Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][O:10][CH2:11]OC.CO>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][O:10][CH3:11])[CH:3]=1
Reactant: Oc1cccc(Cl)c1
Reactant: COCOC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Product: COCOc1cccc(Cl)c1
Reaction time: 24 h
Yield: 12.5 %

Procedure:
To a solution of 3-chlorophenol (8 ml, 77 mmol, ABCR) in DCM (120 ml) was added dimethoxymethane (32 ml, 362 mmol, Aldrich) and then p-toluenesulphonic acid (0.164 g, 0.952 mmol, Alfa Aesar). The solution was heated to reflux under nitrogen using a Soxhlet apparatus containing 3A activated molecular sieves (approximately 20 g)* for 24 h. *The 3A molecular sieves were replaced after 6 h. Approximately a quarter of the reaction mixture was applied to a 70 g aminopropyl cartridge (prewashed with methanol). The cartridge was eluted with methanol (1-2 column volumes) and several fractions collected. Appropriate fractions were combined (TLC 50:50 DCM in cyclohexane) and the solvent removed in vacuo to give 1-chloro-3-{[(methyloxy)methyl]oxy}benzene as a colourless mobile oil (1.66 g). The remaining reaction mixture was applied evenly to 3×70 g aminopropyl cartridges (pre-washed with methanol). The cartridges were eluted with methanol (1-2 column volumes) and several fractions collected. Appropriate fractions were combined (TLC 50:50 DCM in cyclohexane) and the solvent removed in vacuo to leave a colourless mobile oil (first batch). The mixed fractions were combined and the solvent removed in vacuo to leave a colourless mobile oil. The residue from the mixed fractions was applied to a 70 g aminopropyl cartridge (pre-washed with methanol) and eluted with methanol. Appropriate fractions were combined (TLC 50:50 DCM in cyclohexane) and added to the first batch. The solvent was removed in vacuo to give another batch of 1-chloro-3-{[(methyloxy)methyl]oxy}benzene as a colourless mobile oil (5.27 g). To THF (20 ml) under nitrogen at 0° C. was added 1.6 M n-butyllithium in hexanes (18.1 ml, 29.0 mmol, Aldrich). To the solution at −60° C. was added a solution of 2,2,6,6-tetramethylpiperidine (4.90 ml, 29.0 mmol, Alfa Aesar) in THF (5 ml) and then a solution of 1-chloro-3-{[(methyloxy)methyl]oxy}benzene (5.01 g, 29.0 mmol) in THF (10 ml). The temperature was maintained below −50° C. during the addition. The solution was stirred at −60° C. to −70° C. for 1 h. To the solution was added a large excess of freshly ground solid carbon dioxide and the mixture allowed to warm to ambient temperature. The reaction mixture was diluted with water (100 ml) and diethyl ether (130 ml). The phases were separated and aqueous phase carefully acidified to pH1 using concentrated HCl. The suspension was extracted with dichloromethane (3×40 ml). The solvent was removed in vacuo to give the title compound as a white solid (4.36 g);
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([NH2:15])=[O:14])=[CH:12][C:7]=2[CH2:6][O:5]1.CS([O-])(=O)=O.CS(OCC[C@H]1C2C=CC(C(N)=O)=CC=2CCO1)(=O)=O.[CH2:41]1[C:51]2=[C:52]3[C:47](=[CH:48][CH:49]=[CH:50]2)[C:46]([N:53]2[CH2:58][CH2:57][NH:56][C@H:55]([CH3:59])[CH2:54]2)=[CH:45][CH:44]=[C:43]3[CH2:42]1>>[CH2:41]1[C:51]2=[C:52]3[C:47](=[CH:48][CH:49]=[CH:50]2)[C:46]([N:53]2[CH2:58][CH2:57][N:56]([CH2:2][CH2:3][C@H:4]4[C:8]5[CH:9]=[CH:10][C:11]([C:13]([NH2:15])=[O:14])=[CH:12][C:7]=5[CH2:6][O:5]4)[C@H:55]([CH3:59])[CH2:54]2)=[CH:45][CH:44]=[C:43]3[CH2:42]1
Reactant: C[C@@H]1CN(c2ccc3c4c(cccc24)CC3)CCN1
Reactant: NC(=O)c1ccc2c(c1)COC2CCO
Agent: CS(=O)(=O)OCC[C@@H]1OCCc2cc(C(N)=O)ccc21
Agent: CS(=O)(=O)[O-]
Product: C[C@@H]1CN(c2ccc3c4c(cccc24)CC3)CCN1CC[C@@H]1OCc2cc(C(N)=O)ccc21

Procedure:
The title compound was prepared from 1-(2-hydroxyethyl)-1,3-dihydro-2-benzofuran-5-carboxamide by initial formation of the methanesulfonate as described for the preparation of 2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl methanesulfonate, and condensation of this sulfonate with (3R)-1-(1,2-dihydro-5-acenaphthylenyl)-3-methylpiperazine, as described for Example 1b). The mixture of diastereomers was separated by chiral HPLC using a Chiracel OJ column, eluting with hexane/ethanol (1:1) with 0.2% dimethylethylamine. M+H=442.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])(C)(C)C.C(O[C:27](=[O:50])[CH2:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[O:37][CH:38]=[C:39]([CH2:41][O:42]C3CCCCO3)[N:40]=2)[CH:31]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]2[N:7]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]4[O:37][CH:38]=[C:39]([CH2:41][OH:42])[N:40]=4)[CH:31]=3)[CH2:28][C:27](=[O:50])[NH:20][C:9]=2[CH:10]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)co2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CO)co3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(methyl-propyl-amino)-phenyl]-carbamic acid tert-butyl ester (0.16 g) (Example J8) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-oxazol-2-yl]-phenyl]-propionic acid tert-butyl ester (0.22 g) (Example K11) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.10 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:17])=[C:7]([CH2:13][C:14]([OH:16])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:23](O)[CH3:24]>C(OCC)(=O)C>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:17])=[C:7]([CH2:13][C:14]([O:16][CH2:23][CH3:24])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(CC(=O)O)c(=O)oc2cc(O)ccc12
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1c(C)c2ccc(O)cc2oc1=O
Temperature: 25 °C
Yield: 92 %

Procedure:
7-Hydroxy-4-methylcoumarin-3-acetic acid (1) (1 gm, 4.3 mmol) was suspended in anhydrous ethanol (15 mL), concentrated sulfuric acid (1.5 mL) was added and the mixture was heated at reflux for 1 hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with 5% NaHCO3 (5×50 mL), water (2×50 mL), saturated NaCl (2×50 mL) dried with sodium sulfate, filtered and the filtrate was evaporated under reduced pressure to give 1.04 gm (4.0 mmol, 92% yield of 2 as a white solid. 1H NMR (CDCl3 /DMSO-d6): 1.19 (3H,t), 2.29 (3H,s), 3.57 (2H,s), 4.06 (2H,q), 6.65 (1H,d), 6.73 (1H,dd), 7.44 (1H,d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([C:26]2[O:30][N:29]=[C:28]([CH3:31])[N:27]=2)[C:21]1=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[S:17][C:20]3[CH2:25][CH2:24][CH2:23][CH:22]([C:26]4[O:30][N:29]=[C:28]([CH3:31])[N:27]=4)[C:21]=3[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: Cc1noc(C2CCCC(Br)C2=O)n1
Product: COc1cc(Nc2nc3c(s2)CCCC3c2nc(C)no2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (70 mg, 0.27 mmol) and crude 2-bromo-6-(3-methyl-[1,2,4]oxadiazol-5-yl)-cyclohexanone (173 mg, ca. 0.5 mmol) using in analogous manner the procedure described in example 1b). Obtained as a light-brown foam (25 mg, 22%). MS ISP (m/e): 423.1 (100) [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:13]1[CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1(C)OC(=O)CC(=O)[O:18]1.C(Cl)Cl.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH:13]1([C@H:9]2[C:10](=[O:12])[CH2:16][C:17](=[O:18])[N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:15][CH2:14]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(=O)CC(=O)[C@@H]1C1CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(tert-Butoxycarbonylamino)-2-cyclopropylacetic acid (13) (5.47 g, 25.4 mmol), Meldrum's acid (14) (4.02 g, 27.9 mmol), and DMAP (4.34 g, 35.56 mmol) were added to CH2Cl2 (100 mL) under nitrogen at 0° C. After 30 minutes EDAC (6.81 g, 35.56 mmol) was added. The reaction was stirred 16 hr at rt and poured into EtOAc (300 mL), washed with brine (200 ml), 5% citric acid (300 mL), and again brine (200 mL). The organic phase was then refluxed for 1 hr. The mixture was evaporated to give (S)-tert-butyl 2-cyclopropyl-3,5-dioxopyrrolidine-1-carboxylate (15) a yellow oil (4.0 g, 69%) that was taken into the next reaction without further purification.
Reaction SMILES: [N:1](=[C:3]1[C:7]2=[C:8]3[C:13](=[CH:14][CH:15]=[C:6]2[NH:5]C1=O)[N:12]=[CH:11][CH:10]=[CH:9]3)[NH2:2].NN.[OH2:19]>>[NH2:5][C:6]1[CH:15]=[CH:14][C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]=1[C:3]([NH:1][NH2:2])=[O:19]
Reactant: O
Reactant: NN=C1C(=O)Nc2ccc3ncccc3c21
Agent: NN
Product: NNC(=O)c1c(N)ccc2ncccc12
Temperature: 145 °C
Reaction time: 4.5 h

Procedure:
1-Hydrazono-1,3-dihydro-pyrrolo[3,2-f]quinoline-2-one (1.07 g, 5.05 mmol) was combined with 6.0 mL of anhydrous hydrazine and 5.0 mL of water in a 100 mL flask (oversize to allow for foaming) and heated at reflux (145° C. oil bath) under a condenser and nitrogen atmosphere, with stirring. After 4.5 hr, analytical HPLC showed that all of the hydrazone had been consumed. The reaction was cooled, diluted with 75 mL of water, and filtered to give 0.45 g (air dried) of 6-aminoquinoline-5-carboxylic acid hydrazide as an olive brown solid. Mass spectrum (negative ion electrospray): m/z=215 (100%). NMR (DMSO-d6): δ3.64 (s, 2H), 4.22 (s, 2H), 5.66 (s, 2H), 7.25 (d, 1H, J=9.1 Hz), 7.34 (m, 1H), 7.65 (d, 1H, J=9 Hz), 8.34 (d, 1H, J=8.5 Hz), 8.50 (s, 1H), 9.27 (s, 1H).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH2:6]([OH:28])[C@H:7]1[O:12][C@H:11]([O:13][C@:14]2([CH2:23][OH:24])[O:18][C@H:17]([CH2:19]O)[C@@H:16]([OH:21])[C@@H:15]2[OH:22])[C@H:10]([OH:25])[C@@H:9]([OH:26])[C@@H:8]1[OH:27]>N1C=CC=CC=1>[CH2:6]([OH:28])[C@H:7]1[O:12][C@H:11]([O:13][C@@:14]2([CH2:23][OH:24])[O:18][C@H:17]([CH2:19][Cl:4])[C@@H:16]([OH:21])[C@@H:15]2[OH:22])[C@H:10]([OH:25])[C@@H:9]([OH:26])[C@@H:8]1[OH:27]
Reactant: O=S(=O)(Cl)Cl
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: c1ccncc1
Product: OC[C@H]1O[C@H](O[C@@]2(CO)O[C@H](CCl)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Yield: 29 %

Procedure:
Attempts to synthesize cyclic sulfates of unprotected sugars with sulfuryl chloride and pyridine have been reported. However, the reaction has never been clean and several side products were isolated. For example, reaction of sucrose with sulfuryl chloride at −78° C. affords the 6,6′-dichloro-6,6′-deoxysucrose and 6′-chloro-6′-deoxysucrose in 43% and 29% yield. At room temperature, a complex mixture is formed from which 3′,4′-anhydro-1′,6′-dichloro-1′,6′-dideoxy-β-D-ribo-hexulo-furanoside 2,3-cyclic sulfate is isolated in 17% yield, showing that chlorination occurs as well as inversion of configuration during cyclic sulfate formation. Thus, the reaction of sulfuryl chloride with carbohydrates containing free hydroxyl groups has become a well established method for the preparation of chlorodeoxysugars. The conversion of a vicinal cis diol system to a cyclic sulfate in protected carbohydrates is readily accomplished with sulfuryl chloride. By using SO2Cl2, the methyl 4,6-O-benzilidene-β-D-mannopyranoside 2,3-cyclic sulfate, and 1,6-anhydro-4-O-benzyl-β-D-mannopyranoside 2,3-cyclic sulfate [28] were obtained in 60% and 85% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5](O)=[O:6].[OH-].[NH4+:30]>S(Cl)(Cl)=O.C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5]([NH2:30])=[O:6]
Reactant: [NH4+]
Reactant: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reaction time: 16 h

Procedure:
3-Fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzoic acid (107 mg, 0.274 mmol) was dissolved in thionyl chloride at 65° C. for 1 h before it was concentrated. The reaction mixture was dissolved in THF (1.4 mL) before ammonium hydroxide (1.07 mL, 27.40 mmol) was added and stirred at ambient temp. for 16 h. The reaction mixture was diluted with EtOAc, added to a separatory funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed with sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated via rotovap to give the title compound after preparatory LC. MS (ESI) m/z: Calculated: 389; Observed: 390.1 (M++1).
Reaction SMILES: [OH:1][C:2]1([CH2:26][OH:27])[CH2:7][CH2:6][C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[O:11])[CH2:4][CH2:3]1.N1C=CC=CC=1.[CH3:34][O:35][C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39]>C1COCC1.CN(C1C=CN=CC=1)C>[OH:1][C:2]1([CH2:26][O:27][C:38](=[O:39])[C:37]2[CH:41]=[CH:42][CH:43]=[CH:44][C:36]=2[O:35][CH3:34])[CH2:7][CH2:6][C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[O:11])[CH2:4][CH2:3]1
Reactant: COc1ccccc1C(=O)NCC1(c2ccccc2)CCC(O)(CO)CC1
Reactant: COc1ccccc1C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)NCC1(c2ccccc2)CCC(O)(COC(=O)c2ccccc2OC)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To solution of 1-hydroxy-1-hydroxymethyl-4-phenyl-4-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)-cyclohexane (Example 168, 20.2 mg, 0.055 mmol) in 2.0 mL of THF was added DMAP (2 mg), pyridine (0.054 mL, 0.67 mmol) and 2-methoxybenzoyl chloride (0.050 mL, 0.34 mmol). The solution was stirred at rt for 18 h and was quenched with methanol (0.5 mL). The volatiles were removed by vacuum and the residue was filtered through a plug of silica gel, concentrated and the residue was purified by HPLC (Waters RCM, μ Porosil, 25 mm×10 cm) using a mixture of (5:4:1 hexane-methyl tert-butyl ether-acetonitrile:hexane, 3.0/9.0 to 8.0/0.0, mL/min) to give the separated isomers of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:17]=[C:16]([CH2:18][CH3:19])[S:15][C:10]=2[NH:11][CH2:12][CH2:13][N:14]=1.[N:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O>O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:17]=[C:16]([CH2:18][CH3:19])[S:15][C:10]=2[N:11]([C:26]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:27])[CH2:12][CH2:13][N:14]=1
Reactant: O=C(Cl)N1CCCCC1
Reactant: CCc1cc2c(s1)NCCN=C2c1ccccc1Cl
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc2c(s1)N(C(=O)N1CCCCC1)CCN=C2c1ccccc1Cl
Product: Cl

Procedure:
To a solution of 19.3 g of 5-o-chlorophenyl-7-ethyl-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine in 150 ml of tetrahydrofuran is added dropwise a solution of 10.8 g of 1-piperidinecarboxylic acid chloride in 30 ml of tetrahydrofuran with stirring. The whole solution is stirred under reflux for four and half hours. After cooling, the reaction mixture is transferred to water and extracted with ethyl acetate. After the extract is washed with water and dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The residue is treated with ethanolic hydrogen chloride to give 5-o-chlorophenyl-7-ethyl-1-piperidinocarbonyl-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine hydrochloride as yellow crystals. This product, when recrystallized from a mixture of methanol and ethyl acetate, melts at 237°-238° C with decomposition.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2N=CN=[C:11]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26](=[O:35])[CH2:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[O:24])=[CH:18][C:17]=3[F:36])[CH:10]=2)=CC=1.NC1C=CC(OC2C=CN=[C:47]([C:51]([NH2:53])=[O:52])[CH:46]=2)=C(F)C=1>C(Cl)Cl.CN(C=O)C>[C:51]([C:47]1[CH:46]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26](=[O:35])[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[O:24])=[CH:18][C:17]=2[F:36])[CH:10]=[CH:9][N:8]=1)(=[O:52])[NH2:53]
Reactant: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Reactant: NC(=O)c1cc(Oc2ccc(N)cc2F)ccn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)ccn1
Reaction time: 17 h
Yield: 68.5 %

Procedure:
A solution of 2-(4-fluorophenyl)acetyl isocyanate (Compound D of Example 11, 0.29 M in toluene, 54.9 mL, 15.9 mmol, 2.1 eq) was added to 4-(4-amino-2-fluorophenoxy)picolinamide (1.86 g, 7.53 mmol, 1.0 eq) in 10/3 DCM/DMF (65 mL) at room temperature and the reaction mixture was stirred for 17 h. The reaction mixture was concentrated in vacuo and the residue redissolved in CHCl3. The organic layer was washed with saturated aqueous NaCl, the organic fraction separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting ⅓ hexane/EtOAc, then to elute product 5% MeOH in CHCl3), and the appropriate fractions concentrated in vacuo to afford the product (2.2 g, 69%) as a solid. 1H NMR (DMSO-d6) δ 11.07 (s, 1H), 10.62 (s, 1H), 8.54 (d, 1H, J=5.60 Hz), 8.16-8.19 (m, 1H), 7.76-7.84 (m, 2H), 7.35-7.49 (m, 5H), 7.16-7.23 (m, 3H), 3.76 (s, 2H); MS(ESI+) m/z 427 (M+H)+. HRMS (ESI+) calcd.: 427.1218, found: 427.1214.
Reaction SMILES: [C:1]([Cl:4])(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([NH:15][CH2:16][CH2:17][CH2:18][N:19]2[C:23]([CH3:24])=[C:22]([CH2:25][OH:26])[N:21]=[CH:20]2)([CH3:14])[CH3:13])=[CH:8][CH:7]=1.C(N(CC)CC)C.Cl>ClCCl.CCOCC>[ClH:4].[ClH:5].[C:1]([O:26][CH2:25][C:22]1[N:21]=[CH:20][N:19]([CH2:18][CH2:17][CH2:16][NH:15][C:12]([C:9]2[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=2)([CH3:14])[CH3:13])[C:23]=1[CH3:24])(=[O:3])[CH3:2]
Reactant: Cc1c(CO)ncn1CCCNC(C)(C)c1ccc(Cl)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCc1ncn(CCCNC(C)(C)c2ccc(Cl)cc2)c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of acetyl chloride (8.7 g) in dichloromethane (35.5 ml) was added dropwise with stirring to a solution of 1-{3-[1-(4-chlorophenyl)-1-methylethylamino]propyl}-5-methylimidazol-4-yl-methanol (3.55 g) in dichloromethane (88.8 ml) containing triethylamine (11.1 g) at 0° C. The mixture was stirred at 0° C. for 30 minutes and then at ambient temperature for 2 hours. The mixture was diluted with dichloromethane, washed with 5M sodium hydroxide solution, dried and evaporated. The residue obtained was dissolved in ether and acidified with ethereal hydrogen chloride. The solid was collected by filtration and recrystallised from aqueous propan-1-ol to give 1-{3-[1-(4-chlorophenyl)-1-methylethylamino]propyl}-5-methylimidazol-4-ylmethyl acetate dihydrochloride, m.p. 188°-189° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[Al](C)C.[O:13]1[C:23]23[C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:17][O:16][CH2:15][C@H:14]13>C(Cl)Cl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C@H:14]2[C@:23]3([OH:13])[C@H:18]([CH2:19][CH2:20][CH2:21][CH2:22]3)[CH2:17][O:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: C1CCC23O[C@H]2COC[C@@H]3C1
Reactant: Nc1ccc(F)cc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: O[C@]12CCCC[C@@H]1COC[C@H]2Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-fluoroaniline (0.721 g, 6.48 mmol) in CH2Cl2 (6 mL) at 0° C. was added trimethylaluminum (2M in toluene, 3.24 mL) dropwise. The mixture was warmed to rt for 30 min. A mixture of both cis and trans octahydrooxireno[d]isochromene (0.200 g, 1.30 mmol) in CH2Cl2 2 mL+0.5 mL rinse) was then added and the mixture was stirred at rt overnight. The reaction was cooled to 0° C. and treated with 50% NaOH (1 mL) then water (1 mL). The mixture was diluted with more water and extracted 3× with CH2Cl2. The combined organics were dried (anhd. Na2SO4), filtered, and concentrated. The residue was purified by column chromatography to give the title compound. 1H NMR (500 MHz, CDCl3) δ 6.94 (1, 2H, J=8.6 Hz), 6.78 (dd, 2H, J=4.2 Hz, 8.8 Hz), 4.14 (dd, 1H, J=1.5 Hz, 12.0 Hz), 3.64 (d, 1H, J=11.5 Hz), 3.56 (dd, 1H, J=4.6 Hz, 11.0), 3.48 (t, 1H, J=11.5 Hz), 3.10 (s, 1H), 1.17-2.00 (m, 9H). HRMS (ES) m/z M+H calc'd.: 266.1551. found: 266.1554
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].[F:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1>>[Cl:10][C:7]1[CH:6]=[C:3]([C:4]#[N:5])[C:2]([C:13]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=2[F:11])=[CH:9][CH:8]=1
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Reactant: N#Cc1cc(Cl)ccc1Br
Product: N#Cc1cc(Cl)ccc1-c1cc([N+](=O)[O-])ccc1F

Procedure:
2-Bromo-5-chlorobenzonitrile was coupled with 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane in the same way as Example 1 to give 4-chloro-2′-fluoro-5′-nitrobiphenyl-2-carbonitrile as a grey solid: δH (360 MHz, CDCl3) 7.39-7.43 (1H, m), 7.47-7.64 (1H, m), 7.73 (1H, dd, J 8 and 2), 7.82 (1H, d, J 2), 8.26-8.45 (2H, m).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:3]1.O[N:30]=[C:31]([NH2:36])[CH2:32][CH2:33][O:34][CH3:35]>>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:19][CH:20]=3)[CH2:12][CH:11]([C:26]3[O:27][N:36]=[C:31]([CH2:32][CH2:33][O:34][CH3:35])[N:30]=3)[CH2:10]2)=[O:8])[CH2:3]1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)C2)C1
Reactant: COCCC(N)=NO
Product: COCCc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(O)C3)C2)n1

Procedure:
200 mg (0.50 mmol) of the compound from Example 112A and 88 mg (0.75 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted according to the General Method 2. Yield: 67 mg (27% of theory).
Reaction SMILES: C([O:5][C:6](=[O:72])[C@H:7]([CH2:63][CH2:64][C:65]([O:67]C(C)(C)C)=[O:66])[NH:8][C:9](=[O:62])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:61])[CH2:19][CH2:20][S:21][CH2:22][CH:23]([O:43][C:44](=[O:60])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH2:24][O:25][C:26](=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:44]([O:43][CH:23]([CH2:24][O:25][C:26](=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:22][S:21][CH2:20][CH2:19][C:18]([NH:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([NH:8][C@H:7]([C:6]([OH:72])=[O:5])[CH2:63][CH2:64][C:65]([OH:67])=[O:66])=[O:62])=[CH:11][CH:12]=1)=[O:61])(=[O:60])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)NCc1ccc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1)OC(=O)CCCCCCCCCCCCCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)NCc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A solution of 4-[6,7-bis(palmitoyloxy)-4-thiaheptanoylaminomethyl]benzoyl-glutamic acid di-t-butyl ester as obtained in Example 39 (325 mg) in dichloromethane (0.5 ml)-trifiuoroacetic acid (1 ml) was stirred at room temperature for 30 minutes. After solvent concentration under reduced pressure, the resulting residue was crystallized from methanol-water to yield the title compound (231 mg, yield 80%) as a colorless powder.