Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9](=[O:12])[N:8]([CH3:13])[CH2:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][NH:30][CH3:31])[C:19]([Cl:32])=[CH:18][N:17]=1>>[Cl:32][C:19]1[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][NH:30][CH3:31])=[N:21][C:16]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][C:9](=[O:12])[N:8]([CH3:13])[CH2:7][C:6]=3[CH:14]=2)=[N:17][CH:18]=1
Reactant: CN1Cc2cc(N)ccc2CCC1=O
Reactant: CNCc1ccccc1Nc1nc(Cl)ncc1Cl
Product: CNCc1ccccc1Nc1nc(Nc2ccc3c(c2)CN(C)C(=O)CC3)ncc1Cl

Procedure:
Following a procedure analogous to Example 1741e, 8-amino-2-methyl-1,2,4,5-tetrahydro-benzo[c]azepin-3-one and (2,5-dichloro-pyrimidin-4-yl)-(2-methylaminomethyl-phenyl)-amine (TFA salt) was converted to 8-[5-chloro-4-(2-methylaminomethyl-phenylamino)-pyrimidin-2-ylamino]-2-methyl-1,2,4,5-tetrahydro-benzo[c]azepin-3-one. HCl salt: 1H NMR (300 MHz, CD3OD) δ 8.18 (s, 1H), 7.6 (m, 3H), 7.52 (d, 1H), 7.1 (m, 3H), 4.41 (s, 2H), 4.18 (s, 2H), 3.07 (t, 2H), 2.97 (s, 3H), 2.89 (t, 2H), 2.65 (s, 3H); MS (m/e) 437 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][N:19]3S(C3C=CC(C)=CC=3)(=O)=O)=[C:15]([C:32]3[O:33][C:34]([CH2:37]Cl)=[N:35][N:36]=3)[CH:14]=2)=[CH:4][N:3]=1.[CH3:39][C@H:40]1[O:45][C@@H:44]([CH3:46])[CH2:43][NH:42][CH2:41]1>>[Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][NH:19]3)=[C:15]([C:32]3[O:33][C:34]([CH2:37][N:42]4[CH2:41][C@H:40]([CH3:39])[O:45][C@H:44]([CH3:46])[CH2:43]4)=[N:35][N:36]=3)[CH:14]=2)=[CH:4][N:3]=1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(CCl)o4)cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc32)cc1
Product: C[C@@H]1CN(Cc2nnc(-c3cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc4[nH]ncc34)o2)C[C@H](C)O1
Temperature: 90 °C
Reaction time: 3 h
Yield: 27.6 %

Procedure:
N-(2-Chloro-5-{4-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1-[(4-methylphenyl)sulfonyl]-1H-indazol-6-yl}-3-pyridinyl)methanesulfonamide (50 mg, 0.084 mmol) and (2R,6S)-2,6-dimethylmorpholine (0.5 ml, 0.084 mmol) were placed a vial and heated in a microwave at 90° C. for 15 mins. The reaction was heated in the microwave for a further 20 mins. The (2R,6S)-2,6-dimethylmorpholine was removed and the residue placed into isopropanol (3 ml) and 2M sodium hydroxide (1 ml) and the mixture stirred at room temperature for 3 h. The solvent was removed and the residue purified by Mass Directed Automated Preparative HPLC (Method B). The desired product was not collected so the waste was concentrated in vacuo and the residue purified by Mass Directed Automated Preparative HPLC (Method B) to give the title compound as white solid (12 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10]Cl.[OH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10][N:16]1[CH2:17][CH2:18][CH:13]([OH:12])[CH2:14][CH2:15]1
Reactant: ClCCOc1ccccc1Br
Reactant: OC1CCNCC1
Product: OC1CCN(CCOc2ccccc2Br)CC1

Procedure:
The title compound was prepared from 1-bromo-2-(2-chloroethoxy)benzene and 4-hydroxypiperidine in a similar manner to Example 149 (b).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5]O[C:3]=1[CH3:9].[CH2:10]([O:12][C:13](=[O:16])[CH2:14][NH2:15])[CH3:11].[OH-].[Na+].C(OCC)C>C(O)C.CC(C)=O>[CH2:10]([O:12][C:13]([CH2:14][N:15]1[CH:5]=[CH:6][C:7](=[O:8])[C:2]([OH:1])=[C:3]1[CH3:9])=[O:16])[CH3:11]
Reactant: Cc1occc(=O)c1O
Reactant: CCOC(=O)CN
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)Cn1ccc(=O)c(O)c1C
Temperature: 25 °C

Procedure:
3-hydroxy-2-methyl-4-pyrone (15 g) in ethanol (250 ml) has added to it glycine-ethyl ester (14 g) and concentrated aqueous sodium hydroxide to adjust pH to 10.0, the mixture is stirred at room temperature for several days, then rotary evaporated to dryness, resulting in white residue. Dissolution in acetone followed by di-ethyl ether treatment yields white precipitate of 1-ethoxycarbonylmethyl-3-Hydroxy-2-methyl-pyrid-4-one. The molecular ion mass M+=266.7. The compound dissolved in ethanol/water mixture with added iron forms the purple coloured complex. TLC showed a single, purple band separate and of lower rf than the 3-hydroxy-2-methyl-4-pyrone control (orange-red).
Reaction SMILES: [I:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[CH:26]=[O:27].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Mg]Br>>[I:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[CH:26]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[O:29][CH3:28])[OH:27]
Reactant: COc1ccccc1[Mg]Br
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(I)c(C=O)cc(OC)c21
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(I)c(C(O)c3ccccc3OC)cc(OC)c21

Procedure:
The title compound is prepared from 4-iodo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbaldehyde and 2-methoxyphenyl-magnesium bromide as described in example 35.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3].N1C=CC=CC=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C(Cl)Cl.CCOC(C)=O>[CH3:16][O:15][C:14]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[S:2]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)(=[O:4])=[O:3]
Reactant: COC(=O)c1ccc(OC)c(S(=O)(=O)Cl)c1
Reactant: C1COCCN1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)c(S(=O)(=O)N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
To a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate 40 (1.002 g, 3.8 mmol) in CH2Cl2 (20 mL) at 0° C. was added pyridine (0.46 mL, 6 mmol) and morpholine (0.395 mL, 5 mmol). The reaction mixture was warmed to room temperature, stirred for 30 min, and diluted with EtOAc. The organic phase was washed with NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 0% to 20% EtOAc in CH2Cl2) gave methyl 4-methoxy-3-(morpholinosulfonyl)benzoate 41 (0.970 g, 81% yield) as a white solid. Mass spectrum: calculated for C13H17NO6S 315.1. found 316.1 (M++1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[F:9][C:10]1[CH:36]=[CH:35][C:13]([CH2:14][N:15]2[C:24]3[C:19](=[CH:20][C:21]([CH3:25])=[CH:22][CH:23]=3)[C:18]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[C:17]([C:32]#[N:33])[C:16]2=[O:34])=[CH:12][CH:11]=1>N1C=CC=CC=1>[F:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][N:15]2[C:24]3[C:19](=[CH:20][C:21]([CH3:25])=[CH:22][CH:23]=3)[C:18]([N:26]3[CH2:31][CH2:30][N:29]([C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)=[O:7])[CH2:28][CH2:27]3)=[C:17]([C:32]#[N:33])[C:16]2=[O:34])=[CH:35][CH:36]=1
Reactant: Cc1ccc2c(c1)c(N1CCNCC1)c(C#N)c(=O)n2Cc1ccc(F)cc1
Reactant: O=C(Cl)c1ccco1
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)c(N1CCN(C(=O)c3ccco3)CC1)c(C#N)c(=O)n2Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
2-Furoyl chloride (118 μL, 1.2 mmol) was added to a stirred solution of Compound 27 (300 mg, 0.8 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by hexane and ether to yield 320 mg (85%) of white solids. M.P. 276° C. 1H NMR (DMSO-d6): δ 2.37 (s, 3H), 3.69 (m, 4H), 3.97 (m, 4H), 5.45 (s, 2H), 6.67 (dd, J=1.7, 3.7 Hz, 1H), 7.09 (d, J=3.4 Hz, 1H), 7.12 (m, 2H), 7.26 (m, 2H), 7.35 (d, J=8.7 Hz, 1H), 7.45 (d, J=8.8 Hz, 1H), 7.71 (s, 1H), 7.89 (s, 1H). EIMS m/z 493 (M+23). Anal. (C27H23FN4O3) C, H, N.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[C:26]([CH:29]6[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]6)[CH:27]=5)[NH:22][N:21]=4)[N:17]=[N:16]3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[ClH:42]>C1OCCOC1.O>[ClH:42].[N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[C:26]([CH:29]6[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]6)[CH:27]=5)[NH:22][N:21]=4)[N:17]=[N:16]3)=[CH:11][CH:10]=2)=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3[nH]nc(-c4cn(-c5ccc(C(=O)N6CCOCC6)cc5)nn4)c3c2)CC1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccc(-n2cc(-c3n[nH]c4ccc(C5CCNCC5)cc34)nn2)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 4-(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-5-yl)piperidine-1-carboxylate (40 mg; 0.07 mmol; 1.0 eq.) in Dioxane-1,4 (3.0 mL) and water (1.0 mL) was added Hydrogen chloride (1 mL of a 4N solution in dioxane, 4.00 mmol; 56 eq.). The resulting solution was stirred at RT for 12 h. Solvent was removed under reduced pressure, the residue was redissolved in ACN and water and lyophilized to give the title compound as a yellow solid (40 mg, 100%). 1H NMR (300 MHz, DMSO) δ 13.38 (brs, 1H), 9.37 (s, 1H), 8.96 (brs, 1H), 8.76 (brs, 1H), 8.23 (s, 1H), 8.19-8.09 (m, 2H), 7.75-7.53 (m, 3H), 7.34 (dd, J=1.4, 8.7 Hz, 1H), 3.80-3.52 (m, 5H), 3.53-3.21 (m, 3H), 3.04 (d, J=5.3 Hz, 4H), 2.15-1.75 (m, 5H). HPLC (Condition A): Rt 2.44 min (purity 93.2%). MS (ES+): 458.5, MS (ESI−): 456.5.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH:13][CH2:14][C:15]3[C:16](=[O:25])[NH:17][C:18]([CH3:24])=[CH:19][C:20]=3[CH2:21][CH2:22][CH3:23])=[O:12])[CH:10]=1)[N:7]([CH3:26])[CH:6]=[C:5]2[CH:27]([CH3:29])[CH3:28].[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[N:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=2)[CH2:33][CH2:32]1>>[CH3:26][N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:40]3[CH:41]=[N:42][C:37]([N:34]4[CH2:33][CH2:32][N:31]([CH3:30])[CH2:36][CH2:35]4)=[CH:38][CH:39]=3)=[CH:10][C:9]=2[C:11]([NH:13][CH2:14][C:15]2[C:16](=[O:25])[NH:17][C:18]([CH3:24])=[CH:19][C:20]=2[CH2:21][CH2:22][CH3:23])=[O:12])[C:5]([CH:27]([CH3:29])[CH3:28])=[CH:6]1
Reactant: CN1CCN(c2ccc(B(O)O)cn2)CC1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c(C(C)C)cn(C)c12
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCN(C)CC3)nc2)cc2c(C(C)C)cn(C)c12
Yield: 59.2 %

Procedure:
The title compound was prepared in the same manner as described for Example 2 using 5-bromo-1-methyl-3-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indole-7-carboxamide (480 mg, 1.05 mmol) and [6-(4-methyl-1-piperazinyl)-3-pyridinyl]boronic acid (320 mg, 1.45 mmol). Obtained 345 mg of the title compound (59% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (s, 1H), 8.41-8.48 (m, J=2.53 Hz, 2H), 7.86 (dd, J=2.53, 8.84 Hz, 1H), 7.76 (d, J=1.77 Hz, 1H), 7.26 (d, J=1.52 Hz, 1H), 7.08 (s, 1H), 6.92 (d, J=8.84 Hz, 1H), 5.90 (s, 1H), 4.37 (d, J=4.80 Hz, 2H), 3.68 (s, 3H), 3.48-3.56 (m, 4H), 3.20 (quin, J=6.76 Hz, 1H), 2.52-2.58 (m, 2H), 2.44 (br. s., 4H), 2.25 (s, 3H), 2.13 (s, 3H), 1.57 (qt, J=7.36, 7.56 Hz, 2H), 1.30 (d, J=6.82 Hz, 6H), 0.93 (t, J=7.33 Hz, 3H). MS (ES) [M+H]+ 555.1.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH2:11]([O:13][C:14](=[O:22])[CH:15]([C:19](=O)[CH3:20])[C:16](=O)[CH3:17])[CH3:12].N1C=CC=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[C:16]([CH3:17])=[N:10][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([F:2])[CH:4]=2)[C:19]=1[CH3:20])=[O:22])[CH3:12]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: NNc1cccc(F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(-c2cccc(F)c2)c1C

Procedure:
Similar to Example 1, equimolar amounts of 3-fluorophenylhydrazine hydrochloride and 2-acetyl-3-oxo-butyric acid ethyl ester were combined in a solution of 50% pyridine in ethanol. Analysis showed that resulting solid was the named product (m.p. 55° C.–56.1° C.).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][C:14]3[NH:18][N:17]=[N:16][N:15]=3)[CH:10]=[CH:9][C:8]=2[NH2:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[K+].[C:21]([C:23]1[N:24]=[C:25]([C:36]([O-])=[O:37])[N:26]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:27]=1)#[N:22].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][C:14]3[NH:18][N:17]=[N:16][N:15]=3)[CH:10]=[CH:9][C:8]=2[NH:19][C:36]([C:25]2[N:26]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:27]=[C:23]([C:21]#[N:22])[N:24]=2)=[O:37])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Nc1ccc(Cc2nnn[nH]2)cc1C1=CCCCC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(Cc2nnn[nH]2)cc1C1=CCCCC1

Procedure:
The title compound was prepared from 2-cyclohex-1-enyl-4-(1H-tetrazol-5-ylmethyl)-phenylamine (as prepared in the previous step, 40 mg, 0.15 mmol), potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 11, step (d), 67 mg, 0.21 mmol), PyBroP (116 mg, 0.249 mmol) and DIEA (68 μL, 0.39 mmol) according to the procedure in Example 11, step (f) (60 mg, 76%). Mass spectrum (ESI, m/z): Calcd. for C25H32N8O2Si, 505.2 (M+H), found 504.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:20]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N:9]2[C:10](=[O:19])[C:11]3=[CH:18][CH:17]=[CH:16][CH:15]=[C:12]3[C:13]2=[O:14])=[CH:3][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(N2C(=O)c3ccccc3C2=O)cc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1c1ccc(CBr)c(F)c1
Yield: 46.2 %

Procedure:
A mixture of the compound (1.0 g) obtained in Example 248, N-bromosuccinimide (698 mg), α,α′-azobis(isobutyronitrile) (catalytic amount) and carbon tetrachloride (20 ml) was heated under reflux for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=8:2) to give 605 mg of the titled compound (yield, 46%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15](=[O:23])[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:9]=1[O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1.[C:34]1([CH2:40][O:41][C:42](=[O:54])[C:43]2[CH:48]=[CH:47][C:46]([OH:49])=[C:45]([CH2:50][CH2:51][CH3:52])[C:44]=2[OH:53])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:34]1([CH2:40][O:41][C:42](=[O:54])[C:43]2[CH:48]=[CH:47][C:46]([O:49][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15](=[O:23])[C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=4)[C:9]=3[O:24][C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)=[C:45]([CH2:50][CH2:51][CH3:52])[C:44]=2[OH:53])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCCc1c(O)ccc(C(=O)OCc2ccccc2)c1O
Reactant: Cc1ccc(C(=O)Oc2cccc(CCCCCCBr)c2OC(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCCCCCc2cccc(OC(=O)c3ccc(C)cc3)c2OC(=O)c2ccc(C)cc2)ccc(C(=O)OCc2ccccc2)c1O
Yield: 31.7 %

Procedure:
A mixture of 1.91 g (3.75 mmol) of 1-(6-bromohexyl)-2,3-bis[(4-methylbenzoyl)oxy]benzene, 1.07 g (3.75 mmol) 2,4-dihydroxy-3-propylbenzoic acid phenylmethyl ester, 0.94 g (5.63 mmol) of potassium iodide and 0.75 g (5.63 mol) of potassium carbonate in 40 mL of acetone was stirred at reflux for 26 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC using 5% ethyl acetate-hexane to give 0.85 g (32% yield) of 2-hydroxy-4-[6-[2,3-bis[(4-methylbenzoyl)oxy]phenyl]hexyloxy]-3-propylbenzoic acid phenylmethyl ester as an oil.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)[CH:7]=1)=[O:5].I[C:27]1[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][CH:32]=1.C([Mg]Cl)(C)C>C1COCC1>[CH3:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([C:27]3[CH:32]=[N:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[O:5])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(C)n2)c2ccccc2c1=O
Reactant: FC(F)(F)c1ccc(I)cn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1cccc(Cn2cc(C(=O)c3ccc(C(F)(F)F)nc3)c(=O)c3ccccc32)n1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60, from 120 mg (0.36 mmol) of 1-(6-methyl-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 214 mg (0.78 mmol) of 5-iodo-2-trifluoromethyl-pyridine in 1.5 mL THF with 0.41 mL 2M isopropylmagnesium chloride. Yield: 81 mg of a white powder. LC-MSD, m/z for C23H16F3N3O2 [M+H]+=424.1; HPLC retention time: 2.2 min.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]3[C:10]([CH2:11][NH:12][C:13](=O)[C:4]=2[CH:3]=1)=[C:9]([C:15]1[N:19]=[C:18]([CH:20]2[CH2:22][CH2:21]2)[O:17][N:16]=1)[N:8]=[CH:7]3.CN(C)C1C=CC(C)=CC=1.P(Cl)(Cl)([Cl:37])=O>ClC1C=CC=CC=1>[Cl:37][C:13]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=2[N:6]2[C:10]([CH2:11][N:12]=1)=[C:9]([C:15]1[N:19]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[O:17][N:16]=1)[N:8]=[CH:7]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1NCc2c(-c3noc(C4CC4)n3)ncn2-c2ccc(Cl)cc21
Solvent: Cc1ccc(N(C)C)cc1
Solvent: Clc1ccccc1
Product: ClC1=NCc2c(-c3noc(C4CC4)n3)ncn2-c2ccc(Cl)cc21
Yield: 62.2 %

Procedure:
8-Chloro-3-(5-cyclopropyl-[1,2,4]oxadiazol-3-yl)-4,5-dihydro-2,5,10b-triaza-benzo[e]azulen-6-one (0.84 g, 2.5 mmol) was suspended in chlorobenzene (8 mL), N,N-dimethyl-p-toluidine (1.1 mL, 7.4 mmol) and phosphorus oxychloride (0.34 mL, 3.7 mmol) were added and the mixture was refluxed overnight. The resulting solution was evaporated and the residue was purified by chromatography on silica gel in CH2Cl2/acetone 10:1. One obtained a white solid (0.56 g, 63%). mp 200° C. m/z 359(M).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([N:17]([CH3:40])[C:18]3[N:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[C@@H:27]([CH3:38])[CH2:26]4)=[C:20]([CH3:39])[CH:19]=3)=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([N:17]([CH3:40])[C:18]3[CH:19]=[C:20]([CH3:39])[C:21]([CH2:24][N:25]4[CH2:30][CH2:29][NH:28][C@@H:27]([CH3:38])[CH2:26]4)=[CH:22][N:23]=3)=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(N(C)C(=O)c2ccc(Oc3ccc(F)cc3)nc2)ncc1CN1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N(C)C(=O)c2ccc(Oc3ccc(F)cc3)nc2)ncc1CN1CCN[C@@H](C)C1
Temperature: 25 °C
Yield: 71 %

Procedure:
1,1-Dimethylethyl (2S)-4-({6-[({6-[(4-fluorophenyl)oxy]-3-pyridinyl}carbonyl)(methyl)amino]-4-methyl-3-pyridinyl}methyl)-2-methyl-1-piperazinecarboxylate (D118) (26 mg, 0.047 mmol) was dissolved in dry DCM (4 mL). TFA (1 mL) was added and the reaction mixture was stirred at room temperature, under argon. The reaction mixture was concentrated, re-dissolved in methanol (2 mL) and loaded on to a 1 g SCX cartridge. Elution with methanol (20 mL) followed by 2M NH3 in methanol (20 mL) gave a colourless oil. The product was further purified by MDAP. The resulting oil was dissolved in methanol (1 mL) and loaded on to a 1 g SCX cartridge and eluted with methanol (20 mL), followed by 2M NH3 in methanol (20 mL) to give the title compound as a colourless oil (15 mg). MS (ES): MH+ 450.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](/[CH:11]=[CH:12]\[C:13]([OH:15])=O)=[O:10])=[CH:4][CH:3]=1.C[Si](N[Si](C)(C)C)(C)C.Cl>C1C=CC=CC=1.[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:9](=[O:10])[CH:11]=[CH:12][C:13]2=[O:15])=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C\C(=O)Nc1ccc(Cl)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C1C=CC(=O)N1c1ccc(Cl)cc1
Yield: 97 %

Procedure:
In Analogy to the procedure given in Mhaske et al., Synthesis, 2003, p863-870: A solution of 65 g (288 mmol) of (Z)-3-(4-chloro-phenylcarbamoyl)-acrylic acid in 300 ml of benzene was treated with 41.2 g (302 mmol) of zinc dichloride, dropwise with 90.1 ml (432 mmol) of bis(trimethylsilyl)amine and refluxed during 5 hrs. The mixture was poured into 300 ml of aqueous HCl (0.5 M). The aqueous phase was extracted with AcOEt, the combined organic phases were washed successively with saturated aqueous NaHCO3 and brine, and finally dried over Na2SO4. Evaporation of the solvent gave 58 g (97%) of the title compound. Brown amorphous solid. MS: 208 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([NH:12]C(=O)OC(C)(C)C)[N:10]=2)[N:5]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:4]=1[C:28]1[CH:33]=[CH:32][C:31]([C:34]2([CH3:39])OCC[O:35]2)=[CH:30][CH:29]=1)[CH3:2].C(O)(C(F)(F)F)=O.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.O.CCOC(C)=O>[NH2:12][C:9]1[N:10]=[C:11]2[C:3]([CH2:1][CH3:2])=[C:4]([C:28]3[CH:29]=[CH:30][C:31]([C:34](=[O:35])[CH3:39])=[CH:32][CH:33]=3)[N:5]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:25])[CH3:26])[C:6]2=[N:7][CH:8]=1
Reactant: CCc1c(-c2ccc(C3(C)OCCO3)cc2)n(COCC[Si](C)(C)C)c2ncc(NC(=O)OC(C)(C)C)nc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCc1c(-c2ccc(C(C)=O)cc2)n(COCC[Si](C)(C)C)c2ncc(N)nc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.8 %

Procedure:
tert-Butyl 7-ethyl-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (0.35 g, 0.631 mmol) in 1,4-dioxane (5 mL) was treated with TFA (0.073 mL, 0.946 mmol) then the solution was stirred for about 15 min at rt. The mixture was heated to about 60° C. for about 15 min and then TFA (0.145 mL, 1.88 mmol) was added and heating continued at about 75° C. for about 1 h. The solution was cooled to rt then concentrated (37%) aqueous HCl (0.083 mL, 1.015 mmol) was added. The mixture was stirred for about 15 min at rt then warmed to about 75° C. for about 4 h. The mixture was cooled then treated with saturated aqueous NaHCO3 (10 mL), EtOAc (25 mL) and water (10 mL). The layers were separated then the aqueous layer extracted with EtOAc (15 mL). The organics were combined then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The material was purified on a 10 g silica gel column with EtOAc as an eluent to give 1-(4-(2-amino-7-ethyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-6-yl)phenyl)ethanone (0.217 g, 84%): LC/MS (Table 2, Method a) Rt=2.72 min; MS m/z 411 (M+H)+.