Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:20]1([CH2:25]/[CH:26]=[C:27](\[C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=2)/[C:28]([OH:30])=O)[CH2:24][CH2:23][CH2:22][CH2:21]1.[CH3:41][O:42][C:43]([C:45]1[N:46]=[C:47]([NH2:50])[S:48][CH:49]=1)=[O:44]>C(Cl)Cl>[CH3:41][O:42][C:43]([C:45]1[N:46]=[C:47]([NH:50][C:28](=[O:30])/[C:27](/[C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=2)=[CH:26]/[CH2:25][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)[S:48][CH:49]=1)=[O:44]
Reactant: COC(=O)c1csc(N)n1
Reactant: CS(=O)(=O)c1ccc(/C(=C\CC2CCCC2)C(=O)O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1csc(NC(=O)/C(=C/CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
A solution of triphenylphosphine (525 mg, 2 mmol) in methylene chloride (25 mL) was cooled to 0° C. and then treated with N-bromosuecinimide (355 mg, 2 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with (E)-4-cyclopentyl-2-(4-methanesulfonyl-phenyl)-but-2-enoic acid (prepared in Example 21, 308 mg, 1 mmol). The clear solution was stirred for 10 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1 h. The reaction mixture was then treated with 2-aminothiazole-4-carboxylic acid methyl ester (400 mg, 2.52 mmol), and the resulting suspension was stirred at 25° C. over the weekend. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (50 mL) and a 1N aqueous hydrochloric acid solution (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×25 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (2×50 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 3/1 to 1/1 hexanes/ethyl acetate) afforded (E)-2-[4-cyclopentyl-2-(4-methanesulfonyl-phenyl)-but-2-enoylamino]-thiazole-4-carboxylic acid methyl ester (250 mg, 56%) as a white solid: mp 85-90° C.; EI-HRMS m/e calcd for C21H24N2O5S2 (M+) 448.1127, found 448.1117.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C(Cl)(Cl)Cl.Cl.Cl.[NH2:13][C:14]1[CH:25]=[CH:24][C:17]([CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C>[CH2:20]([N:19]([CH2:18][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:2](=[O:3])[O:4][CH2:5][CH3:6])=[CH:25][CH:24]=1)[CH2:22][CH3:23])[CH3:21]
Reactant: CCOC(=O)Cl
Reactant: CCN(CC)Cc1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Nc1ccc(CN(CC)CC)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
At 0° C., ethyl chloroformate (455 μL) was added to a chloroform solution (13 mL) of N-(4-aminobenzyl)-N,N-diethylamine dihydrochloride (1.0 g) obtained in Reference Example 2-1-(2) and triethylamine (2.2 mL), and stirred at 0° C. for 1.5 hours and then at room temperature for 2 hours. Aqueous sodium hydrogencarbonate solution was added to the reaction liquid to stop the reaction, and this was extracted with chloroform. The organic layer was washed with water and saturated saline water, and then dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (chloroform/methanol=9/1) to obtain ethyl N-{4-[(diethylamino)methyl]phenyl}carbamate (530 mg) as an orange oily substance.
Reaction SMILES: [H-].[Na+].[CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][OH:13])[CH2:8][CH2:7]1)([CH3:5])[CH3:4].Cl[C:15]1[N:19]([CH3:20])[C:18]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[O:22])=[CH:17][N:16]=1>C1COCC1>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:21]([C:18]2[N:19]([CH3:20])[C:15]([O:13][CH2:12][CH:9]3[CH2:10][CH2:11][N:6]([CH:3]([CH3:5])[CH3:4])[CH2:7][CH2:8]3)=[N:16][CH:17]=2)=[O:22])=[CH:28][CH:27]=1
Reactant: Cn1c(C(=O)c2ccc(Cl)cc2)cnc1Cl
Reactant: CC(C)N1CCC(CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)N1CCC(COc2ncc(C(=O)c3ccc(Cl)cc3)n2C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a 1-L, three-necked, round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet and an addition funnel was added NaH (1.45 g, 0.061 mol) and THF (300 mL). The stirred suspension was cooled to 0° C. and (1-isopropyl-piperidin-4-yl)-methanol (9.5 g, 0.06 mol) was added. The cooling bath was removed, and the reaction warmed to rt. After 2 h, a solution of (2-chloro-3-methyl-3H-imidazol-4-yl)-(4-chloro-phenyl)-methanone (15.56 g, 0.061 mol) in dry THF (100 mL) was added. The reaction mixture was stirred at 60° C. and monitored by HPLC every 4-8 h. After 36 h, the reaction was judged complete. The reaction mixture was cooled to rt, poured into ice-cold water, and extracted with EtOAc (2×250 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to provide the crude material as a brown solid. Recrystallization from EtOAc afforded the desired product (17.5 g, 78%) as a white crystalline solid. mp 126-127° C. IR (film): 2963, 1615, 1585, 1529, 1481, 1362, 1287, 1213, 1173, 1104, 1020, 897, 846, 727, 698 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.67 (d, J=8.6 Hz, 2H), 7.38 (d, J=8.6 Hz, 2H), 7.13 (s, 1H), 4.22 (d, J=6.0 Hz, 2H), 3.68 (s, 3H), 2.84 (m, 2H), 2.61 (m, 1H), 2.09 (m, 2H), 1.74 (m, 3H), 1.30 (m, 2H), 0.97 (d, J=6.5 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ 183.4, 157.0, 138.3, 138.2, 137.3, 130.2, 128.7, 127.1, 74.9, 54.6, 48.4, 35.9, 30.7, 29.1, 18.3. HRMS (EI): m/z calcd for C20H27ClN3O2 [M+H]+, 376.1792; found, 376.1801. Anal. Calcd for C20H26ClN3O2: C, 63.91; H, 6.97; N, 11.17. Found: C, 63.55; H, 6.77; N, 11.05.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[C:14]2[N:15]=[CH:16][N:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=3)[CH:18]=2)=[CH:4][CH:3]=1.[NH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[C:14]2[N:15]=[CH:16][N:17]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:28][CH:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:25])=[CH:26][CH:27]=3)[CH:18]=2)=[CH:6][CH:7]=1
Reactant: NC1CCOCC1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Product: Cn1nnc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)NC3CCOCC3)cc2)cn1
Yield: 79 %

Procedure:
As described for example 3b, 4-{4-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-imidazol-1-yl}-benzoic acid (75 mg, 0.21 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (73 mg, 79%) which was obtained as a white solid. MS: m/e=447.3 [M+H]+.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[N:4]([CH2:8][C:9]([OH:11])=[O:10])[C:2]1=[S:3].[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:23]=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[C:13]1([CH2:12][O:19][C:20]2[CH:21]=[C:22]([CH:23]=[C:7]3[S:1][C:2](=[S:3])[N:4]([CH2:8][C:9]([OH:11])=[O:10])[C:5]3=[O:6])[CH:25]=[CH:26][C:27]=2[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: O=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)C(=Cc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)SC1=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
A solution of rhodanine-3-acetic acid (1 g, 5.20 mmol, 1 eq), 3,4-dibenzyloxybenzaldehyde (2.04 g, 6.25 mmol, 1.2 eq), and sodium acetate (1.3 g, 15.6 mmol, 3 eq) in acetic acid (30 ml) was heated to reflux, and stirred overnight. As the reaction mixture cooled to room temperature the product precipitated and it was filtered and washed with acetic acid, then petroleum ether. The gummy solid was dissolved in ethyl acetate (20 mL) and extracted into saturated aqueous sodium bicarbonate (2×30 mL). The basic extracts were combined, washed with ethyl acetate, and acidified to pH 1 with concentrated HCl. The aqueous solution was extracted with ethyl acetate (2×10 mL), and the organic extracts combined, dried over sodium sulfate and evaporated in vacuo. Recrystallization from ethyl acetate and petroleum ether gave the product which was suspended in water and freeze-dried overnight in vacuo to give the product as a fluffy yellow powder (2.1 g, 81%). mp 235–238° C.: 1H NMR (d6 DMSO) δ 7.79 (s, 1H, C═C—H), 5.25 (s, 2H, CH2Ph), 5.23 (s, 2H, CH2Ph), 4.73 (s, 2H, CH2CO2H). Anal. Found: C, 63.53; H, 4.31; N, 2.85; S, 13.05. Calcd for C26H21NO5S2: C, 63.39; H, 4.21; N, 2.84; S, 12.92.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:11]=[C:10]([C:20]([O:22]CC)=[O:21])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[N:11]=[C:10]([C:20]([OH:22])=[O:21])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(Cl)c2)n(-c2ccc(F)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(-c2cccc(Cl)c2)n(-c2ccc(F)cc2)n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
23.0 g (66.7 mmol) of the compound of Example 35A are provided in 100 ml of 1,4-dioxane, 100 ml (200 mmol) of a 2N solution of lithium hydroxide in water are added, and the mixture is stirred at 50° C. for 2 h. The mixture is concentrated, a conc. aqueous hydrogen chloride solution is subsequently added until the pH is acidic, the mixture is extracted with dichloromethane, and the organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is stirred in a little diethyl ether, collected by filtration and dried under high vacuum. 17.8 g (84% of theory) of the title compound are obtained.
Reaction SMILES: C(OP([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH:19]=O.O>CCCCCCC>[CH3:16][O:17][CH:18]([O:21][CH3:22])/[CH:19]=[C:9](\[CH3:15])/[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: COC(C=O)OC
Solvent: O
Solvent: CCCCCCC
Product: CCOC(=O)/C(C)=C/C(OC)OC
Temperature: 60 °C
Reaction time: 15 h
Yield: 121.4 %

Procedure:
To a stirred solution of ethyl 2-(diethoxyphosphoryl)propanoate (450 μL, 2.1 mmol) in heptane (5 mL) was added 2,2-dimethoxy acetaldehyde (60% in water, 1.0 mL, 4.2 mmol). The solution was stirred for 15 h at 60° C. After the reaction was cooled, water was added and the mixture was extracted with CH2Cl2 and filtered through a phase separator and a silica plug. Concentration under reduced pressure afforded (E)-ethyl 4,4-dimethoxy-2-methylbut-2-enoate (480 mg, >100%). The procedure was adapted from Tetrahedron 2002, 2533.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([CH3:33])([CH3:32])[CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[N+:29]([O-])=O)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pt].C(#N)C>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([CH3:33])([CH3:32])[CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[NH2:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12)NC(=O)OC(C)(C)C
Agent: [Pt]
Solvent: CC#N
Product: CC(C)(CNc1c(N)cnc2cc(OCc3ccccc3)ccc12)NC(=O)OC(C)(C)C
Yield: 95.8 %

Procedure:
tert-Butyl[2-(7-benzyloxy-3-nitroquinolin-4-ylamino)-1,1-dimethylethyl]carbamate (6.74 g), 5% platinum on carbon (1.02 g), and acetonitrile (125 mL) were combined. The mixture was shaken overnight under 50 psi (3.4×105 Pa) of hydrogen. The reaction was filtered through CELITE filter agent and the filtrate was concentrated under reduced pressure to give 6.04 g of tert-butyl[2-(3-amino-7-benzyloxyquinolin-4-ylamino)-1,1-dimethylethyl]carbamate as an orange foam.
Reaction SMILES: [Si](O[CH2:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][CH:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]([O:18][CH3:19])=[O:17])=[C:12]([CH2:28][CH:29]=[CH2:30])[CH:11]=1)(C(C)(C)C)(C)C.C(Br)(Br)(Br)[Br:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)=O>CC#N>[Br:32][CH2:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][CH:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]([O:18][CH3:19])=[O:17])=[C:12]([CH2:28][CH:29]=[CH2:30])[CH:11]=1
Reactant: C=CCc1cc(CO[Si](C)(C)C(C)(C)C)ccc1OC(C(=O)OC)c1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CC(C)=O
Product: C=CCc1cc(CBr)ccc1OC(C(=O)OC)c1ccccc1
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
To a cooled (0° C.) solution of the product of Step D (156 mg, 0.366 mmol) in CH3CN (2 mL), were added carbon tetrabromide (182 mg, 0.55 mmol) and triphenylphosphine (144 mg, 0.55 mmol). After 30 minutes at 0° C., the reaction mixture was allowed to warm to room temperature, at which point acetone (40 mL, 0.55 mmol) was added. After 16 hours at room temperature, the reaction mixture was filtered, the filtrate was concentrated in vacuo, and the residue was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexanes to afford 86 mg (63 %) of the title compound (Rf =0.13, 5% ethyl acetate/hexanes).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[S:18][CH:19]=[C:20]([C:22]([O:24]CC)=O)[N:21]=4)=[C:13]([NH:27][CH:28]([CH3:30])[CH3:29])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH3:31]>CO>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[S:18][CH:19]=[C:20]([C:22]([NH2:31])=[O:24])[N:21]=4)=[C:13]([NH:27][CH:28]([CH3:29])[CH3:30])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: N
Reactant: CCOC(=O)c1csc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)n1
Solvent: CO
Product: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nc(C(N)=O)cs1
Temperature: 80 °C

Procedure:
The ethyl 2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazole-4-carboxylate (Example 20) (200 mg, 0.455 mmol) was taken in a sealed tube, to it methanol (2 mL) was added, followed by addition of methanolic ammonia (10 mL). The reaction mixture was heated at 80° C. for 3 h. The reaction mixture was concentrated. The crude material was purified by column chromatography through silica gel and MeOH:CHCl3 as eluent. The material obtained was further purified on preparative TLC to obtain 2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazole-4-carboxamide. 1H NMR: 400 MHz, DMSO-d6: δ 1.33 (d, J=6.40 Hz, 6H), 3.64-3.72 (m, 1H), 6.15 (s, 1H), 7.58 (dd, J=2.00, 8.80 Hz, 1H), 7.63 (bs, 1H), 7.69 (bs, 1H), 7.95 (d, J=8.80 Hz, 1H), 8.14 (s, 1H), 8.32 (s, 1H), 8.35 (d, J=6.80 Hz, 1H), 8.49 (s, 1H), 8.72 (d, J=2.00 Hz, 1H), 9.15 (s, 1H), 9.35 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm-2.7 μm; Solvent A=2% ACN: 98% H2O: 10 mM NH4COOH; Solvent B=98% ACN: 2% H2O: 10 mM NH4COOH; gradient 0-100% B over 3 min; retention time: 1.933 min; LCMS (ES-API), m/z 411.0 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 5.137 min; Purity: 99.8%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1>CCO>[Br:11][C:5]1[CH:6]=[C:7]([NH2:8])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Solvent: CCO
Product: Nc1cc(Br)cnc1N
Temperature: 25 °C
Yield: 98 %

Procedure:
To a suspension of 2-amino-5-bromo-3-nitropyridine (2.0 g, 9.17 mmole) in absolute EtOH (50 mL) was added SnCl2 hydrate (9.3 g, 41.3 mmole), then the mixture was heated to reflux. After 3 hr the mixture was cooled to RT and concentrated. The residue was taken up in 2.0 M NaOH and extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated to give the title compound (1.69 g, 98%) which was sufficiently pure for use in the next step: MS (ES) m/e 188/190 (M+H)+.
Reaction SMILES: [N+](C1N=C2N(C=1)CC1(CCN([C:14](=[O:29])[CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22](OC(C)(C)C)=O)[CH2:18][CH2:17]3)CC1)O2)([O-])=O.FC(F)(F)C(O)=O.[F:40][C:41]([F:51])([F:50])[C:42]1[CH:49]=[CH:48][C:45](C=O)=[CH:44][CH:43]=1.[B-]C#N.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)(=O)C>[F:40][C:41]([F:51])([F:50])[C:42]1[CH:49]=[CH:48][C:45]([CH2:22][N:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH:14]=[O:29])[CH2:21][CH2:20]2)=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)N2CCC3(CC2)Cn2cc([N+](=O)[O-])nc2O3)CC1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [B-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: O=CCN1CCN(Cc2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 117.8 %

Procedure:
Tert-butyl 4-[2-(2,3-dihydro-6-nitrospiro[imidazo[2,1-b]oxazole-2,4′-piperidine]-1′-yl)-2-oxoethyl]piperazine-1-carboxylate prepared in Example 653 (300 mg, 0.67 mmol) was dissolved in methylene chloride (5 ml). To the solution, trifluoroacetic acid (10 ml) was added followed by stirring at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure. To the solution, methylene chloride (1 ml) and triethylamine (1 ml) were added followed by stirring at room temperature for 5 minutes. The solution was concentrated under reduced pressure and the residue was dissolved in methanol (10 ml). To the solution, 4-trifluoromethylbenzaldehyde (0.23 ml, 1.67 mmol), sodium cyanotrihydroborate (105 mg, 1.67 mmol) and acetic acid (0.1 ml) were added with cooling on ice-bath followed by stirring at room temperature overnight. To the solution, a saturated aqueous sodium hydrogencarbonate solution and methylene chloride were added followed by stirring. The organic phase was dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) and crystallized from methylene chloride-diisopropyl ether to afford 1-(2,3-dihydro-6-nitrospiro[imidazo[2,1-b]oxazole-2,4′-piperidin])-1′-yl)-2-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]ethanone (226 mg, yield 67%) as a white powder.
Reaction SMILES: [C:1]([C:5]([OH:23])([CH:9]([N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:6][C:7]#[CH:8])([CH3:4])([CH3:3])[CH3:2].[I:24]I.[OH-].[K+]>CO>[C:1]([C:5]([OH:23])([CH:9]([N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1)[CH2:6][C:7]#[C:8][I:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CCC(O)(C(Cc1ccc(Cl)cc1)n1cncn1)C(C)(C)C
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)C(O)(CC#CI)C(Cc1ccc(Cl)cc1)n1cncn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.9 %

Procedure:
9.9 g (0.03 mol) of 4-tert.-butyl-6-(4-chlorophenyl)-5-(1,2,4-triazol-1-yl)-hex-1-in-4-ol are dissolved in 100 ml of methanol, and 9.2 g (0.036 mol) of iodine are introduced into the ice-cooled solution at the same time as 14.5 ml of 50% strength potassium hydroxide solution are being added dropwise. The mixture is stirred for a further 4 hours at room temperature, and the crystalline precipitate is filtered off under suction, washed with water and dried. 10.7 g (78% of theory) of 4-tert.-butyl-6-(4-chlorophenyl)-1-iodo-5-(1,2,4-triazol-1-yl)-hex-1-in-4-ol of melting point 155° C. are obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:5]([CH:14]=[CH2:15])[CH:4]=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][C:28](O)=[O:29])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C.C(OP(C#N)(=O)OCC)C>CN(C=O)C>[C:16]([C:20]1[CH:21]=[CH:22][C:23]([CH:26]=[CH:27][C:28]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:5]([CH:14]=[CH2:15])[CH:4]=2)=[O:29])=[CH:24][CH:25]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(C=CC(=O)O)cc1
Reactant: C=Cc1cc(CN)ccc1NS(C)(=O)=O
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=Cc1cc(CNC(=O)C=Cc2ccc(C(C)(C)C)cc2)ccc1NS(C)(=O)=O
Reaction time: 12 h
Yield: 51 %

Procedure:
A dried 25 ml two-neck round bottom flask was filled with argon gas and the solution of N-(4-aminomethyl-2-vinyl-phenyl)-methanesulfonamide (51 mg, 0.23 mmol) and 3-(4-t-butyl-phenyl)-acrylic acid (1.2 eq, 0.27 mmol, 55.26 mg) in DMF was put into the flask. To the solution were added triethylamine (2 eq, 0.46 mmol, 64.12 mg) and diethylcyanophosphonate (1.2 eq, 0.27 mmol, 41.88 μl) and stirred for 12 hours. After confirming the completion of the reaction with TLC, the reaction solution was extracted with methylenechloride, washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained liquid was column-chromatographed (n-hexane/ethyl acetate=1/1) to yield a white solid (48.4 mg, 43.37%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)[N:12]=[CH:11][C:10]=1[N+:25]([O-])=O>CO.C1COCC1.[Ni]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:17]=2)[N:12]=[CH:11][C:10]=1[NH2:25]
Reactant: O=[N+]([O-])c1cnc2ccc(-c3ccccc3)cc2c1Nc1ccccc1Br
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cnc2ccc(-c3ccccc3)cc2c1Nc1ccccc1Br

Procedure:
The title compound is prepared in analogy to Example 19e by hydrogenation at 0° C. for 86 min starting from 0.697 g (1.502 mmol) of (2-bromo-phenyl)-(3-nitro-6-phenyl-quinolin-4-yl)-amine (Example 53e) and 0.25 g Raney-Ni in 25 ml methanol-THF 2:1. Purification follows by chromatography on silica gel (ethyl acetate-hexane 1:1). mp: 174-177° C.; MS: 390 (M++1); HPLC: tret=10.50 min (Grad 1).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5][CH2:4]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:2]([C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])[CH2:7][CH2:8]1)=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CO)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl [trans-4-(hydroxymethyl)cyclohexyl]carbamate (from Aldrich, 0.61 g, 2.7 mmol) in methylene chloride (10 mL) at 0° C. was added Dess-Martin periodinane (1.35 g, 3.19 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with aq. 1 N NaOH solution, extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over MgSO4, and concentrated. The residue was purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give the desired product (0.3 g, 50%). LCMS calculated for C12H21NO3Na (M+Na)+: m/z=250.2. Found: 250.1.