Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH2:2]([O:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:3].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:35][C:36]1([CH3:54])[CH:45]([N:46]2[C:50]([CH:51]=O)=[CH:49][N:48]=[CH:47]2)[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38](=[O:53])[O:37]1>C1COCC1>[CH2:2]([O:4][CH:5]=[CH:51][C:50]1[N:46]([CH:45]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38](=[O:53])[O:37][C:36]2([CH3:54])[CH3:35])[CH:47]=[N:48][CH:49]=1)[CH3:3]
Reactant: CCOC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC=Cc1cncn1C1c2ccccc2C(=O)OC1(C)C
Reaction time: 0.25 h

Procedure:
To a solution of ethoxymethyltriphenylphosphonium chloride (0.426 g, 1.2 mmol) in THF (5 mL) at ambient temperature is added lithium hexamethyldisilazide (1M in THF, 1.3 mL, 1.3 mmol) and the mixture is stirred for 15 min. 3-(3,3-Dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carbaldehyde (0.27 g, 1.0 mmol) (Example 9a) in THF (5 mL) and the mixture is stirred at ambient temperature overnight, then filtered. The filtrate is concentrated in vacuo to give crude 4-[5-(2-ethoxy-vinyl)-imidazol-1-yl]-3,3-dimethyl-isochroman-1-one, which is redissolved in methanol (5 mL). Pd/C (0.500 g) is added and the reaction vessel is flushed with hydrogen gas and stirred under balloon pressure at 50° C. overnight. The mixture is filtered, and the filtrate is concentrated in vacuo to give a residue which is purified by semi-preparative reverse phase HPLC to give 4-[5-(2-ethoxy-ethyl)-imidazol-1-yl]-3,3-dimethyl-isochroman-1-one as a white solid; MS (ESI) m/z 315.0 (M+H); 1H NMR (400 MHz, MeOD) of the HCl salt δ ppm 1.25 (t, J=6.9 Hz, 3 H), 1.32 (s, 3 H), 1.62 (s, 3 H), 3.29-3.37 (m, 2 H), 3.60-3.69 (m, 2 H), 3.79-3.97 (m, 2 H), 6.09 (s, 1 H), 7.57 (s, 1 H), 7.64 (d, J=7.6 Hz, 1 H), 7.73-7.79 (m, 1 H), 7.81-7.88 (m, 1 H), 8.32 (dd, J=7.7, 1.4 Hz, 1 H), 8.63 (br. s, 1H)
Reaction SMILES: [CH2:1]([NH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[H-].[Na+].Cl[CH2:27][CH:28]([OH:31])[CH2:29][OH:30]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:1]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:27][CH:28]([OH:31])[CH2:29][OH:30])=[O:20])=[CH:22][CH:23]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: OCC(O)CCl
Reactant: CCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1

Procedure:
A solution of 6.36 g. of 4-(n-tridecylamino)benzoic acid in 25 ml. of hexamethylphosphoramide is treated with sodium hydride and the 1-chloro-2,3-propanediol in the manner described in Example 2 to yield 2,3-dihydroxypropyl 4-(n-tridecylamino)benzoate as a white solid.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][NH:11][CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29]CC[Si](C)(C)C)=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.N1C(C)=CC=CC=1C.CN(C=O)C>C(Cl)Cl>[OH:29][C:17]1[C:16]([CH2:15][CH:14]=[C:13]([CH3:36])[CH2:12][NH:11][CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[C:24]([O:25][CH3:26])[C:23]([CH3:27])=[C:22]2[C:18]=1[C:19](=[O:28])[O:20][CH2:21]2
Reactant: CCOP(=O)(CCNCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: COc1c(C)c2c(c(O)c1CC=C(C)CNCCP(=O)(O)O)C(=O)OC2
Yield: 36.8 %

Procedure:
A solution of (2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonic acid diethyl ester (30 mg, 0.055 mmol), TMSBr (72 μL, 0.55 mmol), and 2,6-lutidine (64 μL, 0.55 mmol) was stirred in CH2Cl2 (1 mL) and DMF (0.5 mL) for 1 hour at ambient temperature. The reaction mixture was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 7.8 mg of the product as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.96 (s, 3H), 1.95-2.07 (m, 2H), 2.16 (s, 3H), 3.10-3.24 (m, 2H), 3.51 (d, 2H, J=7 Hz), 3.57 (s, 2H), 3.81 (s, 3H), 5.25 (s, 2H), 5.73 (t, 1H, J=7 Hz) ppm; 31P (121.4 MHz, CD3OD) δ 20.2 ppm; 19F NMR (282.6 MHz, CD3OD) δ -74.0 ppm; MS (m/z) 386.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[F:10].CC(O)=O.S(=O)(=O)(O)O.C1C(=O)N([I:27])C(=O)C1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([I:27])=[CH:4][C:3]=1[F:10]
Reactant: COc1ccc(F)c(Cl)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(Cl)c(F)cc1I
Yield: 70.4 %

Procedure:
A round-bottom flask was charged with 2-chloro-1-fluoro-4-methoxybenzene (Alfa Aesar, Ward Hill, Mass., 2.714 g, 16.90 mmol), DCM (24.86 ml), AcOH (24.86 ml), and sulfuric acid (0.496 ml, 9.30 mmol) to give a solution. n-iodosuccinimide (3.80 g, 16.90 mmol) was added in a single portion. TLC showed what appeared to be conversion of the starting material to a slightly higher, move UV-active spot. The mixture was diluted with DCM, washed with water (2×), washed with saturated aq. sodium thiosulfate, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (50-g SNAP Ultra column, 0-10% EtOAc/Heptane) to give 3.409 g of a clear oil. This oil was used directly in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[C:11]2[C:16]([C:17]=1[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[CH:15][CH:14]=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:12]=2.[OH-].[Na+].Cl.O>O1CCCC1.CO>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:11]2[C:16]([C:17]=1[CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)=[CH:15][CH:14]=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:12]=2
Reactant: CCOC(=O)CCn1c(-c2ccc(Cl)cc2N)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(Cl)cc3N)n(CCC(=O)O)c2c1
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To a suspension of methyl 2-(2-amino-4-chlorophenyl)-3-cyclohexyl-1-(2-ethoxycarbonylethyl)-1H-indole-6-carboxylate (1.05 g, 2.17 mmol) in tetrahydrofuran (11 ml) and methanol (11 ml) was added 4N aqueous sodium hydroxide solution (1.08 ml, 4.34 mmol), and the mixture was stirred for 2 hr. 2N Hydrochloric acid (2.2 ml) and water were added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give methyl 2-(2-amino-4-chlorophenyl)-1-(2-carboxyethyl)-3-cyclohexyl-1H-indole-6-carboxylate (949 mg) as a crude product. The obtained crude product was used for Step 4 without further purification.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:23])[NH:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17](Br)[CH:16]=1)([CH3:14])[CH3:13])[CH2:2]2.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]([NH:11][C:10](=[O:23])[O:9][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)([CH3:14])[CH3:13])=[CH:16][C:17]=1[C:26]1[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=1
Reactant: OB(O)c1cccnc1
Reactant: CC(C)(NC(=O)OC1CN2CCC1CC2)c1ccc(F)c(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(NC(=O)OC1CN2CCC1CC2)c1ccc(F)c(-c2cccnc2)c1
Yield: 38.3 %

Procedure:
Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl[2-(3-bromo-4-fluorophenyl)propan-2-yl]carbamate (110 mg, 0.286 mmol), pyridine-3-boronic acid (53 mg, 0.43 mmol) and tris(dibenzylideneacetone)dipalladium(0) gave the title compound as a white solid (42 mg, 39%). 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.62 (d, J=3.5 Hz, 1H), 7.86 (s, 1H), 7.46 (d, J=7.2 Hz, 2H), 7.38 (dd, J=4.9, 7.9 Hz, 1H), 7.15 (dd, J=8.7, 9.9 Hz, 1H), 5.32 (s, 1H), 4.69-4.57 (m, 1H), 2.68 (s, 6H), 1.70 (d, J=11.3 Hz, 6H), 2.08-0.94 (m, 5H) ppm. 13C NMR (100 MHz, CDCl3) δ 160.0, 157.5, 149.9, 149.0, 136.6, 132.1, 127.3, 126.8, 126.7, 125.5, 125.3, 123.5, 116.4, 116.2, 71.5, 55.9, 55.0, 47.6, 46.7, 30.1, 29.66, 25.6, 24.8, 19.7 ppm. Purity: 100% UPLCMS (210 nm); retention time 0.54 min; (M+1) 367.8.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[N:14]=[C:13]([C:15]3[CH:19]=[CH:18][O:17][C:16]=3[CH3:20])[CH:12]=[CH:11][N:10]=2)[CH2:3]1.[Br:21]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.O>[Br:21][C:12]1[C:13]([C:15]2[CH:19]=[CH:18][O:17][C:16]=2[CH3:20])=[N:14][C:9]([N:4]2[CH2:3][C@H:2]([CH3:1])[O:7][C@H:6]([CH3:8])[CH2:5]2)=[N:10][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1occc1-c1ccnc(N2CC(C)OC(C)C2)n1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1occc1-c1nc(N2C[C@@H](C)O[C@@H](C)C2)ncc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
2,6-Dimethyl-4-[4-(2-methyl-3-furanyl)-2-pyrimidinyl]morpholine (737 mg, 2.70 mmol) was dissolved in chloroform (13 mL), cooled in an ice bath and treated with N-bromosuccinimide (480 mg, 2.70 mmol). The resulting mixture was stirred at 0° C. for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate (×2). The ethyl acetate layers were combined, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by SP4 Biotage column chromatography eluting with a gradient of 0-20% ethyl acetate in iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound (719 mg, 2.041 mmol, 76% yield) as a white solid. LC/MS [M+H]+=352/354.
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:8]2[CH:20]=[C:21]([Cl:23])[CH:22]=[C:7]2[C:6]=1[OH:24])=[O:4].[NH2:25][CH2:26][C:27]([O-:29])=[O:28].[Na+]>>[Cl:23][C:21]1[CH:22]=[C:7]2[C:6]([OH:24])=[C:5]([C:3]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4])[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:8]2[CH:20]=1
Reactant: COC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(Cl)cc2)c1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(Cl)cc2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 6-chloro-4-hydroxy-2-oxo-1-(4-chloro-benzyl)-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 410 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]1[CH2:13][CH:12]2[C:14]3[CH:15]=[CH:16][C:17]([O:23]C)=[C:18]([O:21]C)[C:19]=3[O:20][C:10]3[C:11]2=[C:6]([CH:7]=[CH:8][CH:9]=3)[CH2:5]1)[CH:2]=[CH2:3].B(Br)(Br)Br.CO>ClCCl>[CH2:1]([N:4]1[CH2:13][CH:12]2[C:14]3[CH:15]=[CH:16][C:17]([OH:23])=[C:18]([OH:21])[C:19]=3[O:20][C:10]3[C:11]2=[C:6]([CH:7]=[CH:8][CH:9]=3)[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1Cc2cccc3c2C(C1)c1ccc(OC)c(OC)c1O3
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: C=CCN1Cc2cccc3c2C(C1)c1ccc(O)c(O)c1O3
Temperature: -78 °C
Reaction time: 8 h
Yield: 119.3 %

Procedure:
N-Allyl amine 10 (0.625 g; 1.93 mmol) was dissolved in 50 ml of dichloromethane. The solution was cooled to −78 ° C. and 10.0 ml of BBr3 solution (1.0 M in dichloromethane) was slowly added. The solution was stirred overnight, while the reaction slowly warned to room temperature. After recooling the solution to 78° C., 50 ml of methanol was slowly added to quench the reaction. The reaction was then concentrated to dryness. Methanol was added and the solution was concentrated. This process was repeated three times. Recystallization of the brown solid from ethanol gave 0.68 g (61%) of a white solid: mp 251-253° C. dec; 1H NMR: (300 MHz, D2O): 10.55 (s, 1H); 10.16 (s, 1H); 8.61 (t, 1H, J=9 Hz); 8.42 (d, 1H, J=9 Hz); 8.31 (d, 1H, J=9 Hz); 7.87 (d, 1H, J=9 Hz); 7.82 (d, 1H, J=9 Hz); 7.36 (q, 1H, J=9 Hz); 6.89 (m, 2H); 6.85 (d, 1H, J=15 Hz); 5.58 (m, 3H); 5.28 (m, 2H); 3.76 (d, 1H, J=3 Hz). HRCIMS m/z: Calc'd: 295.1208; Found: 295.1214.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([C:19]([OH:21])=O)[CH:10]=2)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>>[CH2:26]([N:28]([CH2:29][CH3:30])[C:19]([C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)=[O:21])[CH3:27]
Reactant: COc1ccc(-c2cc(C(=O)O)nc3ccccc23)cc1
Reactant: CCNCC
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1cc(-c2ccc(OC)cc2)c2ccccc2n1

Procedure:
Operations are carried out as for Example 1, starting from 21 g of 4-(4-methoxy phenyl) quinoline 2-carboxylic acid, 64 ml of thionyl chloride and 39 ml of diethylamine. 2.2 g of N,N-diethyl 4-(4-methoxy phenyl) quinoline 2-carboxamide are obtained. After recrystallization in isopropyl ether the product melts at 91° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][NH:21][C:15]=2[CH:14]=1.[CH:23]1([N:26]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31](B4OC(C)(C)C(C)(C)O4)[CH:32]=3)[C:27]2=[O:44])[CH2:25][CH2:24]1>>[CH:23]1([N:26]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:19]4[C:16]5[CH:17]=[N:18][C:13]([C:3]6[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=6[Cl:12])=[CH:14][C:15]=5[NH:21][N:20]=4)[CH:32]=3)[C:27]2=[O:44])[CH2:25][CH2:24]1
Reactant: CC1(C)OB(c2ccc3c(c2)CN(C2CC2)C3=O)OC1(C)C
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(I)c3cn2)c1Cl
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4ccc5c(c4)CN(C4CC4)C5=O)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine and 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (Example 21, Step 2). LCMS (M+H)+=495.1/497.1.
Reaction SMILES: Br[C:2]1[C:3](=[O:18])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[CH3:17])[CH:5]=[CH:6][CH:7]=1.[CH2:19](C([Sn])=C(CCCC)CCCC)[CH2:20]CC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:19]=[CH2:20])[C:3]1=[O:18]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Cc1cc([N+](=O)[O-])ccc1-n1cccc(Br)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=Cc1cccn(-c2ccc([N+](=O)[O-])cc2C)c1=O

Procedure:
50 g (162 mmol) of the compound from example 41A are dissolved in 700 ml of anhydrous dioxane and admixed with 62 g (194 mmol) of tributylvinyltin and 4.7 g (4.0 mmol) of tetrakis(triphenylphosphine)palladium, and the mixture is heated at reflux for 15 h. It is allowed to cool and filtered through kieselguhr. It is washed with ethyl acetate, and the combined filtrates are concentrated to dryness under reduced pressure. The residue is applied to silica gel and chromatographed on 800 g of silica gel with a gradient of cyclohexane and ethyl acetate. This affords 27 g (62% of theory) of the desired product.
Reaction SMILES: O1CCC[CH2:2]1.[NH:6]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:7]1.[H-].[Na+].COS(OC)(=O)=O>CCCCCC.C(OCC)C>[CH3:2][N:6]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:7]1
Reactant: C1CCOC1
Reactant: c1cc(-c2cc[nH]n2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cn1ccc(-c2ccncc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To 150 mL tetrahydrofuran was added 4-(1H-pyrazol-3-yl)pyridine (4.96 g; Example 3, Step 1) and the solution cooled in ice. To this was added slowly 1.64 g of a 60% suspension of sodium hydride in mineral oil. After gas evolution ceased, the mixture was stirred at ambient temperature for 30 min, cooled back down in ice, and 3.4 mL dimethylsulfate was added. The mixture was allowed to slowly warm to ambient temperature. After 1 hour the reaction mixture was evaporated and the dark brown residue partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The ethyl acetate was washed with saturated aqueous sodium bicarbonate, brine, dried over magnesium sulfate, filtered, and evaporated under vacuum to afford 4.6 g crude product as a pale yellow solid. The crude material was taken up in a diethyl ether and hexane mixture, filtered through celite, and allowed to crystallize. A total of 2.98 g (55% yield) pale yellow crystals were obtained. 1H NMR (CDCl3) was consistent with a single isomer of the desired structure. LC/MS showed one peak with a M+1 molecular ion of m/z 160.5 by positive ESI.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][NH:6][C:7](=[O:21])[NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=O)[C:15]([O:17]CC)=O)[N:13]=1.[BH3-][C:27]#[N:28].[Na+].[CH3:30][NH2:31]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][NH:6][C:7](=[O:21])[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]([NH:28][CH3:27])[C:15]([NH:31][CH3:30])=[O:17])[N:13]=1
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Reactant: [BH3-]C#N
Reactant: CN
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC(=O)C(NC)c1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-(2-(3-(3,4-dichlorobenzyl)ureido)thiazol-4-yl)-2-oxoacetate (800 mg) was dissolved in 2 M methylamine in tetrahydrofuran (20 ml) and NaCNBH3 (2.2 eq.) was added and stirred at room temperature overnight. The title compound was purified by column using 0-10% gradient of 7 N ammonia/MeOH and DCM.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:4]=1[C:5]([O:7]C)=O.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([C@H:27]([NH2:33])[CH2:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH3:17].C(=O)([O-])O.[Na+]>CN(C)C=O>[N+:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:3]2[C:4]=1[C:5](=[O:7])[N:33]([C@@H:27]([C:21]1[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:19]([O:18][CH2:16][CH3:17])[CH:20]=1)[CH2:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH2:2]2)([O-:15])=[O:14]
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Reactant: CCOc1cc([C@H](N)CS(C)(=O)=O)ccc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Temperature: 72.5 °C
Reaction time: 2 h

Procedure:
(1S)-7-nitro-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindolin-1-one was prepared by the following procedure. A mixture of methyl 2-bromomethyl-6-nitrobenzoate (100.0 g, 365 mmol, prepared previously in Example 6.5.2.), (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethylamine (104.7 g, 383 mmol, prepared previously in Example 6.5.3.), sodium hydrogen carbonate (67.5 g, 8.03 moles, from Aldrich Chemicals) and dimethyl formamide (500 mL) was charged into a 1-L 3-necked flask at room temperature under nitrogen. The reaction mixture was gradually heated to an internal temperature of 70-75° C. for two hours until there was less than <2% of unreacted methyl 2-bromomethyl-6-nitrobenzoate. The reaction mixture was gradually heated to an internal temperature of 95-100° C. for 18 hours. The reaction mixture was cooled to 20-25° C. and transferred to an 1-L addition funnel. After purified water (1500 mL) was charged into a 5-L 3-necked flask, the reaction mixture in the addition funnel was added into water in the 5-L 3-necked flask at room temperature over 1-2 hours maintaining an internal temperature below 30° C. The reaction mixture was stirred for 2 hours at room temperature. The solid was filtered out under vacuum, washed with water (3×300 mL) and methanol (2×400 mL), and then charged into a 2-L 3-necked flask followed by methanol (1000 mL). The mixture was refluxed for 1 hour. The mixture was cooled to room temperature. The solid was collected by filtration under vacuum, washed with 200 mL methanol (2 vol), and dried to a constant weight at 40-45° C. under a vacuum at 100-120 torr. The yield of (1S)-7-nitro-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindolin-1-one was 123.0 g (78%), based on 100.0 g input of methyl 2-bromomethyl-6-nitrobenzoate. The product was found to have a purity of >99% measured by HPLC based on area percentage, and a water content of <0.1% measured by Karl Fisher titration.
Reaction SMILES: [CH2:1]([N:8]([CH:33]([CH3:35])[CH3:34])[C:9](=[O:32])[CH2:10][N:11]1[C:20](=[O:21])[CH2:19][C:18]2[N:14]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][N:17]=2)[C:13]2[CH:28]=[CH:29][CH:30]=[CH:31][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]([O:40][C:41]([N:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]([CH2:52]Br)=[N:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]>>[C:36]([O:40][C:41]([N:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]([CH2:52][CH:19]2[C:18]3[N:14]([C:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:16][N:17]=3)[C:13]3[CH:28]=[CH:29][CH:30]=[CH:31][C:12]=3[N:11]([CH2:10][C:9](=[O:32])[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:33]([CH3:35])[CH3:34])[C:20]2=[O:21])=[N:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2ccccc21
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Product: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21
Yield: 6.1 %

Procedure:
Following the procedure described in Example 3(A), Step A, N-benzyl-N-isopropyl-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-acetamide (Preparation 10) (210 mg, 0.451 mmol) was alkylated with 3-bromomethyl-indazole-1-carboxylic acid tert-butyl ester (150 mg, 0.473 mmol). The reaction was diluted with a pH 6.8 buffer solution and the aqueous solution was washed with EtOAc. The organic solution was washed with brine (3×), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified (2×) by preparative chromatography eluting with 5% acetone in CH2Cl2 followed by medium pressure chromatography eluting with a solvent gradient (2% acetone in CH2Cl2 to 14% acetone in CH2Cl2) to provide 19.1 mg of 3-{6-[(benzyl-isopropyl-carbamoyl)-methyl]-5-oxo-1-phenyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulen-4-ylmethyl}-indazole-1-carboxylic acid tert-butyl ester. 1H NMR (CD2Cl2) δ 8.05 (m, 1H), 7.12-7.71 (m, 15H), 7.03 (m, 1H), 6.92 (d, 1H), 5.21 (d) and 4.90 (d, total 1H), 4.61-4.72 (m, 2H), 4.49 (s, 1H), 4.43 (t, 1H), 4.25-4.32 (m, 1H), 3.96-4.15 (m, 2H), 1.61 (d, 9H), 1.16 (dd, 3H), 1.04 (dd, 3H); MS 696.4 (M+1).