Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC[C@@H](C1C=CC(O)=C2C=1C=CC(=O)N2)O[Si](C(C)(C)C)(C)C.C([O:31][C:32]1[CH:33]=[CH:34][C:35]([C@@H:43]([OH:80])[CH2:44][NH:45][C:46]([CH3:79])([CH3:78])[CH2:47][C:48]2[CH:49]=[C:50]([CH:75]=[CH:76][CH:77]=2)[C:51]([NH:53][CH2:54][C:55]2[C:56]([NH:68][CH:69]3[CH2:74][CH2:73][O:72][CH2:71][CH2:70]3)=[C:57]3[CH:65]=[N:64][N:63]([CH2:66][CH3:67])[C:58]3=[N:59][C:60]=2[CH2:61][CH3:62])=[O:52])=[C:36]2[C:41]=1[NH:40][C:39](=[O:42])[CH:38]=[CH:37]2)C1C=CC=CC=1>>[CH2:66]([N:63]1[C:58]2=[N:59][C:60]([CH2:61][CH3:62])=[C:55]([CH2:54][NH:53][C:51](=[O:52])[C:50]3[CH:75]=[CH:76][CH:77]=[C:48]([CH2:47][C:46]([NH:45][CH2:44][C@H:43]([OH:80])[C:35]4[CH:34]=[CH:33][C:32]([OH:31])=[C:41]5[C:36]=4[CH:37]=[CH:38][C:39](=[O:42])[NH:40]5)([CH3:79])[CH3:78])[CH:49]=3)[C:56]([NH:68][CH:69]3[CH2:70][CH2:71][O:72][CH2:73][CH2:74]3)=[C:57]2[CH:65]=[N:64]1)[CH3:67]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CC(C)(C)NC[C@H](O)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)c1
Agent: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CC(C)(C)NC[C@H](O)c2ccc(O)c3[nH]c(=O)ccc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described in Intermediate 2, using Intermediate 54 as substrate.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])[N:9]=2)[CH2:4]1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH2:38][CH3:39])=[O:35]>C(Cl)Cl>[OH:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:10]1[N:9]=[C:8]([N:5]2[CH2:6][CH2:7][C@@H:3]([CH2:2][NH:1][C:34](=[O:35])[O:36][CH2:37][CH2:38][CH3:39])[CH2:4]2)[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[N:11]=1
Reactant: Cc1ccc2c(N3CC[C@@H](CN)C3)nc(-c3ccccc3O)nc2c1
Reactant: CCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOC(=O)NC[C@@H]1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)C1
Temperature: -30 °C
Yield: 62.4 %

Procedure:
A solution of 2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (301 mg, 0.9 mmol) in CH2Cl2 (10 ml) was stirred under an N2 atmosphere. Triethylamine (0.25 mL, 1.8 mmol) was added, and the solution was cooled to −30° C. A 1 M propyl chloroformate solution (0.1 mL in 0.9 mL CH2Cl2, 0.9 mmol) was added, and the reaction mixture was allowed to warm to room temperature over a period of 30 minutes. After adding CH2Cl2 to the reaction mixture, it was washed 2 times with water, before it was dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 0-20% EtOAc in CH2Cl2 gave propyl ((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate (236 mg, 62%). LC/MS: m/z 421 (M+H)+ at 2.54 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.43 (dd, J=8.2, 1.8 Hz, 1H), 8.21 (d, J=8.7 Hz, 1H), 7.58 (s, 1H), 7.39-7.31 (m, 3H), 6.93-6.89 (m, 2H), 4.09-3.86 (m, 6H), 3.78-3.73 (m, 1H), 3.21-3.09 (m, 2H), 2.49 (s, 3H), 2.15-2.09 (m, 1H), 1.83-1.74 (m, 1H), 1.62-1.48 (m, 2H), 0.89-0.86 (m, 3H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:13]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCc2ccc(O)cc2O1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1CCc2ccc(OCc3ccccc3)cc2O1
Reaction time: 24 h
Yield: 81.4 %

Procedure:
A mixture of 7-hydroxychromanone (10.0 g, 61 mmol), benzyl bromide (7.6 mL,64 mmol), and potassium carbonate (16.5 g, 120 mmol) in acetone (250 mL) was gently refluxed 24 h. The mixture was cooled and filtered through celite. The filtrate 20 was concentrated and the residue was taken up in ethyl acetate. The organic solution was washed with water and brine, driedover calcium sulfate, and concentrated to a tan solid. Recrystallization from ethanol gave 12.63 g (81%) of 7-benzyloxychromanone as tan crystal which had mp 99°-102° C.; NMR δ7.85 (d, J=9 Hz, 1H), 7.44-7.32 (m,5H), 6.66 (dd, J=2.4, 9Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 5.09 (s,2H), 4.52 (t, J=6.5 Hz, 2H), 2.76 (t, J=6.5 Hz, 2H).
Reaction SMILES: [NH2:1][C@:2]1([CH2:14][OH:15])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[CH2:3]1.N1C=CC=CC=1.[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>C1COCC1.CCOC(C)=O>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C@@H:4]2[CH2:5][CH2:6][C@@:2]3([NH:1][C:22](=[O:23])[O:15][CH2:14]3)[CH2:3]2)=[CH:8][CH:9]=1
Reactant: N[C@]1(CO)CC[C@@H](c2ccc(Br)cc2)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1N[C@@]2(CC[C@@H](c3ccc(Br)cc3)C2)CO1
Reaction time: 4 h
Yield: 71.5 %

Procedure:
((1R,3R)-1-Amino-3-(4-bromophenyl)cyclopentyl)methanol (I-4A, 3.19 g, 11.81 mmol) was dissolved in THF (59.0 ml). Pyridine (0.955 ml, 11.81 mmol) and 1,1′-carbonyldiimidazole (5.74 g, 35.4 mmol) were added portionwise. The reaction mixture was stirred for 4 h and was followed by LCMS. After completion, the mixture was diluted with EtOAc and washed with 1M HCl. The aqueous layer was back extracted twice with EtOAc. The organic layers were combined, washed with saturated NaCl, dried over MgSO4, filtered and concentrated to afford (5R,7R)-7-(4-bromophenyl)-3-oxa-1-azaspiro[4.4]nonan-2-one (2.5 g, 8.44 mmol) after flash chromatography (24 g silica gel column; eluent: hexane 2 CV followed by a gradient to 100% EtOAc over 15 CV). HPLC ret time=0.91 min; LC/MS M+1=298. 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=8.5 Hz, 2H), 7.09 (d, J=8.5 Hz, 2H), 5.72-5.81 (m, 1H), 4.35 (dd, J=13 Hz, 8 Hz, 2H), 3.19-3.24 (m, 1H), 2.38-2.44 (m, 1H), 2.15-2.26 (m, 1H), 2.11-2.14 (m, 1H), 1.99-2.05 (m, 1H), 1.79-1.85 (m, 1H), 1.65-1.72 (m, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[C:8]1[CH:9]=[C:10]([CH3:16])[CH:11]=[C:12]([F:15])[C:13]=1[F:14].[CH2:17]([C:22]1[CH:27]=[CH:26][C:25](OB(O)O)=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH2:20][CH3:21]>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].C1(C)C=CC=CC=1.[Pd]>[F:15][C:12]1[CH:11]=[C:10]([CH3:16])[CH:9]=[C:8]([C:25]2[CH:24]=[CH:23][C:22]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:27][CH:26]=2)[C:13]=1[F:14]
Reactant: Cc1cc(F)c(F)c(I)c1
Reactant: CCCCCc1ccc(OB(O)O)cc1
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(-c2cc(C)cc(F)c2F)cc1
Yield: 99 %

Procedure:
5.74 g of TBAB, 9.84 g of potassium carbonate and 0.76 g of Pd/C were added to 9.04 g of the compound (21) having been dissolved in a mixed solvent of 50 mL of toluene and 50 mL of Solmix, and 6.84 g of 4-pentylphenylboric acid, followed by stirring under refluxing by heating for 4 hours. After removing Pd/C by filtration, the filtrate was separated, and the aqueous layer as extracted with toluene, which was added to the organic layer. The organic layer was washed with a saturated potassium hydrogensulfite aqueous solution and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 8.93 g of 3,4-difluoro-5-(4-pentylphenyl)toluene (22).
Reaction SMILES: Br.[NH:2]1[CH2:6][CH2:5][CH:4]([S:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:3]1.CCN([CH2:20][CH3:21])CC>C(Cl)Cl>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([S:7][CH:4]2[CH2:5][CH2:6][N:2]([CH2:9][CH2:10][C:11](=[O:14])[CH2:12][C:21]3[CH:20]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:3]2)=[CH:9][CH:10]=1
Reactant: Oc1ccc(SC2CCNC2)cc1
Reactant: CCN(CC)CC
Agent: Br
Solvent: ClCCl
Product: O=C(CCN1CCC(Sc2ccc(O)cc2)C1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
(RS)-4-(Pyrrolidin-3-ylsulfanyl)-phenol hydrobromide (470 mg, 1.7 mmol), Et3N (0.35 ml, 2.5 mmol) and 1-phenyl-3-butan-2-one (0.25 g, 1.7 mmol) were suspended in CH2Cl2 (10 ml). After stirring overnight at room temperature, the reaction mixture was concentrated and chromatographed over silica gel (hexane-ethylacetate 1:1 then ethylacetate) to provide (RS)-4-[3-(4-hydroxy-phenylsulfanyl)-pyrrolidin-1-yl]-1-phenyl-butan-2-one (90 mg, 16%) as a brown oil, MS: m/e 342.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=3[CH2:18]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]([CH2:46][CH3:47])[CH2:44][CH3:45])=O>>[CH2:44]([N:43]([CH2:46][CH3:47])[CH2:41][CH2:40][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=3[CH2:18]2)=[CH:37][CH:38]=1)[CH3:45]
Reactant: CCN(CC)C(=O)CCl
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)cc2)C(C)C)c1
Product: CCN(CC)CCOc1ccc(CN(c2cc(OC)ccc2C2CCc3cc(O)ccc3C2)C(C)C)cc1
Yield: 73.2 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 2-chloro-N,N-diethyl acetamide (18 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (22 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12](=[O:26])[CH:11]([CH3:27])[CH2:10]1.[F:28][CH2:29][CH2:30]I.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:30][CH2:29][F:28])[C:3]=1[CH:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:17][CH:16]=2)[C:12](=[O:26])[CH:11]([CH3:27])[CH2:10]1
Reactant: FCCI
Reactant: CC1CC(c2c(O)cccc2F)N(Cc2ccc(OC(F)(F)F)cc2)C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CC(c2c(F)cccc2OCCF)N(Cc2ccc(OC(F)(F)F)cc2)C1=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 5-(2-fluoro-6-hydroxyphenyl)-3-methyl-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one (preparation described in example 413; 50 mg; 0.13 mmol), 1-fluoro-2-iodoethane (23 mg; 0.13 mmol), potassium carbonate (36 mg; 0.26 mmol), and cesium carbonate (8.5 mg; 0.026 mmol) in anh. DMF (0.7 ml) was stirred at rt, under nitrogen, for 17 h. Subsequent filtration and purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.92 min.; [M+H]+: 429.96 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([S:23][CH3:24])[C:4]=1[C:5]([NH:7][CH:8]1[C:13](=O)[CH2:12][CH2:11][O:10][CH2:9]1)=[O:6].C(O)(=O)C.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:18]=[C:17]([C:19]([F:20])([F:22])[F:21])[CH:16]=[C:15]([S:23][CH3:24])[C:4]=1[C:5]([NH:7][C@H:8]1[C@@H:13]([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:12][CH2:11][O:10][CH2:9]1)=[O:6]
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1COCCC1=O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)N[C@@H]1COCC[C@@H]1N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
2-Methoxy-6-methylsulfanyl-N-(4-oxo-tetrahydro-pyran-3-yl)-4-trifluoromethyl-benzamide (intermediate C, 300 mg, 0.83 mmol) was dissolved in 5 mL tetrahydrofurane. Acetic acid (86 mg, 1.4 mmol) and pyrrolidine (70 mg, 0.99 mmol) were added and the reaction mixture was stirred 1 h at room temperature. Sodium triacetoxyborohydride (209 mg, 0.99 mmol) was added and stirring was continued at room temperature overnight. The mixture was extracted with 2N sodium carbonate solution and ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (dichloromethane/methanol/ammonia 100:0:0→140:10:1) yielded cis-2-methoxy-6-methylsulfanyl-N-((3RS,4RS)-4-pyrrolidin-1-yl-tetrahydro-pyran-3-yl)-4-trifluoromethyl-benzamide as a light brown solid (80 mg, 40%), MS: m/e=419.1 [(M+H)] and trans-2-methoxy-6-methylsulfanyl-N-((3RS,4SR)-4-pyrrolidin-1-yl-tetrahydro-pyran-3-yl)-4-trifluoromethyl-benzamide as a light brown solid (25 mg, 12%), MS: m/e=419.1 [(M+H)+].
Reaction SMILES: C([O:9][CH2:10][C@@H:11]1[C@@H:22]2[C@H:18]([O:19][C:20]([CH3:24])([CH3:23])[O:21]2)[C@@H:17]2[C@@H:13]([S:14][C:15]([N:25]([CH3:27])[CH3:26])=[N:16]2)[O:12]1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:26][N:25]([CH3:27])[C:15]1[S:14][C@@H:13]2[C@@H:17]([C@@H:18]3[C@@H:22]([C@@H:11]([CH2:10][OH:9])[O:12]2)[O:21][C:20]([CH3:23])([CH3:24])[O:19]3)[N:16]=1
Reactant: CN(C)C1=N[C@@H]2[C@H]3OC(C)(C)O[C@@H]3[C@@H](COC(=O)c3ccccc3)O[C@@H]2S1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN(C)C1=N[C@@H]2[C@H]3OC(C)(C)O[C@@H]3[C@@H](CO)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a solution of 155 (4.0 g, 10 mmol) in methanol (30 mL) was added potassium carbonate (704 mg, 5.1 mmol). The resulting solution was stirred for 2 hours at room temperature, before the reaction was quenched by the addition of water (20 mL), which was then extracted with dichloromethane (3×20 mL). The combined organic layer was washed with brine (2×10 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The crude residue was purified by flash column chromatography with 1%-5% methanol in dichloromethane to afford the title compound as a white solid (2.6 g, 88%). (ES, m/z): [M+H]+ 289.0; 1H NMR (300 MHz, CDCl3) δ 6.34 (d, J=6.0 Hz, 1H), 4.37-4.32 (m, 1H), 4.11-4.05 (m, 1H), 3.94-3.82 (m, 2H), 3.61-3.54 (m, 1H), 3.36-3.23 (m, 1H), 3.08 (s, 6H), 1.46 (s, 6H).
Reaction SMILES: I.[NH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]([C:11]2[N:15]([CH2:16][C:17]3[O:18][CH:19]=[C:20]([Br:22])[CH:21]=3)C(=O)[O:13][N:12]=2)=[N:8][O:9][N:10]=1.[S:24](N)([NH2:27])(=[O:26])=[O:25].[OH-].[Na+].O.C(O)(=O)C>N1C=CC=CC=1>[NH2:27][S:24]([NH:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]([C:11](=[N:12][OH:13])[NH:15][CH2:16][C:17]2[O:18][CH:19]=[C:20]([Br:22])[CH:21]=2)=[N:8][O:9][N:10]=1)(=[O:26])=[O:25]
Reactant: NS(N)(=O)=O
Reactant: NCCNc1nonc1-c1noc(=O)n1Cc1cc(Br)co1
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CC(=O)O
Solvent: O
Product: NS(=O)(=O)NCCNc1nonc1C(=NO)NCc1cc(Br)co1
Temperature: 130 °C
Yield: 40.9 %

Procedure:
In a microwave vial, 3-{4-[(2-aminoethyl)amino]-1,2,5-oxadiazol-3-yl}-4-[(4-bromo-2-furyl)methyl]-1,2,4-oxadiazol-5(4H)-one hydroiodide (30 mg, 0.060 mmol) and sulfamide (29 mg, 0.30 mmol) were suspended in pyridine (1 mL). The reaction mixture was flushed with nitrogen and heated at 130° C. for 3 minutes in a microwave reactor. The solvent was removed and the crude intermediate was suspended in methanol (1 mL). A 2.0 N solution of NaOH in water (0.30 mL, 0.60 mmol) was added in one portion and the reaction was heated to 45° C. for 30 minutes. After neutralization with acetic acid (68 μL, 1.2 mmol), the product was purified by preparative LCMS to give the desired product (10.4 mg, 41%). LCMS calculated for C10H15BrN7O5S (M+H)+: m/z=423.9, 426.0. 1H NMR (400 MHz, DMSO-d6): δ 10.87 (s, 1H), 7.75 (s, 1H), 6.83 (t, J=7.3 Hz, 1H), 6.68 (t, J=6.0 Hz, 1H), 6.56 (s, 2H), 6.30 (t, J=6.0 Hz, 1H), 6.23 (s, 1H), 4.56 (d, J=7.0 Hz, 2H), 3.32 (q, J=6.3 Hz, 2H), 3.07 (q, J=6.3 Hz, 2H).
Reaction SMILES: [C@H]1(NCC2C=C(C(C)(C)C)C=C(C(C)(C)C)C=2O)CCCC[C@@H]1NCC1C=C(C(C)(C)C)C=C(C(C)(C)C)C=1[OH:23].[Cl:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[C:47](=[O:51])[CH:46]([C:52]([O:54][CH3:55])=[O:53])[CH2:45]2.C(OO)(C)(C)C>C1(C)C=CC=CC=1.C(#N)C.CC(C)[O-].[Zr+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[C:47](=[O:51])[C:46]([OH:23])([C:52]([O:54][CH3:55])=[O:53])[CH2:45]2
Reactant: CC(C)(C)c1cc(CN[C@H]2CCCC[C@@H]2NCc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Reactant: COC(=O)C1Cc2cc(Cl)ccc2C1=O
Agent: [Zr+4]
Agent: CC(C)(C)OO
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: COC(=O)C1(O)Cc2cc(Cl)ccc2C1=O
Temperature: 55 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A chiral zirconium complex was prepared by stirring zirconium(IV) isopropoxide (0.0345 g, 0.089 mmol) with 2,2′-[(1S,2S)-1,2-cyclohexanediylbis(iminomethylene)]bis[4,6-bis(1,1-dimethylethyl)phenol] (Formula IIIa wherein R6 is C(CH3)3, 0.0613 g, 0.11 mmol) in toluene (2 mL) at ambient temperature. After stirring overnight, the homogeneous solution was evaporated to dryness in vacuo, and the residue redissolved in toluene (1.34 g). Methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate (0.250 g, 1.11 mmol) (Formula IIa wherein R1 is OCH3 and R4 is Cl) was added to the toluene solution, the solution was heated to 55° C., and then an aqueous solution of tert-butyl hydroperoxide (70%, 0.316 g, 2.46 mmol) was added. After 2 hours at 55° C., the solution was diluted with acetonitrile (11.5 mL). Analysis by quantitative and chiral HPLC showed 100% conversion of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate, forming methyl 5-chloro-2,3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylate in 84% yield (84% chemoselectivity) and 84% enantiomeric excess of the S-enantiomer.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([NH:34][OH:35])=[NH:33])=[CH:30][N:29]=1>>[F:26][C:2]([F:1])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[O:35][N:34]=[C:32]([C:31]4[CH:36]=[CH:37][C:28]([NH2:27])=[N:29][CH:30]=4)[N:33]=3)=[C:7]2[N:6]=[C:5]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[CH:4]=1
Reactant: N=C(NO)c1ccc(N)nc1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Nc1ccc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)n2)cn1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) (188 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane/hexane) as a yellow solid (85 mg, 35%). MS (ISP) 492.1 [(M+H)+]; mp 257° C.
Reaction SMILES: [C-]#N.[K+].[CH2:4]([N:6](CC)CC)C.[Cl:11][C:12]1[CH:21]=[CH:20][C:19]2[N+:18]([O-])=[CH:17][C:16]3[N:23]=[CH:24][N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[Cl:32])[C:15]=3[C:14]=2[CH:13]=1>CN(C=O)C.C[Si](C)(C)Cl>[Cl:11][C:12]1[CH:21]=[CH:20][C:19]2[N:18]=[C:17]([C:4]#[N:6])[C:16]3[N:23]=[CH:24][N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[Cl:32])[C:15]=3[C:14]=2[CH:13]=1
Reactant: CCN(CC)CC
Reactant: [O-][n+]1cc2ncn(-c3ccccc3Cl)c2c2cc(Cl)ccc21
Agent: C[Si](C)(C)Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1nc2ccc(Cl)cc2c2c1ncn2-c1ccccc1Cl
Temperature: 105 °C
Reaction time: 48 h

Procedure:
38.1 mg (0.5679 mmol) potassium cyanide and 239 μl (1.704 mmol) triethylamine (dry; Fluka) in 6 ml dry DMF, 182 μl trimethylchlorosilane (Fluka) are added within 10 min to a solution of 100 mg (0.30 mmol) of 8-chloro-1-(2-chloro-phenyl)-1H-imidazo[4,5-c]quinoline 5-oxide (Example 71). The reaction mixture is stirred for 48 h at ca. 100-110° C. bath temperature. The cold solution is filtered, the solvent is evaporated. The residue is purified by chromatography on silica gel (CH2Cl2-methanol 9:1). The compound can be crystallized from CH2Cl2-hexane. mp: 248-250° C.; MS: 339 (M++1); HPLC: tret=13.19 min (Grad 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH:18]4[CH2:19][CH2:20][CH:14]3[CH2:15][O:16][CH2:17]4)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[Br:21]N1C(=O)CCC1=O.O.[OH-].[Na+]>CN(C=O)C>[Br:21][C:12]1[S:11][C:10]([N:13]2[CH:18]3[CH2:19][CH2:20][CH:14]2[CH2:15][O:16][CH2:17]3)=[N:9][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Clc1ccc(-c2csc(N3C4CCC3COC4)n2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(-c2nc(N3C4CCC3COC4)sc2Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
To a stirred solution of 8-(4-(4-chlorophenyl)thiazol-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (Step-2 of compound 56, 0.27 g, 0.88 mmol) in DMF (5 ml) at 0° C. was added N-bromosuccinimide (0.19 g, 1.06 mmol) in a portion wise manner. The resulting mixture was stirred at room temperature for 30 min. The progress of reaction was monitored by TLC. To the reaction mixture water (20 ml) and 1M NaOH solution (5 ml) were added slowly and aqueous layer was extracted with ethyl acetate (2×30 ml). The reaction mixture was washed with water (1×20 ml). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure to obtain a crude product; which was purified by flash column chromatography using 10% ethyl acetate in hexanes as an eluent to obtain the title compound (0.26 g, 78.0%). MS: m/z 386 (M+1).
Reaction SMILES: OC(C1C=CC(NS(C)(=O)=O)=CC=1)CCCN(CCC1C=CC=C(C)N=1)C.[OH:28][CH:29]([C:45]1[CH:50]=[CH:49][C:48]([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])=[CH:47][CH:46]=1)[CH2:30][CH2:31][CH2:32][N:33]([CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[N:39]=1)[CH2:34][CH3:35]>>[CH2:34]([N:33]([CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[N:39]=1)[CH2:32][CH2:31][CH2:30][C:29]([C:45]1[CH:46]=[CH:47][C:48]([NH:51][S:52]([CH3:55])(=[O:53])=[O:54])=[CH:49][CH:50]=1)=[O:28])[CH3:35]
Reactant: CCN(CCCC(O)c1ccc(NS(C)(=O)=O)cc1)CCc1cccc(C)n1
Agent: Cc1cccc(CCN(C)CCCC(O)c2ccc(NS(C)(=O)=O)cc2)n1
Product: CCN(CCCC(=O)c1ccc(NS(C)(=O)=O)cc1)CCc1cccc(C)n1

Procedure:
The same procedure as that of Example 4-(2) was repeated except that N-[4-[1-hydroxy-4-[N-methyl-2-(6-methyl-2-pyridyl)ethylamino]butyl]phenyl]methanesulfonamide was replaced with N-[4-[1-hydroxy-4-[N-ethyl-2-(6-methyl-2-pyridyl)ethylamino]butyl]phenyl]methanesulfonamide obtained in the above step (1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][CH2:8][OH:9])[S:5][CH:6]=1.CO[CH:12](OC)[CH2:13][NH2:14]>>[Br:1][C:2]1[C:3]2[CH:12]([CH2:13][NH2:14])[O:9][CH2:8][CH2:7][C:4]=2[S:5][CH:6]=1
Reactant: COC(CN)OC
Reactant: OCCc1cc(Br)cs1
Product: NCC1OCCc2scc(Br)c21

Procedure:
The title compound was synthesized from 2-(4-bromothiophen-2-yl)ethanol and amino-acetaldehyde dimethylacetal according to General Procedure A.
Reaction SMILES: C(O[CH:6](N(C)C)[N:7]([CH3:9])[CH3:8])(C)(C)C.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[C:33]([CH3:40])[CH:32]=2)=[CH:16][CH:15]=1>CN(C=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[C:33](/[CH:40]=[CH:6]/[N:7]([CH3:9])[CH3:8])[CH:32]=2)=[CH:16][CH:15]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(Br)cc2)ccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1cc(-c2nc3ccccc3c(=O)n2-c2ccc(Br)cc2)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
tert-Butoxybis(dimethylamino)methane (2.0 mL, 9.60 mmol) was added to a solution of 3-(4-bromophenyl)-2-(3-methyl-4-nitrophenyl)quinazolin-4(3H)-one (1.4 g, 3.20 mmol) in DMF (30 mL). Stirring at 60° C. for 2 hours and concentrating in vacuo afforded (E)-3-(4-bromophenyl)-2-(3-(2-(dimethylamino)vinyl)-4-nitrophenyl)quinazolin-4(3H)-one (1.5 g, quantitative).