Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:12]([CH:13]=[O:14])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[Mn]([O-])(=O)(=O)=[O:16].[K+].[OH-].[K+]>C1COCC1.O>[CH:1]([C:4]1[C:12]([C:13]([OH:16])=[O:14])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)c1nn2ccccc2c1C=O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1nn2ccccc2c1C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 60.2 %

Procedure:
A mixture of 2-isopropylpyrazolo[1,5-a]pyridine-3-carbaldehyde (1.5 g, 1 equivalent) and potassium permanganate (2.9 g, 2.1 equivalents) in 10 mL of THF was stirred at room temperature for 2 days. A solution of potassium hydroxide (2.2 g, 5 equivalents) in 10 mL of water was added and the resulting solution was stirred at room temperature for 2 hours. The mixture was filtered to remove insoluble solids and the filtrate was extracted to remove unreacted aldehyde. The remaining aqueous solution was acidified with concentrated HCl and the precipitates were collected by filtration and dried under reduced pressure to give 2-isopropylpyrazolo[1,5-a]pyridine-3-carboxylic acid (0.98 g, 60% yield) as a solid. Compound 1079.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[Cl:18][C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:17][C:2]([F:1])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][N:13]([C:19]([Cl:18])=[O:21])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: FC(F)(F)Oc1ccc(N2CCNCC2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Cl)N1CCN(c2ccc(OC(F)(F)F)cc2)CC1
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 300.8 %

Procedure:
A mixture of 1-(4-trifluoromethoxyphenyl)piperazine (1.0 g, 4.1 mmol), triphosgene (0.42 g, 1.4 mmol), and pyridine (0.66 ml, 8.2 mmol) in toluene (20 ml) was stirred at 100° C. for 4.5 hours. To which ethyl acetate was added, and the mixture was washed with water, dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 4-(4-trifluoromethoxyphenyl)piperazine-1-carbonylchloride (1.3 g, quantitative) as a brown oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9]C>N1C=CC=CC=1>[F:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1ccc(CCC(=O)O)cc1F
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)CCc1ccc(O)c(F)c1
Temperature: 190 °C
Reaction time: 1.5 h
Yield: 88.8 %

Procedure:
A pyridine/hydrochloric acid complex prepared by mixing pyridine and concentrated hydrochloric acid (30 ml each) and then heating the mixture at 190° C. for 1 hour was added with Intermediate 19 (2.40 g) and stirred at 190° C. for 1.5 hours. The reaction mixture was poured into ice cooled 1 N hydrochloric acid (100 ml) and extracted with ethyl acetate (200 ml). The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure to obtain the title compound (Intermediate 20, 1.98 g).
Reaction SMILES: O=C([O:13][C:14]([C@@H:16]([C@H:18]([C@@H:20]([C@@H:22](CO)[OH:23])O)[OH:19])O)=[O:15])[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[Mg].[Ca].[C:28](=O)([O-:30])[O-:29].[OH2:32]>>[C:14]([OH:13])(=[O:15])[CH2:16][C:18]([CH2:20][C:22]([OH:23])=[O:32])([C:28]([OH:30])=[O:29])[OH:19]
Reactant: O=C(OC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C([O-])[O-]
Reactant: O
Agent: [Ca]
Agent: [Mg]
Product: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reaction time: 18 h

Procedure:
25 grams of gluconic acid anhydride; 80 grams of dried and purified magnesium hydroxycarbonate prepared by heating in a steel tray exposed to the steam and air at 165° C. for 18 hours so that all organic material present has been oxidized; 12 grams of magnesium acid citrate; and 4 grams of calcium as the carbonate were admixed, all in powdered form. Next 20 grams of distilled water was heated to a temperature of 80° C., and then added to the 300 gram heat-resistant glass bottle. The admixed powders were then introduced into the glass bottle containing the heated distilled water and were dissolved therein. The evolvement of carbon dioxide gas from the liquid was observed. When this evolution of carbon dioxide had subsided, the magnesium gluconocitrate solution was filtered, introduced into a glass bottle, stoppered and was placed into the autoclave as is done in the prior art. During autoclaving, the bottle did not break.
Reaction SMILES: [CH:1]([C:3]1[NH:8][C:7]([CH3:9])=[C:6]([C:10]([OH:12])=[O:11])[CH:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:4]=1[C:22]([O:24][CH3:25])=[O:23])=O.S(O)(O)(=O)=O.[NH2:31]O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C.C(OCC)(=O)C>[C:1]([C:3]1[NH:8][C:7]([CH3:9])=[C:6]([C:10]([OH:12])=[O:11])[CH:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:4]=1[C:22]([O:24][CH3:25])=[O:23])#[N:31]
Reactant: NO
Reactant: COC(=O)C1=C(C=O)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C1=C(C#N)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
To a solution of 3-nitrooxy-2,2-bis(nitrooxymethyl)propyl ester of 6-formyl-5-methoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (3.00 g) in acetic acid (15 ml) were added hydroxylamine sulfate (2:1) (0.49 g) and sodium acetate (0.57 g), followed by stirring at ambient temperature for an hour. To the resulting mixture was added acetic anhydride (15 ml), followed by stirring at ambient temperature for 2 hours and under reflux for additional 2 hours. The reaction mixture was evaporated under reduced pressure and the residue obtained was dissolved in ethyl acetate. This solution was successively washed with water, an aqueous sodium bicarbonate and an aqueous sodium chloride, followed by drying over anhydrous magnesium sulfate. After removal of the solvent, the residual oily product (3.6 g) was subjected to column chromatography using silica gel (90 g). Elution was carried out with a mixture of ethyl acetate and toluene (1:10 to 1:4 by volume) and the fractions containing the desired compound were collected and evaporated to give 3-nitrooxy-2,2-bis(nitrooxymethyl)propyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (1.0 g).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][CH:5]([NH:15][C:16]([NH:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[CH2:24][CH2:23][CH2:22]2)=[O:17])[C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1.Cl.Cl.[NH2:31][C:32]1[C:36]([NH2:37])=[CH:35][S:34][CH:33]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[NH2:37][C:36]1[C:32]([NH:31][C:10](=[O:11])[C:9]2[CH:8]=[CH:7][C:6]([CH:5]([NH:15][C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[CH2:24][CH2:23][CH2:22]4)=[O:17])[CH2:4][CH2:3][N:2]([CH3:28])[CH3:1])=[CH:14][CH:13]=2)=[CH:33][S:34][CH:35]=1
Reactant: CN(C)CCC(NC(=O)Nc1ccc2c(c1)CCC2)c1ccc(C(=O)O)cc1
Reactant: Nc1cscc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCC(NC(=O)Nc1ccc2c(c1)CCC2)c1ccc(C(=O)Nc2cscc2N)cc1
Yield: 57.6 %

Procedure:
A solution of 4-[1-(2-dimethylaminoethyl)-3-(indan-5-yl)ureidomethyl]benzoic acid (Reference Compound No. 11-1, 77 mg, 0.20 mmol), 3,4-diaminothiophene dihydrochloride (45 mg, 0.24 mmol), N,N-diisopropylethylamine (77 μL, 0.44 mmol) and HATU (90 mg, 0.24 mmol) in DMF (2.0 mL) was stirred at room temperature overnight. Water (30 mL) was added to the reaction solution, and then the whole was extracted with ethyl acetate (30 mL) three times. The organic layer was washed with water (30 mL) and brine (30 mL), dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel (NH-modified silica gel) column chromatography (chloroform-methanol) to give 55 mg of the title compound as a brown amorphous product. (Yield 58%)
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]=2[CH:5]=[C:4]([CH3:20])[CH:3]=1.[H-].[Na+].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26]>CN(C=O)C>[CH3:28][O:27][C:25](=[O:26])[CH2:24][N:9]1[C:10]2[C:2]([CH3:1])=[CH:3][C:4]([CH3:20])=[CH:5][C:6]=2[N:7]([CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[C:8]1=[O:11]
Reactant: COC(=O)CBr
Reactant: Cc1cc(C)c2[nH]c(=O)n(CC(=O)OC(C)(C)C)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(=O)n(CC(=O)OC(C)(C)C)c2cc(C)cc(C)c21
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (4,6-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate from Step B (100 mg, 0.36 mmol) in DMF (3 mL) was added sodium hydride (17 mg of a 60% dispersion in mineral oil, 0.43 mmol) followed by methyl bromoacetate (0.041 mL, 0.43 mmol) and the reaction mixture was stirred for 2 h. The reaction was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization of the product-containing fractions afforded the title compound. MS: m/z=349 (M+1).
Reaction SMILES: Cl[C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5].[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C(O)CO>[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[N:13]=[CH:12][CH:11]=[CH:10][C:3]=2[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5])=[CH:17][CH:16]=1
Reactant: C#CCNC(=O)c1cccnc1Cl
Reactant: Nc1ccc(Cl)cc1
Solvent: OCCO
Product: C#CCNC(=O)c1cccnc1Nc1ccc(Cl)cc1
Temperature: 140 °C

Procedure:
Compound 8 (194 mg, 1 mmol) and 4-chloroaniline (9c, 127 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-chlorophenylamino)-N-(prop-2-ynyl)nicotinamide 10c as pure product. To a solution of 2-(4-chlorophenylamino)-N-(prop-2-ynyl)nicotinamide (10c 150 mg, 0.52 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12c, 130 mg, 0.57 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 10 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1c (204 mg 76%); mp: 127-129° C.; 1H NMR (300 MHz, CDCl3) δ 10.51 (s, 1H), 8.25 (dd, J=2.2, 1.5 Hz, 1H), 7.84 (dd, J=2.2, 1.5 Hz, 1H), 7.80 (brs, 1H), 7.61-7.58 (m, 3H), 7.35-7.23 (m, 4H), 7.08 (t, J=7.5 Hz, 1H), 6.98-6.91 (m, 7H), 6.67-6.63 (m, 1H), 5.45 (s, 2H), 4.62 (d, J=5.2 Hz, 2H); MS (ESI m/z): 511 [M+H]+. Yield: 76%
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2)([O-:5])=[O:4].I[CH3:16]>CN(C)C=O>[CH3:16][N:11]1[C:12]2[C:8](=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:14][CH:13]=2)[CH:9]=[CH:10]1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2cc([N+](=O)[O-])ccc21
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a stirred suspension of sodium hydride (5.0 g; 167 mM) in dimethylformamide (200 ml) at 0° C. under nitrogen was added 5-nitroindole (25 g; 154 mM) in dimethylformamide. After stirring for 0.5 h, iodomethane (10.5 ml; 168 mM) in dimethylformamide (50 ml) was added, and stirring was continued for 2 h. The reaction mixture was then quenched with water, and poured onto excess water with stirring. Filtration afforded the title compound (27.4 g; 94%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][Cl:6].[SH:7][C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(O)C>[Cl:6][CH2:5][CH2:4][CH2:3][CH2:2][S:7][C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[CH:10][CH:9]=1
Reactant: ClCCCCBr
Reactant: Sc1cccc2nccn12
Solvent: CCN(CC)CC
Solvent: CCO
Product: ClCCCCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a nitrogen atmosphere, 8.87 ml (77 mmol) of 1-bromo-4-chlorobutane was added to a solution of 10.51 g (70 mmol) of 5-mercaptoimidazo[1,2-a]pyridine and 10.73 ml (77 mmol) of triethylamine in 150 ml of ethanol was added, followed by stirring at room temperature for 16 hours. After the solvent was distilled off, the residue was dissolved in dichloromethane. This solution was washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to yield 12.93 g (76.7%, light brown oily substance) of the desired product.
Reaction SMILES: [CH2:1]1[O:4][CH:2]1[CH3:3].C([N:7](CC)[C:8]1[CH:13]=[CH:12][C:11](F)=[C:10](F)[C:9]=1O)C.[CH2:19]=[C:20]([C:24]([O-:26])=[O:25])[C:21]([O-:23])=[O:22].O>C1COCC1>[OH:22][CH:2]([CH3:3])[CH2:1][O:4][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:19]=[C:20]([C:24]([O-:26])=[O:25])[C:21]([O-:23])=[O:22]
Reactant: CC1CO1
Reactant: CCN(CC)c1ccc(F)c(F)c1O
Agent: C=C(C(=O)[O-])C(=O)[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)CONc1ccccc1
Temperature: 40 °C

Procedure:
2,9 mgr (0,06 mmol) of HNa at 60%, 161 mgr (1,26 mmol) of LiClO4 anhydrous and 51 ml (0,32 mmol) of propylene oxide are added to a solution of 100 mgr) 0,32 mmol) of the compound [4] in 0,33 ml of THF. The reaction mixture is heated at 40° C. for two days and then 2 ml of water are added. The aqueous layer is extracted with ACOEt, ethyl acetate, (2×5 ml). The combination of the organic layers is dried with MgSO4 and the solvent is eliminated thus obtaining 77 mgr (65%) of the desired product [5].
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[Cl:48][C:49]1[N:54]=[CH:53][C:52]([CH2:55][NH2:56])=[CH:51][CH:50]=1>>[Cl:48][C:49]1[N:54]=[CH:53][C:52]([CH2:55][NH:56][C:41]([C:39]2[S:40][C:36]([N:33]3[CH2:34][CH2:35][N:31]([CH2:30][C:29]4[CH:28]=[CH:27][C:26]([F:25])=[CH:47][CH:46]=4)[C:32]3=[O:45])=[CH:37][C:38]=2[CH3:44])=[O:42])=[CH:51][CH:50]=1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1ccc(Cl)nc1
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccc(Cl)nc1
Yield: 80 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (6-chloropyridin-3-yl)methanamine, the title compound was obtained as a colorless solid in 80% yield: 1H NMR (300 MHz, CDCl3) δ 8.36 (d, J=1.5 Hz, 1H), 7.68 (dd, J=8.2, 2.4 Hz, 1H), 7.30-7.23 (m, 3H), 7.08-6.99 (m, 2H), 6.13 (t, J=5.8 Hz, 1H), 6.09 (s, 1H), 4.55 (d, J=5.8 Hz, 2H), 4.43 (s, 2H), 3.84-3.76 (m, 2H), 3.48-3.40 (m, 2H), 2.48 (s, 3H); MS (ES+) m/z 459.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]([N:11]1[CH2:18][CH:17]2[CH:13]([CH2:14][NH:15][CH2:16]2)[CH2:12]1)=[O:10].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH2:36][CH2:37][CH2:38]I)[S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:29])=[O:28])=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.C(Cl)Cl>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]([N:11]1[CH2:18][CH:17]2[CH2:16][N:15]([CH2:38][CH2:37][CH2:36][N:26]([C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=3)[S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH2:14][CH:13]2[CH2:12]1)=[O:10]
Reactant: Cc1cccc(C)c1C(=O)N1CC2CNCC2C1
Reactant: O=S(=O)(c1ccccc1)N(CCCI)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cccc(C)c1C(=O)N1CC2CN(CCCN(c3ccc(F)cc3)S(=O)(=O)c3ccccc3)CC2C1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a solution of 66 (0.012 g, 0.05 mmol) in MeCN (1 mL) at RT were added N-(4-fluoro-phenyl)-N-(3-iodo-propyl)-benzenesulfonamide (102, 0.025 g, 0.06 mmol) and K2CO3 (0.01 g, 0.075 mmol). The reaction mixture was shaken at 80° C. for 48 h. After cooling to RT, the mixture was diluted with DCM (5 mL), filtered and evaporated in vacuo. The crude product was purified by reverse phase HPLC to afford II-2: MS (ES+) m/z=536 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].[NH2:32][CH:33](C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)[CH3:34].N1C2C(=CC(C(O)=O)=CC=2)C=C1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:24][O:23][C:21]1[CH:22]=[C:17]([NH:16][C:13]2[N:14]=[N:15][C:10]([CH:8]([NH:7][C:5]([C:4]3[CH:3]=[C:2]4[C:31](=[CH:30][CH:29]=3)[NH:32][CH:33]=[CH:34]4)=[O:6])[CH3:9])=[CH:11][N:12]=2)[CH:18]=[C:19]([O:27][CH3:28])[C:20]=1[O:25][CH3:26]
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1ccc2[nH]ccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccc4[nH]ccc4c3)nn2)cc(OC)c1OC
Yield: 64 %

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (200 mg, 0.65 mmol), 1H-indole-5-carboxylic acid (140 mg, 0.85 mmol), diisopropylethylamine (0.34 mL, 1.95 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (350 mg, 0.92 mmol) in dimethylformamide (5 mL) gave N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)-1H-indole-5-carboxamide (187 mg, 64%) as a yellow solid. MS m/z 448 (M+1).
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[CH:14]([S:17]([N:20]1[C:24]2[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[NH2:32])(=[O:19])=[O:18])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH:14]([S:17]([N:20]1[C:24]2[CH:25]=[C:26]([C:2]3[N:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[N:5]=[C:4]([CH3:13])[CH:3]=3)[CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[NH2:32])(=[O:18])=[O:19])([CH3:16])[CH3:15]
Reactant: Cc1cc(Br)n(-c2ccccc2)n1
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(B(O)O)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2ccc3nc(N)n(S(=O)(=O)C(C)C)c3c2)n(-c2ccccc2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 45.8 %

Procedure:
To a solution of 5-(bromo)-3-(methyl)-1-(phenyl)-pyrazole (264 mg, 1.11 mmol) in 6 mL DME add 1-isopropylsulfonyl-2-amino-benzimidazole-6-boronic acid (694 mg, 2.45 mmol). Add sodium carbonate (354 mg, 3.34 mmol) dissolved in 0.5 mL of water and trans-dichlorobis(triphenylphosphine) palladium (II) (234 mg, 0.33 mmol). Heat the mixture to 100° C. with stirring under nitrogen. After 2 hours, cool and filter over a pad of Celite® and sodium sulfate. Purify the crude product by radial chromatography eluting with 4% methanol in CH2Cl2 to yield 201 mg (46%) of the title compound. MS(ES+): m/z=396.0 (M+H)+
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>>[N:5]1[CH:6]=[CH:7][C:2]([C:1]([Cl:12])=[O:9])=[CH:3][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccncc1
Product: O=C(Cl)c1ccncc1
Temperature: 70 °C

Procedure:
Isonicotinic acid (1.27 g, 10.36 mMole) was added to thionyl chloride (30 mL) and the mixture heated to 70° C. After 1 hour the solution was cooled, concentrated under reduced pressure and co-evaporated with ethyl acetate (2×30 mL). The residue was used as such in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22])[O:5][CH2:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][CH:8]=1.O.[OH-].[Na+]>CO.CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[C:21]([F:22])([F:23])[F:24])[O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1ccc(COc2ccc(C(F)(F)F)c(Cl)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(COc2ccc(C(F)(F)F)c(Cl)c2)cc1
Temperature: 55 °C
Yield: 77.8 %

Procedure:
To a solution of ethyl 4-{[3-chloro-4-(trifluoromethyl)phenoxy]methyl}benzoate (Preparation 18, 125 mg, 0.35 mmol) in methanol (5.0 mL) was added water (2.0 mL) followed by sodium hydroxide (140 mg, 3.5 mmol). The reaction mixture was heated to 55° C. for 18 hours, then cooled and diluted with EtOAc (50 mL) and 2M HCl (50 mL). The aqueous layer was separated and washed with EtOAc (2×50 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo to yield 4-{[3-chloro-4-(trifluoromethyl)phenoxy]methyl}benzoic acid as an off-white solid (90 mg, 78% yield). This solid was dissolved in dichloromethane (3 mL) then EDCI (344 mg, 1.79 mmol) and DMAP (88 mg, 0.70 mmol) were added, followed by the addition of N,N-dimethylsulfamide (86 mg, 0.70 mmol). The reaction was left to stir at room temperature for 2 hours. A solution of 2M HCl (10 mL) was added and the mixture separated using a phase separation cartridge. The organics were dried in vacuo to yield a solid which was triturated with heptane:IPA (4:1, 100 mL) and sonicated. The supernatant was decanted and the residue dried in vacuo to yield an off-white solid as the title compound (57 mg, 38% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:21]3[C:20](=[O:30])[N:19]([CH2:31][O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:18](=[O:39])[N:17](COC(=O)C(C)(C)C)[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N12CCCN=C1CCCCC2.Cl>O1CCCC1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:21]3[C:20](=[O:30])[N:19]([CH2:31][O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:18](=[O:39])[NH:17][C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3c(c(=O)n(COC(=O)C(C)(C)C)c(=O)n3COC(=O)C(C)(C)C)n2-c2ccccc2Cl)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2nc3[nH]c(=O)n(COC(=O)C(C)(C)C)c(=O)c3n2-c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
4-[7-(2-Chlorophenyl)-1,3-bis-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (2.227 g) was dissolved in tetrahydrofuran (10 ml) and methanol (20 ml), and 1,8-diazabicyclo[5,4,0]undec-7-ene (0.518 ml) was added thereto. The reaction mixture was stirred at room temperature overnight, and 1 N hydrochloric acid was added. Deposited solid was collected by filtration and dried to give 1.025 g of the title compound.