Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])[C:11]=1F.Cl>C1COCC1>[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])[C:11]=1[O:6][CH2:5][C:4]([F:8])([F:7])[F:3]
Reactant: CS(=O)(=O)c1c(C(=O)O)ccc(Cl)c1F
Reactant: OCC(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1c(C(=O)O)ccc(Cl)c1OCC(F)(F)F
Yield: 99.9 %

Procedure:
Sodium hydride (1.05 g of 80% powder) was suspended in THF and to this was added a solution of 2,2,2-trifluoroethanol (1.9 g) in THF, followed by a solution of 4-chloro-3-fluoro-2-methylsulphonylbenzoic acid (4 g) in THF. The resultant mixture was stirred for 2 hours and then acidified with 2M HCl. The mixture was extracted with ether, washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness yielding 4-chloro-2-methylsulphonyl-3-(2,2,2-trifluoroethoxy)benzoic acid (5.26 g) as a white solid, NMR (DMSO d6) 2.5(s,3H), 4.8(q,2H), 7.5(d,1H), 8.0(d,1H).
Reaction SMILES: C1(C[N:8]([CH2:22][CH:23]([CH:25]2[CH2:30][CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[O:26]2)[OH:24])[CH2:9][CH:10]([CH:12]2[CH2:17][CH2:16][C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[O:13]2)[OH:11])C=CC=CC=1.[H][H]>[Pd].CO>[NH:8]([CH2:9][CH:10]([CH:12]1[CH2:17][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[O:13]1)[OH:11])[CH2:22][CH:23]([CH:25]1[CH2:30][CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=2[O:26]1)[OH:24]
Reactant: OC(CN(Cc1ccccc1)CC(O)C1CCc2ccccc2O1)C1CCc2ccccc2O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: OC(CNCC(O)C1CCc2ccccc2O1)C1CCc2ccccc2O1

Procedure:
A mixture of 3 parts of (A+A+)-α,α'-[[(phenylmethyl)imino]bis(methylene)]bis[3,4-dihydro-2H-1-benzopyran-2-methanol] and 120 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in dichloromethane. The organic phase was washed with a 10% sodium hydroxide solution and with water, dried, filtered and evaporated. The residue was dried in vacuo at 80° C., yielding 1.2 parts (19%) of (A+A+)-α,α'-[iminobis(methylene)]bis[3,4-dihydro-2H-1-benzopyran-2-methanol]; mp. 130.8° C.; [α]589 =+121.50° (c=1% CH3OH) (compound 74).
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[C:11]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)#[N:12].[NH2:22][C:23]1[CH:24]=[C:25]([CH:36]=[CH:37][N:38]=1)[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>>[CH2:29]([NH:28][C:26](=[O:27])[C:25]1[CH:36]=[CH:37][N:38]=[C:23]([NH:22][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([C:11]#[N:12])=[CH:14][CH:15]=2)[CH:24]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Agent: O=C(Cl)c1ccccc1F
Product: N#Cc1ccc(C(=O)Nc2cc(C(=O)NCc3ccccc3)ccn2)cc1
Yield: 35 %

Procedure:
Following the procedure as describe in Example 6, making variations as required to replace 2-fluorobenzoyl chloride with 4-cyanobenzoyl chloride to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(4-cyanobenzamido)isonicotinamide was obtained as a colorless solid in 35% yield: mp 180-181° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.97 (s, 1H), 8.63 (s, 1H), 8.41 (t, J=5.0 Hz, 1H), 8.03-8.00 (m, 2H), 7.82-7.79 (m, 2H), 7.60 (dd, J=5.1, 1.2 Hz, 1H), 7.36-7.29 (m, 5H), 6.69 (m, 1H), 4.65 (d, J=5.7 Hz, 2H); MS (ES+) m/z 357.5 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]([CH3:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:3]=1.CCCCCC.[Li]CCCC.[CH:39]([N:42]=[C:43]=[O:44])([CH3:41])[CH3:40]>C(OCC)C>[CH:39]([NH:42][C:43]([C:2]1[CH:7]=[C:6]([N:8]([CH3:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:3]=1)=[O:44])([CH3:41])[CH3:40]
Reactant: CC(C)N=C=O
Reactant: CN(Cc1ccccc1)c1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)NC(=O)c1cc(N(C)Cc2ccccc2)cc(Oc2cccc(C(F)(F)F)c2)n1
Reaction time: 0.17 h

Procedure:
2.22 g (0.0051 mol) of 2-bromo-4-{methyl(phenylmethyl)amino}-6-{3-(trifluoromethyl)phenoxy} pyridine was suspended in about 30 ml of diethyl ether. While cooling the obtained suspension in a dry ice-acetone bath in an argon atmosphere, 3.4 ml of a 1.65M-hexane solution of BuLi (0.0051×1.1 mol) was added thereto, followed by stirring the suspension for about 10 minutes. After 0.86 g (0.0051×2.0 mol) of isopropyl isocyanate dissolved in about 10 ml of diethyl ether was added to the reaction solution, the obtained solution was removed from the bath and stirred at room temperature for about one hour. The reaction solution was mixed with about 10 ml of a 1N-hydrochloric acid aqueous solution, and then distributed in ethyl acetate-saturated sodium bicarbonate water, followed by washing with saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:18]=[CH:17][C:16]([CH:19]=[O:20])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.N1C=CN=C1.[CH3:26][C:27]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C=O)C.O>[Si:30]([O:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:8][CH2:9][N:10]([C:13]2[N:18]=[CH:17][C:16]([CH:19]=[O:20])=[CH:15][CH:14]=2)[CH2:11][CH2:12]1)([C:27]([CH3:29])([CH3:28])[CH3:26])([CH3:32])[CH3:31]
Reactant: O=Cc1ccc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC[C@@H]1C[C@@H]1C1CCN(c2ccc(C=O)cn2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
6-{4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl]piperidin-1-yl}pyridine-3-carbaldehyde (1.5 g, 5.47 mmol) was dissolved in DMF (5.47 ml), and imidazole (0.558 g, 8.20 mmol) was added. The mixture was cooled to 0° C., TBDMS-Cl (0.989 g, 6.56 mmol) added and the mixture was allowed to warm to RT and stirred overnight. The mixture was diluted with 4:1 water:saturated sodium bicarbonate (100 ml), extracted with EtOAc (3×75 ml), the organic fractions combined, washed with brine, dried over Na2SO4, filtered and the volatiles removed in vac. The residue was purified by column chromatography on silica gel, Biotage 50 g, using a gradient eluant of 0-100% EtOAc/hexanes to afford the title compound. LC/MS (m/z): 389 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:42])[CH2:4][C:5]([NH:7][CH:8]1[C:40](=[O:41])[N:10]2[C:11]([C:24]([O:26][CH:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[C:12]([C:15]3[S:16][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[N:18][N:19]=3)[CH2:13][S:14][C@H:9]12)=[O:6].[N:43]([O-])=[O:44].[Na+].[Cl-].[Na+]>C(O)(=O)C.O>[Br:1][CH2:2][C:3](=[O:42])[C:4](=[N:43][OH:44])[C:5]([NH:7][CH:8]1[C:40](=[O:41])[N:10]2[C:11]([C:24]([O:26][CH:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])=[C:12]([C:15]3[S:16][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[N:18][N:19]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: O=N[O-]
Reactant: CC(=O)Nc1nnc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)CC(=O)CBr)[C@H]3SC2)s1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1nnc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NO)C(=O)CBr)[C@H]3SC2)s1
Yield: 89.4 %

Procedure:
In 4 ml of acetic acid there was dissolved 0.37 g of benzhydryl 7-(4-bromo-3-oxobutyrylamino)-3-(5-acetylamino-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylate and, under ice-cooling and stirring, a solution of 0.048 g of sodium nitrite in 0.4 ml of water was added dropwise. After this dropwise addition, the mixture was stirred at room temperature for one hour. Then, 20 ml of a saturated aqueous solution of sodium chloride were added and extraction was carried out with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was evaporated off under reduced pressure and the residue was loosened up with a solvent mixture of petroleum ether and ether (2:1 volume/volume). The resultant powder was recovered by filtration and dried. By the above procedure there was obtained 0.345 g of benzhydryl 7-(4-bromo-3-oxo-2-hydroxyiminobutyrylamino)-3-(5-acetylamino-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylate-(syn-isomer).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]C.C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.CO.C1(C)C=CC=CC=1>[CH2:1]([O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCO
Reactant: COc1ccsc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCCCCCCCOc1ccsc1
Yield: 74.2 %

Procedure:
25 cm3 of 3-methoxythiophene (0.25 mole), 50 cm3 of 1-nonanol (0.28 mol) and 30 cm3 of toluene were heated to 120° C. together with 1 g of p-toluenesulfonic acid, and about 9.5 cm3 of a methanol/toluene mixture were distilled off over a period of 3 hours. The workup was carried out as described in Example 1. Fractionation through a 30 cm Vigreux column at 0.26 mbar gave 42 g of 3-n-nonyloxythiophene of boiling point 102° to 105° C., which corresponds to 74% of the theoretical yield. 1H-NMR and mass spectrum confirm the structure.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]=[O:15])([CH3:3])[CH3:2].C[Si]([N:20]=[N+:21]=[N-:22])(C)C.C1(C)C=CC=CC=1>O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[N:13]1[C:14](=[O:15])[NH:22][N:21]=[N:20]1)([CH3:2])[CH3:3]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1-n1nn[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
37.1 g of 2,6-diisopropylphenyl isocyanate and 50 ml of trimethylsilyl azide are stirred for 24 hours at +140° C. The mixture is then cooled to room temperature and stirred with 250 ml of toluene and with 250 ml of water. After 1 hour, the phases are separated and the aqueous phase is extracted with toluene. The combined organic phases are extracted four times with 250 ml of 15% sodium hydroxide solution each time, and then the aqueous phases are combined and washed with ether. After acidification with semi-concentrated hydrochloric acid, crude 1-(2,6-diisopropylphenyl)-5-oxo-2-tetrazoline precipitates. This is recrystallised from a mixture of hexane and toluene in a ratio of 10:1. Melting point 177°-178.5°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)[N:5]=[C:4]([C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]4[CH2:33][CH2:32][CH:31]([N:34]([CH3:36])[CH3:35])[CH2:30]4)=[O:28])=[CH:23][CH:22]=3)[CH:18]=[N:19][CH:20]=2)[CH:3]=1.[CH2:37]([OH:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:37]([O:44][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)[N:5]=[C:4]([C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]4[CH2:33][CH2:32][CH:31]([N:34]([CH3:36])[CH3:35])[CH2:30]4)=[O:28])=[CH:23][CH:22]=3)[CH:18]=[N:19][CH:20]=2)[CH:3]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cc1cccc(-c2nc(Cl)cc(-c3cncc(-c4ccc(C(=O)N5CCC(N(C)C)C5)cc4)c3)n2)n1
Reactant: OCc1ccccc1
Product: Cc1cccc(-c2nc(OCc3ccccc3)cc(-c3cncc(-c4ccc(C(=O)N5CCC(N(C)C)C5)cc4)c3)n2)n1

Procedure:
This compound is prepared from (4-{5-[6-chloro-2-(6-methyl-pyridin-2-yl)-pyrimidin-4-yl]-pyridin-3-yl}-phenyl)-(3-dimethylamino-pyrrolidin-1-yl)-methanone (Ex. 16) and benzyl alcohol analogously to Example 8; [M+H]+=571.
Reaction SMILES: [OH:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:30][CH2:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH:37]([C:40]2[CH:41]=[C:42]([NH:47][C:48](=[O:52])[CH:49]([CH3:51])[CH3:50])[CH:43]=[CH:44][C:45]=2[CH3:46])[CH2:36][CH2:35]1>C(Cl)Cl>[OH:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH:30][CH2:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH:37]([C:40]2[CH:41]=[C:42]([NH:47][C:48](=[O:52])[CH:49]([CH3:50])[CH3:51])[CH:43]=[CH:44][C:45]=2[CH3:46])[CH2:36][CH2:35]1)=[O:5]
Reactant: O=C(O)C(O)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C(O)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of hydroxy(diphenyl)acetic acid (100 mg, 0.44 mmol) and 1,1′-carbonyldiimidazole (78 mg, 0.48 mmol) in CH2Cl2 (5 mL) was stirred at room temperature for 3 h, then a solution of N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methyl propanamide (140 mg, 0.44 mmol) in CH2Cl2 (5 mL) was added. The resulting mixture was stirred at room temperature for overnight, evaporated in vacuo, and dissolved in a mixture of EtOAc and 1N NaOH. The organic layer was separated, washed twice with water, dried over MgSO4 and concentrated. The residue was purified over preparative TLC (10% 2M NH3/MeOH in 50% EtOAc/hexane) to give 111 mg (0.21 mmol, 48%) of (N-{3-[1-(3-{[hydroxy(diphenyl)acetyl]amino}propyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide: 1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1 H), 8.14 (s, 1 H), 7.80 (s, 1 H), 7.64–7.48 (m, 4 H), 7.32–7.16 (m, 6 H), 6.95 (d, 1 H, J=8.0 Hz), 6.64 (d, 1 H, J=8.0 Hz), 5.83–5.62 (br, 1 H), 3.54–3.38 (m, 2 H), 3.11–2.94 (m, 2 H), 2.79–2.59 (m, 1 H), 2.57–2.41 (m, 2 H), 2.26 (s, 3 H), 2.29–2.16 (m, 1 H), 2.16–1.91 (m, 4 H), 1.74–1.53 (m, 4 H), 0.86 (d, 6 H, J=6.8 Hz); ESMS m/e: 528.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[C:4]([CH2:16][S:17][CH3:18])[CH:3]=1.[CH2:19]([O:21][CH:22](OCC)OCC)[CH3:20].C(OC(=O)C)(=O)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9](=[CH:22][O:21][CH2:19][CH3:20])[C:10]([CH:12]2[CH2:13][CH2:14]2)=[O:11])=[C:4]([CH2:16][S:17][CH3:18])[CH:3]=1
Reactant: CSCc1cc(Br)ccc1C(=O)CC(=O)C1CC1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1ccc(Br)cc1CSC)C(=O)C1CC1

Procedure:
A mixture of 1-[4-bromo-2-(methylsulphenylmethyl)phenyl]-3-cyclopropylpropan-1,3-dione [4.4 g, containing approximately 1.0 g methyl 4-bromo-2-(methylsulphenylmethyl)benzoate], triethylorthoformate (3.5 ml) and acetic anhydride (2.9 ml) was heated at reflux for three hours. The mixture was then evaporated giving an impure sample of 1-[4-bromo-2-(methylsulphenylmethyl)phenyl]-3-cyclopropyl-2-ethoxymethylenepropane-1,3-dione as a red oil (4.8 g).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:40])[C@@H:6]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:7][C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19](O)=[O:20])=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[C:41]([S:60][CH2:61][C@@H:62]([C:64]([NH:66][CH2:67][C:68]([NH2:70])=[O:69])=[O:65])[NH2:63])([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:4][C:5](=[O:40])[C@@H:6]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19]([NH:63][C@H:62]([C:64]([NH:66][CH2:67][C:68]([NH2:70])=[O:69])=[O:65])[CH2:61][S:60][C:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)=[O:20])=[O:14])=[CH:30][CH:31]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Reactant: NC(=O)CNC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)NCC(N)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
173 mg (0.31 mmol) of the compound from example 2A was dissolved in 10 ml dichloromethane. 128 mg (0.31 mmol) S-Trityl-L-cysteinylglycinamide, 53 μl (0.31 mmol) N,N-diisopropylethyl-amine and 116 mg (0.31 mmol) HATU were added. The reaction mixture was heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the reaction mixture the solvent was removed under reduced pressure. The raw product was purified by preparative RP-HPLC on a C18 column with a water methanol gradient from 9/1 to 1/9. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 57 mg (0.02 mmol, 18% of theory) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:9])=[CH:5][C:6]=1[C:7]#[N:8].Cl[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].CS(C)=O.O[Li].O>O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:1][C:2]2[S:3][C:4]([CH3:9])=[CH:5][C:6]=2[C:7]#[N:8])=[C:12]([N+:18]([O-:20])=[O:19])[CH:13]=1
Reactant: Cc1cc(C#N)c(N)s1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: [Li]O
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C#N)c(Nc2ccc(Cl)cc2[N+](=O)[O-])s1
Reaction time: 0.17 h
Yield: 81.2 %

Procedure:
Stir in a 3 neck 500 mL round bottom flask, 2-amino-5-methyl-thiophene-3-carbonitrile (124.11 g, 0.898 mol, 1 eauiv.), 1,4-dichloro-2-nitro-benzene (174.15 g, 0.907 mol, 1.01 equiv), and DMSO (1.6 L, 13 vol)) for 15 min. (dark solution). Charge in one portion, LiOH H2O (75.37 g, 1.796 mol, 2 equiv). Began to exotherm from 20.4° C. to 25.5° C. over 10 minutes. After 30 minutes temp reaches 28.1° C. and at 1 hour 30.4° C. Place tap water in the bath around the flask to control the exotherm. Check HPLC at 23 h, which shows 81.2% of desired product. Let continue to stir at ambient temperature for greater reaction conversion. Check HPLC at 39 h, which shows 83.5% of one product. Let stir 40 hours total. Cool with ice/water bath to 17° C. Begin pH adjustment by slowly adding 1 N HCl (1020 mL) to reach pH=7.1. Keep exotherm is at 15-22° C. during the addition. Workup includes: pouring reaction mixture into 22 L bottom outlet flask, rinsing in with CH2Cl2 (5.6 L) and 5% LiCl solution (3.6 L), stirring about 10 min., and allowing layers to separate. The lower layer might be darker than upper layer. Back-extract the aqueous layer with CH2Cl2 (1.5 L). Combine organic layers and wash with 5% LiCl solution (3×1.3 L). Dry organic layer with Na2SO4 (800 g) allowing it to stir 1 hour, filter and evaporate to dryness. Wt.=376 g. Back-extract the combined aqueous layers with CH2Cl2 (0.5 L). Check aq layer by HPLC ˜2 mL aq layer in 15 mL of eluent for product in aq layer. Wash the organic phase with brine (2×500 mL) and finally with 5% LiCl (500 mL). Dry over the weekend with NaSO4 (80 g). Filter and add to other organic layer. For Chromatography, dissolve crude material in methylene chloride (950 g) and charge to a silica gel 60 (2.8 kg pre wetted with heptane) bed on fritted funnel. Some product might crash out on top of silica cake. Rinse flask and add to top of cake with CH2Cl2 (0.3 L) until all of the precipitate is dissolve and onto the column. Elute with heptane (˜16 L), then 25% CH2Cl2 in heptane (˜8 L), then 37.5% CH2Cl2 in heptane (˜8 L), follow by 50% CH2Cl2 in heptane and 100% CH2Cl2. Early Fractions might contain no product. Identify mix fractions containing product and rundown separately until virtually all methylene chloride is gone leaving the product in heptane, cool to 0° C. and filter. Filtrate analysis shows 5% product by area % integration. Combine product only fractions and evaporate to dryness. Add cake from mixed fractions. Combined dry weight=197.4 g. HPLC area percent=97.0% NMR is consistent with desired procduct: Yield 74.8%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24]([OH:26])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.Cl.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2([NH2:41])[CH2:40][CH2:39]2)[N:33]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:26])[NH:41][C:38]5([C:34]6[N:33]=[N:32][CH:37]=[CH:36][CH:35]=6)[CH2:40][CH2:39]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: NC1(c2cccnn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cccnn5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.04 g, 0.099 mmol, 1 eq), 1-(pyridazin-3-yl)cyclopropanamine HCl salt (0.018, 0.099 mmol, 1 eq) and Py-Bop (0.067 g, 0.13 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.026 g, 0.3 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.031 mg (60%). 1H NMR (400 MHz, CDCl3): δ 9.17 (s, 1H), 7.92-7.96 (m, 3H), 7.77-7.69 (m, 4H), 7.65 (s, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.30 (dd, J=1.6, 8.4 Hz, 1H), 7.23-7.19 (m, 2H), 5.94 (bs, 1H), 3.0 (s, 3H), 2.33 (s, 3H), 1.89-1.86 (m, 2H), 1.60-1.57 (m, 2H). 19F NMR (376.47 MHz, CDCl3): δ−75.82 (TFA), −109.29 LCMS: (ES+) m/z=521.0 (M+H)+
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:7]1[C:15]2[CH:14]=[CH:13][NH:12][C:11](=[O:16])[C:10]=2[C:9]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[CH:8]1)[CH2:5][CH3:6].C(=O)([O-])[O-:26].[K+].[K+].OO>CS(C)=O.O>[CH3:1][O:2][CH2:3][CH:4]([N:7]1[C:15]2[CH:14]=[CH:13][NH:12][C:11](=[O:16])[C:10]=2[C:9]([C:17]2[CH:18]=[CH:19][C:20]([C:21]([NH2:22])=[O:26])=[CH:23][CH:24]=2)=[CH:8]1)[CH2:5][CH3:6]
Reactant: O=C([O-])[O-]
Reactant: CCC(COC)n1cc(-c2ccc(C#N)cc2)c2c(=O)[nH]ccc21
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCC(COC)n1cc(-c2ccc(C(N)=O)cc2)c2c(=O)[nH]ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a solution of 4-(1-(1-methoxybutan-2-yl)-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)benzonitrile (20.0 mg) obtained in Example 24 in DMSO (0.5 mL) was added potassium carbonate (10.3 mg) at 0° C., 30% aqueous hydrogen peroxide (0.019 mL) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate to ethyl acetate/methanol) to give the title compound (18.1 mg).