reaction was extracted one time with 1N HCl, two times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 37.3 g of an off-white solid. Recrystallization from 1:1 ethyl acetate: hexane gave 26.4 g (69%) of the title compound as an off-white solid, mp 108-109° C.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1.C(O)(=O)C>C(Cl)(Cl)Cl.ClCCl>[Br:1][C:9]1[CH:8]=[C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:5][C:4]=1[OH:3]
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(O)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
Bromine (16.59 g, 104 mmol) in chloroform (25 mL) was added dropwise to a stirred, cooled (0° C.) mixture of methyl 4-hydroxyphenylethanoate (17.25 g, 104 mmol) and acetic acid (10 mL) in chloroform (140 mL). The mixture was stirred at 0° C. for 1 h., diluted with dichloromethane (100 mL), washed with water (2×200 mL) and brine (200 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (25.43 g, 100%). 1H NMR (360 MHz, CDCl3) δ7.39 (1 H, d, J 2.0 Hz), 7.12 (1 H, dd, J 8.3, 2.0 Hz), 6.96 (1 H, d, J 8.3 Hz), 5.54 (1 H, br s), 3.70 (3 H, s), and 3.54 (2 H, s).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=O)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4].[Cl:25][C:26]1[CH:27]=[C:28]([CH2:33]/[C:34](=[N:37]/[H])/[NH:35]O)[CH:29]=[C:30]([Cl:32])[CH:31]=1.[O-]CC.[Na+]>CCO>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]2[O:21][N:35]=[C:34]([CH2:33][C:28]3[CH:29]=[C:30]([Cl:32])[CH:31]=[C:26]([Cl:25])[CH:27]=3)[N:37]=2)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)n(CCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Reactant: [H]/N=C(/Cc1cc(Cl)cc(Cl)c1)NO
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCn1c(=O)n(CCCc2nc(Cc3cc(Cl)cc(Cl)c3)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 140 °C
Yield: 50.7 %

Procedure:
To ethyl 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate (185 mg, 0.52 mmol) and (1Z)-2-(3,5-dichlorophenyl)-N-hydroxyethanimidamide (126 mg, 0.58 mmol; Entry 23, Table 7) in dry EtOH (2 ml) was added 21% wt. ethanolic sodium ethoxide solution (0.29 ml, 0.78 mmol) and the mixture was heated by microwaves at 140° C. for 10 min. The reaction was worked up by partition between EtOAc and 2M HCl and evaporating the organic phase. Purification by MDAP afforded the title compound as a solid (135 mg).