Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][N:4]1[CH2:8][CH2:7][CH:6]([N:9]2[CH:13]=[C:12]([NH2:14])[N:11]=[CH:10]2)[CH2:5]1.[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([NH:28][CH:29]([CH2:33][CH2:34][CH3:35])[C:30](O)=[O:31])=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1>>[CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][N:4]1[CH2:8][CH2:7][CH:6]([N:9]2[CH:13]=[C:12]([NH:14][C:30](=[O:31])[CH:29]([NH:28][C:26](=[O:27])[CH2:25][C:20]3[CH:21]=[C:22]([F:24])[CH:23]=[C:18]([F:17])[CH:19]=3)[CH2:33][CH2:34][CH3:35])[N:11]=[CH:10]2)[CH2:5]1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CC(C)(C)CN1CCC(n2cnc(N)c2)C1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCN(CC(C)(C)C)C2)cn1

Procedure:
1-[1-(2,2-Dimethyl-propyl)-pyrrolidin-3-yl]-1H-imidazol-4-ylamine was coupled with 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.0, 18.9, 28.6, 33.0, 33.4, 35.9, 43.1, 53.1, 55.7, 57.3, 63.5, 68.3, 102.6, 102.8, 103.1, 106.6, 112.3, 112.5, 112.6, 132.1, 137.7, 138.8, 161.9, 164.5, 169.1; MS m/z 476.2 (M+1).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[N:17]=3)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[NH:33]1[CH2:36][CH:35]([C:37]([OH:39])=[O:38])[CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.ClCCCl>[C:1]1([N:7]2[C:11]([C:12]([F:13])([F:14])[F:15])=[C:10]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([CH2:25][N:33]5[CH2:36][CH:35]([C:37]([OH:39])=[O:38])[CH2:34]5)=[CH:27][CH:28]=4)[N:17]=3)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: O=C(O)C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CO
Product: O=C(O)C1CN(Cc2ccc(-c3noc(-c4cnn(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 56 %

Procedure:
To a solution of 4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde (700 mg, 1.821 mmol) in MeOH (12 mL) and 1,2-dichloroethane (3 mL) was added 0.1 mL of acetic acid and azetidine-3-carboxylic acid (203 mg, 2.0 mmol). The mixture was allowed to stir at room temperature for 40 min. and then sodium triacetoxyborohydride (618 mg, 2.91 mmol) was added. The mixture was allowed to stir at room temperature for 5 hours, then was filtered to afford a white solid that was washed with water (1 mL) and MeOH (3×1 mL). The solid was dried under vacuum to give 1-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid (480 mg, 1.02 mmol). The compound had an HPLC retention time=6.91 min. −Column: Low pH Col-1: Sunfire C18 3.5 um, 4.6×150 mm; Start % B=10; 12 Min. 100%; 15 Min. 100%; Flow Rate=2 mL/min; Wavelength1=220; Wavelength2=254; Solvent Pair=TFA-MeCN/H2O; Solvent A=0.05% TFA in H2O:MeCN (95:5); Solvent B=0.05% TFA in H2O:MeCN (5:95); Column 1=LOW pH-Parallel HPLC; At 220 nm LC/MS M+1=470.1 1H NMR (500 MHz, MeOD) δ ppm 3.41 (dt, J=8.8 Hz, 7.7 Hz, 1H), 4.12-4.18 (m, 4H), 4.38 (s, 2H), 7.57-7.66 (m, 7H), 8.23 (d, J=8.3 Hz, 2H), 8.50 (s, 1H).
Reaction SMILES: C([O:4][C:5](=[O:30])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][C:9]=1[C:18](=[O:29])[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=1[F:28])C=C.N1CCCC1>O.O1CCOCC1.C(OCC)(=O)C>[C:15]([NH:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]([OH:30])=[O:4])=[C:9]([C:18](=[O:29])[NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=2[F:28])[CH:10]=1)(=[O:17])[CH3:16]
Reactant: C=CCOC(=O)COc1ccc(NC(C)=O)cc1C(=O)NCc1ccc(Br)cc1F
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(OCC(=O)O)c(C(=O)NCc2ccc(Br)cc2F)c1
Reaction time: 6 h
Yield: 52.2 %

Procedure:
A solution of [4-acetylamino-2-(4-bromo-2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid allyl ester (0.114 g, 0.24 mmol) in 10% H2O in 1,4-dioxane (8 mL, 0.03 M) was treated with pyrollidine (0.05 mL, 0.60 mmol) and [(C6H5)3P]4Pd (0.01 g, 3.6 mol%) was stirred for 6 h. The reaction was diluted with ethyl acetate and washed with 2 N HCl (3×), H2O (2×), saturated aq NaCl, dried over MgSO4, filtered, concentrated and recrystallized from heptane and ethyl acetate to give [4-acetylamino-2-(4-bromo-2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid (0.055 g, 52%) as a white solid: mp 235° C.; 1H NMR (DMSO-d6, 300 MHz) δ 9.93 (br s, 1H), 9.16 (br t, 1H), 7.98 (br d, J=2.7 Hz, 1H), 7.73 (br dd, J1=9.0 Hz, J2=2.7 Hz, 1 H), 7.44-7.20 (m, 2H), 7.20-7.00 (m, 2H), 4.80 (s, 2H), 4.54 br d, J=4.5 Hz, 2H), 1.99 (s, 3H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1.Cl[C:25]1[NH:29][C:28]2[CH:30]=[CH:31][C:32]([C:34]([F:37])([F:36])[F:35])=[CH:33][C:27]=2[N:26]=1>CN(C=O)C>[F:37][C:34]([F:35])([F:36])[C:32]1[CH:31]=[CH:30][C:28]2[NH:29][C:25]([NH:2][C:3]3[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=3)[CH2:6][NH:7][C:8]3[C:17]4[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][N:9]=3)=[N:26][C:27]=2[CH:33]=1
Reactant: NC(=O)c1cccc2c(NCc3cccc(N)c3)ncnc12
Reactant: FC(F)(F)c1ccc2[nH]c(Cl)nc2c1
Agent: Cl
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2c(NCc3cccc(Nc4nc5cc(C(F)(F)F)ccc5[nH]4)c3)ncnc12
Temperature: 100 °C
Reaction time: 15 h

Procedure:
33 mg (0.11 mmol) 4-(3-Amino-benzylamino)-quinazoline-8-carboxylic acid amide hydrochloride and 24 mg (0.11 mmol) 2-Chloro-5-trifluoromethyl-1H-benzoimidazole were dissolved in 500 μl DMF and stirred at 100° C. for 15 h. The reaction mixture was directly purified using preparative HPLC. The product was treated with HCl in methanol and concentrated in the SpeedVac.
Reaction SMILES: [CH2:1]([C:3]12[CH2:19][CH2:18][C:17](=[O:20])[CH:16]=[C:4]1[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14]C)[CH:11]=[CH:10][C:9]=12)[CH3:2].NC(C(O)=O)CCSC.CS(O)(=O)=O>C(Cl)Cl>[CH2:1]([C:3]12[CH2:19][CH2:18][C:17](=[O:20])[CH:16]=[C:4]1[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:9]=12)[CH3:2]
Reactant: CCC12CCC(=O)C=C1CCCc1cc(OC)ccc12
Agent: CS(=O)(=O)O
Agent: CSCCC(N)C(=O)O
Solvent: ClCCl
Product: CCC12CCC(=O)C=C1CCCc1cc(O)ccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.4 %

Procedure:
A mixture containing 11b-ethyl-9-methoxy-1,2,5,6,7,11b-hexahydro-dibenzo[a,c]cyclohepten-3-one (10.2 g, 37.7 mmol) [prepared as described in US2012/238549 A1] and DL-methionine (18.3 g, 123 mmol) in methanesulfonic acid (100 mL, 1.54 mol) was mechanically stirred under nitrogen at rt over about 3 days. The reaction was diluted with DCM (700 mL) and poured carefully onto ice water (700 mL). The layers were separated and the aqueous layer was extracted again with DCM (500 mL). The combined organic layers were washed with water (2×500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (220 g) using a gradient from 0-50% EtOAc in DCM. Product fractions were combined and concentrated under reduced pressure to yield 11b-ethyl-9-hydroxy-1,2,5,6,7,11b-hexahydro-dibenzo[a,c]cyclohepten-3-one (17, R2=Ethyl) (8.54 g, 88%) as an off-white solid. LC/MS, method 1, 0.73 min, 319 (M+H)+. 1H NMR (400 MHz, DMSO) δ 9.19 (s, 1H), 7.11 (d, J=8.6 Hz, 1H), 6.62 (dd, J=8.5, 2.7 Hz, 1H), 6.51 (d, J=2.7 Hz, 1H), 5.81 (s, 1H), 2.79-2.70 (m, 1H), 2.67-2.52 (m, 1H), 2.44-2.35 (m, 2H), 2.33-2.18 (m, 3H), 2.14-2.04 (m, 1H), 2.01-1.90 (m, 1H), 1.86-1.66 (m, 3H), 0.78 (t, J=7.4 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1([OH:26])[CH2:21][CH2:20][C:19]2[C:6](=[C:7]([OH:25])[C:8]3[C:9](=[O:24])[C:10]4[C:15]([C:16](=[O:22])[C:17]=3[CH:18]=2)=[C:14]([OH:23])[CH:13]=[CH:12][CH:11]=4)[CH2:5]1)(=[O:3])[CH3:2].[CH2:27](O)[CH2:28][OH:29]>C1C=CC=CC=1>[CH2:27]1[CH2:28][O:29][C:1]([C:4]2([OH:26])[CH2:21][CH2:20][C:19]3[C:6](=[C:7]([OH:25])[C:8]4[C:9](=[O:24])[C:10]5[C:15]([C:16](=[O:22])[C:17]=4[CH:18]=3)=[C:14]([OH:23])[CH:13]=[CH:12][CH:11]=5)[CH2:5]2)([CH3:2])[O:3]1
Reactant: OCCO
Reactant: CC(=O)C1(O)CCc2cc3c(c(O)c2C1)C(=O)c1cccc(O)c1C3=O
Solvent: c1ccccc1
Product: CC1(C2(O)CCc3cc4c(c(O)c3C2)C(=O)c2cccc(O)c2C4=O)OCCO1

Procedure:
A solution of (±)-2-acetyl-2,7,12-trihydroxy-1,2,3,4-tetrahydronaphthacene-6,11-dione (740 mg; 2.1 mmol) and ethylene glycol (280 mg; 4.4 mmol) in 400 ml of benzene, in the presence of a catalytic quantity of paratoluenesulfonic acid, is heated under reflux for 12 hours in a 500 ml round-bottomed flask. The flask is equipped with a "Dean Stark" apparatus (making it possible to remove the water formed as an azeotrope with benzene).
Reaction SMILES: F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.N#N.Br[C:22]1[CH:23]=[C:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=[CH:26][CH:27]=1.[CH2:36]([OH:39])[CH:37]=[CH2:38].C1(N(C)C2CCCCC2)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:31]([O:30][C:29](=[O:35])[NH:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([CH2:38][CH2:37][CH:36]=[O:39])[CH:23]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)c1
Reactant: C=CCO
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1cccc(CCC=O)c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 27.3 %

Procedure:
Tris(dibenzylideneacetone)dipalladium (0.10 g, 0.00011 mol) and tri-tert-butylphosphonium tetrafluoroborate (0.064 g, 0.00022 mol) in a flask was evacuated and refilled with N2 (3 times). Then 1,4-dioxane (7.0 mL) was added followed by consecutive addition of tert-butyl (3-bromophenyl)carbamate (2.00 g, 0.00735 mol), 2-propen-1-ol (0.854 g, 0.0147 mol), N-cyclohexyl-N-methyl-cyclohexanamine (1.7 g, 0.0088 mol). The reaction mixture was stirred at 40° C. overnight, filtered, and washed with dichloromethane. The filtrate was concentrated and purified by chromatography on silica gel with 40% EtOAc in hexanes to afford the desired product (0.5 g, 30%).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].[C:12](Cl)(=[O:14])[CH3:13]>C(Cl)Cl.O>[C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH:7][C:12](=[O:14])[CH3:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1ccccc1N
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1ccccc1C(C)(C)C
Temperature: 25 °C
Yield: 106.5 %

Procedure:
A solution of 2-tert-butylaniline (2.0 g, 2.1 mL, 13.4 mmol) and TEA (2.8 mL, 20.1 mmol) in DCM (100 mL) was cooled to 0° C. Acetyl chloride (1.0 mL, 14.7 mmol) was added dropwise. The resulting solution was allowed to stir and warm to rt over 2 h. The reaction mixture was diluted with water and DCM. The organic phase was washed with 1N HCl and brine, dried over Na2SO4, filtered and concentrated to give the title compound as a white solid (2.73 g, >100%). 1H NMR (400 MHz, CDCl3) δ: 7.51-7.53 (m, 1H), 7.39-7.41 (m, 1H), 7.14-7.24 (m, 2H), 2.21 (s, 2.2H), 1.92 (s, 0.9H), and 1.41 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]3[C:15]([C:16]4[CH:28]=[CH:27][O:26][C:17]=4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[C:4](/[CH:29]=[CH:30]\[CH2:31][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:3]=1.C(N(CC)C/C=C\[Sn](CCCC)(CCCC)CCCC)C.BrC1C=C([F:65])C=CC=1S(NC1C(C(OC)=O)=C2C(C3C(F)=COC=3CO2)=CC=1)(=O)=O>>[CH2:36]([N:32]([CH2:33][CH3:34])[CH2:31]/[CH:30]=[CH:29]\[C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]2[C:15]([C:16]3[C:28]([F:65])=[CH:27][O:26][C:17]=3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:9])=[O:10])[CH3:35]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CN2CCCC2)ccc2c1OCc1occc1-2
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1occ(F)c1-2
Agent: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1occ(F)c1-2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 53, starting from N,N-diethyl-N-((Z)-1-tributylstannanylprop-1-en-3-yl)-amine (Intermediate 3) and methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-1-fluoro-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 97).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](I)=[C:5]([O:10][CH3:11])[C:4]=1[O:12][CH3:13].C([Li])CCC.[CH3:19][N:20]([CH3:32])[C:21]1[CH:30]=[C:29]2[C:24]([C:25](=O)[CH2:26][CH2:27][O:28]2)=[CH:23][CH:22]=1>>[CH3:19][N:20]([CH3:32])[C:21]1[CH:30]=[C:29]2[C:24]([C:25]([C:7]3[CH:8]=[C:3]([O:2][CH3:1])[C:4]([O:12][CH3:13])=[C:5]([O:10][CH3:11])[CH:6]=3)=[CH:26][CH2:27][O:28]2)=[CH:23][CH:22]=1
Reactant: CN(C)c1ccc2c(c1)OCCC2=O
Reactant: COc1ccc(I)c(OC)c1OC
Agent: [Li]CCCC
Product: COc1cc(C2=CCOc3cc(N(C)C)ccc32)cc(OC)c1OC

Procedure:
Compounds of this invention having the Formulae I-IV can also be prepared as illustrated by examplary reactions in Scheme V. A phenyl propionitrile is prepared from the condensation of acrylonitrile and dimethylaminophenol. The nitrile was hydrolysed to the acid and the intermediate compound cyclized to yield 7-dimethylamino-chroman-4-one. Trimethoxyiodobenzene was lithiated with butyl lithium and treated with 7-dimethylamino-chroman-4-one to produce dimethyl-[4-(3,4,5-trimethoxy-phenyl)-2H-chromen-7-yl]-amine. Alternatively, 7-dimethylamino-chroman-4-one could be first treated with copper chloride, followed by the addition of lithio trimethoxybenzene, to produce [3-chloro-4-(3,4,5-trimethoxy-phenyl)-2H-chromen-7-yl]-dimethyl-amine.
Reaction SMILES: [C:1]1([N:7]([CH:15]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16]2)[CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:28](C)=O.[Na+].[OH-].[Na+]>ClCCCl.C(Cl)Cl.C(O)(=O)C>[CH3:28][N:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[CH2:8][N:7]([CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: c1ccc(N(CC2CCCCN2)C2Cc3ccccc3C2)cc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CCCCC1CN(c1ccccc1)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of compound 16 (0.2 g, 0.65 mmol) in DCE (10 mL) were added successively formaldehyde (35% in H2O, 0.08 mL, 0.98 mmol), Na(OAc)3BH (0.415 g, 1.95 mmol) and acetic acid (AcOH, 0.1 mL) at ice-cold conditions. The resulting mixture was allowed to stir at rt for 16 hours. The reaction mixture was diluted with DCM and basified with NaOH (1N). The organic layer was separated and washed with water and brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by chromatography on 230-400 mesh silica gel eluting with 5% methanol-DCM to provide compound 17.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1(S(C=C)(=O)=O)C=CC=CC=1.[NH2:21][C@@H:22]([CH2:24][OH:25])[CH3:23].Cl[C:27]1[C:28]2[S:45][C:44](=[O:46])[N:43]([CH2:47][CH2:48][S:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)(=[O:51])=[O:50])[C:29]=2[N:30]=[C:31]([S:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=2[F:42])[N:32]=1>C(#N)CCC.O>[F:42][C:36]1[C:37]([F:41])=[CH:38][CH:39]=[CH:40][C:35]=1[CH2:34][S:33][C:31]1[N:32]=[C:27]([NH:21][C@H:22]([CH3:23])[CH2:24][OH:25])[C:28]2[S:45][C:44](=[O:46])[N:43]([CH2:47][CH2:48][S:49]([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)(=[O:50])=[O:51])[C:29]=2[N:30]=1
Reactant: C[C@@H](N)CO
Reactant: O=c1sc2c(Cl)nc(SCc3cccc(F)c3F)nc2n1CCS(=O)(=O)c1ccccc1
Agent: C=CS(=O)(=O)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCCC#N
Product: C[C@H](CO)Nc1nc(SCc2cccc(F)c2F)nc2c1sc(=O)n2CCS(=O)(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
To a stirred suspension of 7-chloro-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-2-(31)-one (31.62 g), as prepared in Example 1 (c) above, in butyronitrile (150 ml) at room temperature was added diisopropylethylamine (16 ml, 1.0 eq), forming a solution. A butyronitrile line wash was applied (10 ml). Phenylvinylsulfone (20 g, 1.3 eq) was dissolved in butyronitrile (80 ml) in a separate flask and this solution was added to the vessel, followed by a line wash with butyronitrile (70 ml). The orange solution was heated to an internal temperature of 100° C. After 18 hours HPLC showed almost complete consumption of the starting material (3.36% 7-chloro-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-2-(3H)-one remained)*. At this point further diisopropylethylamine (16 ml, 1.0 eq) was added to the mixture at 50° C., followed by a small line wash of butyronitrile (5 ml). D-alaninol (9.25 mLs, 1.3 eq) was added, followed by a line wash of butyronitrile (5 ml). After 6.5 hrs HPLC showed almost complete conversion of the reaction intermediate (2.52% 7-chloro-5-[[(2,3-difluorophenyl)methyl]thio]-3-[2-(phenylsulfonyl)ethyl]thiazolo[4,5-a]pyrimidin-2-(3H)-one remained). The reaction was allowed to cool from 100 to 50° C. over 6.5 hrs and held at 50° C. under nitrogen for 64 hrs. In order to get a homogeneous sample the reaction was re-heated to 100° C. (1.19% 7-chloro-5-[[(2,3-difluorophenyl)methyl]thio]-3-[2-(phenylsulfonyl)ethyl]thiazolo[4,5-d]pyrimidin-2-(3H)-one present by HPLC). The reaction was cooled from 100 to 50° C. over 1 hr and water (200 mLs) was added. A precipitate was observed. The mixture was cooled from 50° C. to 20° C. over 2 hrs. The precipitate was ‘aged’ at 20° C. for 1 hr and collected by filtration. The ‘cake’ was washed with 1:1 water/butyronitrile (70 ml) twice, then with butyronitrile (35 ml). The solid was then dried on the filter for 30 mins, collected and dried in a vacuum oven overnight at 50° C. A pale yellow solid 5-[[(2,3-difluorophenyl)methyl]thio]-7-[[(1R)-2-hydroxy-1-methylethyl]amino]-3-[2-(phenylsulfonyl)ethyl]thiazolo[4,5-d]pyrimidin-2-(3H)-one was obtained with 88% yield (44.33 g, HPLC area=98.75%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22].N1C=CN=C1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][O:20][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27])=[CH:13][CH:12]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1cc(Br)ccc1Oc1ccc(CCCO)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCc1ccc(Oc2ccc(Br)cc2C=O)cc1
Yield: 98.9 %

Procedure:
In a manner similar to the method described in Example 60b, 5-bromo-2-[4-(3-hydroxy-propyl)-phenoxy]-benzaldehyde (9 g, 27 mmol) was reacted with tert-butyldimethylchlorosilane (4.45 g, 30 mmol) and imidazole in N,N-dimethylformamide to give 5-bromo-2-{4-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-phenoxy}-benzaldehyde as a brown oil (Yield 12 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([F:33])[C:26]=1[C:27]([CH3:32])([CH3:31])[CH2:28][O:29][CH3:30])[N:5](CC1C=CC(OC)=CC=1)CC1C=CC(OC)=CC=1>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([F:33])[C:26]=1[C:27]([CH3:31])([CH3:32])[CH2:28][O:29][CH3:30])[NH2:5]
Reactant: COCC(C)(C)c1c(F)cc(N(Cc2ccc(OC)cc2)Cc2ccc(OC)cc2)cc1F
Solvent: O=C(O)C(F)(F)F
Product: COCC(C)(C)c1c(F)cc(N)cc1F
Yield: 99.3 %

Procedure:
A solution of 3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)aniline (1 g, 2.20 mmol) in TFA (10 mL) was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and to the obtained residue was added ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 3→50% ethyl acetate/hexane) to give 3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)aniline (0.470 g, 2.184 mmol, 99%) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][C:6]([O:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[C:30]([NH:33][CH2:34][CH2:35]O)(=[O:32])[CH3:31]>ClCCCl.C1COCC1>[C:30]([NH:33][CH2:34][CH2:35][O:10][C:9](=[O:11])[CH:8]([O:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:24])([F:25])[F:1])=[CH:23][CH:22]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)NCCO
Reactant: O=C(O)C(Oc1ccc(C(F)(F)F)cc1)c1cccc(C(F)(F)F)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CC(=O)NCCOC(=O)C(Oc1ccc(C(F)(F)F)cc1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a slurry of acid 39 (25.8 g, 0.071 mol) in anhydrous 1,2-dichloroethane (380 mL) was added thionyl chloride (16.0 mL, 0.21 mol), and then the resulting mixture was refluxed for 2 h. The mixture was cooled to rt, diluted with dry THF (150 mL) until the cloudy mixture turned clear, and then N-acetylethanolamine (39.12 g, 0.38 mol) was added. The resulting solution was stirred at rt overnight. The reaction was quenched with sat. NaHCO3 carefully, diluted with EtOAc, and washed with water. The organic layer was washed with brine, dried over Na2SO4, concentrated in vacuo, and the residue was recrystallized from iPrOH/hexanes (11 mL/31.5 mL) to afford pure product 136 (22.78 g, 71%) as a off-white solid. 1H NMR (400 MHz, CDCl3): δ 7.89 (1H, s), 7.80 (1H, d), 7.69 (1H, d), 7.57-7.61 (3H, t), 7.06 (2H, t), 5.78 (1H, s), 5.27 (1H, br), 4.24 (2H, m), 3.45 (2H, dd), 1.81 (3H, s) ppm.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31]([OH:33])=[O:32])[CH:20]=[C:19]1[CH3:34])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].[C:35](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[C@H:21]([C:31]([O:33][CH3:35])=[O:32])[CH:20]=[C:19]1[CH3:34])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:7])=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)OC)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 66.8 %

Procedure:
To a solution of (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-1-(tert-butoxycarbonyl)-4-methyl-1,2,5,6-tetrahydropyridine-2-carboxylic acid (Intermediate 19, 3 g, 6.03 mmol) and potassium carbonate (3.33 g, 24.12 mmol) in DMF (30 mL) at room temperature was added methyl iodide (0.454 mL, 7.24 mmol). After 1 hour the reaction mixture was diluted with ethyl acetate and washed three times with water. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-30% ethyl acetate/hexanes) afforded the desired product (2.060 g, 66.8%) as an off-white foam.