Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:27])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:26])[C@H:17]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:27])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:26])[C@H:17]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:18][S:41]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:43])=[O:42])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 86.9 %

Procedure:
L-phenylalanyl-L-proline benzylester hydrochloride (1.94 g, 5 mmole) was dissolved in methylene chloride (30 ml), and triethylamine (1.11 g, 11 mmole) was added thereto at -30° C. Methylene chloride (10 ml) solution of benzene sulfonyl chloride (0.86 g, 5 mmole) was added dropwise to the solution. The mixture was stirred for 1 hour at less than 0° C., and then for 5 hours at room temperature, and methylene chloride (60 ml) was added thereto. The solution was washed with 5% aqueous sodium bicarbonate (100 ml, twice), 1N aqueous hydrochloric acid (100 ml, twice) and water (100 ml) in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give N-benzenesulfonyl-L-phenylalanyl-L-proline benzylester (yield: 2.14 g, 86.9%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][NH:7][C:6]2=[O:13].Br[CH2:17][C:18](=[O:32])[CH2:19][C@H:20]1[C@H:25]([O:26][CH3:27])[CH2:24][CH2:23][CH2:22][N:21]1[C:28]([O:30][CH3:31])=[O:29]>>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]([CH2:17][C:18](=[O:32])[CH2:19][C@H:20]1[C@H:25]([O:26][CH3:27])[CH2:24][CH2:23][CH2:22][N:21]1[C:28]([O:30][CH3:31])=[O:29])[C:6]2=[O:13]
Reactant: O=c1[nH]cnc2ccc(C(F)(F)F)cc12
Reactant: COC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Product: COC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2ccc(C(F)(F)F)cc2c1=O
Yield: 24 %

Procedure:
By the method of Example 4, 6-trifluoromethylquinazolin-4(3H)-one and methyl trans-2-(3-bromo-2-oxopropyl)-3-methoxypiperidine-1-carboxylate were converted into the title compound in 24% yield; m.p. 137°-140° C. 1H-NMR(CDCl3) 1.4-1.9 (m, 4H), 2.9 (d, 3.3 (s, 3H), 3.5-3.9 (m, 4H), 3.7 (s, 3H), 5.2 (s, 2H), 7.7-8.7 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][C:5](Br)=[CH:4][N:3]=1.[OH-].[NH4+:16]>>[OH:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][C:5]([NH2:16])=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: Oc1ncc(Br)nc1N1CCOCC1
Agent: [OH-]
Product: Nc1cnc(O)c(N2CCOCC2)n1

Procedure:
A mixture of 2-hydroxy-3-morpholino-5-bromopyrazine (1 g.) in 100 ml. of concentrated ammonium hydroxide is heated overnight at 100°-140° C. in a sealed tube to give 2-hydroxy-3-morpholino-5-aminopyrazine.
Reaction SMILES: [C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[N:6]1[C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([O:3]C)=[O:2].[OH-].[Na+]>CC(C)=O.O>[C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[N:6]1[C:27](=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([OH:3])=[O:2]
Reactant: COC(=O)C1OC2C(C(=O)N2C(C(=O)OCc2ccccc2)=C(C)C)N1C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C2C1OC(C(=O)O)N2C(=O)c1ccccc1
Yield: 93.1 %

Procedure:
To a solution of 7.02 g of benzyl α-(3ξ-carbomethoxy-2-benzoyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate dissolved in a mixture of 85 ml of acetone and 26.5 ml of water is added 20 ml of 1.012 N aqueous solution of sodium hydroxide at -3° to -4° C. over a period of an hour and the mixture diluted with water and washed with ethyl acetate. The aqueous layer is separated, adjusted to pH 2.0 with 4 N hydrochloric acid, and then extracted with ethyl acetate. The extract is washed with water, dried on sodium sulfate, and concentrated under reduced pressure to yield 6.34 g of benzyl α-(3ξ-carboxy-2-benzoyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate as foamy material.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:28]1[CH2:31][CH:30]([OH:32])[CH2:29]1.C(N(CC)CC)C.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl>[OH:32][CH:30]1[CH2:31][N:28]([C:23]([C:22]2[CH:21]=[CH:20][C:19]([S:16]([N:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:8]3)(=[O:18])=[O:17])=[CH:27][CH:26]=2)=[O:25])[CH2:29]1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Reactant: OC1CNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1)N1CC(O)C1
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
Dissolve 1-Benzhydryl-azetidin-3-ol (250 mg, 1.04 mmoL) in methanol (3.0 mL) and add to Pd(OH)2 (50 mg) under nitrogen. Degas reaction vessel and purge with 60 psi H2 (g). Repeat degass/H2 purge cycle again. Allow to stir under 60 psi H2 for 15 h. Release reaction and filter through celite with additional methanol. Evaporate methanol to yield azetidin-3-ol as a liquid which is used without further purification. Combine 4-(3-Phenyl-indole-1-sulfonyl)-benzoic acid (200 mg, 0.53 mmol) and azetidin-3-ol (50 mg, 0.68 mmol, excess) in dichloromethane (1.0 mL) and triethylamine (0.500 mL, 3.58 mmol, excess) and add benzotriazol-1-yloxytris(dimethylamino)phosphonium hexfluorophosphate (BOP Reagent) (300 mg, 0.66 mmol, excess) at room temperature. Stir for 30 minutes, load entire reaction directly onto pre-packed silica gel column and purify by flash column chromatography (EtOAc/Hexanes) to yield 167 mg of (3-Hydroxy-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone as a white foam (73%). LRMS: MH+ 432.97.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:13][CH:12]=3)=[C:8]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH:32]([CH3:34])[CH3:33])[S:7][C:6]=2[CH:35]=1.[C:36](O)(=[O:38])[CH3:37].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:36]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:15][CH:16]=3)=[C:8]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH:32]([CH3:33])[CH3:34])[S:7][C:6]=2[CH:35]=1)(=[O:38])[CH3:37]
Reactant: CC(C)c1ccccc1-c1sc2cc(O)ccc2c1Oc1ccc(/C=C/C(=O)OC(C)(C)C)cc1
Reactant: CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(Oc3ccc(/C=C/C(=O)OC(C)(C)C)cc3)c(-c3ccccc3C(C)C)sc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.3 %

Procedure:
To a solution of (E)-tert-butyl 3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (63 mg, 0.129 mmol) in DCM (2.5 mL) was added acetic acid (0.030 mL, 0.518 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (99 mg, 0.518 mmol) and 4-dimethylaminopyridine (9.49 mg, 0.078 mmol). The resulting mixture was stirred at room temperature for 16 h after which time the reaction was quenched by addition of 0.1N HCl and diluted with DCM. The phases were separated and the aqueous layer was further extracted with DCM (2×). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO2, 0-40% EtOAc/Heptane) to afford (E)-tert-butyl 3-(4-((6-acetoxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (65 mg, 0.123 mmol, 95% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.50 (d, J=2.0 Hz, 1H), 7.40 (d, J=12.9 Hz, 1H), 7.37 (d, J=5.9 Hz, 1H), 7.28-7.22 (m, 4H), 7.22-7.18 (m, 1H), 7.11-7.02 (m, 1H), 6.98 (dd, J=8.6, 2.1 Hz, 1H), 6.81-6.72 (m, 2H), 6.12 (d, J=15.9 Hz, 1H), 3.11 (p, J=6.8 Hz, 1H), 2.28 (s, 3H), 1.44 (s, 9H), 1.09 (d, J=6.8 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[S:17][C:16]([NH:18]C(=O)C)=[N:15][C:14]=2[CH3:22])[CH:5]=[C:6]([Cl:12])[C:7]=1[S:8](=[O:11])(=[O:10])[NH2:9]>Cl.C(O)C>[NH2:18][C:16]1[S:17][C:13]([C:4]2[CH:5]=[C:6]([Cl:12])[C:7]([S:8]([NH2:9])(=[O:10])=[O:11])=[C:2]([Cl:1])[CH:3]=2)=[C:14]([CH3:22])[N:15]=1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(Cl)c(S(N)(=O)=O)c(Cl)c2)s1
Agent: Cl
Solvent: CCO
Product: Cc1nc(N)sc1-c1cc(Cl)c(S(N)(=O)=O)c(Cl)c1

Procedure:
A solution of N-[5-(3,5-dichloro-4-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 6) (0.70 g, 1.84 mmol) in aqueous hydrochloric acid (5M, 10 ml) and ethanol (20 ml) is heated at reflux for 90 minutes. When cool, the mixture is concentrated to remove ethanol and the aqueous solution is brought to pH 9 by addition of aqueous sodium hydroxide (4M). The product is extracted with n-butanol (50 ml) and the organic extract is dried over MgSO4. Removal of the solvent followed by chromatography on silica (eluting with ethyl acetate-hexane, 2:1 increasing to 4:1) affords the title compd. MH+ (MS, AP+): 337.8, 339.5
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10](Cl)[C:5]=2[S:4][CH:3]=1.[CH:12]([C:15]1[N:19]=[C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[O:17][N:16]=1)([CH3:14])[CH3:13].C(N(C(C)C)CC)(C)C.[OH-].[NH4+]>C(O)(C)C>[Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:23]3[CH2:22][CH2:21][CH:20]([C:18]4[O:17][N:16]=[C:15]([CH:12]([CH3:14])[CH3:13])[N:19]=4)[CH2:25][CH2:24]3)[C:5]=2[S:4][CH:3]=1
Reactant: CC(C)c1noc(C2CCNCC2)n1
Reactant: Clc1ncnc2c(Br)csc12
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1noc(C2CCN(c3ncnc4c(Br)csc34)CC2)n1
Temperature: 100 °C
Reaction time: 12 h
Yield: 61.1 %

Procedure:
7-bromo-4-chlorothieno[3,2-d]pyrimidine (100 mg) was added to isopropyl alcohol (3 mL), and 4-(3-isopropyl-[1,2,4]-oxadiazol-5-yl)piperidine (100 mg) and diisopropylethylamine (200 μL) were further added thereto. The reaction mixture was stirred at 100° C. for 12 hours. Then, the reaction mixture was mixed with saturated ammonium hydroxide solution and extracted twice with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a foamy residue. The residue was crystallized in the presence of diethyl ether to obtain the title compound (100 mg) as a whitish solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[CH2:6][N:7]([C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:8]([C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=1[C:22]([OH:24])=[O:23])=[O:9])=O.[F:38][C:39]1[C:47]([F:48])=[C:46]([F:49])[C:45]([F:50])=[C:44]([F:51])[C:40]=1[CH2:41][O:42][NH2:43]>>[F:38][C:39]1[C:47]([F:48])=[C:46]([F:49])[C:45]([F:50])=[C:44]([F:51])[C:40]=1[CH2:41][O:42][N:43]=[CH:1][C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[CH2:6][N:7]([C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:8]([C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=1[C:22]([OH:24])=[O:23])=[O:9]
Reactant: O=Cc1cccc(CN(C(=O)c2cc(C(=O)O)c(C(=O)O)cc2C(=O)O)[C@H]2CCCc3ccccc32)c1
Reactant: NOCc1c(F)c(F)c(F)c(F)c1F
Product: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(C=NOCc3c(F)c(F)c(F)c(F)c3F)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O

Procedure:
The product from Example 76E and O-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine were processed as described in Example 76F to provide the title compound.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27](O)=[O:28])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:31]=[C:32]([NH2:40])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([C:32]1[N:40]=[C:27]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]3)=[O:10])[CH2:12]2)[O:28][N:31]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Reactant: NC(Cc1ccccc1)=NO
Product: N#CC1CCN(C(=O)N2CC(c3ccc(C(F)(F)F)cc3)CC(c3nc(Cc4ccccc4)no3)C2)CC1

Procedure:
100 mg (0.244 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 100A) and 40.3 mg (0.269 mmol) of N′-hydroxy-2-phenylethanimidamide were reacted according to the General Method 1. Yield: 48.3 mg (38% of theory).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7][OH:8].[CH3:13][S:14]([N:17]([CH2:36][CH2:37][Cl:38])[N:18]([S:32]([CH3:35])(=[O:34])=[O:33])[C:19](OCC1C=CC=CC=1[N+]([O-])=O)=[O:20])(=[O:16])=[O:15]>>[CH3:13][S:14]([N:17]([CH2:36][CH2:37][Cl:38])[N:18]([S:32]([CH3:35])(=[O:33])=[O:34])[C:19]([O:8][CH2:7][C:6]1[CH:9]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])=[O:20])(=[O:15])=[O:16]
Reactant: Cc1ccc([N+](=O)[O-])c(CO)c1
Reactant: CS(=O)(=O)N(CCCl)N(C(=O)OCc1ccccc1[N+](=O)[O-])S(C)(=O)=O
Product: Cc1ccc([N+](=O)[O-])c(COC(=O)N(N(CCCl)S(C)(=O)=O)S(C)(=O)=O)c1

Procedure:
1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(5-methyl-2-nitrobenzyloxy)carbonyl]hydrazine (compound 13e) was prepared from 5-methyl-2-nitrobenzyl alcohol using a procedure similar to that described for compound 13a. The Mp was found to be 112-113° C., and the yield was about 24.3% by weight after recrystallization from ethanol. 1H NMR (acetone-d6): δ 8.1, 7.8 and 7.4 (3H, 2d, s, aromatic H), 5.8 (2H, d, ArCH2), 3.6-4.1 (4H, m, CH2CH2Cl), 3.6 and 3.3 (6H, 2s, 2 CH3SO2), 2.5 (3H, s, ArCH3).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][C@@H:30]([CH3:36])[C:31]([NH:33][CH2:34][CH3:35])=[O:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:34]([NH:33][C:31]([C@@H:30]([NH:29][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])[CH3:36])=[O:32])[CH3:35]
Reactant: CCNC(=O)[C@H](C)N
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)[C@H](C)NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ((S)-1-ethylcarbamoyl-ethyl)-amide (37 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (41 mg), (S)-2-amino-N-ethyl-propionamide (0.37 ml), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 508. 1H NMR (DMSO-d6, 400 MHz): δ 8.38 (d, 1H), 8.13 (s, 1H), 7.92 (s, 2H), 7.86 (br, 1H), 7.73 (br, 1H), 7.48 (d, 1H), 7.36 (d, 1H), 4.46 (p, 1H), 3.66 (s, 3H), 3.12-3.09 (m, 2H), 1.34 (d, 3H), and 1.04 (t, 3H), NH proton signal was not observed.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][C@H:15]1[O:20][C@:16]1([CH3:19])[CH2:17][OH:18]>CO.O.[Ni]>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15][C@:16]([CH3:19])([OH:20])[CH2:17][OH:18]
Reactant: COc1c(C)c(C)c(OC)c(C[C@H]2O[C@]2(C)CO)c1C
Agent: [Ni]
Solvent: CO
Solvent: O
Product: COc1c(C)c(C)c(OC)c(CC[C@](C)(O)CO)c1C
Yield: 86.4 %

Procedure:
185 mg of (2R,3R)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2,3-epoxy-2-methylbutanol were dissolved in 5 ml of methanol and the solution was subsequently diluted with 5 ml of water. Thereupon, Raney-nickel was added and the mixture was heated at reflux for 2 hours under hydrogen. After completion of the hydrogen uptake, the mixture was filtered, washed with methanol and methylene chloride and concentrated on a rotary evaporator. Residual water was distilled off azeotropically by the addition of methylene chloride. The oil obtained was recrystallized from hexane/ether and there were obtained 161 mg of 55% (S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-1,2-butanediol (48% yield; analysis of the acetonide by gas chromatography). Data of the pure substance: m.p. 86°-87° C. [α]D20 +2.55° (c=5.3% in CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10](F)[C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C-:14]#[N:15].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.CCOC(C)=O>[C:14]([C:10]1[C:9]([F:13])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=1)#[N:15]
Reactant: COC(=O)c1cc(F)c(F)cc1F
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)c(C#N)cc1F
Temperature: 60 °C

Procedure:
Methyl 2,4,5-trifluorobenzoate (DSL Chemicals, 950 mg, 5 mmol), sodium cyanide (306 mg, 6.25 mmol) and tetrabutylammonium bromide (2.01 g, 6.25 mmol) were dissolved in DMF (10 mL) and the resulting mixture was heated at 60° C. overnight. Additional amount of sodium cyanide (306 mg, 6.25 mmol) was added and the mixture was stirred at 60° C. for 24 additional hours. The reaction mixture was diluted with EtOAc and washed with brine several times. The organic layer was dried over MgSO4 and concentrated under vacuum. The residue was purified by flash chromatography (silica, EtOAc/cHex) to give the title compound. 1H NMR (DMSO-d6, 300 MHz) δ 7.77 (dd, J=8.4, 5.5 Hz, 1H), 7.42 (dd, J=8.9, 5.0 Hz, 1H), 3.96 (s, 3H). LC/MS (Method B): 463.2 (M−H)−, 465.2 (M+H)+. HPLC (Method A) Rt 3.63 min (Purity: 99.9%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13]([CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])=[CH:12][NH:11][C:10]=1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](#N)C.C(=O)([O-])[O-].[K+].[K+].CI>ClCCl>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13]([CH:16]([OH:21])[C:17]([F:20])([F:18])[F:19])=[CH:12][N:11]([CH3:23])[C:10]=1[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]cc(C(O)C(F)(F)F)c(=O)c1OCc1ccccc1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: ClCCl
Product: Cc1c(OCc2ccccc2)c(=O)c(C(O)C(F)(F)F)cn1C
Temperature: 25 °C
Yield: 70 %

Procedure:
A mixture of 3-benzyloxy-2-methyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (2.07 g, 6.6 mmol), acetonitrile (60 mL), potassium carbonate (2.62 g. 19 mmole) and methyl iodide (15 mL, 0.24 mol) was heated to reflux for 30 min. On cooling to RT, the reaction mixture was filtered over a pad of CELITE™, and the filtrate was concentrated in vacuo to give a solid. The solid was dissolved in dichloromethane, and the resulting solution was washed with brine, dried over Na2S04, filtered and concentrated to afford 3-benzyloxy-1,2-dimethyl5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (1.48 g, 70% yield, HPLC Method 1 (Example 24), RT=15.4 min, HPLC purity (peak percent area): 99.9% at λ=280 nm). 1H NMR (DMSO-d6+D2O) δ ppm: 7.75 (s, 1H), 7.37, (m, 5H), 5.35 (q, J=7.1 Hz, 1H), 5.01 (m, 2H), 3.63 (s, 3H), 2.18 (s, 3H); MS-ESI (m/z) 328.1 [M+1]+, 220.2, 91.2 (100%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:8][O:9][C:10](=[O:13])[CH2:11][NH2:12].Br[CH2:15][CH2:16][S:17][CH2:18][P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>CN(C)C=O>[CH2:21]([O:20][P:19]([CH2:18][S:17][CH2:16][CH2:15][NH:12][CH2:11][C:10]([O:9][CH3:8])=[O:13])([O:23][CH2:24][CH3:25])=[O:26])[CH3:22]
Reactant: CCOP(=O)(CSCCBr)OCC
Reactant: COC(=O)CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(CSCCNCC(=O)OC)OCC

Procedure:
A suspension of potassium carbonate (0.42 g, 3 mmol) in anhydrous dimethylformamide (3 ml) is treated with glycine methyl ester hydrochloride (0.25 g, 2 mmol) and stirred under nitrogen. After 5 minutes diethyl (2-bromoethyl)thiomethylphosphonate (Example G) (0.28 g, 1.08 mmol) is added as a solution in dimethylformamide (0.5 ml). After stirring 48 hours, the dimethylformamide is removed in vacuo, and the residue is dissolved in water and extracted with chloroform (2×30 ml). The organic layer is separated, dried over sodium sulfate, filtered, evaporated, and the residue is purified by silica gel chromatography (60:1 chloroform:methanol as eluant) to give methyl N-[2-[[(diethoxyphosphinyl)methyl]thio]ethyl]glycinate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13](Cl)=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH2:22][C@H:23]([CH2:28][OH:29])[CH2:24][CH:25]([CH3:27])[CH3:26].C(Cl)(Cl)Cl>C(Cl)Cl>[OH:29][CH2:28][CH:23]([NH:22][C:13]([C:6]1[C:7](=[O:12])[NH:8][C:9]2[C:4]([C:5]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)=[O:14])[CH2:24][CH:25]([CH3:27])[CH3:26]
Reactant: O=C(Cl)c1c(-c2ccccc2)c2cc(Cl)ccc2[nH]c1=O
Reactant: CC(C)C[C@H](N)CO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)CC(CO)NC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2[nH]c1=O
Reaction time: 0.08 h
Yield: 52.9 %

Procedure:
To a stirring suspension of 6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinoline-3-carboxylic acid chloride (29 mg, 0.09 mmol) in DCM (0.5 mL) was added (S)-(+)-leucinol (30 μL, 0.23 mmol). Within 5 min, the mixture became homogeneous and the reaction was complete as determined by LCMS. Chloroform (2 mL) was added, and the solution was extracted with IN HCl (4×1 mL) and water (2×1 mL). The chloroform layer was purified directly by flash chromatography eluting with chloroform, then chloroform/methanol (100:1)->(50:1)->(25:1) to afford 6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinoline-3-carboxylic acid (1-hydroxymethyl-3-methylbutyl)amide (b) (19 mg, 52%) as a white powder. MS: 399.2 (M+H).
Reaction SMILES: CO[C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[CH2:13]Br.[CH2:16]([NH2:18])[CH3:17]>>[CH2:16]([N:18]1[CH2:13][C:5]2[C:4](=[CH:9][CH:8]=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=2)[C:3]1=[O:15])[CH3:17]
Reactant: CCN
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1CBr
Product: CCN1Cc2cc([N+](=O)[O-])ccc2C1=O
Reaction time: 3 h
Yield: 85 %

Procedure:
2-Bromomethyl-4-nitro-benzoic acid methyl ester (1.0 g, 3.64 mmol) was stirred in ethylamine (30 ml, 2.0M solution in THF) at room temperature. The reaction was stirred for 3 hrs, after which time the solvent was evaporated in vacuo and the crude residue triturated with diethyl ether. The resulting orange solid was filtered and dried in a vacuum oven (40° C.) to afford the title compound (634 mg, 85%). HPLC retention time 3.56 min. Mass spectrum (ES+) m/z 207 (M+H).