Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH2:12]O)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH3:15])=[CH:7][C:8]=2[CH3:14])[N:3]=1.P(Br)(Br)[Br:17]>C(Cl)Cl.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[Br:17][CH2:12][C:11]1[C:2]([CH3:1])=[N:3][C:4]2[C:9]([CH:10]=1)=[C:8]([CH3:14])[CH:7]=[C:6]([CH3:15])[CH:5]=2
Reactant: Cc1cc(C)c2cc(CO)c(C)nc2c1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(C)c2cc(CBr)c(C)nc2c1
Temperature: 23 °C
Reaction time: 8 h

Procedure:
To a solution of (2,5,7-trimethylquinolin-3-yl)methanol (42.1 mg, 0.205 mmol) in DCM (1.5 ml) was added PBr3 (0.039 ml, 0.410 mmol). Reaction mixture was stirred overnight at 23° C. Reaction mixture was diluted with ethyl acetate/NaHCO3 sat. aq solution. Layers were separated and aqueous layer was extracted once more with ethyl acetate. Organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound. HPLC (Method G) Rt=1.409 min, MS (Method V) [M+H]+=264.2, 266.2.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([NH:7][C@H:8]([C:17]([NH:19][C@@H:20]([C:22]([NH:24][C@H:25]([C:32]([NH:34][C@H:35]([C:43]([N:45]1[CH2:54][CH2:53][CH2:52][C@H:46]1[C:47]([NH:49][CH2:50][CH3:51])=[O:48])=[O:44])[CH2:36][CH2:37][CH2:38][NH:39][C:40](=[NH:42])[NH2:41])=[O:33])[CH2:26][S:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:23])[CH3:21])=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:6])[CH2:3][OH:4].[CH3:55][C:56]([CH2:58][C:59]([OH:61])=[O:60])=[O:57].[NH2:62][C@H:63]([C:69]([NH:71][C@H:72]([C:79]([NH:81][C@H:82]([C:93](NN)=[O:94])[CH2:83][C:84]1[C:92]2[C:87](=[CH:88][CH:89]=[CH:90][CH:91]=2)[NH:86][CH:85]=1)=[O:80])[CH2:73][C:74]1[N:78]=[CH:77][NH:76][CH:75]=1)=[O:70])[CH2:64][CH2:65][C:66](=[O:68])[OH:67]>>[NH2:62][C@H:63]([C:69]([NH:71][C@H:72]([C:79]([NH:81][C@H:82]([C:93]([NH:1][C@H:2]([C:5]([NH:7][C@H:8]([C:17]([NH:19][C@@H:20]([C:22]([NH:24][C@H:25]([C:32]([NH:34][C@H:35]([C:43]([N:45]1[CH2:54][CH2:53][CH2:52][C@H:46]1[C:47]([NH:49][CH2:50][CH3:51])=[O:48])=[O:44])[CH2:36][CH2:37][CH2:38][NH:39][C:40](=[NH:41])[NH2:42])=[O:33])[CH2:26][S:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:23])[CH3:21])=[O:18])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)=[O:6])[CH2:3][OH:4])=[O:94])[CH2:83][C:84]1[C:92]2[C:87](=[CH:88][CH:89]=[CH:90][CH:91]=2)[NH:86][CH:85]=1)=[O:80])[CH2:73][C:74]1[N:78]=[CH:77][NH:76][CH:75]=1)=[O:70])[CH2:64][CH2:65][C:66](=[O:67])[OH:68].[CH3:55][C:56]([CH2:58][C:59]([OH:61])=[O:60])=[O:57]
Reactant: NNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](N)CCC(=O)O
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CSC(C)(C)C)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)CO
Agent: CC(=O)CC(=O)O
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CSC(C)(C)C)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](N)CCC(=O)O

Procedure:
In analogy to Example 7(e) 448.5 mg (0.5 mol) of H-Ser-Tyr-D-Ala-Cys(But)-Arg-Pro-NH-C2H5 -diacetate were reacted with Glu-His-Trp-NH-NH2, worked up and purified over Dowex 1 × 2 (acetate form) and carboxymethyl cellulose. Since the substance was not completely pure, it was purified in analogy to Example 1(a) on Sephadex LH 20.
Reaction SMILES: [C:1]([O:4][C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([NH2:15])([CH2:8]3)[CH2:6]1)[CH2:12]2)(=[O:3])[CH3:2].[C:16](Cl)(Cl)=[O:17]>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([N:15]=[C:16]=[O:17])([CH2:8]3)[CH2:6]1)[CH2:12]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC12CC3CC(CC(N)(C3)C1)C2
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=O)OC12CC3CC(CC(N=C=O)(C3)C1)C2
Reaction time: 6 h
Yield: 85 %

Procedure:
In toluene (100 mL) was dissolved 10 mmole of 1-acetyloxy-3-aminoadamantane obtained by the method of Example 15. To the resultant solution was added 12 mmole of phosgene at room temperature and the mixture was stirred for 6 hours. As a result, the conversion of 1-acetyloxy-3-aminoadamantane was 95% and 1-acetyloxy-3-isocyanatoadamantane (yield 85%) was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1C=CC(S([O-])(=O)=O)=CC=1)(=O)C.[Na+].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: C1CCNCC1
Agent: CC(=O)c1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Product: CC(=O)c1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The damp 4-acetylbenzenesulfonyl chloride from 100 g. of sodium 4-acetylbenzenesulfonate is added to a stirred solution of 500 ml. of 50% aqueous piperidine. The mixture is stirred at room temperature for 16 hours, cooled, and the precipitated 1-(4-acetylbenzenesulfonyl)-piperidine removed by filtration, washed with water and dried; m.p. 113°-114° C. after crystallization from 2-propanol.
Reaction SMILES: Cl.[CH3:2][C@@:3]([C:7]([O:9][CH3:10])=[O:8])([CH2:5][OH:6])[NH2:4].N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].O>CN(C=O)C>[Si:16]([O:6][CH2:5][C@@:3]([CH3:2])([C:7]([O:9][CH3:10])=[O:8])[NH2:4])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@](C)(N)CO
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@](C)(N)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
A mixture of (±)-methyl 2-methylserinate hydrochloride from Step A (14.4 g, 85.0 mmol) and imidazole (19.1 g, 280 mmol) in dry DMF (77 mL) was cooled to 0° C. and treated with tert-butyldimethylsilyl chloride (14.1 g, 93.0 mmol). The mixture was stirred at 0° C. for 25 min, and was then allowed to warm to ambient temperature and stirred for 18 h. Water (500 mL) was added and the mixture extracted with ether (4×150 mL). The combined organic extracts were washed successively with water and brine, dried (anhydrous Na2SO4), filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography, eluting with a gradient of EtOAc:CH2Cl2—0:100 to 100:0, afforded the title compound. MS: m/z=248 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7]Cl.[CH3:9][NH:10][CH2:11][CH2:12][OH:13]>>[CH3:9][N:10]([CH2:11][CH2:12][OH:13])[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: CNCCO
Reactant: ClCc1ccccn1
Product: CN(CCO)Cc1ccccn1

Procedure:
The title compound was prepared from 2-picolyl chloride (3 g) and 2-(methylamino)ethanol (19 ml) by an analogous procedure to that described in preparation 1.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[C:30]=1[CH3:39].O>CN(C)C=O>[Cl:1][C:2]1[N:3]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[C:30]=2[CH3:39])[C:4]2[CH:10]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:8]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[C:5]=2[N:6]=1
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(Cl)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)cc2c1nc(Cl)n2Cc1cccc(C(F)(F)F)c1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To the mixture of methyl 2-chloro-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 65 (0.5 g, 1.691 mmol) in N,N-Dimethylformamide (DMF) (10 ml) was added in potassium carbonate (0.467 g, 3.38 mmol) and 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (0.428 g, 1.691 mmol). The reaction mixture was stirred at 80° C. for 1 h. The reaction was cooled down. Water (100 mL) was added in. The solid precipitated. Filtration gave the solid which was purified on a silica column (20-60% EtOAc/Hexane) to give the product as white solid (0.66 g, 83%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.54 (s, 3H) 3.07-3.16 (m, 4H) 3.68-3.78 (m, 4H) 3.91 (s, 3H) 5.63 (s, 2H) 6.41 (d, J=7.83 Hz, 1H) 7.28 (t, J=7.83 Hz, 1H) 7.39 (d, J=2.27 Hz, 1H) 7.50 (d, J=2.53 Hz, 1H) 7.63 (d, 1H). MS (ES+) m/e 468.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7]Cl)=[CH:5][CH:6]=1.[CH2:9]([NH:16][C:17]([C:19]1[S:23][C:22]([N:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:25]2=[O:31])=[N:21][C:20]=1[CH3:32])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([NH:16][C:17]([C:19]1[S:23][C:22]([N:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:7][C:4]3[S:3][C:2]([Cl:1])=[CH:6][CH:5]=3)=[CH:26][C:25]2=[O:31])=[N:21][C:20]=1[CH3:32])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Reactant: ClCc1ccc(Cl)s1
Product: Cc1nc(-n2ccc(OCc3ccc(Cl)s3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 40 %

Procedure:
Following the procedure as described in Example 21, making variation only as required to use 2-chloro-5-(chloromethyl)thiophene in place of 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole to react with N-benzyl-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 40% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.78 (t, J=5.9 Hz, 1H), 8.60 (d, J=8.1 Hz, 1H), 7.30-7.18 (m, 5H), 7.15 (d, J=3.8 Hz, 1H), 7.05 (d, J=3.8 Hz, 1H), 6.34 (dd, J=8.1, 2.7 Hz, 1H), 6.28 (d, J=2.7 Hz, 1H), 5.30 (s, 2H), 4.38 (d, J=5.9 Hz, 2H), 2.54 (s, 3H); MS (ES+) m/z 471.9 (M+1), 473.8 (M+3).
Reaction SMILES: FC(F)(F)C1C=C(NC2C(=O)C(=O)C=2N[C@@H](C2C3C(=CC=C(OC)C=3)N=CC=2)[C@H]2CC3CCN2CC3C=C)C=C(C(F)(F)F)C=1.[C:46]([O:50][C:51](=[O:75])[C:52]1[CH:57]=[CH:56][C:55]([C:58](=[O:73])/[CH:59]=[C:60](\[C:65]2[CH:70]=[C:69]([Cl:71])[CH:68]=[C:67]([Cl:72])[CH:66]=2)/[C:61]([F:64])([F:63])[F:62])=[CH:54][C:53]=1[CH3:74])([CH3:49])([CH3:48])[CH3:47].[N+:76]([CH3:79])([O-:78])=[O:77].O>ClCCCl>[C:46]([O:50][C:51](=[O:75])[C:52]1[CH:57]=[CH:56][C:55]([C:58](=[O:73])[CH2:59][C@:60]([C:65]2[CH:70]=[C:69]([Cl:71])[CH:68]=[C:67]([Cl:72])[CH:66]=2)([CH2:79][N+:76]([O-:78])=[O:77])[C:61]([F:62])([F:64])[F:63])=[CH:54][C:53]=1[CH3:74])([CH3:49])([CH3:48])[CH3:47]
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Reactant: C[N+](=O)[O-]
Agent: C=CC1CN2CCC1C[C@@H]2[C@@H](Nc1c(Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(=O)c1=O)c1ccnc2ccc(OC)cc12
Solvent: O
Solvent: ClCCCl
Product: Cc1cc(C(=O)C[C@@](C[N+](=O)[O-])(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of 3-(3,5-Bis-trifluoromethyl-phenylamino)-4-{[(S)-(6-methoxy-quinolin-4-yl)-((R)-5-vinyl-1-aza-bicyclo[2.2.2]oct-2-yl)-methyl]-amino}-cyclobut-3-ene-1,2-dione (20 mg, prepared according to the literature: Org. Lett., 2010, 12 (23), 5450-5453) in 1,2-dichloroethane (1.5 mL) under argon, was added 4-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid tert-butyl ester (300 mg) and nitromethane (0.35 ml). The solution was refluxed for 24 hours then more 3-(3,5-Bis-trifluoromethyl-phenylamino)-4-{[(S)-(6-methoxy-quinolin-4-yl)-((R)-5-vinyl-1-aza-bicyclo[2.2.2]oct-2-yl)-methyl]-amino}-cyclobut-3-ene-1,2-dione (20 mg) was added. The solution was refluxed for 48 hours then more nitromethane (0.35 mL) and 3-(3,5-Bis-trifluoromethyl-phenylamino)-4-{[(S)-(6-methoxy-quinolin-4-yl)-((R)-5-vinyl-1-aza-bicyclo[2.2.2]oct-2-yl)-methyl]-amino}-cyclobut-3-ene-1,2-dione (25 mg) were added. The solution was refluxed for another 16 hours and then the heating was stopped. The reaction mixture was cooled to room temperature and water was added. The resulting mixture was extracted with dichloromethane and the combined organic fractions were dried over sodium sulfate. The crude product was purified by flash chromatography (0% to 5% ethyl acetate in cyclohexane) to afford 4-[(S)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl-butyryl]-2-methyl-benzoic acid tert-butyl ester (127 mg). Chiral HPLC analysis (Chiralpack IA, Heptane:2-propanol:diethylamine=90:10:0.1, 1 ml/min, retention time 7.52 minutes (major enantiomer), 6.30 minutes (minor enantiomer) indicated that the reaction proceeded with 93% enantioselectivity in favor of the S enantiomer.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.ClC1C=C(Cl)C=CC=1C1[C:28]([C:29]2[NH:30][CH:31]=[CH:32][N:33]=2)=[CH:27][N:26]=[C:25]([NH:34][CH2:35][CH2:36][NH:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][N:39]=2)[N:24]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[C:28]([C:29]3[NH:33][CH:32]=[CH:31][N:30]=3)=[CH:27][N:26]=[C:25]([NH:34][CH2:35][CH2:36][NH:37][C:38]3[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][N:39]=3)[N:24]=2)=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Product: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(F)cc3C(F)(F)F)n2)nc1

Procedure:
{4-[4-fluoro-2-(trifluoromethyl)phenyl]-5-imidazol-2-ylpyrimidin-2-yl}{2-[(5-nitro(2-pyridyl))amino]ethyl}amine was prepared from 4-fluoro-2-(trifluoromethyl)benzoyl chloride using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=O)[CH:11]([CH3:13])[CH3:12])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH:11]([CH3:13])[CH3:12])=[N:9][N:8]=2)[CH:7]=1
Reactant: CC(C)C(=O)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)c1nnc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Intermediate 1e (1.81 g, 9.18 mmol), triphenylphosphine (4.83 g, 18.4 mmol), and triethylamine (5.12 mL, 36.7 mmol) in THF (25 mL) at 0° C., hexachloroethane (4.36 g, 18.4 mmol) was added in 2 portions at a 1 min intervals. The resulting pale brown solution was allowed to warm to RT then stirred for 2 h. The resulting yellow suspension was filtered, washing with THF (2×25 mL). The combined organics were purified using SCX-2 cartridge (washed with DCM-MeOH (1:1, 100 mL) and MeOH (50 mL), and then the product was eluted with 2M NH3 in MeOH) to give a pale yellow solid (1.60 g, 97%, contaminated with ˜2.5% Ph3P═O). NMR (400 MHz, CDCl3): 1.53 (6H, d), 3.32 (1H, sept), 7.15 (1H, ddd), 7.75 (1H, ddd), 7.84 (1H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[CH:11][N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(-c2cc[nH]n2)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc(-c2ccc(Br)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
To 3-(4-bromophenyl)-1H-pyrazole (2.0 g, 9.0 mmol) in DMF was added sodium hydride (0.54 g, 13 mmol) (60% in oil) and the reaction was stirred at ambient temperature for 30 minutes. (2-(Chloromethoxy)ethyl)trimethylsilane (4.5 g, 27 mmol) was added and the reaction was stirred overnight. Water was added and the aqueous phase extracted with DCM. The combined organic phases were dried over MgSO4, filtered and concentrated. The crude material was purified by reverse phase chromatography (SP4, 25M, water/CH3CN 60:40 to 0:100, 20 column volumes) to yield 3-(4-bromophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (2.4 g, 76% yield) as a clear oil.
Reaction SMILES: C[C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18]C2C=CC=CC=2)=[O:15])=[N:10][CH:9]=1)(C)[C:3]([OH:5])=[O:4].ClC[CH2:34][S:35](C)(=[O:37])=[O:36].C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:34][S:35]([CH2:18][CH2:17][N:16]([C@H:25]1[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]1)[C:14](=[O:15])[NH:13][C:11]1[S:12][C:8]([S:7][CH2:2][C:3]([OH:5])=[O:4])=[CH:9][N:10]=1)(=[O:37])=[O:36]
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: CS(=O)(=O)CCCl
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CS(=O)(=O)CCN(C(=O)Nc1ncc(SCC(=O)O)s1)[C@H]1CC[C@H](C)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl -ureido]-thiazol-5-ylsulfanyl}-propionic acid using 1-chloro-2-methanesulfonyl-ethane (Prepared as described in Chem. Ber. 1894, 27, 3048) and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4](S(OCCCCCC)(=O)=O)=[CH:3][CH:2]=1.[C:18]([C:20]1[C:21]([C:28]#[N:29])=[C:22]([CH:24]=[CH:25][C:26]=1[OH:27])[OH:23])#[N:19].[OH-].[Na+]>>[CH2:5]([O:27][C:26]1[CH:25]=[CH:24][C:22]([OH:23])=[C:21]([C:28]#[N:29])[C:20]=1[C:18]#[N:19])[CH2:6][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: N#Cc1c(O)ccc(O)c1C#N
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCOc1ccc(O)c(C#N)c1C#N
Reaction time: 7 h
Yield: 27.5 %

Procedure:
11.3 g (44.1 mM) of n-hexyl p-toluenesulfonate was added to the mixture of 5.0 g (31.3 mM) of dicyanohydroquinone and 37.5 ml of 5% NaOH aqueous solution, followed by 7 hours of stirring under refluxing. After the reaction, the reaction mixture was washed with toluene and the aqueous layer was acidified with HCl. The resultant precipitate was recovered through filtration and dried. To the precipitate, 1 liter of toluene was added. After the insoluble substrate was filtered out, the filtrate was subjected to recrystallization in a refrigerator and further subjected to recrystallization from a mixture solvent of water/methanol to obtain 2.1 g of an objective product (yield: 27.5%). m.p.: 150°-153° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][N:6]=[CH:5]2.C([Li])(C)(C)C.[C:17](=[O:19])=[O:18]>>[F:11][C:10]1[CH:9]=[C:8]2[C:4]([CH:5]=[N:6][NH:7]2)=[CH:3][C:2]=1[C:17]([OH:19])=[O:18]
Reactant: O=C=O
Reactant: Fc1cc2[nH]ncc2cc1Br
Agent: [Li]C(C)(C)C
Product: O=C(O)c1cc2cn[nH]c2cc1F

Procedure:
This compound was prepared in a manner similar to that shown in Scheme 3, using 5-bromo-6-fluoro-1H-indazole (88d), which was treated with t-butyl lithium and carbon dioxide to yield 6-fluoro-1H-indazole-5-carboxylic acid. This compound in turn was treated with thiosemicarbazide and polyphosphoric acid to form 5-(6-fluoro-1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine. MS (API-ES) m/z (%): 236 (100%, M++1).
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[N:19]C1C=CC=CC=1.Cl.Cl.[CH2:28]([NH:35]N)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:29]1([CH2:28][NH:35][N:19]=[C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[C:9]([C:3]4[CH:2]([CH3:1])[S:7][C:6](=[O:8])[NH:5][N:4]=4)[CH:10]=3)[NH:14][C:13]2=[O:18])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NNCc1ccccc1
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(=Nc1ccccc1)C(=O)N2
Agent: Cl
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(=NNCc1ccccc1)C(=O)N2
Yield: 24 %

Procedure:
Starting from 1,3-dihydro-5-(3,6-dihydro-6-methyl-2-oxo -2H-1,3,4-thiadiazin-5-yl)-3-phenylimino-2H-indol-2-one, and benzylhydrazine dihydrochloride and following the method described in Example 21, the desired compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=O)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[C:11]([O:16][CH3:17])[CH:10]=[CH:9][CH:8]=3.C(N(CC)C(C1C=CC2C(=O)C3C(OC=2C=1)=CC=CC=3)=O)C.[F:41][C:42]([F:55])([F:54])[C:43]([N:45]1[CH:50]2[CH2:51][CH2:52][CH:46]1[CH2:47][C:48](=O)[CH2:49]2)=[O:44]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[C:48]3[CH2:47][CH:46]4[N:45]([C:43](=[O:44])[C:42]([F:54])([F:41])[F:55])[CH:50]([CH2:51][CH2:52]4)[CH2:49]3)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[C:11]([O:16][CH3:17])[CH:10]=[CH:9][CH:8]=3
Reactant: COc1cccc2c(=O)c3ccc(Br)cc3oc12
Reactant: O=C1CC2CCC(C1)N2C(=O)C(F)(F)F
Agent: CCN(CC)C(=O)c1ccc2c(=O)c3ccccc3oc2c1
Product: COc1cccc2c1Oc1cc(Br)ccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F

Procedure:
Using an adaptation of the method described in Procedure 7, substituting 3-bromo-5-methoxy-xanthen-9-one, 3k for 9-oxo-9H-xanthene-3-carboxylic acid diethylamide, 6a and 8-(2,2,2-trifluoro-acetyl)-8-aza-bicyclo[3.2.1]octan-3-one for N-carbethoxynortropinone, the title compound 1-[3-(3-bromo-5-methoxy-xanthen-9-ylidene)-8-aza-bicyclo[3.2.1]oct-8-yl]-2,2,2-trifluoro-ethanone, 4k was obtained. MS m/z (MH+) 467.7, 469.7.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]1([S:25]([N:28](S(C2C=CC=CC=2)(=O)=O)[C:29]2[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][C:30]=2[I:36])(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1.C(OCC)(=O)C.Cl>[Br:35][C:32]1[CH:33]=[CH:34][C:29]([NH:28][S:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:27])=[O:26])=[C:30]([I:36])[CH:31]=1
Reactant: O=S(=O)(c1ccccc1)N(c1ccc(Br)cc1I)S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1ccc(Br)cc1I)c1ccccc1
Reaction time: 18 h
Yield: 90.2 %

Procedure:
A solution of tetrabutylammonium fluoride (1 M in THF, 11 mL) in 30 mL of THF was treated with N,N-bisbenzenesulfonyl-(4-bromo-2-iodoaniline) (5.78 g, 10 mmol) in several portions. After 18 hours, the mixture was diluted with of 40 mL of ethyl acetate and 40 mL of 1 N HCl. The phases were separated and the aqueous layer was extracted with two 40 mL portions of ethyl acetate. The combined organic layers were washed with two 20 mL portions of 1 N HCl, two 20 mL portions of saturated aqueous sodium bicarbonate solution, 20 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 3.95 g (90% yield) of the title compound as a solid, which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.CC([O-])(C)C.[K+].CS(O[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=1)[CH2:28][CH3:29])(=O)=O>C1COCC1.CCOC(C)=O>[C:36]([C:32]1[CH:31]=[C:30]([CH:27]([N:7]2[C:8]3[C:4](=[C:3]([C:2]([F:14])([F:1])[F:15])[C:11]([C:12]#[N:13])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)[CH2:28][CH3:29])[CH:35]=[CH:34][CH:33]=1)#[N:37]
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Reactant: CCC(OS(C)(=O)=O)c1cccc(C#N)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(c1cccc(C#N)c1)n1ccc2c(C(F)(F)F)c(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.7 %

Procedure:
To a suspension of 4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.030 g, 0.143 mmol) in THF (5 mL) was added KOtBu (1M in THF) (0.157 mL, 0.157 mmol). After stirring at rt for a couple of min, a solution of 1-(3-cyanophenyl)propyl methanesulfonate (0.0512 g, 0.214 mmol) in THF (1 mL) was added, and the mixture was heated at 80° C. in a sealed tube. The reaction was monitored by LCMS. After ˜30 min, additional 1-(3-cyanophenyl)propyl methanesulfonate (0.0342 g, 0.143 mmol) in THF (1 mL) was added, and the mixture was heated at 80° C. for another 30 min. Upon cooling, the reaction mixture was diluted with EtOAc (20 mL) and washed with water (20 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed over silica gel using 0-25% EtOAc-hexane gradient. The material was further purified by preparative HPLC (Phenomenex Luna column; gradient: 10-100% MeCN-water with 0.1% TFA). The fractions with product were combined and concentrated down to the aqueous phase, which was then partitioned between EtOAc (25 mL) and saturated aq. NaHCO3 solution (20 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give 1-(1-(3-cyanophenyl)propyl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.014 g, 26% yield): MS (ESI): m/z 354 (M+H).