Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1>CN(C)C=O>[N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([N:1]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[CH:3]=[CH:2]2)=[CH:14][CH:15]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: Clc1ccnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cnc2c(c1)ccn2-c1ccnc2ccccc12
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 35.3 %

Procedure:
9 g (76.3 mmol) of 1H-pyrrolo[2,3-b]pyridine were added with stirring to 100 cm3 of dimethylformamide under an argon atmosphere at a temperature in the region of 20° C., and 2.7 g of 75% sodium hydride (84 mmol) were gradually added. After stirring at a temperature in the region of 20° C. for 10 minutes, a solution of 12.5 g (76.4 mmol) of 4-chloroquinoline in 100 cm3 of dimethylformamide was added and then the reaction mixture was heated at a temperature in the region of 100° C. for 15 h. After concentrating to dryness under reduced pressure (2.7 kPa), the residue was taken up in 300 cm3 of water. A first precipitate formed and then a second, which were filtered off. The 2 batches were combined and dissolved in 300 cm3 of dichloromethane. After separating by settling, the organic phase was dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue was purified by flash chromatography on a column of silica gel (0.04–0.06 mm), elution being carried out with a cyclohexane/ethyl acetate (50/50 by volume) mixture. The fractions comprising the expected product were combined and then concentrated to dryness under reduced pressure (2.7 kPa). 6.6 g of 1-(quinolin-4-yl)-1H-pyrrolo[2,3-b]pyridine were thus obtained in the form of a white solid. Mass spectrum: EI: m/z=245 M+; base peak m/z=244 (M−H)+.
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[CH:9]=[C:10]([NH:14][C:15](=[O:38])[NH:16][CH2:17][C:18]([N:20]2[CH:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:30][CH2:29][CH:21]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:19])[CH:11]=[CH:12][CH:13]=1)=[O:7])C>O.CO>[C:25]([O:24][C:22]([CH:21]1[CH2:29][CH2:30][CH:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:20]1[C:18](=[O:19])[CH2:17][NH:16][C:15](=[O:38])[NH:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[C:6]([OH:7])=[O:5])=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)c1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CCC2c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.6 %

Procedure:
0.9 g of potassium hydroxide dissolved in 60 cm3 of distilled water is added to a solution of 8 g of tert-butyl (2RS,5SR)-1-{2-[3-(3-ethoxycarbonylphenyl)ureido]acetyl}-5-phenylprolinate in 120 cm3 of methanol. The reaction mixture is stirred for 3 hours at a temperature in the vicinity of 25° C. then concentrated to 50 cm3 under reduced pressure. The solution obtained is diluted with 30 cm3 of water, washed with 2 times 50 cm3 of ethyl acetate, acidified to a pH of 2 with a 4N aqueous hydrochloric acid solution and extracted with 3 times 100 cm3 of dichloromethane. The organic phases are combined, washed with 2 times 50 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure at a temperature in the vicinity of 40° C. The crude product obtained is purified by chromatography on silica [eluent: dichloromethane/methanol (90/10 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure. After recrystallization in ethyl acetate, 4.5 g of (2RS,5SR)-3-{3-[2-(2-tert-butyoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoic acid, melting at 236° C., are obtained.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:42]1([CH2:48][CH2:49][O:50][C:51](=[O:72])[C@@:52]([CH2:70][OH:71])([CH3:69])[CH2:53][C@H:54]([NH2:68])[CH2:55][C:56]2[CH:61]=[CH:60][C:59]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[CH:58][CH:57]=2)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>CN(C=O)C>[N:42]1([CH2:48][CH2:49][O:50][C:51](=[O:72])[C@@:52]([CH2:70][OH:71])([CH3:69])[CH2:53][C@H:54]([NH:68][C:6]([C:4]2[NH:3][N:2]=[N:1][CH:5]=2)=[O:8])[CH2:55][C:56]2[CH:57]=[CH:58][C:59]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[CH:60][CH:61]=2)[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)OCCN1CCCCC1
Reactant: O=C(O)c1c[nH]nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1)C(=O)OCCN1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 31.8 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (0.0274 g, 0.242 mmol), DIPEA (169 μL, 969 μmol) and HATU (92 mg, 242 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid 2-piperidin-1-yl-ethyl ester (103 mg, 242 μmol), predissolved in DMF (0.2 mL) and DIPEA (0.5 eq.). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product was purified by preparative HPLC and lyophilized to yield the title compound (40 mg; purity 95%). MS m/z [M+H]+ calc'd for C29H37N5O4, 520.28. found 520.4.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[N+:15]([C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:29])[C:26](O)=[O:27])[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16]>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:26](=[O:27])[C:25]([NH:24][C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=3)=[O:29])[CH2:11][CH2:12]2)=[CH:13][CH:14]=1
Reactant: O=C(O)C(=O)Nc1cccc([N+](=O)[O-])c1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Solvent: CCOCC
Product: O=C(Nc1cccc([N+](=O)[O-])c1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from 4-(4-fluoro-benzyl)-piperidine and N-(3-nitro-phenyl)-oxalamic acid (Example 10a according to the method described in Example 2. Melting Point: 135-138° C. (diethylether)
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]3C(=O)C4=CC=CC=C4C3=O)=[C:18]([C:31](=[O:34])[CH2:32][Cl:33])[N:17]=[CH:16]2)[C@@H:6]1[Cl:35])(=[O:3])[CH3:2].O.NN>ClCCl>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([NH2:20])=[C:18]([C:31](=[O:34])[CH2:32][Cl:33])[N:17]=[CH:16]2)[C@@H:6]1[Cl:35])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)CCl)c2N2C(=O)c3ccccc3C2=O)[C@H](Cl)[C@@H]1OC(C)=O
Agent: NN
Solvent: O
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)CCl)c2N)[C@H](Cl)[C@@H]1OC(C)=O

Procedure:
Compound (38) obtained in step (4) above (310 mg) was dissolved in dichloromethane (12 ml), to which was then added hydrazine monohydrate (0.032 ml) under cooling at 0° C. The resultant mixture was stirred at that temperature for 1 hour to conduct the reaction intended and thereby afford the titled compound (39). The resulting reaction solution containing compound (39) was filtered and the filtrate was concentrated to leave a solid, which was purified by silica gel column chromatography (developer solvent: toluene-ethyl acetate, 1:2), to yield the titled compound (39) as a colorless solid (221 mg). Yield: 95%.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]1[CH:49]=[C:50]([CH:54]=[CH:55][CH:56]=1)[CH2:51][CH2:52][NH2:53]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:53][CH2:52][CH2:51][C:50]4[CH:54]=[CH:55][CH:56]=[C:48]([F:47])[CH:49]=4)=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: NCCc1cccc(F)c1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCCc2cccc(F)c2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 3-fluorophenethyl-amine (Aldrich) to give the title product. LC-MS (ES+) 786 [(M+H)+].
Reaction SMILES: [N:1]([CH:4]([C:14]1[C:15]([O:25][CH2:26][CH3:27])=[C:16]([C:22](=[O:24])[CH3:23])[CH:17]=[C:18]([Cl:21])[C:19]=1[F:20])[CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.[Cl-].[Na+].O>[NH2:1][CH:4]([C:14]1[C:15]([O:25][CH2:26][CH3:27])=[C:16]([C:22](=[O:24])[CH3:23])[CH:17]=[C:18]([Cl:21])[C:19]=1[F:20])[CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CCOc1c(C(C)=O)cc(Cl)c(F)c1C(CO[Si](C)(C)C(C)(C)C)N=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOc1c(C(C)=O)cc(Cl)c(F)c1C(N)CO[Si](C)(C)C(C)(C)C
Temperature: 60 °C
Yield: 99.7 %

Procedure:
1-[3-(1-Azido-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-chloro-2-ethoxy-4-fluorophenyl]ethanone (750 mg, 1.8 mmol) (from Step 5) was stirred in tetrahydrofuran (10 mL) with water (0.33 mL) and triphenylphosphine was added. The mixture was heated to 60° C. for 2 hours and cooled to rt. Brine was added and the mixture was extracted with ethyl acetate. The extracts were dried over sodium sulfate, filtered and evaporated to give the desired compound 700 mg, 100%. LCMS calculated for C18H30ClFNO3Si (M+H)+: m/z=390.2; found: 390.2.
Reaction SMILES: [C:1]([CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])#[N:2]>C1(C)C=CC=CC=1.[Pd]>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])#[N:2]
Reactant: N#CC=CCCCCCC(=O)O
Agent: [Pd]
Solvent: Cc1ccccc1
Product: N#CCCCCCCCC(=O)O

Procedure:
167 g of 8-cyano-7-octenoic acid dissolved in 800 ml of toluene are hydrogenated selectively at 2 bar in an autoclave in the presence of 10 g of Pd on charcoal at 5% at 50° C. for 5 hours. After filtration of the catalyst and evaporation of the solvent, 165 g of an oil that distills at 150° C. at 0.05 torr are recovered. The product has been identified as 8-cyanooctanoic acid by I.R. (film) analysis techniques: 3400, 3000, 2950, 2875, 2260, 1710, 1430 cm-1 and mass spectrometry by electron-impact ionization (70 eV): 170, 152, 140, 123, 110, 94, 83, 69, 55, 41. Analytically calculated values for C9H15NO2 (169.22): C 63.88%, H 8.93%, N 8.28%. Found: C 63.76%, H 9.12%, N 8.37%.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.[CH3:59][O:60][C:61](=[O:83])[CH:62]=[CH:63][CH:64]([NH2:82])[CH2:65][C:66]1[C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[N:68]([CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[CH:67]=1>C1COCC1>[CH3:59][O:60][C:61](=[O:83])[CH:62]=[CH:63][C@H:64]([NH:82][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:65][C:66]1[C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[N:68]([CH2:75][C:76]2[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=2)[CH:67]=1
Reactant: COC(=O)C=CC(N)Cc1cn(Cc2ccccc2)c2ccccc12
Reactant: O=C(O)CCCCCCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C=C[C@@H](Cc1cn(Cc2ccccc2)c2ccccc12)NC(=O)CCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
A solution of 7-phenylheptanoic acid (92 mg, 0.447 mmol), BOP (217 mg, 0.491 mmol) and DIPEA (69 mg, 93 μL, 0.535 mmol) in THF (2.5 mL) was stirred for 10 min. To this was added a solution of the trifluoroacetic acid salt of 4-amino-5-(1-benzyl-1H-indol-3-yl)-pent-2-enoic acid methyl ester (200 mg, 0.446 mmol) and DIPEA (173 mg, 233 μL, 1.34 mmol) in THF (2.5 mL). The mixture was stirred overnight at room temperature. The solvent was removed and the crude material subject to column chromatography (50% EtOAc/petroleum ether, Rf 0.66) to afford the title compound (197 mg, 85%). 1H NMR (CDCl3) δ 7.59 (1H, d, J=7.26 Hz), 6.94-7.28 (15H, m), 5.81 (1H, d, J=15.81 Hz), 5.48 (1H, d, J=8.34 Hz), 3.59 (2H, s), 5.05 (1H, m), 3.12 (1H, dd, J=6.42, 14.49 Hz), 3.04 (1H, dd, J=5.85, 14.49 Hz), 2.57 (2H, t, J=7.64 Hz), 2.07 (2H, t, J=7.67 Hz), 1.9-1.2 (8H, m). 13C NMR (CDCl3) δ 172.5, 166.5, 148.1, 142.6, 137.3, 136.6, 128.7, 128.4, 128.3, 128.2, 127.6, 126.9, 126.7, 125.6, 122.1, 120.8, 119.6, 118.8, 109.9, 109.4. 51.6, 49.9, 50.2, 36.7, 35.8, 31.2, 29.9, 29.0, 28.9, 25.4. ISMS: 523 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH:9]([O:11][CH2:12][CH3:13])[CH3:10])[C:6](=[S:14])[NH:5][C:4](=[O:15])[CH:3]=1.[N:16]([O-])=[O:17].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[N:7]([CH2:8][CH:9]([O:11][CH2:12][CH3:13])[CH3:10])[C:6](=[S:14])[NH:5][C:4](=[O:15])[C:3]=1[N:16]=[O:17]
Reactant: CCOC(C)Cn1c(N)cc(=O)[nH]c1=S
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(C)Cn1c(N)c(N=O)c(=O)[nH]c1=S
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 84.7 %

Procedure:
6-Amino-1-(2-ethoxy-propyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (1.1 g, 4.8 mmol) obtained from Example 5b was suspended in 10% acetic acid (20 mL) and the mixture was stirred for 15 minutes. Sodium nitrite (0.36 g, 5.3 mmol) was added and the resulting mixture was heated at 75° C. for 1 h. The reaction mixture turned pink and then purple. The mixture was cooled to room temperature, and the purple solid was collected by filtration and washed with water to give the title compound (1.05 g, 70% yield). This solid was used in Example 5(d) without further purification.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:15]=1[NH:16][C:17]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:18]=1[C:19]([OH:21])=O.Cl.[CH2:35]([O:42][NH2:43])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C>>[F:13][C:14]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:15]=1[NH:16][C:17]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:18]=1[C:19]([NH:43][O:42][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:21]
Reactant: NOCc1ccccc1
Reactant: O=C(O)c1cc(F)c(F)cc1Nc1cc(F)c(F)cc1F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Product: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1cc(F)c(F)cc1F
Yield: 103.6 %

Procedure:
Using General Method 2, the reaction of carbonyldiimidazole (2.85 g, 17.6 mmol), 2-(2,4,5-trifluoro-anilino)-4,5-difluorobenzoic acid (Example T, 4.54 g, 14.7 mmol), O-benzylhydroxylamine hydrochloride (2.34 g, 14.7 mmol), and triethylamine (2.45 mL, 17.6 mmol) provided 6.22 g of the crude title compound.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[CH:11][C:10]=2[F:25])=[C:5]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[S:4][N:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][C:10]=2[F:25])=[C:5]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[S:4][N:3]=1
Reactant: CC(C)(C)OC(=O)CCc1cc(F)c(OCc2c(Cl)nsc2-c2ccc(Cl)cc2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCc1cc(F)c(OCc2c(Cl)nsc2-c2ccc(Cl)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed tert-butyl 3-(4-[[3-chloro-5-(4-chlorophenyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl)propanoate (50 mg, 0.09 mmol, 1.00 equiv, 90%), CF3COOH (0.4 mL), dichloromethane (2 mL). The resulting solution was stirred overnight at 25° C. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with 2×5 mL of methanol. The solids were collected by filtration. This resulted in 3.8 mg (9%) of 3-(4-[[3-chloro-5-(4-chlorophenyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl)propanoic acid as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.56 (s, 4H), 6.84 (d, J=9.3 Hz, 2H), 5.09 (s, 2H), 2.88 (t, J=7.2 Hz, 2H), 2.61 (t, J=7.5 Hz, 2H). Mass spectrum (ESI, m/z): Calcd. for C19H13C12F2NO3S, 444.0 (M+H). found 444.0.
Reaction SMILES: [CH3:1][NH:2][S:3](=[O:24])([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[C:7]([N+:21]([O-:23])=[O:22])[CH:6]=1)=[O:4].Cl[C:26]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC>[CH2:29]([O:28][C:26]([N:2]([CH3:1])[S:3](=[O:24])([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[C:7]([N+:21]([O-:23])=[O:22])[CH:6]=1)=[O:4])=[O:27])[CH2:30][CH2:31][CH3:32]
Reactant: CCCN(CCC)c1c([N+](=O)[O-])cc(S(=O)(=O)NC)cc1[N+](=O)[O-]
Reactant: CCCCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCCCOC(=O)N(C)S(=O)(=O)c1cc([N+](=O)[O-])c(N(CCC)CCC)c([N+](=O)[O-])c1

Procedure:
A mixture of 4.5 g (0.0125 mol) N1 -methyl-3,5-dinitro-N4,N4 -dipropylsulfanilamide, 3.4 g (0.025 mol) n-butyl chloroformate, 3.5 g (0.25 mol) potassium carbonate and 50 ml dimethoxyethane was reacted to produce N1 -butoxycarbonyl-N1 -methyl-3,5-dinitro-N4,N4 -dipropylsulfanilamide by a procedure similar to that of Example 4. The product was a yellow-orange solid having a melting point of 99°-101°C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[OH-].[Na+].C([O-])=O.[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.[Pd].O>[N:5]1[CH:6]=[CH:7][C:2]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[CH:3][CH:4]=1
Reactant: Clc1ccncc1
Agent: [Pd]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C[O-]
Solvent: O
Product: c1cc(-c2ccncc2)ccn1
Reaction time: 24 h
Yield: 46.2 %

Procedure:
4-Chloropyridine (11.35 parts), benzyltriethylammonium chloride (2.0 parts), sodium hydroxide liquor (32%; 13.5 parts), 3% palladium on charcoal (50% paste; 2.0 parts) and sodium formate (10.2 parts in water (30 parts) are stirred at the boil under reflux for 4 hours. Sodium formate (3.4 parts) is added and then the mixture held at the boil for a further 24 hours. The reaction mixture is cooled and then filtered. The residue is extracted continuously with hot methanol (100 parts) for 6 hours. The extract when evaporated to dryness gives 3.6 parts (46.2%) of 4,4'-bipyridyl.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][CH2:8][Cl:9])[N:5]=[C:4]([CH3:10])[CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[Cl:1][C:2]1[N:6]([CH2:7][CH2:8][Cl:9])[N:5]=[C:4]([CH3:10])[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1cc(Cl)n(CCCl)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1nn(CCCl)c(Cl)c1[N+](=O)[O-]
Reaction time: 0.67 h

Procedure:
3.6 g (0.02 mole) of 5-chloro-1(beta-chloroethyl)-3-methylpyrazole was added slowly to 10 ml of concentrated sulfuric acid with swirling. Thereafter 5 ml of fuming nitric acid was then added slowly also with swirling. During the addition, the mixture became quite warm. It was allowed to stand at room temperature for 40 minutes and then poured onto ice. A white solid was formed and was filtered off, washed well with water and dried in vacuo at 56°C.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:15]([C:16](OC)=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[OH:17][CH2:16][C:15]1[C:9]2[O:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:11][C:10]=2[CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)c1cccc2nc(-c3ccccc3)oc12
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: OCc1cccc2nc(-c3ccccc3)oc12

Procedure:
10 mmol of the compound from Example XV were dissolved in 50 ml of toluene, then 40 ml of DIBAH*(20% strength in toluene) were added at 0° C. and the mixture
Reaction SMILES: [Si:1]([O:18][C@H:19]([CH3:39])[CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1([CH3:38])[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Si:1]([O:18][C@H:19]([CH3:39])[CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1([CH3:38])[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[C@H](CCCCOC1(C)CCN(C(=O)OC(C)(C)C)CC1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](CCCCOC1(C)CCNCC1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
A mixture of (R)-tert-butyl 4-((5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidine-1-carboxylate (8.2 g, 14.81 mmol) and 4M HCl (22.21 mL, 89 mmol) in dioxane in 1,4-Dioxane (5 mL) was stirred at room temp for 2 h. Mixture was then concentrated, diluted with ethyl acetate (100 mL), washed with 1N NaOH, dried (Na2SO4), filtered and concentrated to afford (R)-4-((5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidine (6.35 g, 14.00 mmol, 95% yield) as viscous oil. 1H NMR (500 MHz, CDCl3) δ 7.72-7.65 (m, 4H), 7.47-7.34 (m, 6H), 3.87 (sxt, J=5.9 Hz, 1H), 3.24 (t, J=6.4 Hz, 2H), 2.94-2.86 (m, 2H), 2.77-2.69 (m, 2H), 1.74-1.68 (m, 4H), 1.48-1.32 (m, 6H), 1.14 (s, 3H), 1.10-1.05 (m, 12H). LCMS (M+H)=454.2.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:6]=1[C:16]([F:19])([F:18])[F:17])=[O:4].[BH4-].[Na+].[OH-].[K+]>O1CCOCC1.O>[O:4]1[CH2:2][CH:3]1[C:5]1[CH:10]=[CH:9][C:8]([O:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:6]=1[C:16]([F:19])([F:18])[F:17]
Reactant: CS(=O)(=O)Oc1ccc(C(=O)CBr)c(C(F)(F)F)c1
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)Oc1ccc(C2CO2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93.4 %

Procedure:
To a solution of methanesulfonic acid 4-(2-bromo-acetyl)-3-trifluoromethyl-phenyl ester (33.95 g; 89.3 mmol) in 1,4-dioxane (150 mL) was added dropwise a solution of NaBH4 (2.37 g; 62.5 mmol) in water (47 mL). The resulting mixture was stirred at RT for 2.5 hours, subsequently, quenched with 0.5M aqueous HCl (125 mL), and extracted with EtOAc. The combined organic layers were washed with water, dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in Et2O (500 mL) and treated with a solution of KOH (4.19 g; 74.7 mmol) in water (100 mL). The resulting mixture was heated under reflux for 4 hours. After cooling to RT, the volatiles were removed in vacuo and the residue was partitioned between EtOAc and water. The organic layer was washed with water, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (CH2Cl2) to afford methanesulfonic acid 4-oxiranyl-3-trifluoromethyl-phenyl ester (23.54 g).