Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[OH-:9].[Na+]>>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]([NH2:2])=[O:9]
Reactant: N#Cc1ccccn1
Reactant: [OH-]
Agent: [Na+]
Product: NC(=O)c1ccccn1

Procedure:
As to preparative methods for these compounds, cyanopyridines have frequently been hydrolyzed in batch and continuous processes with catalytic to stoichiometric excesses of a base. A majority of the methods reported have been batch processes. For example, 4-cyanopyridine in the presence of sodium hydroxide at a molar ratio of 1:(0.03-0.075) and at 120°-170° C. is reported to give isonicotinamide. See U.S.S.R. SU 1,553,531 (1990); CA:113:78174f (1990). Similarly, 2-cyanopyridine is reported to react with sodium hydroxide at a molar ratio of 1:(0.03-0.20) and at temperatures ranging from 100°-130° C. to give 2-picolinamide. See U.S.S.R. SU 1,553,530 (1990); CA:113:78173e (1990). With a molar ratio of 4-cyanopyridine:sodium hydroxide of 1:(1.5-1.75) and a hydrolysis temperature of 50°-80° C., the reported hydrolysis product was isonicotinic acid. See U.S.S.R. SU 1,288,183; CA:106:176187n (1987). The hydrolysis of 3-cyanopyridine with excess ammonia at 107°-109° C. for 12 hours was reported to give mixtures of nicotinamide and niacin. See J. Am Chem. Soc. 65, at pages 2256-7 (1943). In still another variation, the hydrolysis of 3-cyanopyridine has been reported with a polymeric base, Dowex 1X4 (in the hydroxide form), to yield nicotinamide. See Dutch Patent Application No. 7706612-A; CA:90:186814e. U.S. Pat. No. 4,314,064 describes the continuous hydrolysis of 3-cyanopyridine with 0.3 to 3.0 moles of an alkali metal hydroxide for each 100 moles of cyanopyridine at pressures of between 3 to 20 bars and with heating or cooling to maintain the prescribed reaction temperature. Similarly, 3-cyanopyridine is reported to react in a continuous process with aqueous ammonia at a molar ratio of 1:0.5 and a contact time of 40-50 minutes at 200°-260° C. to give nicotinamide. See Journal of Applied Chemistry of the USSR (English Translation: 45:2716-2718 (1972).
Reaction SMILES: [Br-:1].[CH:2]1([C:8]([OH:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]([O:11][CH2:12]C2CCC[N+]2(C(C2C=CON=2)C(=O)N)C)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Br-].OC[C@H]1CCC[N+]1(CC(=O)NC1C=CON=1)C.[Br-].OC1[CH2:60][CH2:59][N+:58]([CH3:71])([CH2:61][C:62](=[O:70])[NH:63][C:64]2[CH:69]=[N:68][CH:67]=[CH:66][N:65]=2)[CH2:57][CH2:56]1>>[Br-:1].[CH:2]1([C:8]([OH:34])([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:9]([O:11][CH:12]2[CH2:56][CH2:57][N+:58]([CH3:71])([CH2:61][C:62](=[O:70])[NH:63][C:64]3[CH:69]=[N:68][CH:67]=[CH:66][N:65]=3)[CH2:59][CH2:60]2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C[N+]1(C(C(N)=O)c2ccon2)CCCC1COC(=O)C(O)(c1ccccc1)C1CCCCC1
Reactant: C[N+]1(CC(=O)Nc2cnccn2)CCC(O)CC1
Agent: C[N+]1(CC(=O)Nc2ccon2)CCC[C@@H]1CO
Agent: [Br-]
Product: C[N+]1(CC(=O)Nc2cnccn2)CCC(OC(=O)C(O)(c2ccccc2)C2CCCCC2)CC1

Procedure:
This compound is prepared by an analogous method to (1R/S,2R)-2-((R/S)-(2-Cyclohexyl-2-hydroxy-2-phenyl-acetoxymethyl)-1-(isoxazol-3-yl carbamoylmethyl)-1-methyl-pyrrolidinium bromide (Example 1) by replacing (1R/S,2R)-2-hydroxymethyl-1-(isoxazol-3-ylcarbamoyl-methyl)-1-methyl-pyrrolidinium bromide (Intermediate B) with 4-hydroxy-1-methyl-1-(pyrazin-2-ylcarbamoylmethyl)-piperidinium bromide (Intermediate H).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[O:6]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[O:6]([C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClCC1CO1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: OC(CCl)COc1ccc(Oc2ccccc2)cc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A four-neck flask equipped with a thermometer, dropping funnel, condenser tube and stirrer was charged with 305.3 g (3.3 mol) of epichlorohydrin, and while nitrogen purging was performed, the temperature was raised to 70° C. Into the flask, 204.8 g (1.1 mol) of 4-phenoxyphenol dissolved in 1020 g of ethanol was added dropwise taking 4 hours. Further, stirring was performed for 6 hours, to complete the addition reaction, for obtaining 4-phenoxy-O-(2-hydroxy-3-chloropropyl)phenol. In succession, the temperature in the flask was lowered to 25° C., and into the flask, 229 g (2.75 mol) of 48% NaOH aqueous solution was added dropwise taking 2 hours. Further, stirring was performed for 1 hour. After completion of cyclization reaction, ethanol was distilled away, and 410 g of toluene was used for extraction, 5% saline solution being used for washing twice. Toluene and epichlorohydrin were removed from the organic layer under reduced pressure, to obtain 215.6 g of a viscous liquid (yield 89%). The purity of 4-phenoxyphenyl glycidyl ether as the main product was 92% (GCarea %).
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:39]=[CH:38][C:23]([CH2:24][CH:25]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])=[CH:22][CH:21]=1.C(=O)(O)[O-].[Na+]>Cl.CN1C(=O)CCC1.O>[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:24][CH:25]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[C:32]([O:34][CH:35]([CH3:36])[CH3:37])=[O:33])=[CH:38][CH:39]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: CC(C)OC(=O)C(Cc1ccc(N)cc1)C(=O)OC(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)OC(=O)C(Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1)C(=O)OC(C)C
Temperature: 140 °C
Yield: 38.4 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.070 g, 0.23 mmol), diisopropyl 2-(4-aminobenzyl)malonate (0.136 g, 0.47 mmol) and conc. HCl (1 drop) in NMP (3 mL). The resulting mixture was heated at 140° C. under microwave irradiation for 2 h. After this time, the reaction mixture was cooled, diluted with water (15 mL), and then treated with saturated sodium bicarbonate until pH˜8. The resulting solid was isolated by filtration and purified by preparative HPLC (water/acetonitrile with 0.05% TFA) followed by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent to afford diisopropyl 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)benzyl)malonate (0.046 g, 38%) as an off-white solid. MW=521.05. 1H NMR (DMSO-d6, 500 MHz) δ 8.14 (s, 1H), 7.86 (s, 7.89-7.84 (m, 1H), 7.46-7.38 (m, 2H), 7.25-7.12 (m, 5H), 4.94-4.84 (m, 2H), 3.78-3.72 (m, 1H), 3.04 (d, J=7.5 Hz, 2H), 2.93-2.87 (m, 2H), 2.85-2.77 (m, 2H), 2.12-2.03 (m, 2H), 1.15 (d, J=5.5 Hz, 6H), 1.11 (d, J=5.5 Hz, 6H). MS: ESI, m/z 521 [M+H]+. Treatment with 1.25M HCl in methanol (0.11 mL, 0.13 mmol, 1.5 eq.) afforded the title compound (0.043 g, 88%) as an off-white solid. MW=557.51. M.p. 68-70° C. 1H NMR (DMSO-d6, 500 MHz) δ 13.93 (br s, 1H), 7.86-7.84 (m, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.62-7.50 (m, 2H), 7.34-7.24 (m, 4H), 6.97 (s, 1H), 4.88 (sept, J=6.0 Hz, 2H), 3.79 (t, J=7.5 Hz, 1H), 3.12-3.03 (m, 4H), 2.87 (t, J=7.5 Hz, 2H), 2.23-2.15 (m, 2H), 1.14 (d, J=5.0 Hz, 6H), 1.09 (d, J=5.5 Hz, 6H); ESI MS m/z 451 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:45][C:46]([N:48]1[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]1)=[O:47].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[ClH:1].[CH3:54][N:51]1[CH2:52][CH2:53][N:48]([C:46](=[O:47])[CH2:45][O:36][C:35](=[O:37])[C:34]2[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:42])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]3)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=2)[CH2:49][CH2:50]1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CN1CCN(C(=O)CCl)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)OCC(=O)N2CCN(C)CC2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 154.1 %

Procedure:
In a 15 mL pressure tube, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1, 100 mg, 162 μmol), 2-chloro-1-(4-methylpiperazin-1-yl)ethanone, hydrochloride (34.6 mg, 162 μmol) and cesium carbonate (111 mg, 341 μmol) were combined with dry dimethyl formamide (2 mL) to give a white suspension. The tube was capped and heated at 50° C. with stirring. After 1.5 h, the reaction mixture was cooled down to room temperature. It was poured into water and extracted with methylene chloride (2×). The methylene chloride layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (24 g pre-packed silica gel column, eluted with methanol in methylene chloride) to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl ester, hydrochloride as an off-white solid (99 mg, 81% yield). The product was mixed with acetonitrile (2 mL) to form a suspension. A few drops of 1N aqueous hydrochloric acid were added to the mixture. The suspension became clear solution. It was frozen and lyophilized to give an off-white solid as hydrochloride salt. LCMS (ES+) m/z calcd. for C38H42Cl2F2N5O5 [(M+H)+]: 756. found: 756.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[N:12][CH:13]=2)=[CH:4][C:3]=1[N+:14]([O-])=O>O1CCCC1.CO.[Pd]>[NH2:14][C:3]1[CH:4]=[C:5]([C:8]2[CH:13]=[N:12][CH:11]=[N:10][CH:9]=2)[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(-c2cncnc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2cncnc2)cc1N
Yield: 184.6 %

Procedure:
A suspension of 5-(4-methyl-3-nitrophenyl)-pyrimidine (258 mg) in tetrahydrofuran (5ml) and methanol (5 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 130 mg) under hydrogen atmosphere for 4 hours. The catalyst was filtered off and the filtrate was evaporated to give 5-(3-amino4-methylphenyl)pyrimidine(410 mg, 96.5%).
Reaction SMILES: C(OC[N:9]1[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][C:17]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:37])/[CH:27]=[CH:28]/[C:29]3[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([Cl:36])[CH:30]=3)[CH2:22][CH2:21]2)=[O:18])[N:11]=[N:10]1)(=O)C(C)(C)C.[OH-].[Na+].Cl>CO>[Cl:35][C:33]1[CH:34]=[C:29](/[CH:28]=[CH:27]/[C:26]([N:23]2[CH2:22][CH2:21][CH:20]([NH:19][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][C:12]3[N:11]=[N:10][NH:9][CH:13]=3)[CH2:25][CH2:24]2)=[O:37])[CH:30]=[C:31]([Cl:36])[CH:32]=1
Reactant: CC(C)(C)C(=O)OCn1cc(CCCC(=O)NC2CCN(C(=O)/C=C/c3cc(Cl)cc(Cl)c3)CC2)nn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(CCCc1c[nH]nn1)NC1CCN(C(=O)/C=C/c2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of (E)-(4-(4-((1-(3-(3,5-dichlorophenyl)acryloyl)piperidin-4-yl)amino)-4-oxobutyl)-1H-1,2,3-triazol-1-yl)methyl pivalate (284 mg, 0.516 mmol) in MeOH (1 mL) was added 1M NaOH (1.135 mL, 1.135 mmol) and the mixture allowed to stir at RT for 1.5 hrs. An equivalent of 1M HCl (1.1 ml) was added to neutralise the reaction mixture and the MeOH was removed under reduced pressure. The reaction mixture was diluted with EtOAc and washed with water. The organic portion was dried over MgSO4, filtered and concentrated under reduced pressure. Purification was carried out by chromatography on silica using 0-10% MeOH in DCM to afford the title product;
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.Cl[C:18]1[N:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26]>>[CH3:24][C:22]1[N:23]=[C:18]([N:14]2[CH2:13][CH2:12][C:11](=[CH:10][C:9]#[C:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=3)[CH2:16][CH2:15]2)[C:19]([N+:25]([O-:27])=[O:26])=[CH:20][CH:21]=1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)n1
Product: Cc1cccc(C#CC=C2CCN(c3nc(C)ccc3[N+](=O)[O-])CC2)n1
Yield: 54.8 %

Procedure:
A well homogenised mixture of the Compound of Example 3 (23 mg, 0.11 mmol) and 6-chloro-5-nitro-2-picoline (26.2 mg, 0.15 mmol) was stirred at 120° C. for 0.5 h. The reaction crude was purified by flash chromatography (EtOAc—Petroleum Ether gradient from 3:7 to 4:6) affording the title product (21 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[N:18]=2)[CH:12]=1)[S:6]([CH3:9])(=[O:8])=[O:7].[C:33](O)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[OH:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][NH:23][C:19]2[N:18]=[C:17]([C:13]3[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=3)[CH2:10][N:5]([S:6]([CH3:9])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2][NH:1][C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:22]=[CH:21][N:20]=2)=[CH:31][CH:30]=1
Reactant: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Reactant: O=C(O)c1ccccc1
Product: CS(=O)(=O)N(CCCNC(=O)c1ccccc1)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Compound 2 was coupled with benzoic acid by procedure K. LC-MS showed the product had the expected M+H+ of 560. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.35 ppm) 8.5 (d, 1H) 8.2 (d, 1H) 8.1 (s, 1H) 8.0 (d, 2H) 7.6 (d, 2H), 7.4 (m, 5H), 7.1 (m, 2H), 6.7 (d, 2H), 4.4 (s, 2H), 3.6 (t, 2H), 3.23 (d, 2H), 2.9 (s, 3H), 2.8 (t, 2H), 1.8 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@:6]1([C:14](=[O:15])[NH:13][C:12](=[O:16])[N:11]1[CH3:17])[CH2:5]2.[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:3]([Br:18])=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@:6]1([C:14](=[O:15])[NH:13][C:12](=[O:16])[N:11]1[CH3:17])[CH2:5]2
Reactant: CN1C(=O)NC(=O)[C@]12Cc1ccc(N)cc1C2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CN1C(=O)NC(=O)[C@]12Cc1ccc(N)c(Br)c1C2
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
(R)-5′-Amino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione (580 mg, 2.51 mmol, described in Intermediate 8) was suspended in CHCl3 (250 mL) and N-bromosuccinimide (335 mg, 1.88 mmol) was added in one portion. The resulting mixture was stirred at ambient temperature for 40 min, then washed with dilute aqueous NaHCO3 (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 0:100, to give (R)-5′-amino-4′-bromo-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione, which eluted first, and the title compound, which eluted second. MS: m/z=353 (M+1+CH3CN).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:18]([F:21])([F:20])[F:19])=[C:15]([CH:17]=3)[NH2:16])[N:10]=2)[CH:7]=1.C(#N)C.[CH3:25][C:26]([CH3:31])([CH3:30])[C:27](Cl)=[O:28]>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:18]([F:20])([F:19])[F:21])=[C:15]([NH:16][C:27](=[O:28])[C:26]([CH3:31])([CH3:30])[CH3:25])[CH:17]=3)[N:10]=2)[CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cc(-c2cn3cc(Cl)ncc3n2)ccc1C(F)(F)F
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1cc(-c2cn3cc(Cl)ncc3n2)ccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 24.8 %

Procedure:
A 20 mL vial is charged with 5-(6-chloroimidazo[1,2-a]pyrazin-2-yl)-2-(trifluoromethyl)aniline (0.813 g, 2.6 mmol), acetonitrile (14 mL) and pyridine (0.420 mL). The mixture is added trimethylacetyl chloride (0.640 mL, 5.2 mmol) and stirred for 20 min at 80° C. The acetonitrile solution is concentrated onto celite and purified by silica gel chromatography (0-100% EtOAc in Hexanes) to give the title compound (256 mg, 25% yield). LCMS m/z=397.5 [M+H]+, tR=2.62 min. (compound same as Example 85)
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([N:21]([CH3:23])[CH3:22])=[CH:13][CH:12]=1)=[O:10].Cl.[NH2:26][OH:27].C[O-].[Na+]>CO>[CH3:22][N:21]([CH3:23])[C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([C:9]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([NH:26][OH:27])=[O:2])=[O:10])=[CH:12][CH:13]=1
Reactant: NO
Reactant: COC(=O)CCCCNC(=O)c1ccc(N(C)C)c2ccccc12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN(C)c1ccc(C(=O)NCCCCC(=O)NO)c2ccccc12
Reaction time: 0.5 h
Yield: 19.4 %

Procedure:
(Method J9B) To the solution of 5-[[[4-(dimethylamino)-1-naphthalenyl]carbonyl]amino]-pentanoic acid methyl ester (3/62) (0.31 g, 0.94 mmol) and hydroxylamine hydrochloride (0.26 g, 3.8 mmol) in absolute methanol was added NaOMe solution made by dissolving Na (0.18 g, 8 mmol) in absolute methanol. A white precipitate immediately appeared. After 0.5 h the reaction was complete (TLC), and the reaction mixture was evaporated, suspended in 1M phosphate buffer (pH 4), and extracted with 3 portions of methylene chloride. The organic phase became turbid, therefore the solvent was removed, and the residue was dried under reduced pressure yielding the crude product (0.27 g). Recrystallisation from acetonitrile gave the title product (0.06 g, 19%) of acceptable purity. Rf 0.50 (CHCl3-MeOH 4:1). M.p. 129° C. 1H NMR (DMSO-d6, TMS) δ: 1.53-1.57 (4H, m), 1.97-2.01 (2H, m), 2.84 (6H, s), 3.32-3.33 (m, overlapped with a signal from DMSO), 7.08 (1H, d, J=8.2 Hz), 7.46-7.56 (3H, m), 8.14-8.24 (2H, m), 8.39 (1H, br t, J=5.2 Hz), 8.69 (1H, br s), 10.37 (1H, br s). HPLC analysis on Symmetry 18 column: impurities <1% (column size 3.9×150 mm; mobile phase acetonitrile−0.1M phosphate buffer (pH 2.5), 10:90; detector UV 220 nm; flow rate 1.3 ml/min). Anal. Calcd for C18H23N3O3: C, 65.63; H, 7.04; N, 12.76. Found: C, 65.50; H, 6.90; N, 12.73.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH2:36][CH3:37])=[C:19]([CH2:23][CH:24]4[CH2:29][CH2:28][N:27]([CH2:30][C:31]([O:33]CC)=[O:32])[CH2:26][CH2:25]4)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH2:36][CH3:37])=[C:19]([CH2:23][CH:24]4[CH2:25][CH2:26][N:27]([CH2:30][C:31]([OH:33])=[O:32])[CH2:28][CH2:29]4)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CN1CCC(Cc2cccc(-c3nsc(-c4ccc(OC(C)C)c(Cl)c4)n3)c2CC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCc1c(CC2CCN(CC(=O)O)CC2)cccc1-c1nsc(-c2ccc(OC(C)C)c(Cl)c2)n1
Temperature: 90 °C
Yield: 77.5 %

Procedure:
To a solution of ethyl (4-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]methyl}-1-piperidinyl)acetate (D145) (80 mg, 0.148 mmol) in Isopropanol (6 mL) and Water (6.00 mL) was added NaOH (1.476 mL, 0.738 mmol). The reaction solution was heated to 90° C. for 2 hours. The solvent was removed in vacuo and the residue was acidified to pH=3-4, extracted with ethyl acetate. The combined organic phases were dried, concentrated and purified by Mass Directed AutoPrep to afford (4-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]methyl}-1-piperidinyl)acetic acid (E105) (59 mg) as a TFA salt. δH (DMSO-d6, 400 MHz): 1.01 (3H, t), 1.28 (6H, d), 1.55 (2H, m), 1.72 (3H, m), 2.62 (2H, d), 2.87 (4H, m), 3.38 (2H, m), 3.98 (2H, s), 4.79 (1H, m), 7.23 (2H, m), 7.32 (1H, d), 7.59 (1H, dd), 7.95 (1H, dd), 8.07 (1H, d). δF (DMSO-d6, 376 MHz): −73.5. MS (ES): C27H32ClN3O3S requires 513.2. found 514.2 (M+H+).
Reaction SMILES: [Na+:1].[CH3:2][C:3]1([CH2:28][CH2:29][CH2:30][S:31]([OH:34])(=[O:33])=[O:32])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N+:5]([CH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:17])=[O:16])=[C:4]1/[CH:19]=[CH:20]/NC1C=CC=CC=1.[I-].[C:36]([CH2:39][CH2:40][CH2:41][C:42]1([CH3:54])[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[N+:44]([CH2:51][CH3:52])=[C:43]1[CH3:53])([OH:38])=[O:37].N1C=CC=CC=1>C(O)(=O)C.C(OC(=O)C)(=O)C>[Na+:1].[C:36]([CH2:39][CH2:40][CH2:41][C:42]1([CH3:54])[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[N:44]([CH2:51][CH3:52])/[C:43]/1=[CH:53]/[CH:20]=[CH:19]/[C:4]1[C:3]([CH3:2])([CH2:28][CH2:29][CH2:30][S:31]([OH:34])(=[O:32])=[O:33])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N+:5]=1[CH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:16])=[O:17])([OH:38])=[O:37]
Reactant: CC[N+]1=C(C)C(C)(CCCC(=O)O)c2ccccc21
Reactant: CC1(CCCS(=O)(=O)O)C(/C=C/Nc2ccccc2)=[N+](CCCS(=O)(=O)O)c2ccccc21
Agent: [I-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCN1/C(=C/C=C/C2=[N+](CCCS(=O)(=O)O)c3ccccc3C2(C)CCCS(=O)(=O)O)C(C)(CCCC(=O)O)c2ccccc21

Procedure:
500 mg (1 mmol) 1-ethyl-3-methyl-2-((E)-2-phenylamino-vinyl)-5-sulfo-3-(3-sulfo-propyl)-3H-indolium sodium salt 8 and 387 mg (1 mmol) 3-(3-carboxypropyl)-2,3-dimethyl-1-ethyl-3H-indolium iodide salt 3 are dissolved in a mixture of 10 ml acetic acid and 10 ml acetic anhydride. Subsequently, 5 ml of pyridine is added. The solution is stirred under reflux for 15 minutes.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Solvent: ClCCl
Product: CCOC(=O)C=Cc1cccc(OC(F)(F)F)c1
Temperature: 15 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
A mixture of 3-(trifluoromethoxy)benzaldehyde 158a (10.0 g, 52.6 mmol) and ethyl 2-(triphenylphosphoranylidene)acetate 158b (27.5 g, 78.9 mmol) in DCM (200 mL) was stirred at 15° C. for 2 h. See FIG. 4. The resulting mixture was concentrated under reduced pressure, and the crude was purified by column chromatography on silica gel (ethyl acetate:petroleum ether=1:8) to afford ethyl 3-(3-(trifluoromethoxy)phenyl)acrylate 158c (12.0 g, 88%) as yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:5][N:4]=1.[CH3:15][C:16]1([CH3:26])[C@H:18]([CH:19]=[C:20]([CH3:22])[CH3:21])[C@H:17]1[C:23]([OH:25])=[O:24].C(=O)([O-])[O-].[K+].[K+].O1CCOCCOCCOCCOCCOCC1>C(C(C)=O)C>[CH3:15][C:16]1([CH3:26])[C@H:18]([CH:19]=[C:20]([CH3:21])[CH3:22])[C@H:17]1[C:23]([O:25][CH2:2][C:3]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:5][N:4]=1)=[O:24]
Reactant: CC(C)=C[C@@H]1[C@@H](C(=O)O)C1(C)C
Reactant: ClCc1nsc(Oc2ccccc2)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)=C[C@@H]1[C@@H](C(=O)OCc2nsc(Oc3ccccc3)n2)C1(C)C
Yield: 30.9 %

Procedure:
A mixture of 4.5 g of 3-chloromethyl-5-phenoxy-(1,2,4)-thiadiazole, 3.7 g of (1R,3R) 2,2-dimethyl-3-(2-methyl-1-propenyl)-cyclopropane-1-carboxylic acid, 50 ml of methyl ethyl ketone, 3.2 g of potassium carbonate and 0.1 gof 1,4,7,10,13,16-hexaoxacyclooctadecane was refluxed for 18 hours and was cooled and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution withbenzene yielded 2.2 g of [5-phenoxy-(1,2,4)-thiadiazol-3-yl]-methyl (1R,3R)2,2-dimethyl-3-(2-methyl-1-propenyl)-cyclopropane-1-carboxylate.