Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:16])[NH:11][CH2:12][C:13](O)=[O:14])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CS(O)(=O)=O.O>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH2:12][NH:11][C:10]2=[O:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)CNC(=O)Nc1cc(Cl)cc(Cl)c1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: Clc1ccccc1
Product: O=C1CNC(=O)N1c1cc(Cl)cc(Cl)c1
Temperature: 15 °C
Yield: 95.3 %

Procedure:
To a suspension of 3-(3,5-dichlorophenyl)-ureidoacetic acid (526 g.) in chlorobenzene (2,250 cc.) is added methanesulphonic acid (d = 1.48) (10 cc., representing 0.077 mol per mol of ureidoacetic acid). The water formed in the reaction is removed by azeotropic distillation. After 45 minutes' distillation, a limpid solution is obtained. After cooling to about 15° C, the precipitate formed is filtered off and washed on the filter with ethanol (500 cc.) at 10° C. After drying, 3-(3,5-dichlorophenyl)-hydantoin (467 g.) melting at 199° C is obtained. Yield: 94%.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[H-].[Na+].F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:11][CH:10]([O:12][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1
Reactant: Fc1ccccc1
Reactant: CN1Cc2ccccc2C(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1Cc2ccccc2C(Oc2ccccc2)C1
Temperature: 95 °C
Reaction time: 4 h
Yield: 65.5 %

Procedure:
A solution of 2-methyl-1,2,3,4-tetrahydro-4-isoquinolinol (6.0 g, 0.037 mole) in 30 ml dry DMF is added dropwise under nitrogen to a suspension of sodium hydride 50% (98%) (2.2 g, 0.044 mole), previously washed with hexane, in 50 ml dry DMF. After one hour the mixture is slowly warmed to 75° C. at which time fluorobenzene (7.1 g. 0.074 mole) in 30 ml dry DMF is added dropwise. The reaction mixture is stirred at 95° C. for four hours then at 75° C. for about 16 hours. Most of the solvent is removed under reduced pressure and the resultant mixture is stirred in 500 ml water then extracted with chloroform. The combined organic extracts are washed twice with water and then dried (saturated NaCl, anhydrous MgSO4). Removal of solvent yields 5.8 g (65%) of an oil which is purified by dry column chromatography over silica gel using ethyl acetate as the eluent. The desired product is extracted with chloroform to yield 1.5 g (17%) of an oil of 2-methyl-4-phenoxy-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28].[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[N:38]([CH3:42])[N:37]=[C:36]2[C:43]1[N:44]=[C:45]2[C:51]([C:52](O)=[O:53])=[CH:50][N:49]([CH2:55][O:56][CH2:57][CH2:58][Si:59]([CH3:62])([CH3:61])[CH3:60])[C:46]2=[N:47][CH:48]=1>CN(C=O)C>[OH:28][CH2:27][C:26]([NH:25][C:52]([C:51]1[C:45]2[C:46](=[N:47][CH:48]=[C:43]([C:36]3[C:35]4[C:39](=[CH:40][CH:41]=[C:33]([O:32][CH3:31])[CH:34]=4)[N:38]([CH3:42])[N:37]=3)[N:44]=2)[N:49]([CH2:55][O:56][CH2:57][CH2:58][Si:59]([CH3:60])([CH3:62])[CH3:61])[CH:50]=1)=[O:53])([CH3:30])[CH3:29]
Reactant: CC(C)(N)CO
Reactant: COc1ccc2c(c1)c(-c1cnc3c(n1)c(C(=O)O)cn3COCC[Si](C)(C)C)nn2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cnc3c(n1)c(C(=O)NC(C)(C)CO)cn3COCC[Si](C)(C)C)nn2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
In a 16×100 mm screw cap test tube were added HATU (40.2 mg, 106 μmol.20) and 2-amino-2-methylpropan-1-ol (31.4 mg, 353 μmol) then 2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (40 mg, 88.2 mmol) dissolved in DMF (2.00 mL) was added to give a light yellow solution. The reaction mixture stirred at 25° C. overnight, solvents evaporated and residue purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 50% EtOAc in hexanes over 25 min to yield N-(1-hydroxy-2-methylpropan-2-yl)-2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (46.3 mg, 88.2 μmol, 100%) as an off-white solid. MS (M+Na)+=547 (>90% purity); 1H NMR (CDCl3) δ: 9.14 (s, 1H), 8.49 (s, 1H), 8.32 (s, 1H), 7.85 (d, J=2.3 Hz, 1H), 7.41 (d, J=9.1 Hz, 1H), 7.20 (dd, J=9.3, 2.5 Hz, 1H), 5.72 (s, 2H), 4.18 (s, 3H), 3.92 (s, 3H), 3.78 (s, 2H), 3.54-3.65 (m, 2H), 1.53 (s, 6H), 0.91-1.01 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[C:16]([Cl:23])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH3:15])=[CH:10][CH:9]=2.[NH4+].[Cl-]>CCO.C1COCC1.O.[Fe]>[Cl:1][C:2]1[CH:19]=[C:18]([NH2:20])[CH:17]=[C:16]([Cl:23])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH3:15])=[CH:10][CH:9]=2
Reactant: Cc1ccc2ncc(Oc3c(Cl)cc([N+](=O)[O-])cc3Cl)cc2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cc1ccc2ncc(Oc3c(Cl)cc(N)cc3Cl)cc2c1
Yield: 99.6 %

Procedure:
To a solution of 3-(2,6-Dichloro-4-nitro-phenoxy)-6-methyl-quinoline (309) (1.30 g, 3.71 mmol) and NH4Cl (992 mg, 18.55 mmol) in EtOH/THF/H2O=12 ml/12 ml/3 ml, was added Iron Powder (1.04 g, 18.55 mmol). The mixture was refluxed for 4 hr. Insoluble materials were removed by Celite filtration. The filtrate was concentrated and sat NaHCO3 was added to the residue, which was then extracted twice with AcOEt. Organic layer was washed with Brine, dried over anhydrous MgSO4, and concentrated to afford compound 339 (1.18 g, 98%).
Reaction SMILES: C[C@H]1N(C)CCN(C2C=CC(NC3C(=O)N(C)C=C(C4C(CO)=C(N5CCN6C7CCCCC=7C=C6C5=O)C=C(F)C=4)C=3)=NC=2)C1.C([O:50][CH2:51][C:52]1[C:57]([N:58]2[CH2:70][CH2:69][N:61]3[C:62]4[CH2:63][CH2:64][CH2:65][CH2:66][C:67]=4[CH:68]=[C:60]3[C:59]2=[O:71])=[CH:56][C:55]([F:72])=[CH:54][C:53]=1[C:73]1[CH:78]=[C:77]([NH:79][C:80]2[CH:85]=[CH:84][C:83]([N:86]3[CH2:91][CH2:90][N:89]([CH3:92])[CH2:88][C@H:87]3[CH3:93])=[CH:82][N:81]=2)[C:76](=[O:94])[N:75]([CH3:95])[CH:74]=1)(=O)C.[OH-].[Li+]>>[CH3:93][C@@H:87]1[CH2:88][N:89]([CH3:92])[CH2:90][CH2:91][N:86]1[C:83]1[CH:84]=[CH:85][C:80]([NH:79][C:77]2[C:76](=[O:94])[N:75]([CH3:95])[CH:74]=[C:73]([C:53]3[C:52]([CH2:51][OH:50])=[C:57]([N:58]4[CH2:70][CH2:69][N:61]5[C:62]6[CH2:63][CH2:64][CH2:65][CH2:66][C:67]=6[CH:68]=[C:60]5[C:59]4=[O:71])[CH:56]=[C:55]([F:72])[CH:54]=3)[CH:78]=2)=[N:81][CH:82]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C)C[C@H]4C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: C[C@@H]1CN(c2ccc(Nc3cc(-c4cc(F)cc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)nc2)CCN1C
Agent: [Li+]
Agent: [OH-]
Product: C[C@@H]1CN(C)CCN1c1ccc(Nc2cc(-c3cc(F)cc(N4CCn5c(cc6c5CCCC6)C4=O)c3CO)cn(C)c2=O)nc1
Yield: 48.6 %

Procedure:
Following the procedures as described for compound 108, hydrolysis of 109f (337 mg, 0.5 mmol) with lithium hydroxide gave 109 as a yellow solid (152 mg, 48%). LCMS: (M+H)+ 626. 1H NMR (500 MHz, DMSO) δ 8.57 (t, J=2.5, 1H), 8.39 (s, 1H), 7.83 (d, J=3.0, 1H), 7.31-7.36 (m, 3H), 7.23 (d, J=9.0, 1H), 7.17-7.20 (m, 1H), 6.53 (s, 1H), 4.86-4.88 (m, 1H), 4.32 (d, J=4.5, 2H), 4.09-4.20 (m, 3H), 3.87-3.91 (m, 1H), 3.66 (s, 1H), 3.59 (s, 3H), 3.04-3.08 (m, 1H), 2.90-2.94 (m, 1H), 2.57-2.65 (m, 3H), 2.47 (t, J=5.5, 2H), 2.35-2.42 (m, 2H), 2.19-2.21 (m, 1H), 2.18 (s, 3H), 1.79 (t, J=6.0, 2H), 1.66-1.69 (m, 2H), 0.91 (d, J=6.0, 3H)
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]2=[O:31])=[C:4]([OH:32])[CH:3]=1.[C:33](=O)([O-])[O-].[Cs+].[Cs+].ClCI>O1CCCC1>[C:19]1([CH:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]3([C:5]4[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=4[O:32][CH2:33]3)[C:10]2=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1C(c2cc(F)c(F)cc2O)c2ccccc2N1C(c1ccccc1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: ClCI
Agent: [Cs+]
Solvent: C1CCOC1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc(F)c(F)cc12
Reaction time: 20 h
Yield: 69.8 %

Procedure:
To a solution of 3-(4,5-difluoro-2-hydroxyphenyl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one (6.30 g, 14.7 mmol) in anhydrous tetrahydrofuran (120 mL) under argon was added cesium carbonate (14.4 g, 44.2 mmol), followed by the addition of chloroiodomethane (3.21 mL, 44.2 mmol) dropwise. After 20 h, the reaction mixture was concentrated in vacuo and re-dissolved in ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (6×50 mL). Some product was filtered off as a colorless precipitate. The combined organic solution was washed with water (2×150 mL) and brine (150 mL), dried over sodium sulfate, filtered, and concentrated. Precipitation from diethyl ether/hexanes afforded 1′-(diphenylmethyl)-5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (4.51 g, 70%) as a colorless solid: mp 213-216° C.; 1H NMR (300 MHz, CDCl3) δ 7.41-7.26 (m, 10H), 7.15-7.12 (m, 1H), 7.08-6.97 (m, 3H), 6.78 (dd, J=10.5, 6.3 Hz, 1H), 6.54 (d, J=8.4 Hz, 1H), 6.44 (dd, J=9.0, 7.8 Hz, 1H), 5.03 (d, J=9.0 Hz, 1H), 4.77 (d, J=9.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 176.8, 156.6 (d, J=11.0 Hz), 151.2 (dd, JC-F=248.2, 14.5 Hz), 145.6 (dd, JC-F=241.5, 13.85 Hz), 141.7, 137.4, 137.1, 131.5, 128.8, 128.8, 128.7, 128.3, 128.3, 128.1, 128.0, 124.2 (dd, J=6.4, 3.3 Hz), 123.8, 123.3, 112.4, 111.5 (dd, J=20.4, 1.6 Hz), 100.1 (d, J=22.4), 80.8, 58.9, 57.5; MS (ES+) m/z 440.2 (M+1), 462.2 (M+23).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH:20]=[CH:21][N:22]=[C:23]4[CH2:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[ClH:37]>O1CCOCC1>[ClH:37].[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH:20]=[CH:21][N:22]=[C:23]4[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)OC(C)(C)C)nccc34)no2)cc1C#N
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)O)nccc34)no2)cc1C#N
Reaction time: 2 h

Procedure:
1,1-Dimethylethyl 3-[5-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]propanoate (D52; 66 mg, 0.133 mmol) was dissolved in 4M hydrogen chloride in 1,4-dioxane (4 ml) and the mixture allowed to stand at room temperature for 2 h. The solvent was evaporated in vacuo to give a colourless gum which was triturated under dry ether (5 ml) to give the title compound as a white solid (54 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13](=[S:15])[NH2:14])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:22]([O:24][C:25](=[O:31])[CH:26](Cl)[C:27](=O)[CH3:28])[CH3:23].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CN(C)C=O.O>[CH2:22]([O:24][C:25]([C:26]1[S:15][C:13]([C:7]2[C:8](=[O:12])[O:9][C:10]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([OH:1])[CH:11]=3)=[N:14][C:27]=1[CH3:28])=[O:31])[CH3:23]
Reactant: NC(=S)c1cc2ccc(O)cc2oc1=O
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1sc(-c2cc3ccc(O)cc3oc2=O)nc1C
Temperature: 25 °C
Reaction time: 19 h
Yield: 14.7 %

Procedure:
To a solution of 7-hydroxy-2-oxo-2H-chromene-3-carbothioic acid amide (66 mg, 0.3 mmol) in anhydrous N,N-dimethylformamide (5 mL), freshly dried K2CO3 (263 mg, 1.9 mmol) was added followed by 2-chloro-3-oxo-butyric acid ethyl ester (79 μL, 94 mg, 0.54 mmol) and the mixture was stirred at room temperature for 19 h. The mixture was poured into water (25 mL) and extracted first with chloroform (3×10 mL) and, after saturation with NaCl, with tetrahydrofuran (3×10 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was dissolved in chloroform (8 mL), pyridinium p-toluenesulfonate (7.5 mg, 0.03 mmol) was added and the mixture was stirred at 60° C. for 4.5 h. After cooling, the solution was washed with brine (3×5 mL), dried over MgSO4 and concentrated. The residue was purified by column chromatography on silica, eluting with a 9:1:0.1 mixture of chloroform, methanol and cc. NH4OH. The title compound (14.5 mg, 0.044 mmol, 14.7%) was obtained as a yellow solid.
Reaction SMILES: O[C:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)=[C:3]1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[CH3:32][O:31][C:27]1[CH:26]=[C:25]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]([C:11]3[CH:16]=[CH:15][C:14]4[O:17][CH2:18][O:19][C:13]=4[CH:12]=3)=[C:3]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1cccc(OC)c1
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1cccc(OC)c1
Reaction time: 0.5 h
Yield: 31 %

Procedure:
To a solution of ethyl(1RS)-1-hydroxy-1-(3-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)-indene-2-carboxylate (150 mg, 0.35 mmol) in CH2Cl2 was added triethylsilane (67 μl, 0.42 mmol), followed by boron trifluoride etherate (213 μl, 1.73 mmol). The reaction mixture was allowed to stir for 30 min, at which time was added slowly 5% aqueous HCl. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3, H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 10% EtOAc/hexanes to provide the title compound (45 mg, 31%) as a mixture of Δ1 and Δ2 double bond isomers.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12])[CH:5]=[O:6].OOS([O-])=O.[K+].[CH3:20][OH:21]>>[CH3:20][O:21][C:5](=[O:6])[C:4]1[CH:7]=[CH:8][C:9]([O:10][CH:11]([F:13])[F:12])=[C:2]([OH:1])[CH:3]=1
Reactant: CO
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Agent: O=S([O-])OO
Agent: [K+]
Product: COC(=O)c1ccc(OC(F)F)c(O)c1
Temperature: 52.5 °C
Yield: 70 %

Procedure:
100 g of 3-hydroxy-4-(difluoromethoxy)-benzaldehyde (0.53 mol) were dissolved in MeOH (600 ml), solid Oxone® (325 g, 1.06 mol) was added portion-wise in 1 hour and solution was stirred and warmed to 50-55° C. for 2 hours. The solvent was concentrated under vacuum to 200 ml and water (1 L) was added. The resulting heterogeneous solution was stirred at 50 to 55° C., then toluene (500 ml) was added, and the biphasic mixture vigorously stirred. Aqueous phase was discharged and the organic one was washed with water (500 ml). Active charcoal (10 g) was added and the organic solution stirred for 20 minutes. It was filtered on a celite pad, the solvent was concentrated under vacuum to 2 to 3 volumes, and the obtained solution was warmed to 80 to 90° C. n-Heptane (400 ml) was slowly added. The mixture was cooled to 0° C. and the suspension was stirred at 0° C. over-night. The solid was filtered on a Buchner funnel and washed with n-heptane (100 ml). The obtained white solid was dried under vacuum at room temperature. (yield 70%).
Reaction SMILES: [CH2:1]([C:5]1[N:13]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Sn](CCCC)(CCCC)CCCC)=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].I[C:38]1[CH:47]=[CH:46][CH:45]=[CH:44][C:39]=1[C:40]([O:42][CH3:43])=[O:41].O>CN(C=O)C>[CH3:43][O:42][C:40](=[O:41])[C:39]1[CH:44]=[CH:45][CH:46]=[CH:47][C:38]=1[C:20]1[CH:21]=[CH:22][C:23]2[C:18](=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]2[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:7]3[N:6]=[C:5]2[CH2:1][CH2:2][CH2:3][CH3:4])[CH:19]=1
Reactant: COC(=O)c1ccccc1I
Reactant: CCCCc1nc2cccnc2n1-c1cccc2cc([Sn](CCCC)(CCCC)CCCC)ccc12
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc2cccnc2n1-c1cccc2cc(-c3ccccc3C(=O)OC)ccc12
Temperature: 105 °C
Yield: 41.7 %

Procedure:
A mixture of 2-butyl-3-(6-tributylstannanyl-naphthalen-1-yl)-3H-imidazo[4,5-b]-pyridine (120 mg, 0.22 mmol), methyl 2-iodobenzoate (79 mg, 0.3 mmol) and PdCl2 (PPh3)2 (15 mg, 0.02 mmol) in 1.0 mL DMF was heated at 105° C. for 20 hours. The cooled reaction mixture was poured into H2O (20 mL). The aqueous solution was extracted with EtOAc (3×50 mL). The combined extracts were washed with saturated aqueous NaHCO3 (25 mL), dried MgSO4) and concentrated in vacuo. The residue was chromatographed on SiO2 -gel using a gradient of 20% ethyl acetate/hexanes to 100% ethyl acetate to give 40 mg of product. 1H NMR (250 MHz, CDCl3): d 8.27 (dd, 1H, J=1.15, 4.85 Hz), 8.14 (dd, 1H, J=1.21, 7.96 Hz), 8.08 (d, 1H, J=8.2 Hz), 7.94 (d, 1H, J=1.4 Hz), 7.89 (d, 1H, J=7.9 Hz), 7.69 (t, 1 H), 7.58 (m), 7.48 (m), 7.26 (m), 7.14 (d, 1H, J=8.5 Hz), 3.57 (s, 3 H), 2.72 (t, 2 H), 1.78 (m, 2 H), 1.27 (m, 2 H), 0.83 (t, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]4[S:21][CH:22]=[C:23]([C:25](O)=[O:26])[N:24]=4)[C:15](=[O:28])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:29]=1.[CH3:30][N:31](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:32].[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.CNC>CN1CCCC1=O>[CH3:30][N:31]([CH3:32])[C:25]([C:23]1[N:24]=[C:20]([CH2:19][N:16]2[CH2:17][CH2:18][N:13]([S:10]([C:8]3[S:7][C:6]4[CH:29]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[CH:9]=3)(=[O:12])=[O:11])[CH2:14][C:15]2=[O:28])[S:21][CH:22]=1)=[O:26]
Reactant: O=C(O)c1csc(CN2CCN(S(=O)(=O)c3cc4ccc(Cl)cc4s3)CC2=O)n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1csc(CN2CCN(S(=O)(=O)c3cc4ccc(Cl)cc4s3)CC2=O)n1
Reaction time: 3 h

Procedure:
To a solution of 2-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-thiazol-4-yl-carboxylic acid (14 mg, 0.03 mmol) in N-methyl-pyrolidinone (0.3 mL) is added TBTU (0.05 mmol) and diisopropylethylamine (0.06 mmol) and dimethylamine hydrochloride (0.06). The reaction is stirred 3 h and an additional aliquot of TBTU, DIEA and amine are added. The reaction is stirred 1 h and the reaction is concentrated and purified by column chromatography (silica, 2% MeOH/EtOAc) to provide 2-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-thiazole-4-carboxylic acid dimethylamide. 1H NMR (300 MHz, CDCl3) δ 7.87-7.77 (m, 4H), 7.47 (dd, 1H), 4.83 (s, 2H), 3.92 (s, 2H), 3.63-3.60 (m, 2H), 3.47-3.43 (m, 2H), 3.18 (s, 3H), 3.10 (s, 3H); MS (Ion Spray) 499 (M+H)+.
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]([C:15]([O:17]CC)=[O:16])[CH:6]=1.O.[OH-].[Li+]>C(Cl)Cl.O>[CH3:1][NH:2][CH2:4][C:5]1[N:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[N:8]=[C:7]([C:15]([OH:17])=[O:16])[CH:6]=1
Reactant: CCOC(=O)c1cc(CBr)nc(C(F)(F)F)n1
Reactant: CN
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CNCc1cc(C(=O)O)nc(C(F)(F)F)n1

Procedure:
A solution of methylamine (33 wt % in Ethanol, 1.12 mmol, Aldrich) was added portionwise to a solution of ethyl 6-(bromomethyl)-2-(trifluoromethyl)pyrimidine-4-carboxylate (0.150 g, 0.321 mmol, Example 5, Step A) in methylene chloride (3.0 mL), until reaction was complete. Solvent was removed in vacuo. The residue was dissolved in tetrahydrofuran (7.0 mL) and water (2.0 mL), and lithium hydroxide monohydrate (0.135 g, 3.21 mmol) was added. After a 5 minute reaction time, the mixture was treated with 1N HCl to adjust the pH to 7, then was purified using preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). LC-MS: 236.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:18]1[C:22]([C:23]2[C:28]([CH3:29])=[CH:27][N:26]=[C:25](Cl)[N:24]=2)=[CH:21][C:20]2[CH:31]=[CH:32][CH:33]=[CH:34][C:19]1=2.C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH:16]([NH2:17])[C:25]2[N:24]=[C:23]([C:22]3[S:18][C:19]4[CH:34]=[CH:33][CH:32]=[CH:31][C:20]=4[CH:21]=3)[C:28]([CH3:29])=[CH:27][N:26]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cnc(Cl)nc1-c1cc2ccccc2s1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCN)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1cnc(C(N)CCN2CCN(C(=O)OC(C)(C)C)CC2)nc1-c1cc2ccccc2s1
Yield: 70.9 %

Procedure:
4-(3-Aminopropyl)-piperazine-1-carboxylic acid tert-butyl ester (261 mg, 1.07 mmol) is added to a stirred suspension of 4-(benzo[b]thiophen-2-yl)-2-chloro-5-methyl-pyrimidine (140 mg, 0.537 mmol) and diisopropylethylamine (140 μL, 0.805 mmol) in anhydrous 1,4-dioxane (3.5 mL) at ambient temperature under nitrogen. The resultant mixture is heated in an oil bath at 95° C. for 36 hours. At ambient temperature the mixture is concentrated and chromatographed on silica gel, eluting with 2 M NH3/CH3OH in dichloromethane 0-6%, to give 4-{3-[4-(benzo[b]thiophen-2-yl)-5-methyl-pyrimidin-2-yl]-amino-propyl}-piperazine-1-carboxylic acid tert-butyl ester as a white solid (178 mg, 70% yield).
Reaction SMILES: [OH:1]CCCNC(=O)[C@H](C(CO)(C)C)O.[CH3:15][O:16][C:17]1[CH:27]=[CH:26][C:20]([CH:21]=[CH:22][C:23](Cl)=[O:24])=[CH:19][CH:18]=1.N1C=CC=CC=1>C1COCC1>[CH3:15][O:16][C:17]1[CH:27]=[CH:26][C:20]([CH:21]=[CH:22][C:23]([OH:1])=[O:24])=[CH:19][CH:18]=1
Reactant: CC(C)(CO)[C@H](O)C(=O)NCCCO
Reactant: COc1ccc(C=CC(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(C=CC(=O)O)cc1
Reaction time: 3 h
Yield: 55 %

Procedure:
11.3 g of D-panthenol (0.055 mol) are placed in 100 ml of THF while gassing with argon in a 500 ml 4-necked sulphonation flask provided with a thermometer, a 100 ml dropping funnel, a magnetic stirrer and a reflux condenser. A solution of 27.8 g of 4-methoxycinnamic acid chloride (0.14 mol) in 100 ml of tetrahydrofuran is then added dropwise within about 15 minutes. A solution of 11.1 g of pyridine (0.14 mol) is now added dropwise within about 30 minutes and the mixture is stirred for a further 3 hours. The precipitate is filtered off under suction and the filtrate is concentrated on a rotary evaporator. The residue is dissolved in 300 ml of CH2Cl2. This solution is washed with 2× 60 ml of 5% HCl and then with 2× 60 ml of 5% NaHCO3. After drying (Na2SO4) the organic phase is concentrated on a rotary evaporator. The yellow, viscous residue (33.8 g) is chromatographed (toluene/ethyl acetate, 8:2) on 1 kg of silica gel (0.04-0.063 mm) under 0.5 bar pressure. There are obtained 15.9 g of yellowish <R>-panthenol diester of p-methoxycinnamic acid (yield 55%).
Reaction SMILES: C([NH:4][CH:5]([CH:9]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7])(=O)C.[ClH:24]>>[ClH:24].[NH2:4][CH:5]([CH:9]([C:10]1[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=1)[C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)[C:6]([OH:8])=[O:7]
Reactant: CC(=O)NC(C(=O)O)C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Product: NC(C(=O)O)C(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
A solution (144 mL) of 2-acetylamino-3,3-bis(4-fluorophenyl)propanoic acid (25.34 g, 79.9 mmol) in concentrated hydrochloric acid was stirred at 90° C. for 5 hrs, and cooled in an ice bath to allow solid precipitation. The solid was collected by filtration and dried to give the title compound (22.79 g).
Reaction SMILES: N(OCCC(C)C)=O.[CH3:9][O:10][C:11]([C:13]1[S:17][C:16](N)=[N:15][CH:14]=1)=[O:12].C(OCC)(=O)C>O1CCOCC1>[CH3:9][O:10][C:11]([C:13]1[S:17][CH:16]=[N:15][CH:14]=1)=[O:12]
Reactant: COC(=O)c1cnc(N)s1
Agent: CC(C)CCON=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cncs1
Temperature: 80 °C
Yield: 48.5 %

Procedure:
The mixture of 2.15 g of isoamyl nitrite and 10 ml of dioxane was stirred at 80° C. under a nitrogen atmosphere. A solution of 1.23 g of 2-aminothiazole-5-carboxylic acid methyl ester (7-3) in 20 ml of dioxane was added drop wise. The mixture was refluxed for 2 hours. After cooling to room temperature 30 ml of ethyl acetate was added. The mixture was washed with brine and dried and the solvent evaporated under reduced pressure. The crude product is purified on silica, thus yielding 0.54 g (48%) of thiazol 5-carboxylic acid methyl ester (7-4).