Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:34])([CH3:33])[CH:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:12]([O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:13])(=[O:7])=[O:6].[N-:35]=[N+:36]=[N-:37].[Na+]>CS(C)=O>[N:35]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:34])([CH3:33])[CH:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:12]([O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:13])(=[O:7])=[O:6])=[N+:36]=[N-:37]
Reactant: COc1ccc(COC(C(=O)OCCN2CCOCC2)C(C)(C)COS(=O)(=O)CCCCl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(COC(C(=O)OCCN2CCOCC2)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-])cc1

Procedure:
Following the general procedure for the preparation of azides of Description 16, 2-morpholin-4-ylethyl (2R/S)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoate (27a) (0.22 g, 0.42 mmol) dissolved in 5 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 68 mg (1.0 mmol) of sodium azide (NaN3). After work-up, the crude material (27b) was used in the next step without further purification. MS (ESI) m/z 523.07 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:18]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCNC3)c2n1
Reactant: IC1CCCC1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCCN(C4CCCC4)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[2-(3-piperidinyl)ethyl]-9H-purin-6-amine and iodocyclopentane.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:28]([C:30]1[O:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29]>>[CH3:21][S:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:3][C:2]([C:33]4[O:34][C:30]([CH:28]=[O:29])=[CH:31][CH:32]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: O=Cc1ccc(B(O)O)o1
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccc(C=O)o4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 5-formyl-2-furanboronic acid in General Procedure A. Purification on silica yielded 5-[6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl]-furan-2-carbaldehyde.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH:18][N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25].C(N(CC)CC)C>CN(C)C=O>[CH2:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH:18][N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCBr
Reactant: O=C1CCC(=O)N1C=CCCCCCCCCCCO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOCCCCCCCCCCC=CN1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
0.14 mole of butyl bromide and 0.14 mole of N-hydroxy dodecenylsuccinimide are dissolved in 100 milliliters of dimethylformamide. 50 milliliters of triethylamine are added and the mixture is stirred overnight at room temperature. The solvent is then removed under vacuum and the reaction product is water washed until salt free and then dried. A yield of 85% of N-butoxy dodecenylsuccinimide is recovered.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([N:15]([CH2:22][CH3:23])[CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:14]>>[C:1]([N:19]1[CH2:20][CH2:21][CH:16]([N:15]([CH2:22][CH3:23])[CH2:13][CH3:14])[CH2:17][CH2:18]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CCN(CC)C1CCNCC1
Product: CCCCCCC/C=C/C(=O)N1CCC(N(CC)CC)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and 4-diethylaminopiperidine as starting raw materials, to produce an intended compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH:9]2[CH2:11][O:10]2)=[CH:5][CH:4]=1.Br.Br.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]2[NH:33][CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].CO>C1C=CC=CC=1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]2[NH:33][CH:34]2[CH2:35][CH2:36][N:37]([CH2:11][CH:9]([CH2:8][O:7][C:6]3[CH:12]=[CH:13][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[OH:10])[CH2:38][CH2:39]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(OCC2CO2)cc1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COc1ccc(OCC(O)CN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Yield: 51 %

Procedure:
A mixture of 3.6 parts of [(4-methoxyphenoxy)methyl]oxirane, 4.9 parts of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine dihydrobromide, 2.1 parts of sodium carbonate, 40 parts of methanol and 90 parts of benzene is stirred and refluxed overnight. The reaction mixture is filtered and the filtrate is evaporated. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane. The product is filtered off and dried, yielding 2.6 parts (51%) of 4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-α-(4-methoxyphenoxymethyl)-1-piperidineethanol; mp. 174.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]([NH:14]C(=O)C(C)(C)C)=[C:4]([N+:21]([O-:23])=[O:22])[C:3]=1[F:24].OS(O)(=O)=O.[OH-].[Na+]>>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]([NH2:14])=[C:4]([N+:21]([O-:23])=[O:22])[C:3]=1[F:24]
Reactant: CC(C)(C)C(=O)Nc1c(-c2ccccn2)cc(Br)c(F)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1c(-c2ccccn2)cc(Br)c(F)c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 84 %

Procedure:
A solution of N-(4-bromo-3-fluoro-2-nitro-6-(pyridin-2-yl)phenyl)pivalamide (7.50 g, 18.93 mmol) in 70% aqueous solution of H2SO4 (31.2 mL) was heated up to 80° C. for 30 min. After completion of reaction (by TLC), the mixture was poured onto 100 mL of crushed ice and basified up to pH 6 to 7 by 20% NaOH solution. Precipitated solid was filtered and dried under vacuum to obtain the desired product as a yellow solid (4.96 g, 84%).
Reaction SMILES: Cl.Cl[CH:3]([C:8]1[C:9](=[O:17])[C:10]([OH:16])=[C:11]([CH3:15])[N:12]([CH3:14])[CH:13]=1)[C:4]([F:7])([F:6])[F:5].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[OH:16][C:10]1[C:9](=[O:17])[C:8]([CH:3]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:4]([F:7])([F:6])[F:5])=[CH:13][N:12]([CH3:14])[C:11]=1[CH3:15]
Reactant: Cc1c(O)c(=O)c(C(Cl)C(F)(F)F)cn1C
Reactant: C1CCNCC1
Agent: Cl
Product: Cc1c(O)c(=O)c(C(N2CCCCC2)C(F)(F)F)cn1C
Reaction time: 0.33 h
Yield: 73 %

Procedure:
3-Hydroxy-1,2-dimethyl-5-[2,2,2-trifluoro-1-(piperidin-1-yl)ethyl]pyridin-4(1H)-one (Apo7054) was prepared from the reaction of 5-(1-chloro-2,2,2-trifluoroethyl)-3-hydroxy-1,2-dimethylpyridin-4(1H)-one hydrochloride (304 mg, 1.0 mmol) and piperidine (2.0 mL, 20.3 mmol). The reaction was completed within 20 min, and Apo7054 was obtained as a solid product (232 mg). Yield=73%; HPLC Method 1, purity (AUC)=99.4% at 280 nm; 1H NMR (DMSO-D6) δ (ppm): 7.66 (s, 1H), 4.83-4.94 (m, 1H), 3.71 (s, 3H), 2.56 (m, 2H), 2.41 (m, 2H), 2.27 (s, 3H), 1.46 (br, 4H), 1.28 (br, 2H); MS-ESI m/z 305 [M+1]+ (100%), 220. (ii) 3-Hydroxy-1,2-dimethyl-5-[2,2,2-trifluoro-1-(1H-imidazol-1-yl)ethyl]pyridin-4(1H)-one (Apo7055) was prepared from 5-(1-chloro-2,2,2-trifluoroethyl)-3-hydroxy-1,2-dimethylpyridin-4(1H)-one hydrochloride (505 mg, 1.7 mmol) and imidazole (3.5 g, 51.4 mmol). The reaction was stopped when analysis of the HPLC chromatogram (Method 1) of the reaction mixture indicated higher than 98% conversion. The reaction mixture was concentrated to give a solid. The solid was dissolved in de-ionized water (4 mL), and the pH of the solution was adjusted to 6.5 with a 6.00 N hydrochloric acid solution. The resulting solution was repeatedly extracted with dichloromethane (15 mL×4, 30 mL×2). The organic fractions were combined, dried over sodium sulfate, filtered, and concentrated. The desired compound Apo7055 was obtained as a solid from dichloromethane (320 mg). Yield=64%; HPLC purity (AUC): 99.7% at 280 nm); 1H NMR (DMSO-D6) δ (ppm): 8.15 (s, 1H), 7.98 (s, 1H), 7.52 (s, 1H), 6.96 (s, 1H), 6.66 (q, J=9.1 Hz, 1H), 3.76 (s, 3H), 2.29 (s, 3H). MS-ESI m/z 288 [M+1]+, 220 (100%). (iii) 3-Hydroxy-1,2-dimethyl-5-[2,2,2-trifluoro-1-(methylamino)ethyl]pyridin-4(1H)-one (Apo7056) was prepared from 5-(1-chloro-2,2,2-trifluoroethyl)-3-hydroxy-1,2-dimethylpyridin-4(1H)-one hydrochloride (400 mg, 1.4 mmol) and methylamine (3.0 mL, 34.4 mmol). The reaction was essentially completed within 15 min. The reaction mixture was concentrated to give a solid. A sample of salt free Apo7056 product was obtained by purification using the Biotage instrument (C18 reversed phase; eluant: water and acetonitrile; gradient, 100:0 to 100:4). (48 mg).
Reaction SMILES: [C:1]([OH:10])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[N:11]1([CH2:16][CH2:17][CH2:18][NH2:19])[CH:15]=[CH:14][N:13]=[CH:12]1>O1CCCC1>[N:11]1([CH2:16][CH2:17][CH2:18][NH:19][C:1](=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: NCCCn1ccnc1
Reactant: CCCCCCCC(=O)O
Solvent: C1CCOC1
Product: CCCCCCCC(=O)NCCCn1ccnc1

Procedure:
The requisite starting amine was prepared as follows: reaction of n-octanoic acid and 1,1'-carbonyldi(1-imidazole) in tetrahydrofuran solution with 3-(1H-imidazol-1-yl)propanamine gave N-3-(1H-imidazolyl) propyl-n-octanamide, which upon reduction with BH3 in tetrahydrofuran solution gave N-(3-(1H-imidazol-1-yl) propyl-N-(n-octyl))amine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]=12.[Cl:16][C:17]1[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][C:18]=1[OH:19]>CN(C=O)C.O>[Cl:13][C:5]1[C:4]([Cl:14])=[C:3]([Cl:15])[C:2]([Cl:1])=[C:7]2[C:6]=1[C:11](=[O:12])[O:10][C:8]12[C:20]2[CH:21]=[CH:22][C:23]([OH:24])=[C:17]([Cl:16])[C:18]=2[O:19][C:23]2[C:22]1=[CH:21][CH:20]=[C:18]([OH:19])[C:17]=2[Cl:16]
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: Oc1cccc(O)c1Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C1OC2(c3ccc(O)c(Cl)c3Oc3c2ccc(O)c3Cl)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Yield: 91.8 %

Procedure:
Treatment of tetrachlorophthalic anhydride (5 g, 17.49 mmol) and 2-chlororesorcinol (7.58 g, 41.98 mmol) according to the procedure described in Example 1, Step 1, provided 9.3 g of the crude product. Suspension of 8 g of the crude 9.3 g in DMF:water (1:1), followed by filtration provided 8.65 g (16.05 mmol, 91.7% AUC yield) of 4,4′,5,5′,6,7-hexachloro-3′,6′-dihydroxy-3H-spiro[isobenzofuran-1,9′-xanthen]-3-one that was isolated as an orange solid. 1H NMR (300 MHz; DMSO d6) δ 11.09 (S, 2H), 7.03 (d, J=9 Hz, 2H), 6.81 (d, J=8.7 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:15]=[C:14]([C:23]([F:26])([F:25])[F:24])[CH:13]=2)=[O:10])=[CH:4][C:3]=1[O:27]C.B(Br)(Br)Br>C(Cl)Cl>[C:2]1([N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([OH:27])[CH:4]=2)[C:9]([NH:11][C:12]2[N:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:15]=[C:14]([C:23]([F:25])([F:24])[F:26])[CH:13]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(NC(=O)Nc2cc(C(F)(F)F)nn2-c2ccccc2)ccc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(Nc1cc(C(F)(F)F)nn1-c1ccccc1)N(c1ccccc1)c1ccc(F)c(O)c1
Reaction time: 2 h
Yield: 57.3 %

Procedure:
To a solution of 1-(4-fluoro-3-methoxyphenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea (0.985 g, 2.5 mmol) in DCM (30 mL) at ice-water bath was dropped a 1.0 M solution of BBr3 in DCM (25 mL) and it was stirred for 2 hours. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with DCM. Extracts were dried over MgSO4 and concentrated. The crude product was purified on a silica gel column using a mixture of EtOAc-hexane as eluent to give phenyl 1-(4-fluoro-3-hydroxyphenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea as solid (0.327 g, 34%). 1H NMR (300 MHz, DMSO-d6) δ 6.59 (s, 1H), 6.65 (d, 1H), 6.78 (dd, 1H), 7.34 (m, 2H), 7.49 (m, 2H), 7.57 (d, 1H), 7.65 (d, 1H), 8.54 (s, 1H), 8.94 (s, 1H), 10.00 (s, 1H); LC-MS (ESI) m/z 381 (M+H)+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[S:18][C:17]([CH2:19][CH2:20][CH3:21])=[N:16][C:10]=3[C:11]([NH2:15])=[N:12][C:13]=2[CH:14]=1)(=O)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.BrCC[N:36]1[CH:40]=[CH:39][CH:38]=[CH:37]1>ClCCl>[CH2:19]([C:17]1[S:18][C:9]2[C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:1][CH2:2][N:36]4[CH:40]=[CH:39][CH:38]=[CH:37]4)=[CH:14][C:13]=3[N:12]=[C:11]([NH2:15])[C:10]=2[N:16]=1)[CH2:20][CH3:21]
Reactant: CCCc1nc2c(N)nc3cc(OC(C)=O)ccc3c2s1
Reactant: BrCCn1cccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCc1nc2c(N)nc3cc(OCCn4cccc4)ccc3c2s1
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 40.6 %

Procedure:
A mixture of 4-amino-2-propylthiazolo[4,5-c]quinolin-7-ol acetate (318 mg, 1.0 mmol), cesium carbonate (1.3 g, 4.0 mmol), and DMF (20 mL) was stirred at 75° C. for 10 minutes. 1-(2-Bromoethyl)pyrrole (200 mg, 1.1 mmol) was added dropwise over a period of 10 minutes. After 3 hours an additional equivalent of cesium carbonate was added in a single portion followed by the dropwise addition of an equivalent of 1-(2-bromoethyl)pyrrole. The reaction mixture was stirred overnight and then an additional equivalent of both cesium carbonate and 1-(2-bromoethyl)pyrrole were added. After 1 hour the heat source was removed; the reaction mixture was diluted with water (250 mL), stirred for 1 hour, and then filtered. The isolated solid was rinsed with water and then dried to provide a brown powder. This material was dissolved in dichloromethane and then purified by HPFC eluting with a gradient of 0-15% CMA in chloroform over 1500 mL. The resulting solid was recrystallized from acetonitrile to provide 143 mg of 2-propyl-7-[2-(pyrrol-1-yl)ethoxy]thiazolo[4,5-c]quinolin-4-amine as an off-white solid, mp 158.0-160.0° C. MS (ESI) m/z 353 (M+H)+; Anal. calcd for C19H20N4OS: C, 64.75; H, 5.72; N, 15.90. Found C, 64.86; H, 5.38; N, 16.00.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)=O)[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:17][C:16]1[N:18]=[C:19]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[N:12]2[C:13]=1[CH:14]=[N:15][C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[N:11]2
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3cccs3)nn2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc(Nc2ncc3c(C)nc(-c4cccs4)n3n2)cc1
Yield: 41.7 %

Procedure:
Applying the Cyclization Procedure 1, using N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-2-thiophenecarboxamide (Intermediate 61) (115 mg, 0.32 mmol), 1,2-dichloroethane (5 mL) and phosphorus oxychloride (0.24 mL, 2.57 mmol), to afford 5-methyl-N-[4-(methyloxy)phenyl]-7-(2-thienyl)imidazo[5,1-f][1,2,4]triazin-2-amine (45 mg) as a yellow solid. MS m/z 338 (M+1).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:17]3[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH:13]2[CH2:14][C:15](=[O:24])[CH2:16]3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CC(O[CH:32](N(C)C)[N:33]([CH3:35])[CH3:34])(C)C>>[CH3:32][N:33]([CH:35]=[C:14]1[C:15](=[O:24])[CH2:16][CH:17]2[N:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:25])[F:26])=[CH:4][CH:5]=3)(=[O:10])=[O:11])[CH:13]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=12)[CH3:34]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=C1CC2c3ccccc3C(C1)N2S(=O)(=O)c1ccc(C(F)(F)F)cc1
Product: CN(C)C=C1C(=O)CC2c3ccccc3C1N2S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 16 (15 mg, 0.04 mmol) was mixed with 0.3 mL of Bredereck's reagent and the mixture was stirred at room temperature for 30 min. The reaction was quenched with water (1 mL) and extracted with EtOAc. After evaporation of the solvent, the crude product was obtained as a yellow oil and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:28])[C:7]=1[NH:8][C:9]1[N:13]([CH3:14])[C:12]2[C:15]3[CH2:16][C:17]([CH3:27])([CH3:26])[O:18][C:19]=3[C:20]([C:22]([O:24]C)=O)=[CH:21][C:11]=2[N:10]=1.[F:29][C:30]([F:39])([F:38])[C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:28][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]1[N:13]([CH3:14])[C:12]2[C:15]3[CH2:16][C:17]([CH3:27])([CH3:26])[O:18][C:19]=3[C:20]([C:22]([NH:34][C:33]3[CH:35]=[CH:36][CH:37]=[C:31]([C:30]([F:29])([F:38])[F:39])[CH:32]=3)=[O:24])=[CH:21][C:11]=2[N:10]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)n(C)c2c2c1OC(C)(C)C2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cn1c(Nc2c(Cl)cncc2Cl)nc2cc(C(=O)Nc3cccc(C(F)(F)F)c3)c3c(c21)CC(C)(C)O3
Yield: 38.3 %

Procedure:
The title compound was prepared following the procedure described for Example-143 by using methyl 2-((3,5-dichloropyridin-4-yl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (Intermediate-60, 0.100 g, 0.237 mmol), 3-(trifluoromethyl) aniline (0.057 g, 0.356 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (5.0 mL) to afford 0.050 g of the desired product. 1HNMR (DMSO-d6): δ 1.61 (s, 6H), 3.49 (s, 2H), 3.59 (s, 3H), 7.24 (s, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 8.31 (s, 1H), 8.47 (s, 2H), 9.90 (s, 1H), 10.91 (s, 1H); MS [M]+: 550.11.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.C([O-])(=O)C.[Na+].[H][H]>[Pd].CO>[NH2:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(F)(F)F)nc1Cl
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1ccc(C(F)(F)F)nc1
Yield: 92.1 %

Procedure:
3-Amino-2-chloro-6-trifluoromethylpyridine (15.0 g, 76 mmol), sodium acetate (12.53 g, 153 mmol) and 10% palladium on carbon (1.5 g) in methanol (300 ml) were hydrogenated at 50 psi hydrogen for 18 h, then the suspension was filtered. The filtrate was concentrated to give the product as a tan solid (11.38 g, 70 mmol, 92% yield).
Reaction SMILES: O(CC)[C:2]([S-])=[S:3].[K+].[NH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[OH:16]>C(O)C>[CH3:15][C:13]1[CH:12]=[CH:11][C:10]2[O:16][C:2]([SH:3])=[N:8][C:9]=2[CH:14]=1
Reactant: Cc1ccc(O)c(N)c1
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CCO
Product: Cc1ccc2oc(S)nc2c1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
Potassium ethyl xanthate (4.4 g, 27.5 mmol.) was added to solution of 2-amino-4-methyl-phenol (2 g, 16.2 mmol.) in ethanol (40 mL). The reaction mixture was heated at reflux for 4 h then allowed to cool to rt. Upon cooling to rt the mixture was concentrated and the resulting residue was dissolved in water. Acetic acid was added until pH=5 and a white solid precipitated from the solution. The solid was collected by filtration, washed with water and dried to afford 5-methylbenzo[d]oxazole-2-thiol as a powder (2.4 g, 92.3%) which was used without further purification. MS (ESI) m/e (M+H+) 166.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:21])[NH:5][N:6]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:2].[CH2:22]([S:24]([CH:27]=[CH2:28])(=[O:26])=[O:25])[CH3:23]>N1C=CC=CC=1>[CH2:22]([S:24]([CH2:27][CH2:28][N:5]1[C:4](=[O:21])[C:3]([C:1]#[N:2])=[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:6]1)(=[O:26])=[O:25])[CH3:23]
Reactant: C=CS(=O)(=O)CC
Reactant: N#Cc1c(-c2ccccc2)c(-c2ccccc2)n[nH]c1=O
Solvent: c1ccncc1
Product: CCS(=O)(=O)CCn1nc(-c2ccccc2)c(-c2ccccc2)c(C#N)c1=O
Yield: 72.7 %

Procedure:
8.0 grams (0.0175 mole) of the product of Example 1 was reacted with 2.1 grams of ethyl-vinyl sulfone in 60 mls of pyridine. This solution was heated on a steam bath for 2 hours, cooled and the solvent distilled at reduced pressure. The residual oil was taken up in ethyl alcohol. 5.0 grams (72% yield) of a solid precipitated and was filtered, washed with petroleum ether and air dried. The infrared spectrum showed the nitrile band at 4.5μ, the carbonyl band at 6.0μ, the SO2 band at 8.7μ.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].CCCCCCC.C1COCC1.[Cl:21][C:22]1[CH:27]=[C:26]([O:28][C:29]2[CH:41]=[CH:40][C:39]([C:42]3[CH:43]=[N:44][CH:45]=[N:46][CH:47]=3)=[CH:38][C:30]=2[C:31](N(CC)CC)=[O:32])[CH:25]=[CH:24][N:23]=1>C1COCC1>[Cl:21][C:22]1[C:27]2[C:31](=[O:32])[C:30]3[CH:38]=[C:39]([C:42]4[CH:47]=[N:46][CH:45]=[N:44][CH:43]=4)[CH:40]=[CH:41][C:29]=3[O:28][C:26]=2[CH:25]=[CH:24][N:23]=1
Reactant: CCN(CC)C(=O)c1cc(-c2cncnc2)ccc1Oc1ccnc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: O=c1c2cc(-c3cncnc3)ccc2oc2ccnc(Cl)c12
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
Lithium diisopropylamide, 1.8 M in heptane/THF (5.80 mL, 10.45 mmol) was added dropwise to a −78° C. solution of 2-(2-chloropyridin-4-yloxy)-N,N-diethyl-5-(pyrimidin-5-yl)benzamide (1.000 g, 2.61 mmol) in THF (20.0 mL). The reaction mixture was stirred at −78° C. for 2.5 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and the mixture was partitioned between EtOAc and water. The aqueous phase was separated and extracted with DCM. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford an orange solid. This material was purified via column chromatography on silica gel (RediSep 40 g column, eluting with 100% EtOAc) to afford 1-chloro-8-(pyrimidin-5-yl)-10H-chromeno[3,2-c]pyridin-10-one as an off-white solid. MS m/z=310.0 [M+H]+. Calcd for C16H8ClN3O2: 309.7.
Reaction SMILES: FS(C1C=CC([O:11][CH:12]([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])=CC=1)(=O)=O.[F:21][C:22]([F:40])([F:39])[CH:23]([C:35]([F:38])([F:37])[F:36])[O:24]C1C=CC(S([O-])(=O)=O)=CC=1>>[F:14][C:13]([F:16])([F:15])[CH:12]([OH:11])[C:17]([F:20])([F:19])[F:18].[CH:23]([OH:24])([C:35]([F:38])([F:37])[F:36])[C:22]([F:40])([F:39])[F:21]
Reactant: O=S(=O)([O-])c1ccc(OC(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=S(=O)(F)c1ccc(OC(C(F)(F)F)C(F)(F)F)cc1
Product: OC(C(F)(F)F)C(F)(F)F

Procedure:
Diazonium salt 1 (106.8 mg, 0.3359 mmol) was dissolved in HFIP (7.16 g) and the mixture was heated at 60° C. for 4 h. After cooling, Na2CO3 was added and the mixture was filtered. Most of the solvent was evaporated to give a pale-yellow oil, which was purified by SiO2 column chromatography with hexane/CH2Cl2 (9:1) to afford 1-(pentafluorosulfanyl)-4-[2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]benzene (colorless oil; 2.0 mg, 1.6%), 1-fluoro-4-(fluorosulfonyl)benzene (Ferm & VanderWerf, J. Am. Chem. Soc. 1950, 72, 4809-4810) (colorless oil; 7.7 mg, 13%), and 2,2,2-trifluoro-1-(trifluoromethyl)-ethyl 4-fluorophenylsulfonate (Popov, et al., Ukrainskii Khim. Zh. 1991, 57, 843-849) (colorless oil; 15.7 mg, 14.3%). Elution with hexane/CH2Cl2 (8:2) gave 1-(fluorosulfonyl)-4-[2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]benzene (colorless oil, 6.6 mg, 6.0%), a 2:1 mixture of 1-(fluorosulfonyl)-4-[2,2,2-trifluoro-1-(trifluoromethyl) ethoxy]benzene and 2,2,2-trifluoro-1-(trifluoromethyl)ethyl-4-[2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]phenylsulfonate (colorless oil, 27.2 mg, 19.1%), and 4-[2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]phenylsulfonate (colorless oil, 3.8 mg, 2.4%).