Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@H:19]([OH:26])[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[CH2:27]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[C:37]([O:39][CH3:40])=[O:38])[CH:28]([CH3:30])[CH3:29].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:13]([O:12][C:11]([N:10]([CH2:18][C@H:19]([OH:26])[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:33]2[CH:34]=[CH:35][C:36]([C:37]([O:39][CH3:40])=[O:38])=[C:31]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH:32]=2)=[CH:3][CH:4]=1)=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Br)cc1)C[C@H](O)c1cccnc1
Reactant: COC(=O)c1ccc(B(O)O)cc1CC(C)C
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)cc1CC(C)C
Temperature: 90 °C
Reaction time: 3 h
Yield: 62.5 %

Procedure:
To a mixture of tert-butyl [2-(4-bromophenyl)ethyl]-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]carbamate (500 mg), [3-isobutyl-4-(methoxycarbonyl)phenyl]boronic acid (336 mg), [1,1′-bis(diphenylphosphino)feffocene]palladium(II) dichloride (48.5 mg) and 1,1′-bis(diphenylphosphino)ferrocene (16.4 mg) in N,N-dimethylformamide (3.75 ml) was added 2.0M aqueous sodium carbonate solution (2.08 ml) and the mixture was stirred at 90° C. for 3 hours. After cooling to room temperature, the mixture was partitioned between ethyl acetate (30 ml) and water (30 ml). The organic layer was separated, washed with brine (30 ml) and dried over magnesium sulfate. Filtration followed by evaporation under reduced pressure gave a crude product which was purified by column chromatography on silica gel (hexane/ethyl acetate=1/1 to 1/3) to give methyl 4′-[2-[[tert-butoxycarbonyl]-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-3-isobutyl-4-biphenylcarboxylate (395 mg) as a yellow solid (foam).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:42][O:43][CH2:44][C:45](=O)[CH3:46].C(O)(=O)C.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:23][CH2:24][N:25]([CH:45]([CH3:46])[CH2:44][O:43][CH3:42])[CH2:26][CH2:27]2)=[CH:20][CH:21]=1
Reactant: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCNCC2)cc1
Reactant: COCC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COCC(C)N1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)cc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 71.4 %

Procedure:
(4Z)-6-Iodo-4-{[(4-piperazin-1-ylphenyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (47.4 mg, 0.1 mmol) is dissolved in N-methylpyrrolidinone (1 mL) and methylene chloride (0.3 mL), followed by addition of sodium triacetoxyborohydride (244 mg, 1.15 mmol), 1-methoxy-propan-2-one (0.232 mL, 2.58 mmol) and acetic acid (0.15 mL, 2.6 mmol). After stirring at room temperature for 40 min, methylene chloride and saturated sodium bicarbonate solution were added. The organic layer is separated and dried to give 39 mg (71%) of the title compound as a yellow solid. MS (ESI) m/z 547.4 (M+H)+1.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[CH2:23]([N:25]=[C:26]=[O:27])[CH3:24]>CC#N>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:26]([NH:25][CH2:23][CH3:24])=[O:27])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: CCN=C=O
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Product: CCNC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 30.2 %

Procedure:
(0.29 g, 1.90 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.60 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, ethyl isocyanate (0.16 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with 1N HCL (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:CH3CN 6:4) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(ethylamino)carboxamide (0.2 g, 30%) as a white solid: mp 173-175° C.; 1H NMR (DMSO-d6) δ d 11.13 (s, 1H), 7.86-7.69 (m, 3H), 6.44 (t, J=6.1 Hz, 1H), 6.11 (t, J=5.55 Hz, 1H), 5.18-5.11 (dd, J=5.4 and 12.6 Hz, 1H), 4.63 (d, J=6.1 Hz, 2H), 3.07-2.83 (m, 3H), 2.64-2.49 (m, 2H), 2.08-2.04 (m, 1H), 0.99 (t, J=7.1 Hz, 3H); 13C NMR (DMSO-d6) δ d 172.73, 169.80, 167.58, 167.03, 157.93, 141.15, 134.61, 133.37, 131.49, 126.96, 121.61, 48.83, 38.71, 34.17, 30.92, 21.98, 15.58; Anal. Calcd. For C17H18N4O5+0.14H2O: C, 56.58; H, 5.11; N, 15.53. Found: C, 56.56; H, 5.05; N, 15.28.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([NH:13][CH2:14][CH:15]=[CH2:16])[CH:11]=[CH2:12].C(=O)([O-])[O-].[Na+].[Na+].CN(C)P(N(C)C)(N(C)C)=O>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C1(C=CC(O)=CC=1)O.O>[CH2:10]([N:13]([CH2:14][CH:15]=[CH2:16])[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH:11]=[CH2:12]
Reactant: C=CCNCC=C
Reactant: O=Cc1ccc(F)cc1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=C([O-])[O-]
Agent: Oc1ccc(O)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCN(CC=C)c1ccc(C=O)cc1
Temperature: 110 °C
Reaction time: 113 h
Yield: 110.8 %

Procedure:
A mixture of 25.0 g (0.10 mol) of 4-fluorobenzaldeyde, 19.6 g (0.20 mol) of diallylamine, 21.3 g (0.20 mol) of sodium carbonate, 150 mL of hexamethylphosphoramide (HMPA), 0.20 g of hydroquinone, and 4 drops of tricaprylmethylammonium chloride was heated under nitrogen with stirring at 110° C. for 113 hr. The reaction mixture was cooled and poured into 1.5 L of water, and the resulting solution was extracted with toluene (4×300 mL). The combined extracts were washed with water (3×250 mL), dried (MgSO4), and the solvent was removed at reduced pressure. The brown residue was fractionally distilled in vacuo to provide 22.3 g (55%) of a pale yellow oil, bp 128°-142° C. (0.16 mm).
Reaction SMILES: [C:1]([C:4]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:24])([C:21]([OH:23])=[O:22])[CH2:17][C:18](O)=[O:19])=[CH:12][CH:11]=1)([CH3:9])[CH2:5][C:6](O)=[O:7])([OH:3])=[O:2].C(OC(=O)C)(=O)C>>[CH3:9][C:4]1([C:10]2[CH:11]=[CH:12][C:13]([C:16]3([CH3:24])[CH2:17][C:18](=[O:19])[O:22][C:21]3=[O:23])=[CH:14][CH:15]=2)[CH2:5][C:6](=[O:7])[O:3][C:1]1=[O:2]
Reactant: CC(CC(=O)O)(C(=O)O)c1ccc(C(C)(CC(=O)O)C(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Product: CC1(c2ccc(C3(C)CC(=O)OC3=O)cc2)CC(=O)OC1=O

Procedure:
The product was then hydrolyzed by refluxing according to the procedure of Example 1 above. The product, 1,4-bis(1,2-dicarboxy-1-methylethyl)benzene, was heated with acetic anhydride according to the process employed in Example 1. After heating at 70° C. for 20 hours the desired dianhydride having the following analysis was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([C:17]([O:19][CH3:20])=[O:18])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[I-:21].[Na+]>CC(C)=O>[I:21][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([C:17]([O:19][CH3:20])=[O:18])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: [I-]
Reactant: COC(=O)C(CCCCCCCBr)C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)C(CCCCCCCI)C(=O)OC(C)(C)C

Procedure:
t-Butyl methyl 7-bromoheptylmalonate (8.81 g, 25.1 mmol) is dissolved in acetone (50 ml). Sodium iodide (3.7 g, 25.1 mmol) is added and the mixture is stirred at reflux for 2 hours. The reaction mixture is filtered and the filtrate is concentrated to dryness. The residue is dissolved in methylene chloride and filtered again. The filtrate is concentrated to dryness to give t-butyl methyl 7-iodoheptylmalonate as an oil.
Reaction SMILES: [N:1]([C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:11])=[N+:2]=[N-:3].[CH2:12]([O:14][C:15](=[O:21])[C:16]#[C:17][CH:18]([CH3:20])[CH3:19])[CH3:13]>C1(C)C=CC=CC=1>[CH2:12]([O:14][C:15]([C:16]1[N:1]([C:4]2[C:5]([Cl:11])=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:10])[N:2]=[N:3][C:17]=1[CH:18]([CH3:20])[CH3:19])=[O:21])[CH3:13]
Reactant: [N-]=[N+]=Nc1c(Cl)cccc1Cl
Reactant: CCOC(=O)C#CC(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C(C)C)nnn1-c1c(Cl)cccc1Cl

Procedure:
A solution of 2-azido-1,3-dichloro-benzene (1.0 g) and 4-methyl-pent-2-ynoic acid ethyl ester (1.8 g) in toluene (5 mL) is heated to 120° C. overnight. Two regioisomers are observed in a range of 1:1 to 3:1 in favor of the desired product. The reaction is concentrated under reduced pressure and the residue is purified by flash chromatography, eluting with 5% ethyl acetate in hexanes. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, 2H), 7.42 (t, 1H), 4.22 (q, 2H), 3.64 (m, 1H), 1.46 (d, 6H), 1.15 (t, 3H).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][N:14]=[C:13]([N:18]3[CH:22]=[C:21]([CH2:23][O:24][CH3:25])[N:20]=[CH:19]3)[CH:12]=[C:7]12.C([Sn](CCCC)(CCCC)[C:31]1[S:32][CH:33]=[CH:34][N:35]=1)CCC>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>[CH3:25][O:24][CH2:23][C:21]1[N:20]=[CH:19][N:18]([C:13]2[CH:12]=[C:7]3[C:8]4[C:3]([CH2:4][CH2:5][N:6]3[C:16](=[O:17])[CH2:15][N:14]=2)=[C:2]([C:31]2[S:32][CH:33]=[CH:34][N:35]=2)[CH:11]=[CH:10][CH:9]=4)[CH:22]=1
Reactant: COCc1cn(C2=NCC(=O)N3CCc4c(I)cccc4C3=C2)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COCc1cn(C2=NCC(=O)N3CCc4c(cccc4-c4nccs4)C3=C2)cn1
Temperature: 150 °C
Yield: 36.7 %

Procedure:
Example 71. To a degassed solution of 9-iodo-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (191 mg, 0.43 mmol) and 2-(tributylstannyl)thiazole (239 mg, 0.64 mmol) in dioxane (4 mL) was added Pd(PPh3)4 (25 mg, 0.021 mmol) and the mixture was heated in the microwave at 150° C. for 2 h. The solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, eluent: from 1% MeOH in DCM to 5% MeOH in DCM in 18 min) to yield the title compound (64 mg). UPLC-MS: MS 406.1 (M+H+); UPLC rt 0.81 min. 1H NMR (600 MHz, DMSO-d6): δ ppm 3.18-3.31 (m, 5 H), 3.78 (t, J=6.0 Hz, 2 H), 4.30 (s, 4 H), 7.18 (s, 1 H), 7.55 (t, J=7.9 Hz, 1 H), 7.67 (s, 1 H), 7.86 (d, J=7.7 Hz, 1 H), 7.93 (d, J=3.3 Hz, 1 H), 8.04 (d, J=3.3 Hz, 1 H), 8.13 (d, J=8.1 Hz, 1 H), 8.24 (s, 1 H).
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=1[O:18][CH3:19])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[Si:5]([O:8][C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[O:18][CH3:19])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])cc1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(N)cc1O[Si](C)(C)C(C)(C)C
Yield: 74 %

Procedure:
A mixture of tert-butyl-(2-methoxy-5-nitrophenoxy)dimethylsilane (3.0 g, 10.6 mmol) and 5% Pd—C (0.3 g) in 30 mL of ethyl acetate was hydrogenated under 50 psi of hydrogen gas for 14 hours. The mixture was filtered through Celite and the filtrate was evaporated. The residue was chromatographed using a hexanes-ethyl acetate gradient, eluting 2.0 g of the product at 85:15 hexanes-ethyl acetate, in 74% yield: 1H NMR (CDCl3) δ 0.15 (s, 6H), 0.99 (s, 9H), 3.37 (br, 2H), 3.72 (s, 3H), 6.23-6.29 (m, 2H), 6.68 (d, J=8.1 Hz, 1H).
Reaction SMILES: Cl[CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C@H:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.[N-:22]=[N+:23]=[N-:24].[Na+].C(OCC)(=O)C>CS(C)=O>[N:22]([CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C@H:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1ccc(C[C@H]2CC[C@@H](N3CCC[C@H]3CCl)CC2)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: [N-]=[N+]=NC[C@@H]1CCCN1[C@H]1CC[C@@H](Cc2ccc(F)cc2)CC1
Temperature: 50 °C

Procedure:
To a stirring solution of (2S)-2-(chloromethyl)-1-[cis-4-(4-fluorobenzyl)cyclohexyl]pyrrolidine in 2 ml of DMSO (Aldrich) at 25° C. under N2 was added sodium azide (28 mg, 2.90 mmol, Aldrich). The reaction was heated at 50° C. for 16 hours. Worked up by adding ethyl acetate then rinsing 5 times with H2O. The organic was dried over magnesium sulfate, and concentrated in vacuo to obtain 45 mg of an amber oil as product. MS (ESI) detects 317 (M+H).
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:21])[C:4]=2[CH:3]=1.[Na+].[C:23]1([S:29]([O-:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CS(C)=O>[C:23]1([S:29]([C:2]2[CH:19]=[CH:18][C:17]3[C:16](=[O:20])[C:15]4[C:6](=[CH:7][C:8]5[C:13]([CH:14]=4)=[CH:12][CH:11]=[CH:10][CH:9]=5)[C:5](=[O:21])[C:4]=3[CH:3]=2)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1c2ccc(F)cc2C(=O)c2cc3ccccc3cc21
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C1c2ccc(S(=O)(=O)c3ccccc3)cc2C(=O)c2cc3ccccc3cc21

Procedure:
1 g (3.62 mmol) of 2-fluoro-naphthacene-5,12-dione, 0.89 g (5.43 mmol) of benzenesulfinic acid sodium salt (sodium benzenesulfinate) and 10 ml of DMSO are stirred at 100° C. for 3 hours. After cooling, the mixture is poured onto water. The crystals are filtered off and dissolved in THF/toluene. The solution is dried over sodium sulfate and evaporated. The residue is recrystallized from THF/toluene/pentane. Yield: 1.35 g (94%), melting point >260° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C(N(C(C)C)C(C)C)C.C1N=CN([S:26](N2C=NC=C2)(=[O:28])=[O:27])C=1>C(#N)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]2[NH:1][S:26](=[O:28])(=[O:27])[O:11][C:3]=2[CH:4]=1)([O-:10])=[O:9]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=S(=O)(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc2c(c1)OS(=O)(=O)N2
Temperature: 25 °C

Procedure:
A solution of 2-amino-5-nitrophenol (7.7 g, 50 mmol) in acetonitrile (300 ml) is treated with N-ethyldiisopropylamine (18.7 ml, 110 mmol) and N,N′-sulfuryldiimidazole (10.8 g, 55 mmol) and boiled at reflux for 18 h. After cooling to RT, the solvent is distilled off under reduced pressure, the residue is taken up in 1 N HCl and the product is extracted with ethyl acetate. The product is then purified by flash chromatography (17:2:1, EtOAc/MeOH/H2O).
Reaction SMILES: [NH2:1][N:2]1[C:7]([NH2:8])=[CH:6][C:5]([NH2:9])=[N:4][C:3]1=[S:10].[CH:11](O)=O>>[NH2:9][C:5]1[N:4]=[C:3]([SH:10])[N:2]2[N:1]=[CH:11][N:8]=[C:7]2[CH:6]=1
Reactant: Nc1cc(N)n(N)c(=S)n1
Reactant: O=CO
Product: Nc1cc2ncnn2c(S)n1

Procedure:
A mixture of 1,4,6-triamino-2(1H)-pyrimidinethione (2.0 g) and 40 ml of formic acid was refluxed for seven hours. After concentrating under reduced pressure, 80 ml of water was added to the residue, the mixture was refluxed for one hour, and the crystals formed upon cooling were collected by filtration and washed with methanol, giving 1.6 g of the objective compound as faint yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20][C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=1)[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.[NH2:31][CH2:32][CH2:33][OH:34].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20][C:21]1[CH:22]=[N:23][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:25][CH:26]=1)[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:31][CH2:32][CH2:33][OH:34])=[O:18])=[N:14][CH:15]=1
Reactant: NCCO
Reactant: Cc1cc(C(=O)O)ncc1C(Sc1ccc(C(F)(F)F)nc1)c1cc(F)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)NCCO)ncc1C(Sc1ccc(C(F)(F)F)nc1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[[6-(trifluoromethyl)pyridin-3-yl]thio]methyl]-4-methylpyridine-2-carboxylic acid (132 mg, 0.30 mmol) obtained in Example 26 in methylene chloride (5 ml), 2-aminoethanol (0.020 ml, 0.33 mmol), 1-hydroxybenzotriazole (45 mg, 0.33 mmol), 4-methylmorpholine (0.036 ml, 0.33 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (63 mg, 0.33 mmol) were added at room temperature. After stirring for 6 hours at room temperature, the reaction mixture was washed with 0.5 N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=1:1 was concentrated under reduced pressure to obtain the title compound (143 mg, 0.30 mmol, 99%) as a colorless oily substance.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:27][C:26]4[CH:29]=[CH:30][C:23]([Cl:22])=[CH:24][CH:25]=4)[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccn(Cc3ccc(Cl)cc3)n2)sc1C(=O)NCc1cccnc1
Temperature: 90 °C
Yield: 25 %

Procedure:
To a solution of 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide (0.2 g, 0.67 mmol) in dimethyl sulfoxide (5 mL) was added with 4-chlorobenzyl bromide (0.14 g, 0.67 mmol) and potassium carbonate (0.30 g, 2.0 mmol). The reaction mixture was heated to 90° C. for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with brine (2×50 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by preparative thin layer chromatography over silica gel (methylene chloride:methanol, 95:5) to provide 2-[1-(4-chloro-benzyl)-1H-pyrazol-3-yl]-4-methyl-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)amide as a white solid (0.071 g, 51% yield). 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.54-8.56 (m, 1H), 7.71 (d, J=8 Hz, 1H), 7.39 (s, 1H) 7.26-7.33 (m, 3H), 7.18 (d, J=4 Hz, 2H), 6.84 (d, J=4 Hz, 1H), 6.18-6.21 (m, 1H), 5.31 (s, 2H), 4.62 (d, J=4 Hz, 2H), 2.74 (s, 3H). MS (M+H)+=423.9; Rt=1.29 min; HRMS (M+H)+=424.10.
Reaction SMILES: CC[O:3]C(CC1N=C(NC(CSC2[N+](CC=C)=C(N)CC(=O)N=2)=O)SC=1)=O.[Cl:28][C:29]1[CH:30]=[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[N:46]([CH3:51])[S:47]([CH3:50])(=[O:49])=[O:48])[N:32]2[C:37]=1[CH:36]=[N:35][C:34](SC)=[N:33]2.C(Cl)Cl.ClC1C=CC=C(C(OO)=O)C=1.[OH-].[Na+].C(O)(=O)C>O>[Cl:28][C:29]1[CH:30]=[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[N:46]([CH3:51])[S:47]([CH3:50])(=[O:49])=[O:48])[N:32]2[C:37]=1[CH:36]=[N:35][C:34]([OH:3])=[N:33]2
Reactant: CSc1ncc2c(Cl)cc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Reactant: C=CC[N+]1=C(N)CC(=O)N=C1SCC(=O)Nc1nc(CC(=O)OCC)cs1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(c1ccccc1-c1cc(Cl)c2cnc(O)nn12)S(C)(=O)=O
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 47.2 %

Procedure:
1553d) N-[2-(5-Chloro-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide was dissolved in Methylene chloride (10 mL, 200 mmol) and m-Chloroperbenzoic acid (235 mg, 1.05 mmol) was added. After 90 min, additional m-Chloroperbenzoic acid (135 mg, 0.602 mmol) was added. Formation of the sulfoxide was concomitant with sulfone formation. After 1 h, the mixture was partitioned between satd. NaHCO3 (20 mL) and EtOAc (50 mL); the aq. was extracted with EtOAc (2×20 mL) and the comb. org. washed with brine:satd. NaHCO3 (40 mL). After drying, the mixture was conc. in vacuo. The crude N-[2-(5-Chloro-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide was dissolved in 1,4-Dioxane (4.00 mL) then treated with 5.0 M of Sodium hydroxide in Water (1.00 mL, 5.00 mmol) and heated to 60° C. for 2 h. The mixture was cooled, treated with Acetic acid (0.400 mL, 7.04 mmol) and water (2 mL), then partitioned between water and DCM (30 mL each), sept. and extr. with DCM (3×20 mL), dried and conc. in vacuo. The residue was applied to a 5 g ISCO cartridge, then purified (24 g SiO2, 10-100% EtOAc:Hex) to afford N-[2-(5-Chloro-2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (0.129 g; Yield=47.2% over 4 steps) as an orange foam. LCMS (HPLC): 0.76 min, m/z=353 (M+H); 1H-NMR (DMSO-d6): 11.87 (br s, 1H), 9.01 (s, 1H), 7.69 (m, 2H), 7.59 (m, 2H), 7.50 (m, 1H), 6.99 (s, 1H), 3.19 (s, 3H), 2.84 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br:13]N1C(=O)CCC1=O>C(#N)C>[Br:1][C:2]1[C:3]([CH2:12][Br:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(Br)c1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COC(=O)c1cccc(Br)c1CBr
Temperature: 25 °C
Yield: 107.2 %

Procedure:
A mixture of methyl 3-bromo-2-methylbenzoate (17.0 g, 74.22 mmol) and N-bromosuccinimide (15.85 g, 89.06 mmol) in acetonitrile (200 mL) was heated under gently refluxing for 17 hours while a 200 W bulb situated 2 cm away was shining on the reaction flask. The mixture was cooled to room temperature and solvent was removed. The residue was dissolved in ethyl acetate (200 mL) and washed with water (3×80 mL), brine (80 mL) and dried (MgSO4). Solvent was removed to give methyl 3-bromo-2-bromomethylbenzoate (24.5 g, 97% by HPLC): 1H NMR (CDCl3) δ 7.90-7.86 (dd, J=1.0 and 7.9 Hz, 1H), 7.78-7.74 (dd, J=1.2 and 8.2 Hz, 1H), 7.22 (t, J=7.9 Hz, 1H), 5.12 (s, 2H), 3.95 (s, 3H).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][CH2:12][CH2:13][NH2:14]>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:10][O:11][CH2:12][CH2:13][NH:14][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: COCCN
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: COCCNc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 17.2 %

Procedure:
To phenylboronic acid (5 g, 41.0 mmol) in DCM (50 mL) was added copper (II) acetate (0.78 g, 4.1 mmol) and the mixture was stirred for 5 min at room temperature. 2-Methoxyethanamine (3.08 g, 41.0 mmol) was added and the mixture was stirred at 40 C for 19 h. The mixture was then passed through a silica plug and then purified by FCC, eluting with 10% EtOAc in heptane to afford the title compound (1.065 g, 17% yield). Method B HPLC-MS: MH+ requires m/z=152 Found: m/z=152, Rt=1.08 min (87%).