Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([C:9]1[CH:14]=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].Cl[C:27]1[N:32]=[C:31]([NH:33][C:34]([C:36]2([C:39]3[CH:49]=[CH:48][C:42]4[O:43][C:44]([F:47])([F:46])[O:45][C:41]=4[CH:40]=3)[CH2:38][CH2:37]2)=[O:35])[CH:30]=[CH:29][C:28]=1[CH3:50]>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:47][C:44]1([F:46])[O:43][C:42]2[CH:48]=[CH:49][C:39]([C:36]3([C:34]([NH:33][C:31]4[CH:30]=[CH:29][C:28]([CH3:50])=[C:27]([C:12]5[CH:13]=[CH:14][C:9]([C:3]([OH:8])([C:4]([F:6])([F:5])[F:7])[C:2]([F:1])([F:25])[F:24])=[CH:10][CH:11]=5)[N:32]=4)=[O:35])[CH2:38][CH2:37]3)=[CH:40][C:41]=2[O:45]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: CC1(C)OB(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 120 °C
Yield: 74.9 %

Procedure:
To a mixture of 1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (110 mg, 0.30 mmol) and N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (73 mg, 0.20 mmol) in DME (2 mL) and 2 M Na2CO3 (0.2 mL) was added Pd(PPh3)4 (12 mg, 0.010 mmol). The mixture was heated in microwave oven at 120° C. for 30 min. The mixture was partitioned between ethyl acetate and H2O, and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography (10-20% ethyl acetate-hexane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-5-methylpyridin-2-yl)cyclo-propanecarboxamide (86 mg, 75%). 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.3 Hz, 2H), 7.65 (s, 1H), 7.54-7.48 (m, 1H), 7.45 (d, J=8.6 Hz, 2H), 7.13 (td, J=10.0, 1.7 Hz, 2H), 6.99 (d, J=8.2 Hz, 1H), 2.21 (s, 3H), 1.68 (q, J=3.6 Hz, 2H), 1.09 (q, J=3.6 Hz, 2H). MS (ESI) m/e (M+H+) 575.3.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[C:25]1(=O)[CH2:28][CH2:27][CH2:26]1>CN(C)C(=O)C>[C:25]1(=[N:1][N:2]2[C:7](=[O:8])[C:6]([C:9]3[NH:14][C:13]4[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=4[S:11](=[O:20])(=[O:19])[N:10]=3)=[C:5]([OH:21])[C:4]3[S:22][CH:23]=[CH:24][C:3]2=3)[CH2:28][CH2:27][CH2:26]1
Reactant: O=C1CCC1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Solvent: CC(=O)N(C)C
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1N=C1CCC1
Temperature: 25 °C
Yield: 76.9 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with cyclobutanone (1.0 g, 14.3 mmol) in N,N-dimethylacetamide (2 mL) in a sealed tube at 135° C. for 60 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.086 g 77%).
Reaction SMILES: [ClH:1].[NH:2](C(OC(C)(C)C)=O)[C@H:3]([C:7]([N:9]1[CH2:32][CH2:31][CH2:30][C@H:10]1[C:11]([NH:13][C@H:14]([C:18]([C:20]([C:23]([C:26]([F:29])([F:28])[F:27])([F:25])[F:24])([F:22])[F:21])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])=[O:8])[CH:4]([CH3:6])[CH3:5]>C(OCC)(=O)C>[NH2:2][C@H:3]([C:7]([N:9]1[CH2:32][CH2:31][CH2:30][C@H:10]1[C:11]([NH:13][C@H:14]([C:18]([C:20]([C:23]([C:26]([F:29])([F:27])[F:28])([F:24])[F:25])([F:21])[F:22])=[O:19])[CH:15]([CH3:16])[CH3:17])=[O:12])=[O:8])[CH:4]([CH3:5])[CH3:6].[ClH:1]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)C(F)(F)C(F)(F)C(F)(F)F)C(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)C(F)(F)C(F)(F)C(F)(F)F)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bubble HCl gas into a stirred solution of Boc-Val-Pro-Val-CF2CF2CF3 (0.21 g, 0.37 mmol) in ethyl acetate (50 mL) and cool in an ice water bath. Treat with hydrogen chloride gas for 4 minutes. Stir the reaction mixture for 1 hour and warm to ambient temperature. Concentrate the reaction mixture and azeotrope with CCl4. Place under a high vacuum to give the title compound as a white solid. (Yield: 185 mg, 100%).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:37]=[CH:36][C:17]([CH2:18][N:19]4[CH:23]=[C:22](/[CH:24]=[CH:25]/[C:26]([O:28]CC)=[O:27])[C:21]([C:31]5[S:32][CH:33]=[CH:34][CH:35]=5)=[N:20]4)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:37]=[CH:36][C:17]([CH2:18][N:19]4[CH:23]=[C:22](/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])[C:21]([C:31]5[S:32][CH:33]=[CH:34][CH:35]=5)=[N:20]4)=[CH:16][CH:15]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)/C=C/c1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Temperature: 50 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
After a mixture of ethyl(E)-3-[1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazol-4-yl]propenoate (1.25 g), 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at 50° C. for 2 hours, 1N hydrochloric acid (5 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain (E)-3-[1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazol-4-yl]propenoic acid (970 mg, yield 82%). This was recrystallized from ethyl acetate-hexane. Melting point: 137˜138° C.
Reaction SMILES: C(OC(=O)C)(=[O:3])C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][N+:13]([O-])=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][NH:13][C:12](=[O:3])[CH:11]=1
Reactant: COc1cc[n+]([O-])cc1
Reactant: CC(=O)OC(C)=O
Product: COc1cc[nH]c(=O)c1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
Acetic anhydride (36.3 mL) was added to 4-Methoxy pyridine N-oxide (1.09 g) and the resulting solution was warmed to 130° C. and stirred overnight. After 16 h of stirring, the crude mixture was concentrated on the rotavap. 10 mL of a 1:1 MeOH—H2O solution was added and the resulting mixture was stirred overnight. After 10 h, the mixture was concentrated to a solid. The solid was recrystallized in AcCN, filtered and rinsed with ether.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16](O)=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:23]=[CH:22][O:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[CH2:56]([O:58][C:59](=[O:71])[C@H:60]([CH2:62][C:63]1[CH:68]=[CH:67][C:66]([C:69]#[N:70])=[CH:65][CH:64]=1)[NH2:61])[CH3:57]>CS(C)=O>[CH2:56]([O:58][C:59](=[O:71])[C@@H:60]([NH:61][C:16]([C:14]1[CH:13]=[CH:12][C:11]2[N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]([C:19]3[CH:23]=[CH:22][O:21][CH:20]=3)=[N:9][C:10]=2[CH:15]=1)=[O:17])[CH2:62][C:63]1[CH:68]=[CH:67][C:66]([C:69]#[N:70])=[CH:65][CH:64]=1)[CH3:57]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(C#N)cc1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](Cc1ccc(C#N)cc1)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
The carboxylic acid of example 2 (0.060 g, 0.20 mmol) and TBTU (1.3 equiv., 0.26 mmol, 0.084 g) were dissolved in DMSO (0.6 mL) and DIEA (5 equiv., 1.0 mmol, 0.18 mL) was added followed by (S)-4-cyanophenylalanine ethyl ester hydrochloride (1.3 equiv., 0.26 mmol, 0.065 g). The mixture was stirred at room temperature for 1 h and quenched with water. The precipitated solid was collected by filtration, washed with water and dried. The title amide (0.081 g) was obtained as a beige solid.
Reaction SMILES: Br[C:2]1[CH:21]=[N:20][C:5]2[NH:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]3[C:16]([F:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=3[Cl:19])[C:4]=2[C:3]=1[CH3:22].[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:19][C:12]1[C:13]([F:18])=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH2:10][N:9]1[CH2:8][CH2:7][NH:6][C:5]2[N:20]=[CH:21][C:2]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([N:26]4[CH2:25][CH2:24][O:23][CH2:28][CH2:27]4)[CH:34]=3)=[C:3]([CH3:22])[C:4]1=2
Reactant: Cc1c(Br)cnc2c1N(Cc1c(F)ccc(F)c1Cl)CCN2
Reactant: CC1(C)OB(c2cccc(N3CCOCC3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2cccc(N3CCOCC3)c2)cnc2c1N(Cc1c(F)ccc(F)c1Cl)CCN2
Yield: 39.4 %

Procedure:
To a solution of 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-8-methyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (0.048 g, 0.124 mmol) and 3-morpholinophenylboronic acid pinacol ester (0.035 g, 0.124 mmol) in DMF-H2O (9:1, 2 mL) was added PdCl2(PPh3)2 (0.0087 g, 0.0124 mmol) and K2CO3 (0.043 mg, 0.31 mmol). The resulting solution was subjected to microwave irradiation at 125° C. for 20 min. The solvent was filtered using a PTFE frit and then directly purified by prep HPLC using a gradient mixture of ACN—H2O— 0.1% TFA to yield the desired product (0.023 g 40%).
Reaction SMILES: [C:1]([N:4]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=2)[C:20]([O:22]C)=[O:21])=[O:16])[C@@H:7]([CH3:27])[CH2:6]1)(=[O:3])[CH3:2].[OH-].[Li+].O.CO>O1CCCC1>[C:1]([N:4]([C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=2)[C:20]([OH:22])=[O:21])=[O:16])[C@@H:7]([CH3:27])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2cccc(C(=O)O)c2)c2ccccc21

Procedure:
3-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}benzoic acid was prepared following general procedure H, substituting methyl 3-(chlorocarbonyl)benzoate for 6-trifluoromethyl nicotinyl chloride. (Methyl 3-(chlorocarbonyl)benzoate was prepared in one step from 3-(methoxycarbonyl)benzoic acid. Treatment of this carboxylic acid with oxalyl chloride and catalytic DMF afforded methyl 3-(chlorocarbonyl)benzoate in decent yield). Hydrolysis of methyl 3-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}benzoate with lithium hydroxide, water, methanol and tetrahydrofuran yielded 3-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}benzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12](Cl)[N:11]3[CH:15]=[CH:16][N:17]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][N:35]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:36]=2)O1.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:32]3[CH:33]=[N:34][N:35]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:36]=3)[N:11]3[CH:15]=[CH:16][N:17]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1nc(-c2ccc(Br)cc2)cc2nccn12
Reactant: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(-c2nc(-c3ccc(Br)cc3)cc3nccn23)cn1
Temperature: 70 °C
Yield: 39.8 %

Procedure:
To a flask charged with 7-(4-bromophenyl)-5-chloroimidazo[1,2-c]pyrimidine (2.68 g, 8.685 mmol), potassium carbonate (3.601 g, 26.06 mmol), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (Preparation E; 6.628 g, 17.37 mmol) were combined in a glass bomb and the vessel was evacuated and backfilled with argon. To the reaction was added 100 mL of DME and then water (1.252 mL, 69.48 mmol) and argon was bubbled through the reaction for 20 minutes before tetrakis(triphenylphosphine)palladium (0) (1.004 g, 0.8685 mmol) was added in one portion. The reaction was fitted with a septum and argon was bubbled through for 10 minutes before the reaction was sealed and heated to 70° C. for 4 hours 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (Preparation E; 3.3 g, 8.6 mmol) was added. Argon was bubbled through for 10 minutes before the reaction was sealed and heated to 70° C. for 3 hours. The reaction was diluted with 10% methanol in DCM (300 mL), dried with MgSO4, filtered, and then concentration under reduced pressure. The resultant crude was purified by silica gel chromatography eluting with a gradient of 30-75% ethyl acetate in hexanes to afford the title compound (1.625 g, 3.454 mmol, 39.77% yield). MS (apci) m/z=470.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[NH:12][CH:13]=O.[CH2:15]([O:17][C:18](=[O:23])[CH2:19][NH:20][CH:21]=O)[CH3:16].C(N(CC)CC)C.O=P(Cl)(Cl)Cl.N1CCC[C@H]1C(O)=O.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>ClCCl.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:12]1[CH:13]=[C:19]([C:18]([O:17][CH2:15][CH3:16])=[O:23])[N:20]=[CH:21]1
Reactant: COc1cc([N+](=O)[O-])ccc1NC=O
Reactant: CCOC(=O)CNC=O
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cn(-c2ccc([N+](=O)[O-])cc2OC)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 24.5 %

Procedure:
Step N (1): Followed the method of R. Roy et. al Tetrahedron 2007, 63, 4912. To a solution of N-(2-methoxy-4-nitrophenyl)formamide (4.0 g, 28 mmol, U. Mario et. al General Pharmacology, 1979, 10, 309) and N-formylglycine ethyl ester (16.6 g, 153 mmol) in dichloromethane (20 mL) were added triethylamine (28 mL, 72 mmol) and POCl3 (8.0 mL, 200 mmol) dropwise at 0° C. The reaction was stirred at 0° C. for 2 h. The mixture was filtered over silica using dichloromethane/diethyl ether (4/1) and concentrated under reduced pressure. The crude residue was dissolved in THF (100 mL) to which Cu2O (400 mg, 2.8 mmol) and L-proline (644 mg, 5.6 mmol) were added and the resulting solution stirred at rt for 4 h. A solution of aq EDTA (5%) was added to the reaction mixture, which was then extracted with EtOAc. The crude residue was purified using silica gel column chromatography (EtOAc/dichloromethane) to afford ethyl 1-(2-methoxy-4-nitrophenyl)-1H-imidazole-4-carboxylate (2.0 g, 24% yield).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]2[CH:11]=[CH:10][C:9]3=[N:12][S:13][CH:14]=[CH:15][C:8]3=[C:6]2[N:7]=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:1][CH2:2][C:3]2[N:4]=[C:5]3[CH:11]=[CH:10][C:9]4=[N:12][S:13][CH:14]=[CH:15][C:8]4=[C:6]3[N:7]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCc1nc2ccc3nsccc3c2n1
Product: Cc1ccc(S(=O)(=O)OCc2nc3ccc4nsccc4c3n2)cc1

Procedure:
2-Hydroxymethyl-thiazinobenzimidazole derivative (Ia) is reacted with p-toluenesulfonyl chloride to produce 2-p-toluenesulfonyloxymethyl-thiazinobenzimidazole derivative (Ib).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:26][CH3:27])[C:14]([CH2:28][CH2:29][CH2:30][CH2:31]I)=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1.[CH3:33][NH:34][CH3:35].COC1C=CC2NC3C=C(C(OCC4C=CC=CC=4)=O)C4C(=O)NC(=O)C=4C=3C=2C=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:26][CH3:27])[C:14]([CH2:28][CH2:29][CH2:30][CH2:31][N:34]([CH3:35])[CH3:33])=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1
Reactant: COc1cc2c(cc1CCCCI)[nH]c1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Reactant: CNC
Agent: COc1ccc2[nH]c3cc(C(=O)OCc4ccccc4)c4c(c3c2c1)C(=O)NC4=O
Product: COc1cc2c(cc1CCCCN(C)C)[nH]c1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Reaction time: 6 h
Yield: 64 %

Procedure:
Reaction of the iodide (173) prepared as described in example 312 with aqueous dimethylamine using the procedure described in example 179 of Scheme 3 except that the reaction conditions were 6 h at room temperature gave (174) (64%) as an orange powder, mp 162–164° C. 1H NMR δ [(CD3)2SO] 11.85 (s, 1H), 11.04 (br s, 1H), 8.42 (s, 1H), 7.57 (dd, J=8.0, 2.2 Hz, 1H), 7.55 (s, 1H), 7.51–7.43 (m, 3H), 7.42 (s, 1H), 3.93 (s, 3H), 2.77 (t, J=7.4 Hz, 2H), 2.24 (t, J=7.3 Hz, 2H), 2.11 (s, 6H), 1.63 (m, 2H), 1.47 (m, 2H). EIMS found M+=475.1657, 477.1650. C27H26ClN3O3 requires 475.1663, 477.1633.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]([OH:18])=O)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.C(N(C(C)C)CC)(C)C.[Si]([O:41][C@@H:42]([C:56]1[CH:61]=[CH:60][C:59](/[C:62](=[N:64]/O)/[NH2:63])=[CH:58][CH:57]=1)[CH2:43][N:44]1[CH2:49][CH2:48][CH2:47][C@H:46]([CH2:50][C:51]([O:53]CC)=[O:52])[CH2:45]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(Cl)Cl.C1COCC1.CN(C=O)C>[OH:41][C@@H:42]([C:56]1[CH:61]=[CH:60][C:59]([C:62]2[N:64]=[C:16]([C:9]3[S:10][C:11]([C:12]([F:13])([F:14])[F:15])=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[O:18][N:63]=2)=[CH:58][CH:57]=1)[CH2:43][N:44]1[CH2:49][CH2:48][CH2:47][C@H:46]([CH2:50][C:51]([OH:53])=[O:52])[CH2:45]1
Reactant: O=C(O)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Reactant: CCOC(=O)C[C@H]1CCCN(C[C@@H](O[Si](C)(C)C(C)(C)C)c2ccc(/C(N)=N/O)cc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(Cl)C(=O)Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)C[C@H]1CCCN(C[C@@H](O)c2ccc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)cc2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To a solution of commercially available 4-phenyl-5-(trifluoromethyl)thiophene-2-carboxylic acid (44.0 mg, 0.162 mmol) in DCM (4 mL) was added oxalyl chloride (45 μL, 0.514 mmol) followed by a drop of DMF. The solution bubbled. After 1 h, diisopropylethylamine (45 μL, 0.258 mmol) was added followed by ethyl 2-((R)-1-((S)-2-(tert-butyldimethylsilyloxy)-2-(4-((Z)—N′-hydroxycarbamimidoyl)phenyl)ethyl)piperidin-3-yl)acetate (50.0 mg, 0.108 mmol) in THF (2 mL). The reaction mixture was stirred overnight and the next day LCMS showed the product had formed so the reaction was treated with TBAF (216 μL, 0.216 mmol) and then heated to 60° C. overnight. The next day, the reaction was extracted from 1 M HCl using EtOAc×3 and the organics layers were combined and concentrated in vacuo. This residue was taken up in a 1:1 mixture of THF and 6 M HCl and heated for 2 h. LCMS after this time showed the desired product so the reaction was concentrated and then purified by HPLC to give 2-((R)-1-((S)-2-hydroxy-2-(4-(5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid (42 mg, 98% yield). MS (M+1)=558.3; HPLC RT=2.11 minutes. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.27 (1H, br. s.), 9.72 (1H, br. s.), 8.14-8.26 (1H, m), 8.05 (2H, m, J=8.36 Hz), 7.61 (2H, m, J=8.14 Hz), 7.41-7.53 (5H, m), 6.35 (1H, br. s.), 5.18 (1H, br. s.), 3.42-3.71 (2H, m), 3.10-3.21 (1H, m), 2.63-2.94 (2H, m), 2.08-2.31 (3H, m), 1.66-1.91 (3H, m), 0.99-1.24 (1H, m).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:8][CH2:9][CH:10]2[O:14]C(C3C=CC=CC=3)[N:12]([CH:21]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:22])[CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl>C(O)C>[OH:14][CH:10]([CH2:11][NH:12][CH:21]([CH3:22])[CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:9][O:8][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Cc1cccnc1OCC1CN(C(C)CCc2ccccc2)C(c2ccccc2)O1
Agent: Cl
Solvent: CCO
Product: Cc1cccnc1OCC(O)CNC(C)CCc1ccccc1

Procedure:
A solution of 45 g of crude 3-methyl-2-{[2-phenyl-3-(4-phenyl-2-butyl)-oxazolidin-5-yl]-methoxy}-pyridine in 200 ml of ethanol is hydrolysed with 120 ml of 4 N hydrochloric acid for 3 hours at 20° C. analogously to Example 31, and the mixture is worked up. Distillation in a bulb tube at 140°-150° C./0.04 mm Hg gives 2-[2'-hydroxy-3'-(1-methyl-3-phenyl-propylamino)-propoxy]-3-methyl-pyridine as a light yellow oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH2:10][OH:11])[CH:7]=[N:8][CH:9]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].O>O1CCCC1>[CH3:12][S:13]([O:11][CH2:10][C:6]1[CH:7]=[N:8][CH:9]=[C:4]([Br:3])[CH:5]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)OCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) suspension of sodium hydride (60% dispersion in mineral oil, 0.064 g, 1.60 mmol) in tetrahydrofuran (5 mL) was added a solution of (5-bromopyridin-3-yl)methanol (0.200 g, 1.06 mmol) in tetrahydrofuran (5 mL). After stirring for 1 hour, methanesulfonyl chloride (0.099 mL, 1.28 mmol) was added. The reaction was then warmed to room temperature and stirred until complete. The reaction was then poured into water and extracted with ethyl acetate. The organic extracts were combined, washed with water and saturated aqueous sodium chloride solution, dried, filtered, and concentrated under reduced pressure to provide the title compound: LCMS m/z 267.86 [M+2+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([OH:13])=[O:12].OS(O)(=O)=O>C(O)(C)C.OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH:2]([CH3:7])[CH3:3])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([O:13][CH:5]([CH3:6])[CH3:4])=[O:12]
Reactant: O=C(O)c1ccc(C(=O)O)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC(C)OC(=O)c1ccc(C(=O)OC(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 2.0 g of product from Example 1 suspended in 25 ml of isopropyl alcohol was added 0.3 ml of conc. H2SO4 and the reaction mixture heated at reflux for about 18 hours. Conc. H2SO4 (5 drops) was then added and heating continued for an additional 24 hours. The reaction mixture was cooled to room temperature. The solvent was removed and the residue treated with 50 ml of saturated sodium bicarbonate solution and 50 ml of ethyl acetate. The organic phase was dried over sodium sulfate and the solvent removed under nitrogen. Dissolution in pentane followed by removal of the solvent gave the above product.