Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[NH:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]#[N:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[NH:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[S:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1](=[O:10])[N:18]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1ccc[nH]1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2ccc[nH]2)sc2ccccc12
Yield: 70.5 %

Procedure:
A mixture of methyl thiosalicylate (2.00 g, 11.8 mmol), pyrrole-2-carbonitrile (1.10 g, 11.9 mmol), triethylamine (2.00 ml, 14.3 mmol) and toluene (4.0 ml) was refluxed for 15 hrs as described in Example 1. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-ethanol to give the titled compound (1.90 g, 73%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.Br[C:30]1[CH:35]=[C:34]([CH3:36])[N+:33]([O-:37])=[C:32]([CH3:38])[CH:31]=1>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C@:13]2([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[O:12][C:11](=[O:28])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[CH:35]=[C:34]([CH3:36])[N+:33]([O-:37])=[C:32]([CH3:38])[CH:31]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:22][CH:23]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Reactant: Cc1cc(Br)cc(C)[n+]1[O-]
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccc(F)cc4)OC3=O)cc2)cc(C)[n+]1[O-]

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 4-bromo-2,6-dimethylpyridine-N-oxide in Step 4. LC-MS Method 2 tR=1.354, m/z=493; 1H NMR (CDCl3) 1.18 (d, 6H), 1.48 (d, 3H), 2.08-2.21 (m, 5H), 2.36 (m, 1H), 2.53 (s, 6H), 2.82 (m, 1H), 5.65 (m, 1H), 6.98 (m, 4H), 7.18 (m, 4H), 7.28 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH2:11][CH:12](OC)[C:13]([O:15]C)=O)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C(O)(=O)C.O.[NH2:25][NH2:26]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:15])[NH:25][N:26]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: NN
Reactant: COC(=O)C(CC(=O)c1cc(Cl)c(C)c(Cl)c1)OC
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(Cl)cc(-c2ccc(=O)[nH]n2)cc1Cl
Yield: 86.2 %

Procedure:
1.53 g (0.005 mole) of methyl 4-(3,5-dichloro-4-methylphenyl)-2-methoxy-4-oxobutyrate were added to 4 ml of acetic acid and the mixture was heated to form a solution, to which was then added 0.275 g (0.0055 mole) of hydrazine monohydrate. The mixture was heated under reflux for 3 hours and then cooled, after which it was diluted with 40 ml of water and stirred. The resulting crystals were collected by filtration, washed successively with water and with a small amount of ethyl acetate and then air-dried, to give 1.1 g (yield 86.2%) of the desired 6-(3,5-dichloro-4-methylphenyl)-3(2H)pyridazinone, having properties the same as those of the preceding Examples.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[CH2:8]([CH:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1)[C:9]#[CH:10]>CO.ClCCl>[CH2:8]([CH:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH3:1])=[O:18])[CH2:13][CH2:12]1)[C:9]#[CH:10]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C#CCC1CCC(C(=O)O)CC1
Solvent: CO
Solvent: ClCCl
Product: C#CCC1CCC(C(=O)OC)CC1

Procedure:
(Trimethylsilyl)diazomethane (2.0 M) solution in hexanes (1 mL, 2 mmol) was added to a solution of 5.4 (0.34 g, 2 mmol) in 15 mL of methanol:dichloromethane (3:7). The solvents were removed under reduced pressure resulting in 100% conversion of starting material to product. 1H NMR (300 MHz, CDCl3) δ 2.24 (dt, J=3.66, 12.1 Hz, 1H), 2.10 (dd, J=2.7, 6.5 Hz, 2H), 2.06 (dd, J=1.54, 6.54 Hz, 1H), 2.00–1.89 (m, 3H), 1.76 (d, J=2.3 Hz, 1H), 1.43 (dq, J=3.28, 13.1 Hz, 2H), 1.03 (dq, J=3.28, 13.1 Hz, 2H). 13C NMR (300 MHz, CDCl3) δ 176.8, 83.3, 69.8, 51.9, 43.4, 36.7, 31.9, 29.2, 26.3.
Reaction SMILES: [C:1]([C:4]12[CH2:11][O:10][C:7]([CH3:12])([O:8][CH2:9]1)[O:6][CH2:5]2)([OH:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:28][C:29](O)([CH3:31])[CH3:30]>C(#N)C>[C:29]([O:2][C:1]([C:4]12[CH2:9][O:8][C:7]([CH3:12])([O:6][CH2:5]1)[O:10][CH2:11]2)=[O:3])([CH3:31])([CH3:30])[CH3:28]
Reactant: CC(C)(C)O
Reactant: CC12OCC(C(=O)O)(CO1)CO2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)C12COC(C)(OC1)OC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-carboxy-1-methyl-2,6,7-trioxabicyclo[2.2.2]octane (9.3 g, 0.053 mol) and 1,3-dicyclohexylcarbodiimide (10.9 g, 0,053 mol) in 100 mL of acetonitrile is stirred at 25° C. for 30 min. Then 2-methyl-2-propanol (3.9 g, 5.0 mL, 0.053 mol) is added and the resulting mixture is stirred for 15 hrs. The solids are filtered and the filtrate is evaporated under reduced pressure to yield 4-(t-butoxycarbonyl)-1-methyl-2,6,7-trioxabicyclo[2.2.2]octane as a crude oil. This material is dissolved in 100 mL of tetrahydrofuran and stirred with 50 mL of 10% hydrochloric acid for 1 hr. The pH of the solution is adjusted to 7 with solid sodium bicarbonate and the solvents are removed under reduced pressure. The solids are triturated with methanol and the combined methanol solutions are evaporated to give t-butyl-tris(hydroxymethyl)acetate.
Reaction SMILES: [CH:1]1([N:6]2[CH:21]=[C:9]3[CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12][CH2:13][C:8]3=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:22]>O1CCOCC1>[ClH:22].[CH:1]1([N:6]2[CH:21]=[C:9]3[CH2:10][NH:11][CH2:12][CH2:13][C:8]3=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCC3)cc2C1
Agent: Cl
Solvent: C1COCCO1
Product: c1c2c(nn1C1CCCC1)CCNC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 2-cyclopentyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (720 g, 2.47 mmol) in dioxane (5 mL) is added 4N HCl in dioxane (5 mL, 20 mmol) and the mixture is stirred at rt overnight. The solvent is removed and the residue is washed with ether to give the title compound as a white solid. MS (M+1): 192.1
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16].O[Li].O>CCO>[CH3:16][CH:15]([CH3:17])[CH2:14][CH2:13][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CC(C)CCBr
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: [Li]O
Solvent: CCO
Solvent: O
Product: CC(C)CCOc1ccc(N)c([N+](=O)[O-])c1
Yield: 91 %

Procedure:
A 500 mL 3-neck flask fitted with a stir-bar, condenser, and an Ar inlet was charged with 4-amino-3-nitrophenol (12.0 g, 77.9 mmol), 1-bromo-3-methylbutane (14.7 g, 97.3 mmol), LiOH.H2O (6.55 g, 156 mmol), and EtOH (120 mL). The resultant solution was heated at reflux overnight. Another 3 mL of 1-bromo-3-methylbutane and 1 g of LiOH.H2O were added, and the mixture was heated at reflux overnight again. The solution was cooled and partitioned with EtOAc (250 mL) and H2O (200 mL). The organic phase was washed with 1% aqueous LiOH (2×200 mL), H2O (200 mL), and brine (200 mL), filtered through phase separation paper, and concentrated to a dark red solid. The material was dried to give 15.9 g of 46b as a red solid (91%). 1H NMR (60 MHz, CDCl3): δ 7.2 (d, 1H), 7.0 (dd, 1H), 6.7 (d, 1H), 6.0 (bs, 2H), 3.9 (t, 2H), 1.8-1.4 (m, 3H), 1.0 (d, 6H) ppm. HPLC analysis (15:10:75 H2O:A1:MeOH) showed a purity of 94% with a retention time of 8.6 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:34])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=3[O:31][CH2:32][CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[C:35](Cl)([Cl:37])=[O:36]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:34])[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:35]([Cl:37])=[O:36])[C:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][C:22]=3[O:31][CH2:32][CH3:33])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Solvent: CCN(CC)CC
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with phosgene in the presence of triethylamine to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](Cl)(=O)C>CO>[CH3:13][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([F:12])[C:9]([F:11])=[CH:10][C:2]=1[Cl:1]
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1cc(F)c(F)cc1Cl
Yield: 84 %

Procedure:
To a stirred suspension of 5.0 g (26 mmol) 2-Chloro-4,5-difluoro-benzoic acid (Apollo) and 50 ml methanol were added 7.41 ml (104 mmol) acetyl chloride drop wisely at 0° C. The reaction mixture was stirred over night, filtered and concentrated. The residue was diluted with dichloromethane, washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The residue was purified by column chromatography (hexane:ethylacetate). The desired product 22a was obtained in 84% yield (4.51 g, 21.8 mmol).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:24])[NH:4][C:5](=[O:23])[N:6]([CH:8]2[CH2:13][S:12][CH:11]([CH2:14][O:15]CC3C=CC=CC=3)[CH2:10][O:9]2)[CH:7]=1.CO.C(Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:3](=[O:24])[NH:4][C:5](=[O:23])[N:6]([CH:8]2[CH2:13][S:12][CH:11]([CH2:14][OH:15])[CH2:10][O:9]2)[CH:7]=1
Reactant: O=c1[nH]c(=O)n(C2CSC(COCc3ccccc3)CO2)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]c(=O)n(C2CSC(CO)CO2)cc1F
Temperature: -78 °C
Reaction time: 4 h
Yield: 32.1 %

Procedure:
5-Fluoro-1-(5-benzyloxymethyl-1,4-oxathian-2-yl)uracil (0.46 g) was dissolved in methylene chloride (50 ml), and the solution cooled to -78° C. To the solution, t-boron trichloride (13.1 ml) was added dropwise, and the mixture stirred at the same temperature for 4 hours. After adding a mixture of methanol-methylene chloride (1/1, 14 ml) and then sodium bicarbonate thereto, the resultant mixture was stirred at room temperature. Upon filtering the mixture to remove solid materials, the filtrate was concentrated, and the residue was purified on a silica gel column chromatography (eluent: chloroform/methanol=15/1) to obtain the desired product (0.11 g) as pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:20])[C:10]3[N:14]=[C:13]([O:15]CC)[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[F:28][C:29]([F:35])([F:34])[CH2:30][CH2:31][Mg]Br>C1COCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([OH:20])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:31][CH2:30][C:29]([F:35])([F:34])[F:28])[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: FC(F)(F)CC[Mg]Br
Reactant: CCOc1nc2c(C(=O)c3ccccn3)cc(-c3c(C)noc3C)cc2[nH]1
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1cc(C(O)(CCC(F)(F)F)c2ccccn2)c2[nH]c(=O)[nH]c2c1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone (50 mg, 0.14 mmol) was dissolved in dry THF (1.4 mL) and cooled to 0° C. (3,3,3-trifluoropropyl)magnesium bromide (0.5 M, 0.55 mL, 0.28 mmol) was added dropwise and the reaction was allowed to stir for 10 mins and then quenched with water. Reaction was extracted three times with EtOAc and combined organic layers were washed once with water and concentrated. Residue was taken up in EtOH (1.5 mL) and 4.0M HCl/dioxane (0.75 mL), heated to 65° C. for two hours, concentrated, then purified by reverse-phase HPLC to afford the desired product as a white powder.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=O)=[C:6]([OH:10])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.CCCCCCC.[C:20](OCC)(=[O:22])[CH3:21]>ClCCl>[F:1][C:2]1[C:7]([CH2:8][CH2:21][CH2:20][OH:22])=[C:6]([OH:10])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c(C=O)c1O
Reactant: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCCC
Product: COc1ccc(F)c(CCCO)c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4.46 g of 6-fluoro-2-hydroxy-3-methoxybenzaldehyde in 50 ml of dichloromethane there was added 10 g of (triphenyl phosphoranilidene)acetic acid ethyl ester while cooling on ice. After stirring at room temperature for 30 minutes, the reaction mixture was poured into a silica gel column and elution was performed with heptane-ethyl acetate=3:1. The eluate was concentrated under reduced pressure. The residue was dissolved in 100 ml of ethyl acetate, 1 g of 10% palladium-carbon was added, and the mixture was stirred at room temperature for 7 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 100 ml of THF, and then 2 g of lithium borohydride was added while cooling on ice and the mixture was stirred overnight at room temperature. After adding 1N hydrochloric acid to the reaction mixture while cooling on ice, extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (4.78 g) as a solid.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[OH:28][CH2:29][C:30](O)=[O:31]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:29](=[O:28])[CH2:30][OH:31])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)CO
Agent: Cl
Product: O=C(CO)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (11 mg, 50%), MS (ISP) m/z=390.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (20 mg, 0.0543 mmol) and 2-hydroxyacetic acid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:15][N:14]([CH2:16][C:17]([F:20])([F:19])[F:18])[C:13](=[O:21])[C@H:12]([NH:22][C:23]([N:25]2[CH2:30][CH2:29][CH:28]([N:31]3[C:39]4[C:34](=[N:35][CH:36]=[CH:37][CH:38]=4)[NH:33][C:32]3=[O:40])[CH2:27][CH2:26]2)=[O:24])[CH2:11][CH2:10]1.[K].[P:42]([O:60][CH2:61]Cl)([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43]>>[P:42]([O:60][CH2:61][N:33]1[C:34]2=[N:35][CH:36]=[CH:37][CH:38]=[C:39]2[N:31]([CH:28]2[CH2:29][CH2:30][N:25]([C:23]([NH:22][C@@H:12]3[CH2:11][CH2:10][C@@H:9]([C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=4[F:1])[CH2:15][N:14]([CH2:16][C:17]([F:18])([F:19])[F:20])[C:13]3=[O:21])=[O:24])[CH2:26][CH2:27]2)[C:32]1=[O:40])([O:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:43]
Reactant: O=P(OCCl)(OCc1ccccc1)OCc1ccccc1
Reactant: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(CC(F)(F)F)C1=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Agent: [K]
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(CC(F)(F)F)C1=O)N1CCC(n2c(=O)n(COP(=O)(OCc3ccccc3)OCc3ccccc3)c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyri din-1-yl)piperidine-1-carboxamide, potassium salt, [Burgey et al. U.S. Pat. No. 6,953,790 B2] (1.00 g, 1.65 mmol) in anhydrous, degassed DMF (200 mL) at ambient temperature was added dibenzyl chloromethyl phosphate [Mäntylä et al. Tetrahedron Lett. 2002, 43, 3793] (0.54 g, 1.65 mmol). The resulting mixture was stirred at ambient temperature for 4 h, filtered, and purified by preparative HPLC on a C18 reversed phase column, eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 0:100:0.1. The product-containing fractions were poured into saturated aqueous NaHCO3 and extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=857.7 (M+1).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][CH2:15][CH2:16][OH:17].C(Cl)(Cl)Cl>CO>[OH:17][CH2:16][CH2:15][NH:14][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: NC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NCCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NC(=O)c1ccc(NCCO)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
Add 6.0 g (0.03 moles) 4-chloro-3-nitrobenzamide to 60 ml 2-aminoethanol and stir at ambient temperature. When TLC (silica support; 9:1 CHCl3 :MeOH eluent) shows no starting material, ca. 3 hrs., pour onto ice. Filter, wash (3×15 ml) with cold H2O, and recrystallize from MeOH/IPA. Yield is 4.5 g (66%) of orange crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[O:22]CC2C=CC=CC=2)[NH:15][CH:14]=1)=[O:12].CO.[H][H]>[Pd].C(O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[OH:22])[NH:15][CH:14]=1)=[O:12]
Reactant: COc1ccc(NC(=O)c2c[nH]c3cccc(OCc4ccccc4)c23)c(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: COc1ccc(NC(=O)c2c[nH]c3cccc(O)c23)c(F)c1

Procedure:
N-(2-Fluoro-4-methoxyphenyl)-4-benzyloxy-1H-indole-3-carboxamide (1.34 g, 3.4 mmol), prepared using the method above, was slurried with 10% palladium on carbon (134 mg) in ethanol (35 mL) in a Parr bottle and placed under a hydrogen atmosphere (50 psi) for 5 h. Methanol (5 ml) was added and the mixture returned to the Hydrogen atmosphere for an additional 18 h. The solution was filtered through Celite, concentrated in vacuo, and the residue purified by flash chromatography to afford N-(2-fluoro-4-methoxyphenyl)-4-hydroxy-1H-indole-3-carboxamide (Compound 2) as a beige solid; mp 259-261° C. (d).
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH:35]1[CH2:40][CH2:39][O:38][C:36]1=[O:37]>>[CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=2)[O:31][CH:35]2[CH2:40][CH2:39][O:38][C:36]2=[O:37])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OCCC1O
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(O)c3)cc2)cccc1[N+](=O)[O-]
Product: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(OC4CCOC4=O)c3)cc2)cccc1[N+](=O)[O-]

Procedure:
The product from Example 61F and α-hydroxy-γ-butyrolactone were processed as described in Example 62A to provide the title compound.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:38])/[C:6](/[NH:17][C:18](=[O:37])[C:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])=[CH:21][C:20]=1[Cl:36])=[CH:7]/[C:8]1[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=1[CH3:16]>CO.O1CCCC1>[Cl:36][C:20]1[CH:21]=[C:22]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])[CH:23]=[CH:24][C:19]=1[C:18]([NH:17]/[C:6](=[CH:7]\[C:8]1[S:12][C:11]([CH:13]([CH3:14])[CH3:15])=[N:10][C:9]=1[CH3:16])/[C:5]([OH:38])=[O:4])=[O:37]
Reactant: COC(=O)/C(=C/c1sc(C(C)C)nc1C)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(C(C)C)sc1/C=C(\NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.9 %

Procedure:
An aqueous 1N solution of sodium hydroxide (1 mL, 1 mmol) was added to a solution of (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-[2-(1-methylethyl)-4-methylthiazol-5-yl)]propenoic acid methyl ester (Example 233; 65 mg, 0.123 mmol) in methanol/tetrahydrofuran (1:1; 2 mL). The solution was stirred at room temperature for 18 h, then at 50° C. for 6 h and finally at room temperature for 16 h. The reaction mixture was evaporated to dryness and after the addition of water the solution was acidified with 1N hydrochloric acid solution. The gelatinous colorless solid that precipitated was recovered by filtration and washed thoroughly with water. It was re-suspended in water and lyophilized. The obtained tacky material was dissolved in methanol (0.25 mL) and treated to constant turbidity with water. The resulting off-white solid was filtered off, washed with water/methanol (9:1) and dried in vacuo (45° C., 66 h) to give (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-[2-(1-methylethyl)-4-methylthiazol-5-yl]propenoic acid (41 mg, 65% yield) as an off-white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:15])[C:7]=1[N:8]1[CH2:12][CH2:11][CH:10]([C:13]#[N:14])[CH2:9]1.[OH-:16].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:15])[C:7]=1[N:8]1[CH2:12][CH2:11][CH:10]([C:13]([NH2:14])=[O:16])[CH2:9]1
Reactant: N#CC1CCN(c2c(Cl)cncc2Cl)C1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)C1CCN(c2c(Cl)cncc2Cl)C1
Yield: 73 %

Procedure:
A solution of 1-(3,5-dichloropyridin-4-yl)pyrrolidine-3-carbonitrile 14 (83 mg, 0.34 mmol) in sulphuric acid (3 mL) was stirred for 90 min and then poured onto ice/water (100 g). The mixture was made basic by the addition of a 2 M solution of sodium hydroxide and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried (MgSO4) and concentrated under reduced pressure, to furnish the title compound as a white solid (65 mg, 73%), m.p. 161-163° C.; umax (CHCl3)/cm−1 3053, 2985, 1689, 1558, 1465; m/z (ESI) C10H12Cl2N3O requires 260.0352 found [M+H]+ 260.0355.