Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4](CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:34][C:35]([C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][C:38]=1NCC1CC1)=[O:36]>CN(C)C=O.CO>[C:37]1([C:35]([NH2:34])=[O:36])[CH:45]=[CH:44][C:40]([C:41]([NH2:4])=[O:42])=[CH:39][CH:38]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: NC(=O)c1ccc(C(=O)O)cc1NCC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: NC(=O)c1ccc(C(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N,N-Diisopropylethylamine (101 uL, 0.66 mmol) was added to a mixture of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (53 mg, 0.14 mmol), and 4-(aminocarbonyl)-3-[(cyclopropylmethyl)amino]-benzoic acid (synthesized according to reagent preparation 39) (31 mg, 0.13 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. A solution of 1-[6-(3-endo-amino-8-azabicyclo[3.2.1]oct-8-yl)pyridin-3-yl]-3-(1-methylpiperidin-4-yl)propan-1-one hydrochloride salt (51 mg, 0.13 mmol) in N,N-dimethylformamide (0.5 mL) was added and stirring was continued for 18 hours. The reaction mixture was diluted with methanol (1.5 mL), and purified by preparatory reverse phase HPLC (ammonium acetate buffered aqueous acetonitrile eluent) to give 2-[(cyclopropylmethyl)amino]-N4-(8-{5-[3-(1-methylpiperidin-4-yl)propanoyl]pyridin-2-yl}-8-azabicyclo[3.2.1]oct-3-endo-yl)benzene-1,4-dicarboxamide as the acetate salt, (54 mg, 66% yield). 1H NMR (400 MHz, d4-Methanol): 8.65 (d, 1H), 7.97 (dd, 1H), 7.54 (d, 1H), 6.96 (d, 1H), 6.82 (dd, 1H), 6.67 (d, 1H), 4.57, (Br, 2H), 3.89 (tr, 1H), 3.04 (m, 2H), 2.95 (d, 2H), 2.87 (tr, 2H), 2.44 (s, 3H), 2.37 (tr, 2H), 2.21-2.01 (m, 6H), 1.91 (br, 1H), 1.88 (br, 1H), 1.80 (s, 3H), 1.78 (m, 1H), 1.58 (q, 4H), 1.38 (br, 1H), 1.22 (m, 2H), 1.02 (m, 1H), 0.47 (m, 2H), 0.20 (m, 2H); MS (EI) for C33H44N6O3: 573 (MH+).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[C:9]([C:13]1[CH:14]=[CH:15][C:16]([S:19][C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:18]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1ccc(S)cc1
Reactant: Oc1cccc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: CC(C)(C)c1ccc(Sc2cccc(O)c2)cc1
Yield: 89.8 %

Procedure:
The general procedure in example 39 was followed. 3-Iodophenol (220 mg, 1.0 mmol), 4-tert-butylthiophenol (168 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the 3-(4-tert-butylphenyl)sulfanylphenol (232 mg, 90% yield) as the colorless oil. Workup procedure: ethyl acetate (approx. 5 mL) and dodecane (227 μL, GC standard) were added to the reaction mixture after the reaction was completed. The organic layer was neutralized by dilute HCl to pH 8. The aqueous layer was extracted by ethyl acetate (4×10 mL). The combined organic layers were concentrated and purified by column chromatography on silica gel using hexane/ethyl acetate=10/1 as the eluent to afford the titled product. Rf=0.2 (hexane/ethyl acetate=10/1) (Note: same Rf value as the starting material). 1H NMR (CDCl3, 300 MHz) δ 7.21-7.34 (m, 2 H), 7.14 (t, 1 H, J=8.1 Hz), 6.95 (t, 1 H, J=8.1 Hz), 6.84-6.88 (m, 1 H), 6.78-6.81 (m, 1 H), 6.64-6.71 (m, 2 H). 13C NMR (CDCl3, 75 MHz) δ 156.0, 132.5, 131.2, 130.3, 130.1, 124.8, 122.1, 116.3, 115.2, 113.8, 35.0, 31.7. IR (neat, cm−1) 3375 (broad), 2962, 2904, 2867. MS (EI) m/z (relative intensity) 258 (100). HRMS (EI), Cald. for C16H18OS, 258.1073. Found 258.1068.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[CH2:18][C:19]([OH:21])=O)=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[F:52][C:53]1[CH:54]=[C:55]([CH:63]=[C:64]([F:67])[C:65]=1[F:66])[O:56][CH:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>CN(C=O)C.O>[C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:22])[CH2:18][C:19](=[O:21])[N:60]2[CH2:61][CH2:62][CH:57]([O:56][C:55]3[CH:54]=[C:53]([F:52])[C:65]([F:66])=[C:64]([F:67])[CH:63]=3)[CH2:58][CH2:59]2)=[CH:14][CH:15]=1
Reactant: Fc1cc(OC2CCNCC2)cc(F)c1F
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCC(Oc2cc(F)c(F)c(F)c2)CC1)Nc1ccc(-c2ccccc2)cc1
Reaction time: 0.03 h
Yield: 16 %

Procedure:
DIPEA (170 mg, 1.3 mmol) was added to a stirred solution of N-biphenyl-4-yl-malonamic acid (100 mg, 0.4 mmol) in DMF (2.0 mL) followed by HOBt (81 mg, 0.6 mmol) and EDCI.HCl (114 mg, 0.6 mmol). After 2 minutes of stirring, 4-(3,4,5-trifluoro-phenoxy)-piperidine hydrochloride (100 mg, 0.4 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with water, extracted with ethylacetate, washed with brine and concentrated. The remaining residue was purified by column chromatography (using neutral alumina and 5% MeOH in CHCl3) to afford 30 mg (17% Yield) of N-biphenyl-4-yl-3-oxo-3-[4-(3,4,5-trifluoro-phenoxy)-piperidin-1-yl]-propionamide. LC/MS [M+H]+: 469.17, 98.06%, 1H NMR (300 MHz, DMSO-d6): δ7.6 (m, 6H), 7.4 (m, 2H), 7.3 (m, 1H), 7.1 (m, 2H), 4.6 (m, 1H), 3.9 (m, 1H), 3.8 (m, 1H), 3.6 (m, 2H), 3.4 (m, 1H), 3.2 (m, 1H), 2.0 (m, 2H), 1.7 (m, 1H), 1.5 (m, 1H).
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][O:20][CH2:21][CH3:22])[N:12]=1.[Cl-].[NH4+]>CC(P(C1C=CC=CC=1)C1C=CC=CC=1)C.C1C=CC(PC2C=CC=CC=2)=CC=1.[Cl-].[Ni].O1CCCC1>[CH2:1]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][O:20][CH2:21][CH3:22])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCCOc1cccc(Br)n1
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Ni]
Agent: CC(C)P(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOCCOc1cccc(Cc2ccccc2)n1

Procedure:
A 1.09 mol tetrahydrofuran solution containing benzylmagnesium chloride was slowly added dropwise into a mixture of 1 g of 2-bromo-6-(2-ethoxyethyl)oxypyridine, 145 mg of 1,3-bis(diphenylphosphino)propanenickel(II) chloride and 5 ml of tetrahydrofuran with stirring under ice-cooling in a nitrogen atmosphere. After stirring for 2.5 hours, an aqueous saturated ammonium chloride solution was added thereto and the mixture was extracted with ethyl acetate. The organic phase was further washed with brine, dried over anhydrous sodium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 5% ethyl acetate/hexane as an eluent for separation and purification, to give 1 g of the target compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH:42]3[CH2:44][CH2:43]3)[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH:42]3[CH2:43][CH2:44]3)[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C3CC3)c2)c1
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C4CC4)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(2-cyclopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K60) (253 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous off-white substance (328 mg, 79%).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[C:6]2[CH:13]=[C:12]([CH3:14])[C:11]([OH:15])=[CH:10][C:7]=2[S:8][CH:9]=1.[F:17][C:18]([F:36])([F:35])[C:19]1[CH:34]=[CH:33][C:22]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31]O)=[CH:21][CH:20]=1.COC(=O)CC1C2C=CC=C(O)C=2SC=1>>[CH3:14][C:12]1[C:11]([O:15][CH2:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][CH2:23][C:22]2[CH:33]=[CH:34][C:19]([C:18]([F:17])([F:35])[F:36])=[CH:20][CH:21]=2)=[CH:10][C:7]2[S:8][CH:9]=[C:5]([CH2:4][C:3]([OH:2])=[O:16])[C:6]=2[CH:13]=1
Reactant: COC(=O)Cc1csc2cc(O)c(C)cc12
Reactant: OCc1ccccc1OCc1ccc(C(F)(F)F)cc1
Agent: COC(=O)Cc1csc2c(O)cccc12
Product: Cc1cc2c(CC(=O)O)csc2cc1OCc1ccccc1OCc1ccc(C(F)(F)F)cc1
Yield: 43 %

Procedure:
The title compound was prepared using compound 78C from the preceding step and compound 7A in a manner analogous to compound 77B. Thus, recrystallization from methanol afforded 0.42 g (43% yield) of the title compound as a cream-colored powder, mp 108-109° C. Calc for C27H23F3O4S: C, 64.79; H, 4.63; found: C, 64.64; H, 4.46. Step 5. Preparation of {5-Methyl-6-[2-(4-trifluoromethyl-benzyloxy)-benzyloxy]-benzo[b]thiophen-3-yl}-acetic acid (Compound 78)
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH3:10][C:11]1([CH3:36])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21](O)=[O:22])[CH:19]=2)[NH:14][CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]3[N:34]([CH3:35])[N:33]=[N:32][N:31]=3)[CH:25]=2)[CH2:12]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:10][C:11]1([CH3:36])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:22])[CH:19]=2)[NH:14][CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]3[N:34]([CH3:35])[N:33]=[N:32][N:31]=3)[CH:25]=2)[CH2:12]1
Reactant: Cn1nnnc1-c1cccc(C2CC(C)(C)c3cc(C(=O)O)ccc3N2)c1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nnnc1-c1cccc(C2CC(C)(C)c3cc(C(=O)NS(=O)(=O)C4CC4)ccc3N2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
To a suspension of 60% sodium hydride (267.5 mg, 6.9 mmol) in N,N-dimethylformamide (2.5 mL) was added cyclopropanesulfonamide (0.83 g, 6.9 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A42. A solution of 4,4-dimethyl-2-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (254.1 mg, 0.7 mmol) and 1,1′-carbonyldiimidazole (221.0 mg, 1.4 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B42. Solution B42 was added to Solution A42 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid {4,4-dimethyl-2-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-amide (97.8 mg, 30%) as a white solid: MS (ESI) M+1=467.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[CH:11][O:10][N:9]=2)=[N:6][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:55][CH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[O:59]1[CH2:60][CH2:61][CH:56]([NH:55][C:21]([C:17]2[S:16][C:15](/[CH:14]=[CH:13]/[C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][CH:11]=3)=[N:19][C:18]=2[CH3:20])=[O:23])[CH2:57][CH2:58]1
Reactant: NC1CCOCC1
Reactant: Cc1nc(/C=C/c2conc2-c2ccc(F)cn2)sc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(/C=C/c2conc2-c2ccc(F)cn2)sc1C(=O)NC1CCOCC1
Reaction time: 1 h
Yield: 82.8 %

Procedure:
To a solution of 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-yl]-vinyl}-4-methyl-thiazole-5-carboxylic acid (99 mg, 0.3 mmol) in DMF (1.5 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (106 mg, 0.33 mmol), N,N-diisopropyl ethyl amine (257 μL, 1.5 mmol) and 4-aminotetrahydropyran (33 mg, 0.33 mmol). The resulting reaction mixture was stirred for 1 h. The reaction mixture was then evaporated and purification by trituration from methanol/water afforded the title compound (103 mg, 83%) as an off white solid. MS: m/e=415.2 [M+H]+.
Reaction SMILES: C(C1N(C2C(F)=CC=CC=2Cl)C(C=O)=C(C)N=1)CCC.[H-].[Na+].C(COC)OC.C(C1N(CC2C=CC=CC=2Cl)C(/C(/C)=C(\CC2C=CSC=2)/C(O)=O)=CN=1)CCC.[CH2:58]([C:62]1[N:63]([CH2:79][C:80]2[C:85]([F:86])=[CH:84][CH:83]=[CH:82][C:81]=2[Cl:87])[C:64](/[CH:67]=[C:68](\[CH2:73][C:74]2[S:75][CH:76]=[CH:77][CH:78]=2)/[C:69]([O:71]C)=[O:70])=[CH:65][N:66]=1)[CH2:59][CH2:60][CH3:61]>C(OCC)(=O)C.CCCCCC>[CH2:58]([C:62]1[N:63]([CH2:79][C:80]2[C:85]([F:86])=[CH:84][CH:83]=[CH:82][C:81]=2[Cl:87])[C:64](/[CH:67]=[C:68](\[CH2:73][C:74]2[S:75][CH:76]=[CH:77][CH:78]=2)/[C:69]([OH:71])=[O:70])=[CH:65][N:66]=1)[CH2:59][CH2:60][CH3:61]
Reactant: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)OC)n1Cc1c(F)cccc1Cl
Agent: CCCCc1nc(C)c(C=O)n1-c1c(F)cccc1Cl
Agent: CCCCc1ncc(/C(C)=C(\Cc2ccsc2)C(=O)O)n1Cc1ccccc1Cl
Agent: [H-]
Solvent: CCCCCC
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)O)n1Cc1c(F)cccc1Cl

Procedure:
The procedure of Example 1, Method A is used. 2-n-Butyl-1-(2-chloro-6-fluorophenyl)-methyl-1H-imidazole-5-carboxaldehyde, trimethyl 3-(2-thienyl)-2-phosphonopropionate, sodium hydride and glyme are held at 60° C. for 1 hour to give, after chromatography over silica gel with 50% of hexane in ethyl acetate, methyl (E)-[2-n-butyl-1-{(2-chloro-6-fluorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate and corresponding cis or (Z)-isomer. The (E)-isomer is hydrolyzed to afford (E)-3-[2-n-butyl-1-{(2-chloro-6-fluorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:11])=[O:12])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: CS(=O)(=O)c1ccc(C=O)c(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(CO)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred dispersion of 2-chloro-4-methanesulfonyl-benzaldehyde (25 g, 0.11 mol) in absolute ethanol (120 ml) is added sodium borohydride (4.6 g, 0.12 mol) whilst cooling with an ice-bath to maintain room temperature. After stirring at room temperature for 3 hours, the reaction mixture is poured carefully onto ice-water (600 ml) and acidified to pH 1-2 with 1N HCl. The resulting suspension is extracted with ethyl acetate (400 ml) and the organic portions are combined, washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting crude product is dried in a vacuum oven at 40° C. overnight to yield the titled product which is used crude in the next step.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[CH2:14][CH2:15][O:16]C1CCCCO1)(O)[CH3:4].Cl>O>[CH3:13][O:12][C:9]1[CH:8]=[C:7]2[C:6](=[CH:11][CH:10]=1)[C:3]([CH3:4])([C:2]([F:1])([F:23])[F:24])[O:16][CH2:15][CH2:14]2
Reactant: COc1ccc(C(C)(O)C(F)(F)F)c(CCOC2CCCCO2)c1
Agent: Cl
Solvent: O
Product: COc1ccc2c(c1)CCOC2(C)C(F)(F)F
Temperature: 120 °C
Reaction time: 3 h
Yield: 138.4 %

Procedure:
A mixture of 1,1,1-Trifluoro-2-(4-methoxy-2-(2-(tetrahydropyran-2-yloxy)ethyl)phenyl)propan-2-ol (470 mg, 1.35 mmol) and conc. hydrochloric acid (4 ml) was stirred at 120° C. for 3 hr. After cooling, the reaction mixture was diluted with water, and the aqueous layer was extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, and concentrated to give the title compound as a brown oil (460 mg). This was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[B:9]1[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]1)[NH2:5].[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19].[N-]=C=O>C(Cl)Cl>[CH2:18]([NH:20][C:21]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[C:2]([F:1])[CH:3]=1)=[O:22])[CH3:19]
Reactant: CC1(C)OB(c2ccc(N)cc2F)OC1(C)C
Reactant: CCN=C=O
Agent: [N-]=C=O
Solvent: ClCCl
Product: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Temperature: 35 °C
Reaction time: 20 h
Yield: 54 %

Procedure:
To a stirred solution of 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.5 g, 6.33 mmol) in DCM (30 ml) was added ethyl isocyanate (1503 μL, 19 mmol). Reaction mixture was stirred at 35° C. for 20 hours. Additional isocyanate was added and reaction mixture left for sufficient time to ensure reaction completion. The crude reaction mixture was then partitioned between water and DCM. The organic layer was recovered, passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by flash chromatography using 0-60% ethyl acetate/petroleum ether 40-60 to yield a yellow solid (1.054 g, 3.42 mmol, 54%).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([Cl:15])=[C:13]([Cl:16])[CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([O:19][CH3:20])[C:9]([O:17][CH3:18])=[N:10]2)(=O)[CH3:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:30]2)=CC=1>C1(C)C=CC=CC=1>[Cl:15][C:14]1[C:5]([NH:4][C:1](=[S:30])[CH3:2])=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:16])[N:10]=[C:9]([O:17][CH3:18])[C:8]([O:19][CH3:20])=[N:7]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1nc2cc(Cl)c(Cl)c(NC(C)=O)c2nc1OC
Solvent: Cc1ccccc1
Product: COc1nc2cc(Cl)c(Cl)c(NC(C)=S)c2nc1OC
Yield: 135.7 %

Procedure:
5-Acetamido-6,7-dichloro-2,3-dimethoxyquinoxaline (20.49 g, 64.8 mmol) was added to a stirred suspension of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide (Lawesson's reagent) (15.7 g, 38.9 mmol) in toluene (432 ml) at room temperature under nitrogen. The mixture was warmed to the reflux temperature 25 minutes and was maintained at that temperature for a further 90 minutes. After being cooled the mixture was concentrated under reduced pressure and the residue purified by flash chromatography on silica gel, eluting with dichloromethane. 6,7-Dichloro-2,3-dimethoxy-5-thioacetamidoquinoxaline (17.54 g, 81%) was obtained as a yellow foam.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[CH3:26][C:27]1[CH:31]=[C:30]([NH:32][NH2:33])[S:29][N:28]=1>>[CH3:26][C:27]1[CH:31]=[C:30]([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:33]2)[S:29][N:28]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: Cc1cc(NN)sn1
Product: Cc1cc(-n2nccc2-c2nn(-c3ccc(OC(F)(F)F)cc3)ccc2=O)sn1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and (3-methyl-isothiazol-5-yl)-hydrazine according to the method described for example 43. MS: M=420.0 (M+H)+
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:9](=[O:10])[CH:8]=[CH:7][N:6]([CH2:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:5]1=[O:16].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:22][C:21]=1[S:31]([NH2:34])(=[O:33])=[O:32]>O1CCOCC1>[CH:12]1([CH2:11][N:6]2[CH:7]=[CH:8][C:9]([OH:10])=[C:4]([C:3]3[NH:19][C:20]4[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:22][C:21]=4[S:31](=[O:33])(=[O:32])[N:34]=3)[C:5]2=[O:16])[CH2:13][CH2:14][CH2:15]1
Reactant: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Reactant: CSC(SC)=C1C(=O)C=CN(CC2CCC2)C1=O
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)ccn(CC3CCC3)c1=O)N2
Temperature: 110 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
A solution of the product of Example 468C (0.050 g, 0.176 mmol) in dioxane (5 mL) was treated with the product of Example 425D (0.030 g, 0.113 mmol), stirred at 110° C. for 1 hour, and cooled to 25° C. The solid precipitate was collected by filtration and dried to provide the title compound (0.018 g, 35%). 1H NMR (300 MHz, DMSO-d6) δ 1.88 (m, 6 H) 2.74 (dt, J=15.17, 7.68 Hz, 1 H) 3.08 (s, 3 H) 4.03 (d, J=7.35 Hz, 2 H) 6.32 (d, J=7.72 Hz, 1H) 7.56 (dd, J=8.82, 2.57 Hz, 1 H) 7.62 (d, J=2.21 Hz, 1 H) 7.66 (m, 1 H) 8.06 (d, J=7.35 Hz, 1 H) 10.24 (s, 1 H) 13.83 (s, 1 H) 14.28 (s, 1 H). MS (ESI−) m/z 451 (M−H)−.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH3:16]C(C)=O>S([O-])(OC)(=O)=O.O>[CH3:16][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CC(C)=O
Agent: COS(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1c2ccccc2c2ccccc21
Yield: 90 %

Procedure:
To a vigourously stirred solution of 10 g of carbazole in 50 ml of acetone, 10 ml methyl sulphate was added, followed by dropwise addition of a solution of 10 g NaOH in 7 ml water. After a few minutes the solution was poured into water. N-methyl carbazole was purified by two ethanol recrystallization, extraction with boiling petroleum ether and another ethanol recrystallization (yield 90% m.p.=88° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[C:5]2[NH:6][C:7]([CH3:11])=[CH:8][C:9](=O)[N:4]2[N:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:24])=O.[OH-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:24][C:9]1[N:4]2[N:3]=[C:2]([CH3:1])[CH:12]=[C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=1
Reactant: Cc1cc2[nH]c(C)cc(=O)n2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)c1ccccc1
Product: Cc1cc(Cl)n2nc(C)cc2n1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
To a suspension of 2,5-dimethyl-4H-pyrazolo[1,5-a]pyrimidin-7-one (10.0 g, 61.3 mmol) in toluene (150 mL), add N,N-dimethylaniline (9.7 mL, 76.7 mmol). Add phosphorus oxychloride (11.2 mL, 122.6 mmol) dropwise to this white suspension. Reflux for 3 h under an inert atmosphere, cool to room temperature, and concentrate the reaction to a brown oil using reduced pressure. Dissolve the oil in ethyl acetate (250 mL) and basify with 1 N NaOH. Separate and extract the basic aqueous phase with additional ethyl acetate (2×100 mL). Combine the organic phases, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure to yield a brown solid. Purify the material using flash chromatography, eluting with 80% hexane/20% (30% THF/hexane) to 0% hexane/100% (30% THF/hexane) in a step gradient of 20% increments to provide a light green solid (6.65 g, 59%). ES/MS m/z (35Cl) 182.3 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[N:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N:3]=1.[C:14](OC)(=[O:17])[NH:15][NH2:16].C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[CH3:9][N:6]1[C:5]2[N:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N:3]2[C:14](=[O:17])[NH:15][N:16]=[C:2]2[C:7]1=[O:8]
Reactant: COC(=O)NN
Reactant: Cn1c(=O)c(Cl)nc2cccnc21
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: Cn1c(=O)c2n[nH]c(=O)n2c2cccnc21
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
A mixture of 7.5 g. of 2-chloro-4-methyl-pyrido(2,3-b)pyrazine-3-one, and 4 g. of methyl carbazate in 200 ml. of Dowtherm A was stirred and heated at 80° C. for 1 hour and then at 230° C. for 20 minutes.