Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1SC=[C:5]([C:7]2C=CC=[CH:9][CH:8]=2)[N:6]=1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[N:6]1[CH:5]=[CH:7][CH:8]=[CH:9][C:2]=1[S:1][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1
Reactant: Sc1nc(-c2ccccc2)cs1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(Sc2ccccn2)cc1
Temperature: 65 °C
Yield: 145.7 %

Procedure:
4-(2-(4-Phenyl)thiazolyl)thio-1-nitrobenzene: A solution of 2-mercapto-4-phenylthiazole (4.0 g, 20.7 mmoles) in DMF (40 mL) was treated with 1-fluoro-4-nitrobenzene (2.3 mL, 21.7 mmoles) followed by K2CO3 (3.18 g, 23 mmol), and the mixture was heated at approximately 65° C. overnight. The reaction mixture was then diluted with EtOAc (100 mL), sequentially washed with water (100 mL) and a saturated NaCl solution (100 mL), dried (MgSO4) and concentrated under reduced pressure. The solid residue was triturated with a Et2O/hexane solution to afford the desired product (6.1 g): TLC (25% EtOAc/75% hexane) Rf 0.49; 1H-NMR (CDCl3) δ 7.35-7.47 (m, 3H), 7.58-7.63 (m, 3H), 7.90 (d, J=6.9 Hz, 2H), 8.19 (d, J=9.0 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]=3)[CH:9]2[CH2:26][C:27]2[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35](O)=[O:36])=[CH:29][CH:28]=2)=[CH:4][CH:3]=1.Cl.[CH2:39]([O:46][NH2:47])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]=3)[CH:9]2[CH2:26][C:27]2[CH:28]=[CH:29][C:30](/[CH:33]=[CH:34]/[C:35]([NH:47][O:46][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:36])=[CH:31][CH:32]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1ccc(CC2c3ccc(OCc4ccccc4)cc3CCN2c2ccc(F)cc2)cc1
Reactant: NOCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Product: O=C(/C=C/c1ccc(CC2c3ccc(OCc4ccccc4)cc3CCN2c2ccc(F)cc2)cc1)NOCc1ccccc1
Yield: 72.9 %

Procedure:
The title compound was prepared as described in Example 34.B using (2E)-3-(4-{[2-(4-fluorophenyl)-6-(phenylmethoxy)(1,2,3,4-tetrahydroisoquinolyl)]methyl}phenyl)prop-2-enoic acid (0.365 g, 0.74 mmol), O-benzylhydroxylamine hydrochloride (0.16 g, 1.0 mmol), and 4-(N,N-dimethylamino)pyridine (0.121 g, 1.0 mmol) to provide the title compound (0.323 g, 73% yield): 1H NMR (CDCl3) 8.00 (br, 1H), 7.70 (d, 1H), 7.30-7.42 (m, 12H), 7.01 (d, 2H), 2.92 (m, 2H), 6.66-6.82 (m, 6H), 5.03 (s, 2H), 4.97 (s, 2H), 4.75 (t, 1H), 3.56 (m, 1H), 3.47 (m, 1H), 3.17 (dd, 1H), 2.88-3.00 (m, 2H), 2.66 (dt, 1H); ES-MS m/z 599 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[F:15])[N:11]=[CH:10][CH:9]=[CH:8]2.N1C=CC=CC=1.[Br:23]Br>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[F:15])[N:11]=[CH:10][C:9]([Br:23])=[CH:8]2
Reactant: BrBr
Reactant: COC(=O)Cc1cc2cccnc2cc1F
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)Cc1cc2cc(Br)cnc2cc1F
Temperature: 25 °C
Yield: 73 %

Procedure:
To a mixture of (7-fluoro-quinolin-6-yl)-acetic acid methyl ester (14.0 g, 63.9 mmol) and pyridine (10.4 mL, 127.8 mmol) in 200 mL of carbon tetrachloride was added bromine (6.6 mL, 127.8 mmol) in a dropwise fashion. The mixture was heated to reflux for 2 hrs before being cooled to ambient temperature. The liquid in the flask was decanted and washed with NaHCO3 and water. The dark solid on the bottom of the flask was treated with NaHCO3 and dichloromethane. The combined organic layers were washed with water, dried (Na2SO4) and evaporated to dryness. The crude product was purified via flash column chromatography eluting with petroleum ether/ethyl acetate (40/1˜3/1) to return 13.9 g (75% yield) of the title compound as white crystalline solid. 1H NMR (DMSO-d6): δ 8.89 (s, 1H), 8.27 (m, 1H), 7.66˜7.74 (m, 2H), 3.87 (s, 2H), 3.74 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7]([CH2:10][CH2:11]O)=[CH:8][O:9][C:5]=2[CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:34]I.N1C=CN=C1>C1COCC1>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7]([CH2:10][CH2:11][I:34])=[CH:8][O:9][C:5]=2[CH:4]=1
Reactant: II
Reactant: COc1ccc2c(CCO)coc2c1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc2c(CCI)coc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-(6-methoxy-1-benzofuran-3-yl)ethanol (960 mg, 5 mmol) in anhydrous THF (50 ml), triphenylphosphine (1.572 g, 6 mmol), iodine (1.518 g, 6 mmol) and imidazole (408 mg, 6 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 4 hrs and quenched with water. It was then extracted with chloroform, washed well with 5% NaS2O3 solution and the organic layer was dried over anhydrous MgSO4. It was filtered and concentrated. The residue was purified by silica-gel column chromatography by eluting it with 30% ethyl acetate:hexane. The product, namely 2-(6-methoxy-1-benzofuran-3-yl)ethyl iodide, was obtained as brown liquid; Yield: 1.2 g (80%); 302 (M+H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C@@H:11]2[C@H:15]([OH:16])[C@@H:14]([CH2:17][OH:18])[O:13][C@H:12]2[N:19]2[C:29]3[N:28]=[C:26]([NH2:27])[NH:25][C:23](=[O:24])[C:22]=3[N:21]=[CH:20]2)[CH:5]=[CH:4][N:3]=[CH:2]1.C[Si](Cl)(C)C.[C:35](Cl)(=[O:39])[CH:36]([CH3:38])[CH3:37]>N1C=CC=CC=1>[C:35]([NH:27][C:26]1[NH:25][C:23](=[O:24])[C:22]2[N:21]=[CH:20][N:19]([C:29]=2[N:28]=1)[C@@H:12]1[O:13][C@H:14]([CH2:17][OH:18])[C@@H:15]([OH:16])[C@H:11]1[O:10][CH2:9][CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:39])[CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)C(=O)Cl
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCCCn2ccnc2)c(=O)[nH]1
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCCCn2ccnc2)c(=O)[nH]1

Procedure:
2'-O-(imidazol-1-yl)butylguanosine in pyridine will be treated with trimethylsilyl chloride (5 eq) and isobutyryl chloride (5 eq) as per the procedure of Example 4 to yield the product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[N+:10]([O-])([OH:12])=[O:11].C1(O)C=CC=CC=1>C(O)(=O)C>[N+:10]([C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([Cl:1])[C:7]=1[Cl:8])([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: Oc1cccc(Cl)c1Cl
Solvent: CC(=O)O
Solvent: Oc1ccccc1
Product: O=[N+]([O-])c1ccc(O)c(Cl)c1Cl
Temperature: 25 °C
Yield: 71 %

Procedure:
A solution was prepared from 200 g of 2,3-dichlorophenol and 540 ml of glacial acetic acid. The solution was cooled, and a solution of 58 ml of 90% nitric acid in 160 ml of glacial acetic acid was added in dropwise fashion with stirring to the solution of the phenol. After half of the solution of the phenol had been added, the reaction mixture was allowed to warm to ambient temperature. It was stirred for 15 minutes at ambient temperature after all of the dichlorophenol had been added. The reaction mixture was then poured over 3,000 ml of an ice/water mixture. The yellowish product which precipitated was collected. The product was heated in a sublimation apparatus over a 4 day period at 80° C. at 4 torr. to remove any 2-nitro-5,6-dichlorophenol formed as a by-product in the above nitration. The residue was recrystallized from toluene to yield 80.3 g of 4-nitro-2,3-dichlorophenol; m.p.=148°-150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Co](Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)C=CC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3.27 g (7 mmol) of methyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-oct-2-enoate (example 3) in 32 ml methanol, 0.446 g (1.87 mmol) cobalt (II) chloride hexahydrate is added. The solution is cooled in an ice bath and 0.573 g (15 mmol) sodium borohydride is added in small portions. Vigorous gas evolution and formation of a black precipitate is observed during the addition of sodium borohydride. After completion of the addition, the ice bath is removed and the mixture stirred at room temperature for 1 h. The black precipitate is filtered off and washed with methanol. The combined filtrate is evaporated and the residue suspended in a mixture of 30 ml methylene chloride and 150 ml ether. The organic layer is washed with water. The aqueous phase is extracted with ether (2×50 ml). The combined organic extract is dried (MgSO4), filtered and the solvent evaporated. The residue is subjected to flash chromatography on silica using 3:2 ethyl acetate/hexane as the eluent to give methyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanoate, m.p. 81°-82°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=O)[CH2:6][C:7](=O)[C:8]1[S:9][CH:10]=[CH:11][N:12]=1)[CH3:2].O.[NH2:17][NH2:18]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[NH:18][N:17]=1)=[O:15])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)c1nccs1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(-c2nccs2)[nH]n1
Yield: 33.2 %

Procedure:
A mixture of 2,4-diketo-4-(thiazol-2-yl)butyric acid ethyl ester (9.88 g), hydrazine hydrate (1.74 g), and ethanol (25 ml) was refluxed for one hour, concentrated and the residue chromatographed (silica gel, EtOAc/Hex 1/2) to afford 2.58 g of 5-(thiazol-2-yl)pyrazole-3-carboxylic acid ethyl ester. NMR: 1.42 (t, 3H), 4.44 (q, 2H), 7.37 (s, 1H, 4-pyrazolyl H), 7.40, 7.75 (2d, 2H, thiazolyl H's).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[NH:13][C:14]3[C:19]([C:20]=1[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:6]=[CH:5]2.CC([O-])=O.[K+].[Br:31]Br>CC(O)=O.O>[Br:31][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:12]1[NH:13][C:14]3[C:19]([C:20]=1[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8]2
Reactant: BrBr
Reactant: CCCCCc1c(-c2ccc3cc(O)ccc3c2)[nH]c2ccccc12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCCc1c(-c2ccc3c(Br)c(O)ccc3c2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.7 %

Procedure:
To a stirred solution of 2-(6-hydroxy-2-naphthyl)-3-pentyl-1H-indole (1.27 g, 3.85 mmol) in HOAc (25 mL) at 0° C. was added KOAc (0.453 g, 4.62 mmol). The reaction was stirred at this temperature for 10 min., and then a solution of Br2 (0.218 mL, 4.24 mmol) in HOAc (5 mL) was added dropwise to it over a period of −10 min. The reaction mixture was allowed to warm to rt and stirred for 4 h. The reaction mixture was then diluted with H2O (50 mL) and extracted with EtOAc (200 mL). The organic layer was washed with brine (20 mL) and then dried (Na2SO4). After concentration, the residue was purified by the Biotage Flash 40 apparatus (10 to 30% EtOAc:petroleum ether gradient) to afford the product (0.782 g, 50%) as a solid (inseparable mixture of mono- and di-bromo-substituted analogs which were separated in the next step); monobrominated compound: mass spectrum [(−) ESI], m/z 406/408 (M−H)− and dibrominated analog: mass spectrum [(−) ESI], m/z 486 (M−H)−.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[N:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([CH2:23][CH2:24]Br)=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([CH2:23][CH2:24][N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[N:14]=4)[CH2:9][CH2:8]3)[CH2:5][CH2:6]2)=[CH:21][CH:20]=1
Reactant: Clc1ccc2c(n1)N(C1CCNCC1)CC2
Reactant: COc1ccc(CCBr)cc1
Product: COc1ccc(CCN2CCC(N3CCc4ccc(Cl)nc43)CC2)cc1
Yield: 16 %

Procedure:
1-(Piperidin-4-yl)-6-chloro-7-azaindoline (0.8 g) and 4-methoxyphenethyl bromide (0.72 g) were treated as in Example 2 to give the hydrochloride (220 mg) of the title compound as a pale yellow powder (yield: 16%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][CH2:12][CH:13]=[O:14])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.N1CCC[C@@H]1C(O)=O.[Cl:23]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:23][CH:12]([CH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[N:4]2)[CH:13]=[O:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=CCCc1ccc2nccnc2c1
Agent: O=C(O)[C@H]1CCCN1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=CC(Cl)Cc1ccc2nccnc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a cooled (0° C.) solution of 3-quinoxalin-6-ylpropanal (0.195 g, 0.00105 mol) in chloroform (3 mL) was added D-proline (24 mg, 0.00021 mol) followed by N-chlorosuccinimide (147 mg, 0.00110 mol). The mixture was stirred at 0° C. for 2 h, and then at RT overnight. The mixture was diluted with methylene chloride. The solution was washed with water, brine, dried over Na2SO4, filtered, and concentrated to yield the desired product (220 mg, 95%). LCMS: (M+H)=221.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[CH:30]1([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCOCC1.CN(C=O)C>[CH:30]1([O:36][C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: OC1CCCCC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(OC4CCCCC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and cyclohexanol in dioxane and DMF. ES-MS m/e (%): 469 (M+H+, 100).
Reaction SMILES: CCN(CC)CC.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:19]>C1COCC1>[CH2:8]([NH:15][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)CNCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of Et3N (13.55 g, 133.9 mmol) and benzylamine (11.96 g, 111.6 mmol) in THF (25 ml) was added 2-bromo-1-(4-methoxy-phenyl)-ethanone (25.56 g, 111.6 mmol). The reaction was stirred at RT for 60 minutes, then filtered and the filtrate concentrated in vacuo. The residue was purified via flash chromatography (SiO2, gradient column 35% to 80% EtOAc/hexanes) to give the title product (17.12 g, 67.0 mmol, 60% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:2]1.C1C=C[NH+]=CC=1.[Br:29][Br-]Br>O1CCCC1.C(Cl)(Cl)Cl>[Br:29][C:2]1[NH:1][C:9]2[C:4]([C:3]=1[CH2:10][CH2:11][N:12]1[C:13](=[O:22])[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]1=[O:21])=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccccc12
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCc1c(Br)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
To a solution of 2-[2-(1H-indol-3-yl)-ethyl]-isoindole-1,3-dione (1.0 g in a mixture of 10 mL dry tetrahydrofuran and 10 mL dry chloroform) at 0° C. was added pyridinium bromide perbromide (1.14 g) and the reaction stirred at 0° C. After 50 minutes, the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate. The organic portion was washed with saturated sodium bicarbonate (3x) and 0.3M sodium bisulfate (3x) then dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (hexane:ethyl acetate, 3:1) gave the title compound (1.2 g).
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[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21](/[C:23](=[N:27]/[C@H:28]([CH:33]([CH3:35])[CH3:34])[C:29]([O:31][CH3:32])=[O:30])/[S:24][CH2:25][CH3:26])[O:20][N:19]=2)=[CH:14][CH:13]=1>>[CH2:25]([S:24]/[C:23](=[N:27]\[C@H:28]([CH:33]([CH3:34])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])/[C:21]1[O:20][N:19]=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:9]([NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[O:10])=[CH:13][CH:14]=2)[CH:22]=1)[CH3:26]
Reactant: CCS/C(=N\[C@@H](C(=O)OC)C(C)C)c1cc(-c2ccc(N)cc2)no1
Reactant: O=C=Nc1ccccc1F
Product: CCS/C(=N\[C@@H](C(=O)OC)C(C)C)c1cc(-c2ccc(NC(=O)Nc3ccccc3F)cc2)no1
Yield: 76 %

Procedure:
The title compound was prepared according to the procedure as set forth in example 151, except that 1-fluoro-2-isocyanatobenzene was used in place of 1-fluoro-3-isocyanatobenzene and (R,Z)-methyl 2-((3-(4-aminophenyl)isoxazol-5-yl)(ethylthio) methyleneamino)-3-methylbutanoate was used in place of methyl 2-(3-(4-aminophenyl)isoxazole-5-carboxamido)-3-methylbutanoate to yield 76% of the title compound. MS (ESI): m/z 499 (M+H)+; 1HNMR (DMSO-d6, 300 MHz): δ 8.124 (s, 1H), 8.101 (d, 1H), 7.858 (s, 1H), 7.593 (m, 1H), 7.406 (m, 1H), 7.260 (s, 2H), 7.095 (m, 2H), 6.991 (m, 1H), 6.701(d, 1H), 4.583 (d, 1H), 3.843 (s, 3H), 3.075 (m, 2H), 2.450 (s, 1H), 1.331 (t, 3H), 1.076 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:11][CH2:12][CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:11][CH2:12][CH2:13][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Sc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCSc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 74.4 %

Procedure:
3,4-Dichlorobenzenethiol (500 mg, 2.79 mmol) and 2-(3-bromopropyl)isoindoline-1,3-dione (823 mg, 3.07 mmol) were stirred in DMF (2 mL) at rt. Cs2CO3 (1.64 g, 5.03 mmol) was added. The reaction mixture was stirred at rt for 14 h. H2O was added and the aqueous phase was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to give crude product. It was then triturated with ether to yield a white precipitate which was filtered and dried to give Intermediate 7A (760 mg, 2.075 mmol, 74.3% yield). LC-MS (ESI) 365.8 (M+H). RT=4.00 min (Method A).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[N:16][C:5]2[NH:6][C:7]3[CH2:15][CH:14]4[N:10]([CH2:11][CH2:12][CH2:13]4)[CH2:9][C:8]=3[C:4]=2[CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH2:31][CH2:32][C:33]2[CH:34]=[N:35][C:36]([CH3:39])=[CH:37][CH:38]=2)(=O)=O)=CC=1>CN(C=O)C.O>[CH3:1][C:2]1[CH:17]=[N:16][C:5]2[N:6]([CH2:31][CH2:32][C:33]3[CH:34]=[N:35][C:36]([CH3:39])=[CH:37][CH:38]=3)[C:7]3[CH2:15][CH:14]4[N:10]([CH2:11][CH2:12][CH2:13]4)[CH2:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Reactant: Cc1cnc2[nH]c3c(c2c1)CN1CCCC1C3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc2c(c1)c1c(n2CCc2ccc(C)nc2)CC2CCCN2C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-methyl-7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine (80 mg, 0.352 mmol) in DMF (1 mL) was added a suspension of NaH (42.0 mg, 1.05 mmol) in DMF (1 mL). After stirring for 5 min at rt, a solution of 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (307 mg, 1.05 mmol) in DMF (1 mL) was added dropwise into the reaction mixture and stirring continued for another 2 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×25 mL). The organic layer was washed with water (3×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 3-methyl-11-(2-(6-methylpyridin-3-yl)ethyl)-7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine;
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])(=[O:21])=[O:20])[O:13][C:14]=1[CH:15]=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S(C(N)C2OC(C(O)=O)=C(OCC3C=CC=CC=3)C(=O)C=2)(=O)=[O:37])C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])(=[O:21])=[O:20])[O:13][C:14]=1[C:15]([OH:37])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(c1cc(=O)c(OCc2ccccc2)c(C(=O)O)o1)S(=O)(=O)c1ccccc1
Reactant: O=Cc1oc(CNS(=O)(=O)c2ccccc2Cl)cc(=O)c1OCc1ccccc1
Product: O=C(O)c1oc(CNS(=O)(=O)c2ccccc2Cl)cc(=O)c1OCc1ccccc1

Procedure:
3-Benzyloxy-6-[(2-chloro-benzenesulfonylamino)-methyl]-4-oxo-4H-pyran-2-carboxylic acid (12-03) (2 g, crude) was synthesized as a white solid from N-(5-benzyloxy-6-formyl-4-oxo-4H-pyran-2-ylmethyl)-2-chloro-benzenesulfonamide (11-03) (2.8 g, 6.46 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid (12-01).
Reaction SMILES: I[C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24].C(N(C(C)C)CC)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[CH:17]([C:5]1[CH:4]=[C:3]([O:20][CH3:21])[C:2]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])=[CH:16][C:6]=1[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)([CH3:19])[CH3:18]
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C#C[Si](C)(C)C
Temperature: 50 °C
Reaction time: 17 h
Yield: 91.8 %

Procedure:
5-(5-Iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (2.0 g, 5 mmol), bis(triphenylphosphine)-Palladium dichloride (700 mg, 1 mmol) and CuI (100 mg, 0.5 mmol) were added to 14 mL dry THF under nitrogen. Trimethylsilyl acetylene (1.4 mL, 10 mmol) was added, followed by 7 mL diisopropylethylamine. The reaction mixture was stirred at 50° C. under nitrogen for 17 hours, then was allowed to cool for two hours with stirring. The reaction mixture was poured into 15% aqueous NHCl and extracted into EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed on 150 g of flash silica (2%-4% MeOH/CH2Cl2) to give 1.70 g of 5-(2-Isopropyl-4-methoxy-5-trimethylsilanylethynyl-phenoxy)-pyrimidine-2,4-diamine, MS (M+H)=371.