Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])(I)[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[C:11]1[N:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=1.O.[NH4+].[Cl-]>CS(C)=O.[Cu]>[F:1][C:2]([F:9])([C:11]1[N:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(F)(F)I
Reactant: Cc1ccc(Br)nn1
Agent: [Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(F)(F)c1ccc(C)nn1
Reaction time: 0.83 h
Yield: 97.1 %

Procedure:
This procedure is derived from the general method of T. Taguchi, et al. (Tetrahedron Lett., 1986, 27, 6103-6106). Ethyl difluoroiodoacetate (0.355 mL, 651 mg, 2.60 mmol) was added to a rapidly stirred suspension of copper powder (333 mg, 5.24 mmol) in DMSO (6.5 mL) at rt. After 50 min., 3-bromo-6-methylpyridazine (300 mg, 1.73 mmol) was added in DMSO (1.0 mL). After 20 h, the mixture was transferred to a separatory funnel containing water (25 mL) and saturated aq. NH4Cl (25 mL), and extracted with ethyl acetate (2×50 mL). The organic extracts were washed with saturated aq. brine, dried (sodium sulfate), decanted, and evaporated. Purification by flash column chromatography on silica gel, eluting with 70:30 v/v hexanes/ethyl acetate, gave 363 mg of the title compound as an amber liquid. For the title compound:
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]=[CH:29][N:28]=1)N>>[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]=[CH:29][N:28]=1
Reactant: CN(C)C=Nc1[nH]nc(OCCO)c1C#N
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Product: OCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12

Procedure:
The procedure described in Example 1 was repeated using N′-[4-cyano-3-(2-hydroxyethoxy)-1H-pyrazol-5-yl]-N,N-dimethylimidoformamide (1.50 g, 6.72 mmol) and 3-chloro-4-(pyridin-2-ylmethoxy)aniline (1.58 g, 6.72 mmol) to give the title compound as a while solid (2.40 g, 87%); NMR Spectrum: 3.80 (t, 2H), 4.32 (t, 2H), 5.30 (s, 2H), 7.26 (d, 1H), 7.36-7.38 (m, 1H), 7.55-7.59 (m, 2H), 7.86-7.90 (m, 2H), 8.28 (s, 1H), 8.48 (br s, 1H), 8.59 (d, 1H); Mass Spectrum: 413 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH3:10].Cl.[N:13]([O-])=O.[Na+]>O>[F:8][C:6]1[CH:7]=[C:2]2[C:3]([C:9]([CH3:10])=[N:13][NH:1]2)=[CH:4][CH:5]=1
Reactant: O=N[O-]
Reactant: CC(=O)c1ccc(F)cc1N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1n[nH]c2cc(F)ccc12
Temperature: -10 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
1-(2-Amino-4-fluorophenyl)ethanone (9.618 g, 62.9 mmol) was treated with concentrated hydrochloric acid (16 mL) and water (16 mL), and the resulting white suspension was cooled to -10° C. and treated with a solution of sodium nitrite (4.338 g, 62.9 mmol) in 10 mL H2O, maintaining the temperature below 0° C. The resulting solution was filtered directly into a rapidly stirred solution of SnCl2.2H2O (34 g in 200 mL H2O) and the resulting mixture was stirred for 1 h at 20° C., basified (32 g NaOH in 200 mL H2O) and extracted with EtOAc. The combined organic extracts were dried (MgSO4), concentrated and the residue purified by flash chromatography (25% EtOAc in hexane) to give the title compound (3.10 g, 33%) as a white solid; mp 116°-117° C. (from hexane); 1H NMR (360 MHz, CDCl3) δ12.89 (bs, 1H, NH), 7.62 (dd, J=8.8, 5.1 Hz, 1H, indazole), 7.09 (dd, J=9.1, 2.0 Hz, 1H, indazole), 6.93 (dt, J=9.1, 2.0 Hz, 1H, indazole), 2.60 (s, 3H, Me); MS (CI+) m/e 151 (M+H+); Anal. calcd for C8H7FN2 : C, 63.99, H, 4.70; N, 18.66. Found: C, 63.94; H, 4.72; N, 19.10.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[S:9]1[C:13]([C:14]2[N:22]3[C:17]([CH2:18][CH2:19][CH2:20][CH2:21]3)=[C:16]([C:23]([NH2:25])=[O:24])[CH:15]=2)=[CH:12][N:11]=[CH:10]1>C(#N)C.C(OCC)C>[Cl:1][C:15]1[C:16]([C:23]([NH2:25])=[O:24])=[C:17]2[N:22]([C:14]=1[C:13]1[S:9][CH:10]=[N:11][CH:12]=1)[CH2:21][CH2:20][CH2:19][CH2:18]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: NC(=O)c1cc(-c2cncs2)n2c1CCCC2
Solvent: CCOCC
Solvent: CC#N
Product: NC(=O)c1c(Cl)c(-c2cncs2)n2c1CCCC2
Temperature: 20 °C
Reaction time: 2 h

Procedure:
N-Chlorosuccinimide is added in 0.05 g portions to a solution of 0.1 g of 3-(5-thiazolyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide in 10 cm3 of acetonitrile at 65° C. After 2 hours a precipitate is seen to form. The mixture is allowed to cool to approximately 20° C., the solid is filtered off and washed with two times 0.5 cm3 of acetonitrile. The operation was repeated another two times on 0.1 g of 3-(4-thiazolyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide. The solids obtained in the three tests were combined and chromatographed on a column of 1.8 cm diameter containing 40 g of silica (0.063-0.220). Elution is carried out with a 95/5 mixture of dichloromethane and methanol, 2-cm3 fractions being collected. The homogeneous fractions are combined and concentrated at reduced pressure (2.7 kPa) at a temperature close to 40° C., to give a white solid which is taken up in ethyl ether and then filtered off and dried in air. 0.12 g of 2-chloro-3-(5-thiazolyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide are thus obtained in the form of a white solid which melts at 227° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=3)[N:6]=2)[CH2:2]1.[CH3:17][C:18]1[N:19]=[C:20]2[N:25]=[C:24]([C:26]3[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=3)[C:23]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:22][N:21]2[CH:40]=1>>[CH3:17][C:18]1[N:19]=[C:20]2[N:25]=[C:24]([C:26]3[CH:27]=[CH:28][C:29]([CH2:30][N:1]4[CH2:4][CH:3]([C:5]5[N:6]=[C:7]([C:10]6[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=6)[NH:8][N:9]=5)[CH2:2]4)=[CH:32][CH:33]=3)[C:23]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:22][N:21]2[CH:40]=1
Reactant: Cc1cccc(-c2n[nH]c(C3CNC3)n2)n1
Reactant: Cc1cn2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Product: Cc1cccc(-c2nc(C3CN(Cc4ccc(-c5nc6nc(C)cn6cc5-c5ccccc5)cc4)C3)n[nH]2)n1

Procedure:
The compound is prepared in analogy to example 37.0. 306 mg 2-(5-Azetidine-3-yl-[1,2,4]triazole-3-yl)-6-methylpyridine×2HCl (60% pure) are reacted with 200 mg (0.64 mmol) 4-(2-methyl-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-benzaldehyde. After the usual work-up and purification 146 mg (42.6%) of the title compound are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([N:15]([CH2:17][C@H:18]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:19][CH:20]=C)[CH3:16])=[O:14])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].FC1C=CC([C@H](CC=C)CN(C)C(=[O:54])C2C=C(C(F)(F)F)C=C(C(F)(F)F)C=2)=CC=1>>[C:1]([C:3]1[CH:4]=[C:5]([C:13]([N:15]([CH2:17][C@H:18]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:19][CH:20]=[O:54])[CH3:16])=[O:14])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2]
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(F)cc1
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(C#N)cc2ccccc12)c1ccc(F)cc1
Product: CN(C[C@@H](CC=O)c1ccc(F)cc1)C(=O)c1cc(C#N)cc2ccccc12

Procedure:
The compound was synthesized in an analogous way to that of Method 20b but using 3-cyano-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methyl-1-naphthamide rather than N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methyl-3,5-bis(trifluoromethyl)benzamide (yield, 78%). 1H NMR (400 MHz, CDCl3): 2.4-2.6 (m, 1H), 2.7 (s, 3H), 2.8-4.4 (cm, 4H), 6.2 (s, <1H), 6.8-7.8 (cm, 9H), 8.2 (s, 1H), 9.8 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[F:22][C:23]([F:47])([F:46])[CH2:24][NH:25][C:26]([C:28]1([CH2:41][CH2:42][CH2:43][CH2:44]Br)[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:27]>>[F:22][C:23]([F:46])([F:47])[CH2:24][NH:25][C:26]([C:28]1([CH2:41][CH2:42][CH2:43][CH2:44][N:17]2[CH2:18][CH2:19][N:14]([C:12]3[CH:11]=[CH:10][CH:9]=[C:8]([O:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=4)[N:13]=3)[CH2:15][CH2:16]2)[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:27]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: COc1ccc(Oc2cccc(N3CCNCC3)n2)cc1
Product: COc1ccc(Oc2cccc(N3CCN(CCCCC4(C(=O)NCC(F)(F)F)c5ccccc5-c5ccccc54)CC3)n2)cc1

Procedure:
Prepared analogously to Example 2 b from 1-[6-(4-methoxy-phenoxy)-pyridin-2-yl]-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)[CH2:4][CH2:3]1.Cl[C:18]1[N:19]=[N:20][C:21]([C:24]2[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=2)=[CH:22][CH:23]=1>>[CH3:29][N:27]1[CH:28]=[C:24]([C:21]2[N:20]=[N:19][C:18]([N:2]3[CH2:7][CH2:6][CH:5]([N:8]4[C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[CH:10]=[CH:9]4)[CH2:4][CH2:3]3)=[CH:23][CH:22]=2)[CH:25]=[N:26]1
Reactant: Cn1cc(-c2ccc(Cl)nn2)cn1
Reactant: c1ccc2c(c1)ccn2C1CCNCC1
Agent: Cl
Product: Cn1cc(-c2ccc(N3CCC(n4ccc5ccccc54)CC3)nn2)cn1

Procedure:
The title compound was prepared according to the procedure as described in Example 1, Method B, reacting 1-(piperidin-4-yl)indole HCl salt and 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C@@H:6]([OH:9])[CH2:5][C:4]([CH3:11])([CH3:10])[C:3]=1/[CH:12]=[CH:13]/[C:14](/[CH3:44])=[CH:15]/[CH:16]=[CH:17]/[C:18](/[CH3:43])=[CH:19]/[CH:20]=[CH:21]/[CH:22]=[C:23](\[CH3:42])/[CH:24]=[CH:25]/[CH:26]=[C:27](\[CH3:41])/[CH:28]=[CH:29]/[C:30]1[C:36]([CH3:38])([CH3:37])[CH2:35][C@H:34]([OH:39])[C:32](=[O:33])[C:31]=1[CH3:40].O>N1C=CC=CC=1>[CH3:40][C:31]1[C:32](=[O:33])[C@@H:34]([OH:39])[CH2:35][C:36]([CH3:37])([CH3:38])[C:30]=1/[CH:29]=[CH:28]/[C:27](/[CH3:41])=[CH:26]/[CH:25]=[CH:24]/[C:23](/[CH3:42])=[CH:22]/[CH:21]=[CH:20]/[CH:19]=[C:18](\[CH:17]=[CH:16]\[CH:15]=[C:14](\[CH:13]=[CH:12]\[C:3]1[C:4]([CH3:11])([CH3:10])[CH2:5][C@H:6]([OH:9])[C:7](=[O:8])[C:2]=1[CH3:1])/[CH3:44])/[CH3:43]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)C(=O)[C@@H](O)CC2(C)C)C(C)(C)C[C@H](O)C1=O
Solvent: c1ccncc1
Solvent: O
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C\C=C\C=C(C)\C=C\C=C(C)\C=C\C2=C(C)C(=O)[C@@H](O)CC2(C)C)C(C)(C)C[C@H](O)C1=O
Temperature: 70 °C

Procedure:
20 mg analytical grade astaxanthin (97.2 mol % all-trans-astaxanthin and 1.6 mol % 9-cis-astaxanthin and 1.2 mol % 13-cis-astaxanthi) is dissolved in 1 ml pyridine and heated at 70° C. for 30 min. After addition of 8.0 ml cold water, the formed crystals are washed with water and the Raman spectrum shows the presence of crystal Form I as seen in the spectrum in FIG. 2. The X-Ray diffraction pattern is shown in FIG. 1. HPLC determination confirms the total amount of all-trans-astaxanthin and cis-astaxanthin isomers to be 100%. The astaxanthin comprises 78 mol % all-trans-astaxanthin, 3 mol % 9-cis-astaxantlhn and 19 mol % 13-cis-astaxanthin. The level of carotenoidal products is about 22 mol %. Similarly, when the pyridine solution is heated at 80° for 40 min, 28 mol % 13-cis -astaxanthin is formed and the resulting crystal is assigned as astaxanthin crystal Form I by the characteristic X-ray diffraction pattern and Raman spectrum.
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:21][C:20]=2[NH2:32])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:32][C:20]1[CH:21]=[C:22]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH:23]=[CH:24][C:19]=1[O:18][CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:33])=[O:5])[S:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(-c3ccc(F)cc3)cc2N)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(CCOc2ccc(-c3ccc(F)cc3)cc2N)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.7 %

Procedure:
2-[(4-{2-[(3-Amino-4′-fluorobiphenyl-4-yl)oxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (230 mg) obtained in Example 98-1 was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (the objective compound was extracted in the ethyl acetate layer). The ethyl acetate layer was washed with aqueous 10% citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1 to 1:1) to give the title compound (148 mg) as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:3]1=[O:23].Br[CH:25]([CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>C(OCC)(=O)C.C(Cl)Cl>[CH2:29]([O:28][C:26]([CH:25]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:3]1=[O:23])[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:27])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)CN1CC(c2ccccc2)SCC(N)C1=O
Reactant: O=C(OCc1ccccc1)C(Br)CCc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CN1CC(c2ccccc2)SCC(NC(CCc2ccccc2)C(=O)OCc2ccccc2)C1=O

Procedure:
0.34 g of t-butyl α-(6-amino-5-oxo-2-phenylperhydro-1,4-thiazepin-4-yl)acetate [prepared as described in Example 7(g)] was N-alkylated with 0.50 g of benzyl 2-bromo-4-phenylbutyrate in the same manner as in Example 1(h). The reaction product was subjected to silica gel column chromatography using a 1:40 by volume mixture of ethyl acetate and methylene chloride as eluent, to separate it into two isomers, A and B, (ascribed to the asymmetric carbon atom to which the phenethyl group is attached).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]2[N:19]([CH2:20][CH2:21][CH3:22])[C:18](=[O:23])[N:17]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[N:16]=2)=[CH:9][CH:8]=1)[CH3:2].[I:35]I>S([O-])([O-])(=O)=O.[Ag+2].C(O)C>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]2[N:19]([CH2:20][CH2:21][CH3:22])[C:18](=[O:23])[N:17]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=3)[N:16]=2)=[CH:9][C:8]=1[I:35])[CH3:2]
Reactant: II
Reactant: CCCn1c(CCc2ccc(OCC(=O)OCC)cc2)nn(-c2ccc(C(F)(F)F)cc2)c1=O
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CCCn1c(CCc2ccc(OCC(=O)OCC)c(I)c2)nn(-c2ccc(C(F)(F)F)cc2)c1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 94.6 %

Procedure:
A mixture of (4-{2-[5-Oxo-4-propyl-1-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H-[1,2,4]triazol-3-yl]-ethyl}-phenoxy)acetic acid ethyl ester (180 mg, 0.38 mmol), iodine (105 mg, 0.42 mmol), silver sulfate (131 mg, 0.42 mmol) and ethanol were stirred at room temperature. After 3.5 h, more iodine (86 mg) and silver sulfate (106 mg) were added and stirred for another 0.5 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried and evaporated to dryness to afford the product (217 mg, 95%). 1HMR (400 MHz, CDCl3) δ 8.15 (d, 2H, J=8.4 Hz), 7.73 (s, 1H), 7.67 (d, 2H, J=8.4 Hz), 7.18 (m, 1H), 6.67 (d, 1H, J=8.0 Hz), 4.66 (s, 2H), 4.26 (q, 2H, J=7.6 Hz), 3.68 (t, 2H, J=7.3 Hz), 3.05 (t, 2H, J=7.4 Hz), 2.82 (t, 2H, J=7.3 Hz), 1.7 (m, 2H), 1.29 (t, 3H, J=7.6 Hz), 0.96 (t, 3H, J=7.6 Hz); ESMS m/z (relative intensity) 604.2 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21](OC)=[O:22])=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[CH3:26][N:27]([CH3:43])[CH:28]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([CH2:40][NH:41][CH3:42])=[CH:36][CH:35]=2)[CH2:29]1.C[Al](C)C>ClCCCl>[CH3:43][N:27]([CH3:26])[CH:28]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([CH2:40][N:41]([CH3:42])[C:21]([C:19]3[O:20][C:16]([CH2:15][N:13]([S:10]([C:6]4[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH3:25])(=[O:11])=[O:12])[CH3:14])=[N:17][N:18]=3)=[O:22])=[CH:36][CH:35]=2)[CH2:29]1
Reactant: CNCc1ccc(CN2CCC(N(C)C)C2)cc1
Reactant: COC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)o1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N(C)Cc3ccc(CN4CCC(N(C)C)C4)cc3)o2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AT using methyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3,4-oxadiazole-2-carboxylate (30 mg, 0.08 mmol), N,N-dimethyl-1-{4-[(methylamino)methyl]benzyl}pyrrolidin-3-amine (32 mg, 0.13 mmol) and trimethylaluminium (2 M in toluene, 0.08 mL) in DCE (5 mL). A portion of the crude product was purified using prep method D to afford the title compound.
Reaction SMILES: [Br:1]Br.[CH2:3]([CH:10]1[CH2:14][CH2:13][CH2:12][N:11]1[CH3:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+]>[Fe]>[Br:1][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])=[CH:5][CH:6]=1
Reactant: CN1CCCC1Cc1ccccc1
Reactant: BrBr
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Product: CN1CCCC1Cc1ccc(Br)cc1
Reaction time: 2 h

Procedure:
Add 11.4 moles of bromine at room temperature to 2 g of 2-benzyl-1-methylpyrrolidine and 50 mg of iron powder. Allow the resulting mixture to stand for 2 hours before rendering it alkaline 1 N sodium hydroxide solution. Extract the base with diethyl ether. Distil the ether extract to obtain the title compound as almost-colorless liquid of b.p. 72° at 0.001 mm of Hg.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:3]1[C:4]2[N:5]=[CH:6][NH:7][C:8](=[O:11])[C:9]=2[S:10][C:2]=1[Cl:1]
Reactant: BrBr
Reactant: O=c1[nH]cnc2cc(Cl)sc12
Solvent: CC(=O)O
Product: O=c1[nH]cnc2c(Br)c(Cl)sc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 43.9 %

Procedure:
A solution of 1.12 g (0.006 mole) of 6-chlorothieno[3,2-d]pyrimidin-4(3H)-one and 15 ml of acetic acid at 80° C. was treated with 2.88 g (0.92 ml, 0.018 mole) of bromine. Heating was continued for 2.5 hours during which time solids precipitated. After cooling to room temperature, the mixture was filtered and washed with acetic acid, water and acetone. There was obtained 0.70 g (44%) of the title compound: m.p. above 280° C.; mass spectrum 264 (molecular ion and parent peak with expected isotope pattern), 239 (-27), 186 (some starting material) among others; 1H-nmr (trifluoroacetic acid) delta 7.5 ppm (starting material, s 0.1H), 9.3 (s, 1.0H). The nmr spectrum indicates that the reaction product is about 90% of the desired product; the remainder is starting material. This material is sufficiently pure for use in further reactions.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:19][CH3:20])[C:12]2([C:15]([O:17]C)=[O:16])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.O[Li].O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:19][CH3:20])[C:12]2([C:15]([OH:17])=[O:16])[CH2:14][CH2:13]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCN(C1(C(=O)OC)CC1)S(=O)(=O)c1ccc(Cl)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CCN(C1(C(=O)O)CC1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
Compound 14B (750 mg, 2.36 mmol) dissolved in THF (10 ml) and water (5 ml) was added with LiOH.H2O (3 equiv., 297 mg) and the reaction was stirred at rt 3 hours. The reaction was concentrated under vacuum. Water was added and 10% HCl till precipitation of the acid. The acid was extracted with ethyl acetate and the organic phase was washed with Brine, dried over sodium sulfate and concentrated under vacuum to give 650 mg of 15B as a white solid. Yield=90%. 1HNMR (DMSO, 200 MHz) δ 1.06 (3H, t, J=7.2 Hz), 1.38 (2H, m), 1.35 (2H, bs), 3.33 (2H, m), 7.43 (2H, m), 7.77 (2H, m), 12.46 (1H, bs)
Reaction SMILES: [Br:1][C:2]1[C:3](Br)=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:14]B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Br:1][C:2]1[C:3]([CH3:14])=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CB(O)O
Reactant: CCOC(=O)c1cnc(Br)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(C)c(Br)c1
Temperature: 110 °C
Reaction time: 72 h
Yield: 48 %

Procedure:
An oven-dried resealable Schlenk tube was charged with ethyl 5,6-dibromonicotinate (preparation 47b, 1.09 g, 3.5 mmol), methylboronic acid (0.24 g, 4.0 mmol), potassium carbonate (1.46 g, 10.6 mmol) and 1,4-dioxane (27 mL). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and then tetrakis(triphenylphosphine)palladium(0) (0.41 g, 0.35 mmol) was added. After three new cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated in an oil bath to 110° C. After 3 days, the mixture was cooled, filtered through Celite® and the filtrate was evaporated. Purification of the residue by flash chromatography (97:3 to 9:1 hexanes/ethyl acetate) gave the title compound (0.41 g, 45%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[NH:9]1[C:17]2[C:12](=[C:13]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[C:12](=[C:13]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Reactant: Clc1ccccc1I
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4c3ccn4-c3ccccc3Cl)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-chloro-2-iodobenzene and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 486.1 (M+H)+.