Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([O:13][CH2:14][CH2:15][OH:16])=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)N>C(O)(=O)C.C(OCC)C>[Cl:17][C:18]1[CH:19]=[C:20]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([O:13][CH2:14][CH2:15][OH:16])[C:3]=23)[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: CN(C)C=Nc1[nH]nc(OCCO)c1C#N
Solvent: CC(=O)O
Solvent: CCOCC
Product: OCCOc1n[nH]c2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 150 °C
Yield: 70.1 %

Procedure:
A suspension of N′-[4-cyano-3-(2-hydroxyethoxy)-1H-pyrazol-5-yl]-N,N-dimethylimidoformamide (500 mg, 2.24 mmol) and 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (564 mg, 2.24 mmol) in acetic acid (2.5 ml) was heated under microwave at 150° C. for 2 minutes. The crude mixture was diluted with diethyl ether and the precipitated solid was filtered, rinsed with ether and dried under vacuum to give the title compound as a white solid (675 mg, 70%); NMR spectrum: 3.79 (t, 2H), 4.31 (t, 2H), 5.26 (s, 2H), 7.18 (t, 1H), 7.25 (d, 1H), 7.29-7.33 (m, 2H), 7.44-7.49 (m, 1H), 7.57 (d, 1H), 7.87 (s, 1H), 8.27 (s, 1H), 8.47 (s, 1H); Mass Spectrum: 430 (MH+).
Reaction SMILES: [C:1]([S:4][C@H:5]1[CH2:9][C@@H:8]([C:10]([OH:12])=O)[N:7]([C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:6]1)(=[O:3])[CH3:2].C[N+](C)=CCl.[Cl-].ClCCl.[CH2:28]([O:31][C:32]([NH:34][CH2:35][C:36]1[N:43]2[C:39]([S:40][CH:41]=[C:42]2[CH2:44][NH:45][CH3:46])=[CH:38][N:37]=1)=[O:33])[CH:29]=[CH2:30]>C(N(CC)CC)C>[C:1]([S:4][C@H:5]1[CH2:9][C@@H:8]([C:10]([N:45]([CH2:44][C:42]2[N:43]3[C:36]([CH2:35][NH:34][C:32]([O:31][CH2:28][CH:29]=[CH2:30])=[O:33])=[N:37][CH:38]=[C:39]3[S:40][CH:41]=2)[CH3:46])=[O:12])[N:7]([C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)NCc1ncc2scc(CNC)n12
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1C(=O)O
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)NCc1ncc2scc(CN(C)C(=O)[C@@H]3C[C@H](SC(C)=O)CN3C(=O)OCC=C)n12
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 65.5 %

Procedure:
The procedure of Synthesis Example 1 is repeated, except that 255 mg of (3S,5S)-3-acetylthio-1-allyloxycarbonylpyrrolidin-5-carboxylic acid, 0.93 ml of a 1.1 M Vilsmeier reagent/dichloromethane solution, and 262 mg of 5-allyloxycarbonylaminomethyl-3-(N-methylamino-methyl)imidazo[5,1-b]thiazole are used and 0.145 ml of triethylamine is finally added at 4° C. followed by stirring at room temperature for additional 50 min. Thus, 327.5 mg of the title compound is prepared as a colorless amorphous material.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH:47]([CH3:49])[CH3:48])[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH:47]([CH3:48])[CH3:49])[CH:42]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Reactant: CC(C)c1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: CC(C)c1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(2-isopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K39) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as a light brown solid (360 mg, 75%).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:8][CH2:7][CH:6]1[OH:15])([CH3:4])([CH3:3])[CH3:2]>[Cu].[Cr]>[C:1]([CH:5]1[CH2:10][CH:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:8][CH2:7][C:6]1=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1CCC(O)C(C(C)(C)C)C1
Agent: [Cr]
Agent: [Cu]
Product: CC(C)(C)C1CCC(=O)C(C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.7 %

Procedure:
200 g (0.944 mole) of the 2,4-di-tert-butylcyclohexanol as prepared in Synthetic Example 2 and 2.0 g of a copper/chromium catalyst were introduced into a 500 ml four-necked flask and vigorously stirred therein at a temperature of 215° to 220° C. under a reduced pressure of 200 to 300 mmHg. This dehydrogenation procedure was carried out for 15 hours. After completion of the reaction, the heating and stirring were ceased and the reaction mixture was cooled to room temperature. Then the catalyst was filtered off. Thus 194 g of crude 2,4-di-tert-butylcyclohexanone having a cis/trans ratio of 81/19 was obtained. This product was rectified under reduced pressure in a Helipack packing column of a number of theoretical plates of 5 to give 158 g of 2,4-di-tert-butylcyclohexanone (b.p.: 93° to 94° C./3 mm Hg). This product had a cis/trans ratio of 85/15.
Reaction SMILES: [ClH:1].[CH2:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:5]=1[NH:12][C:13]([NH:15][C:16](=[NH:19])[NH:17][CH3:18])=[O:14])[CH3:3].[CH3:20]N(C(OC)OC)C.Cl.CO>>[ClH:1].[CH2:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:2][CH3:3])[C:5]=1[N:12]1[CH:18]=[N:17][C:16]([NH:19][CH3:20])=[N:15][C:13]1=[O:14])[CH3:11]
Reactant: COC(OC)N(C)C
Reactant: CCc1cccc(CC)c1NC(=O)NC(=N)NC
Agent: Cl
Solvent: CO
Product: CCc1cccc(CC)c1-n1cnc(NC)nc1=O
Yield: 47 %

Procedure:
To a suspension of 22.8 g. (80.0 mmol) of 1-(2',6'-diethylphenyl)-3-methylamidinourea hydrochloride in CH2CN (100 ml.) are added 19.1 g. (160.0 mmol) of DMF-DMA and the reaction mixture is heated at reflux for 3 hours. The CH3CN is removed under reduced pressure and the residue partitioned between CHCl3 and H2O. The layers are separated and the aqueous layer extracted with CHCl3 (1×100). The combined CHCl3 extracts are washed with H2O (1×100 ml.), dried (MgSO4) and concentrated under reduced pressure to give an off-white solid, which by NMR confirms the desired free base. The solution is dissolved in H2OH and acidified with HCl/MeOH and the MeOH removed under reduced pressure to give an off-white solid which is crystallized from CH3CN to give after vacuum drying over the weekend (105° C., house vacuum) 16.7 g. (71%) of crude product. The material is recrystallized from CH3CN (a hot filtration is necessary to remove some undissolved solid) to give 11.0 g. (47%) of desired product as a white crystalline solid.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7](Cl)=[CH:8][CH:9]=2)[N:4]=1.P(OCC)(OCC)OCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Br:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Clc1ccc2ccc(CBr)nc2c1
Agent: CCOP(OCC)OCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: BrCc1ccc2ccccc2n1
Yield: 13.8 %

Procedure:
A magnetically stirred solution of 2-bromomethyl-7-chloroquinoline (1.0 g, 3.91 mmol) and triethyl phosphite (0.74 g, 4.45 mmol) in dry toluene (10.0 ml) was heated under reflux for 24 h. The cooled solution was adsorbed onto a quantity of silica (ca. 5.0 g) and column chromatography (ethyl acetate--light petroleum (b.p. 40-60° C.), 1:4) provided unreacted 2-bromomethylquinoline (0.12 g, 0.469 mmol--12%) as brown crystals. Further elution (ethyl acetate) secured the title compound (0.88 g, 72%) as a yellow/brown oil. Distilled at 240° C. at 0.05 mmHg using a Kugelrohr short-path distillation apparatus as a bright yellow oil which crystallised on standing (m.p. 33-37° C.); (Found: C, 53.17; H, 5.40; N; 4.31; Cl, 11.22. C14H17ClNO3P requires C, 53.6; H, 5.46; N, 4.46; Cl, 11.3%); Vmax (thin film)/cm-1 3060.5, 2981.5, 1612.5, 1598.5, 1559.5. δH (270 MHz) 1.27 (6H, t, 2×CH2CH3, 3J=6.9 Hz); 3.60 (2H, d, CH2P, 2J=22.4 Hz); 4.11 (4H, m, 2×CH2CH3); 7.47 (1H, dd, 3-H, Jo =7.0, 4J3M.P =0.8 Hz); 7.51 (1H, dd, 6-H, Jo =8.4, Jm =1.5 Hz); 7.72 (1H, d, 5-H, Jo =8.9 Hz); 8.05 (1H, d, 8-H, Ja6b =1.7 Hz); 8.06 (1H, d, 4-H, Jo =8.3 Hz). δc (67.8 MHz) 16.15 (CH2CH3, d, 3JC,P =6.1 Hz); 37.0 (CH2P, d, 1JC,P =134.3 Hz); 62.3 (CH2CH3, d, 2JC.P =6.1 Hz); 122.3 (3-C, d, 3JC,P =2.5 Hz), 125.1 (4a-C), 135.5 (7-C), 136.2 (4-C); 147.9 (8a-C), 154.3 (2-C, d, 2JC,P =8.6 Hz). Remaining signals fall in the narrow range 127.1-128.6 ppm; m/z 315.3, 313.2 (7.52, 22.18, M+), 277.3 (2.21), 242.1, 240.1 (1.79, 5.13), 193.1 (6.84), 179.1, 177.1 (33.1, 100), 142.2 (3.65), 109.1 (4.57).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[NH2:9][CH2:10][C:11]1[O:15][C:14]([C:16]2[N:17]=[C:18]([N:21]=[C:22]([NH2:24])[NH2:23])[S:19][CH:20]=2)=[CH:13][CH:12]=1>CN(C)C=O>[NH2:23][C:22](=[N:21][C:18]1[S:19][CH:20]=[C:16]([C:14]2[O:15][C:11]([CH2:10][NH:9][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])=[CH:12][CH:13]=2)[N:17]=1)[NH2:24]
Reactant: O=C(Cl)c1ccco1
Reactant: NCc1ccc(-c2csc(N=C(N)N)n2)o1
Solvent: CN(C)C=O
Product: NC(N)=Nc1nc(-c2ccc(CNC(=O)c3ccco3)o2)cs1
Yield: 17.9 %

Procedure:
2-Furoyl chloride (0.48 g) was added slowly to a solution of 4-(5-aminomethylfuran-2-yl)-2-(diaminomethyleneamino)thiazole (0.80 g) in N,N-dimethylformamide (20 ml) with cooling on an ice bath and the mixture was stirred for an hour with cooling on an ice bath. The solvent was removed under reduced pressure and the residue was chromatographed on a silica gel column eluting with a mixture of chloroform and methanol (30:1, (V/V). Recrystallization from methanol afforded 2-(diaminomethyleneamino)-4-[5-(2-furoyl)aminomethylfuran-2-yl]thiazole (0.20 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH2:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][C:14]=1[C:23]1[NH:28][C:27](=[O:29])[N:26]2[C:30]([CH3:36])=[N:31][C:32]([CH2:33][CH2:34][CH3:35])=[C:25]2[N:24]=1)[CH3:11]>ClCCl>[CH2:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]2)(=[O:21])=[O:20])=[CH:15][C:14]=1[C:23]1[NH:28][C:27](=[O:29])[N:26]2[C:30]([CH3:36])=[N:31][C:32]([CH2:33][CH2:34][CH3:35])=[C:25]2[N:24]=1)[CH3:11]
Reactant: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nc12
Reactant: OCCN1CCNCC1
Solvent: ClCCl
Product: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(CCO)CC4)ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
86 mg (0.66 mmol) of hydroxylethylpiperazine are added to a solution of 90 mg (0.22 mmol) of 4-ethoxy-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-a][1,3,5]triazin-2-yl)-benzenesulfonyl chloride (example VI) in 5 ml of dichloromethane and the reaction mixture is stirred at room temperature for 16 hours. After chromatographic purification (dichloromethane/methanol=95:5), 63 mg (57%) of 2-{2-ethoxy-5-[4-(2-hydroxy-ethyl)-piperazine-1-sulfonyl]-phenyl}-6-methyl-8-propyl-3H-imidazo[1,5-a][1,3,5]triazin-4-one are obtained.
Reaction SMILES: [CH2:1]([N:4]([CH2:27][CH2:28][CH3:29])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:18][NH:19][CH2:20][C:21]3[NH:22][CH:23]=[CH:24][N:25]=3)[CH:15]=2)[C:10]1=[O:26])[CH2:2][CH3:3].[CH3:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]=O.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[CH2:27]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:18][N:19]([CH2:20][C:21]3[NH:22][CH:23]=[CH:24][N:25]=3)[CH2:36][C:32]3[N:31]([CH3:30])[CH:35]=[CH:34][N:33]=3)[CH:15]=2)[C:10]1=[O:26])[CH2:28][CH3:29]
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)CCCCN1Cc2cc(CNCc3ncc[nH]3)ccc2C1=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCN1Cc2cc(CN(Cc3ncc[nH]3)Cc3nccn3C)ccc2C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.6 %

Procedure:
The compound (20.3 mg) obtained in Example 7-7 was dissolved in methanol (2.0 ml). The solution was added with 1-methyl-2-imidazole carboxaldehyde (6.8 mg) and sodium cyanoborohydride (6.4 mg). The solution was adjusted to pH 4 by addition of acetic acid, followed by stirring at room temperature for 6 hours. Then, the solution was added with a saturated aqueous sodium hydrogen carbonate solution to stop the reaction and then subjected to extraction with chloroform. After that, the organic layer was washed with water and a saturated saline solution and then dried with anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining a hydrochloride (24.0 mg) of the subject compound as a pale-yellow solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[N:6]2)[CH2:2]1.[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[C:34](O)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH2:34][N:1]1[CH2:2][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)=[N:6]2)[CH2:4]1
Reactant: Cn1ccnc1C(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cn1ccnc1CN1CC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Yield: 25.9 %

Procedure:
A mixture of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.06 g, 0.00017 mol), 1-methyl-1H-2-imidazolecarboxylic acid (0.056 g, 0.0005 mol), and acetic acid (0.03 g, 0.0005 mol) in dichloroethane (2.5 mL) was stirred at room temperature under an atmosphere of nitrogen for one and a half hours. Sodium triacetoxyborohydride (0.072 g, 0.00034 mol) was added into the mixture and stirred at ambient temperature under an atmosphere of nitrogen for two hours. The solvent was removed under reduced pressure, and the residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 25 min with 0.1 M ammonium acetate, 21 mL/min) to yield 1-{1-[(1-methyl-1H-2-imidazolyl)methyl]-3-azetanyl}-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.020 g, 0.000044 mol).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([OH:10])[C:4]=2[CH:3]=[CH:2]1.[C:11]([Si:15]([CH3:18])([CH3:17])Cl)([CH3:14])([CH3:13])[CH3:12].N1C=CN=C1>CN(C=O)C>[Si:15]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc2[nH]ccc12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 1H-indole-4-ol (2.4 g) in DMF (50 mL) was added tert-butyldimethylchlorosilane (2.7 g) and 1H-imidazole (1.5 g) at ambient temperature. The reaction mixture was stirred for 17 hours at ambient temperature. The resulting mixture was evaporated in vacuo and diluted with EtOAc. The organic layer was washed with water and brine and then dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silicagel column chromatography (n-hexane:EtOAc=80:20-60:40) to give 4-{[tert-butyl(dimethyl)silyl]oxy}-1H-indole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2=[N:13][C:14](Cl)=[CH:15][CH:16]=[C:11]2[N:10]=[N:9]1.FC1C=CC=CC=1N.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:31]>CS(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2=[N:13][C:14]([OH:31])=[CH:15][CH:16]=[C:11]2[N:10]=[N:9]1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: Fc1ccccc1-n1nnc2ccc(Cl)nc21
Agent: Nc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Oc1ccc2nnn(-c3ccccc3F)c2n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
A solution of 3-(2-fluorophenyl)-5-chloro-1,2,3-triazolo[4,5-b]pyridine (1.01 g, 4.06 mmol; prepared following the procedure described in GB Patent No. 1268772 but using 2-fluoroaniline instead of aniline) and 2M sodium hydroxide (4 ml) in DMSO (15 ml) was stirred at 100° C. under nitrogen for 3 h. The mixture was cooled, diluted with water (250 ml) and neutralised with aqueous citric acid. After standing for 18 h, the brown precipitate was collected, dissolved in dichloromethane (100 ml), dried (Na2SO4), filtered and concentrated to give 3-(2-fluorophenyl)-5-hydroxy-1,2,3-triazolo[4,5-b]pyridine (0.80 g, 86%) as a brown solid. δH (360 MHz; d6-DMSO) 6.81 (1H, broad d, J=9), 7.50 (1H, dd, J=8 and 8), 7.60 (1H, dd, J=8 and 7), 7.68-7.72 (1H, m), 7.81 (1H, ddd, J=8, 8 and 2), 8.44 (1H, broad d, J=9) and 12.15 (1H, broad s); m/z (ES+) 231 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][CH3:19])[C:15]2[CH:14]=[C:13]([Br:16])[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][C:6](Br)=[CH:7][CH:8]=2)[CH3:2].C([Li])CCC.CN([CH:28]=[O:29])C>C1COCC1.Cl.C1(C)C=CC=CC=1>[Br:16][C:13]1[CH:14]=[C:15]2[C:10]([C:9]3[CH:8]=[CH:7][C:6]([CH:28]=[O:29])=[CH:5][C:4]=3[C:3]2([CH2:1][CH3:2])[CH2:18][CH3:19])=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: CCC1(CC)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCC1(CC)c2cc(Br)ccc2-c2ccc(C=O)cc21
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 78.4 %

Procedure:
To a mechanically stirred solution of 9,9-diethyl-2,7-dibromofluorene (59.38 g, 0.1563 mol) in THF (325 ml) cooled in a dry ice-ethanol bath, n-butyl lithium (104 ml of 1.6 M solution in hexanes, 0.1664 mol, 1.06 eq.) was added drop-wise over 25 minutes. After 20 minutes, DMF (17 ml, 0.22 mol) in THF (30 ml) was added, and the mixture was stirred in the cooling bath for 1.5 hours and outside the bath for 1 hour. The reaction was then cooled to 5° C. and treated with hydrochloric acid (12.5 ml of concentrated hydrochloric acid diluted with 50 ml water). The mixture was diluted with 200 ml of toluene, and the aqueous phase was separated and extracted with 200 ml of toluene. The combined organic phase was washed with dilute sodium bicarbonate solution, dried over magnesium sulfate, and concentrated. The residual solids were recrystallized from heptane-ethyl acetate (9:1) to obtain colorless solids, 40.29 g (78.4% yield) m.p. 126-128° C. The mother liquor, after chromatography over 150 g silica gel, elution with 1:1 heptane-toluene, and trituration of residual solids in hexanes, gave additional product, 6.56 g (12.8% yield, total 91% yield), m.p. 126-128° C. Mass Spec: m/z 328, 330, (M+). A sample for analysis was prepared by recrystallization from hexanes, m.p. 127-129° C. Analysis: Calculated for C18H17BrO, C, 65.55, H, 5.20, and Br 24.27%. Found, C, 65.60, H, 5.51, and Br 24.71%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[OH:17])=[CH:3][N:2]=1.[C:18]([C:20]1[CH:21]=[C:22]([S:27]([N:30]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][C:38]=2[O:45][CH3:46])[C:31]2[S:35][N:34]=[CH:33][N:32]=2)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1F)#[N:19].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:18]([C:20]1[CH:21]=[C:22]([S:27]([N:30]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][C:38]=2[O:45][CH3:46])[C:31]2[S:35][N:34]=[CH:33][N:32]=2)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[O:17][C:8]1[CH:9]=[CH:10][C:11]([C:13]([F:15])([F:16])[F:14])=[CH:12][C:7]=1[C:4]1[CH:5]=[CH:6][N:1]=[N:2][CH:3]=1)#[N:19]
Reactant: Oc1ccc(C(F)(F)F)cc1-c1ccnnc1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3-c3ccnnc3)c(C#N)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
To a solution of 2-pyridazin-4-yl-4-(trifluoromethyl)phenol (Preparation 712, 60.6 mg, 0.25 mmol) in dimethylsulfoxide (2.5 mL) was added 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 68, 109.2 mg, 0.25 mmol) followed by potassium carbonate (101.7 mg, 0.74 mmol). The resulting mixture was stirred overnight at room temperature under nitrogen. The reaction mixture was poured into water (125 mL), and extracted with ethyl acetate (3×25 mL). The combined organic extract was washed successively with aqueous sodium hydroxide solution (1M, 15 mL) and saturated aqueous sodium chloride solution (4×25 mL), dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. The resulting residue was purified by column chromatography using a gradient of 25-40% v/v ethyl acetate in heptane to give the title compound as a white foam (59.7 mg, 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)[CH2:14][O:15][CH2:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: BrCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COCC3CCCCC3)C3CCCCC3)c2cc1F
Reaction time: 8 h
Yield: 39 %

Procedure:
To a solution of 0.58 g (1.48 mmol) 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) in 6 mL N,N-dimethylformamide, 71 mg (1.5 mmol, 55% dispersion in mineral oil) sodium hydride and after 5 min. 0.32 g (1.78 mmol) bromomethylcyclohexane were added. The reaction mixture was warmed to 50° C. and after 4 h another 71 mg sodium hydride and 0.32 g (1.78 mmol) bromomethylcyclohexane were added. A third batch sodium hydride and bromomethylcyclohexane were added after 3 h. After stirring overnight the reaction mixture was poured on water and ethyl acetate, extracted, the aqueous phase extracted twice with ethyl acetate and the aqueous phase extracted twice with ethyl acetate. The combined organic layers were washed twice with water and once with brine, dried over magnesium sulfate and evaporated. The crude product was purified by silica gel column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethylacetate (1:0 to 4:1) to yield the title compound as a white solid (39%). MS (Turbo Spray): m/z=487.3 [M+H].
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:5]([NH:7][C:8](=[O:10])[CH:9]=1)=[O:6].CCN(CC)CC.[C:18](Cl)(=[O:21])[CH:19]=[CH2:20]>C(Cl)Cl>[C:18]([CH2:2][CH2:3][C:4]1[C:5]([NH:7][C:8](=[O:10])[CH:9]=1)=[O:6])(=[O:21])[CH:19]=[CH2:20]
Reactant: C=CC(=O)Cl
Reactant: O=C1C=C(CCO)C(=O)N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)CCC1=CC(=O)NC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Hydroxyethyl maleimide (5 g, 35.4 mmol) and Et3N (4.25 g, 43.0 mmol) was dissolved in 75 mL of methylene chloride and cooled to 0° C. Acryloyl chloride (3.20 g, 35.4 mmol) in 25 mL of methylene chloride was added dropwise over 30 minutes. The solution was stirred at room temperature for 30 minutes followed by refluxing for 1 hour. The triethylamine hydrochloride was removed by filtration and the yellow solution was concentrated. The yellow crystals were purified by sublimation yielding white crystals, m.p. 77-78° C. (5.00 g, 72.3%). 1H-NMR (CDCl3, δ, ppm): 3.81-3.87 (2H, --NCH2 --, t) 4.22-4.33 (2H, --OCH2 --, t), 5.81-5.85 (2H, CH2 =CH, cis), 6.00-6.13 (1H, CH2 =CH--, q), 6.34-6.42 (1H CH2 =CH, trans), 6.73 (2H, --OC--CH=CH--CO--, s). 13C-NMR (CDCl3, δ, ppm): 170.4 (2C, C=O, maleimide), 165.8 (1C, C=O, ester), 134.2 (2C, --CH=CH--), 131.45 (1C, --CH=), 127.9 (1C, CH2 =), 61.5 (1C, β--CH2 --), 36.8 (1C, α--CH2 --).