Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[NH:8][C:9]([C:14]#[N:15])=[C:10]([C:12]#[N:13])[N:11]=1)[CH2:4][CH2:5][CH3:6].[C:16](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OCC)(=O)C>CN(C)C=O.O>[CH2:3]([C:7]1[N:11]([C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:10]([C:12]#[N:13])=[C:9]([C:14]#[N:15])[N:8]=1)[CH2:4][CH2:5][CH3:6]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCc1nc(C#N)c(C#N)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C#N)c(C#N)n1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
1.25 g of sodium hydride (as a 55% w/w dispersion in mineral oil) were added, whilst ice-cooling, to a solution of 5 g of 2-butylimidazole-4,5-dicarbonitrile (prepared as described in Preparation 1) in 50 ml of N,N-dimethylformamide, and the resulting mixture was stirred for 15 minutes. 10 g of trityl chloride were then added, and the reaction mixture was stirred at 50° C. for 6 hours. At the end of this time, it was mixed with ethyl acetate and water, and the product was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:5 by volume mixture of ethyl acetate and hexane as the eluent, to give 9.83 g of the title compound as a syrup, which solidified on being allowed to stand. The solid melted at 144°-147° C. (with decomposition and coloration at 94°-98° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16]C(=O)C)[S:15][C:11]=3[CH:10]=2)[CH:5]=[N:6][C:7]=1[Cl:8].[Cl:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.O.C(OCC)(=O)C>[NH2:16][C:14]1[S:15][C:11]2[CH:10]=[C:9]([C:4]3[CH:3]=[C:2]([NH:1][S:33]([C:24]4[CH:25]=[CH:26][C:27]([C:29]([F:30])([F:31])[F:32])=[CH:28][C:23]=4[Cl:22])(=[O:35])=[O:34])[C:7]([Cl:8])=[N:6][CH:5]=3)[CH:21]=[CH:20][C:12]=2[N:13]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Reactant: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(N)c3)cc2s1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Nc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4ccc(C(F)(F)F)cc4Cl)c3)cc2s1
Reaction time: 8 h

Procedure:
To a 50 ml round-bottom flask equipped with a stirbar and charged with N-(6-(5-amino-6-chloropyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (0.300 g, 0.9 mmol) in Pyridine (5 ml), was added DMAP (0.030 g, 0.2 mmol) and 2-chloro-4-(trifluoromethyl)benzene-1-sulfonyl chloride (1 g, 5 mmol). The flask was allowed to stir under inert atmosphere overnight. The progress of the reaction was monitored by LC/MS, which showed desired (N-Acyl, m/z=562) and bis-sulfonated material. The mixture was diluted with water (30 ml) and ethyl acetate and then allowed the mixture to stir 10 minutes. The organic layer was extracted with EtOAc (3×25 ml). Then combined organics, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was diluted with MeOH (6 ml), then added the mixture into two microwave vials equipped with stirbars (with the organics equally distributed). Potassium carbonate (0.300 g) was added to each vial, then capped and placed into a CEM Microwave for 10 minutes at 80° C., while 60 watts of energy was supplied via Powermax® (Simultaneous heating while cooling technology). The progress of the de-sulfonylation/de-acylation reaction was monitored by LC/MS, which showed mostly desired product. The two mixtures were combined and concentrated in vacuo. Water (30 ml) was added to the flask, along with a stirbar and then neutralized the mixture with 1N HCl. The precipitate was collected by filtration and washed with Hexanes. The solid was dissolved in ethyl acetate, and then purified the crude material by ISCO Silica-Gel Chromatography (120 gram column) in a gradient of 1-5% MeOH/DCM over 30 minutes. The fractions with desired product were combined and concentrated in vacuo. The residue was recrystallized from EtOAc/Hexanes to give N-(5-(2-aminobenzo[d]thiazol-6-yl)-2-chloropyridin-3-yl)-2-chloro-4-(trifluoromethyl)benzenesulfonamide (0.040 g, 8% yield) as a tan crystalline solid. MS (ESI pos. ion) m/z: 520 (MH+). Calc'd exact mass for C19H11Cl2F3N4O2S2: 519. 1H NMR (400 MHz, DMSO-d6): 7.38-7.44 (m, 1H), 7.49 (d, J=8.53 Hz, 1H), 7.68 (s, 2H), 7.89 (d, J=8.53 Hz, 1H), 7.99 (d, J=19.07 Hz, 2H), 8.12 (d, J=8.03 Hz, 1H), 8.58 (s, 1H).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH2:6][CH:5]1[CH:4]([C:9]([OH:11])=O)[CH2:3][CH:2]2[C:12]([OH:14])=O.C(OC(=O)C)(=O)C.[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[N:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[CH2:29][CH2:28]1>O>[N:34]1[CH:35]=[CH:36][CH:37]=[N:38][C:33]=1[N:30]1[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][CH2:24][CH2:23][N:22]2[C:12](=[O:14])[CH:2]3[CH2:3][CH:4]([CH:5]4[CH2:6][CH2:7][CH2:8][CH:1]43)[C:9]2=[O:11])[CH2:28][CH2:29]1
Reactant: O=C(O)C1CC(C(=O)O)C2CCCC12
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=C1C2CC(C(=O)N1CCCCN1CCN(c3ncccn3)CC1)C1CCCC21

Procedure:
Bicyclo[3.3.0]-octane-2,4-dicarboxylic acid (1.6 g., 8.1 mmole) was converted to the anhydride by refluxing for three hours in 100 ml. of acetic anhydride. The excess reagent was removed in vacuo. Two hundred fifty (250) ml. of xylene was added along with 1.9 g. (8.1 mmole) of 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine. The mixture was refluxed under nitrogen for 48 hours with water removal via a Dean-Stark trap. The solvent was then removed in vacuo and the residue filtered through 75 g. of silica gel with 2% ethanol/chloroform as eluent. Removal of solvent and recrystallization of the residue from isopropanol with the addition of 4N isopropanolic HCl, followed by a second recrystallization from isopropanol, gave 750 mg. of white solid title compound as hydrochloride, one quarter hydrate, m.p. 188°-189° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([NH:25][CH:26]([CH3:28])[CH3:27])[C:5]([C:6]([NH:8][NH:9][C:10](=[O:22])[CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:12][OH:13])=[O:7])=[CH:4][N:3]=1.N1C=CN=C1.[C:34]([Si:38](Cl)([CH3:40])[CH3:39])([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl>[Si:38]([O:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:18])[CH3:19])[C:10]([NH:9][NH:8][C:6](=[O:7])[C:5]1[C:23]([NH:25][CH:26]([CH3:28])[CH3:27])=[CH:24][C:2]([Cl:1])=[N:3][CH:4]=1)=[O:22])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:40])[CH3:39]
Reactant: CC(C)Nc1cc(Cl)ncc1C(=O)NNC(=O)C(CO)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)Nc1cc(Cl)ncc1C(=O)NNC(=O)C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
tert-butyl (1-(2-(6-chloro-4-(isopropylamino)nicotinoyl)hydrazinyl)-3-hydroxy-1-oxopropan-2-yl)carbamate (53) (1 g, 2 mmol) in DCM (10 mL), imidazole (7 mmol, 3 equiv.) was added and stirred at room temperature for 10 min. Reaction mixture was cooled to 0° C., t-butyl dimethyl silyl chloride (3.6 mmol, 1.5 equiv.) was added in portions and stirred the reaction mixture overnight at room temperature. Diluted the reaction mixture using DCM, the DCM layer was washed with water. The organic layer was collected, dried over Na2SO4, filtered and concentrated to get tert-butyl (3-((tert-butyldimethylsilyl)oxy)-1-(2-(6-chloro-4-(isopropylamino)nicotinoyl)hydrazinyl)-1-oxopropan-2-yl)carbamate (54). LC/MS: Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90% H2O: 20 mM NH4OAc; Solvent B=90% ACN: 10% H2O: 20 mM NH4COOAc; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 2.319 min; LCMS (ES-API), m/z 530.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[CH2:7][CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[CH2:7][CH2:8][N+:9]([O-:29])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1CCN=C(c2ccccc2F)c2cc(Cl)ccc21
Solvent: ClCCl
Product: O=C1CC[N+]([O-])=C(c2ccccc2F)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6.4 g (22 mmole) of 8-chloro-1-(2-fluorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one and 6.4 g (34 mmole) of m-chloroperbenzoic acid in 350 ml of methylene chloride was stirred at room temperature for 2 hr. The methylene chloride solution was washed with saturated aqueous sodium bicarbonate and water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a yellow oil. The oil was crystallized from a mixture of ether and petroleum ether to give off-white prisms, mp 166°-168° C. Recrystallization from a mixture of ether and methylene chloride gave colorless prisms, mp 168°-170° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][NH:13][CH2:12][C@H:11]([OH:15])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:16][CH2:17][O:18][C:19](C)=[O:20]>O1CCOCC1.O>[Si:1]([O:8][C@@H:9]1[CH2:10][C@@H:11]([OH:15])[CH2:12][N:13]([C:19]([O:18][CH2:17][C:16]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:14]=2)=[O:20])[CH2:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CNC[C@H](O)C1
Reactant: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
To a solution of (3R,5R)-5-(tert-butyldimethylsilyloxy)piperidin-3-ol (1 eq) in 20 mL of 1,4-dioxane and 8 mL of water was added benzyl chloro formate (1.5 eq). The mixture was stirred at room temperature for 4 hours. The crude mixture was diluted with 100 mL of EtOAc, washed with brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc:hexanes=1:3) to yield (3R,5R)-benzyl 3-(tert-butyldimethylsilyloxy)-5-hydroxypiperidine-1-carboxylate (74%). LC/MS (m/z): 366.2 (MH+).
Reaction SMILES: CN1CCOCC1.O.[C:9]([NH:16][C@H:17]([C:22]([OH:24])=O)[CH2:18][CH:19]([CH3:21])[CH3:20])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C1C=CC2N(O)N=NC=2C=1.[NH2:35][C@H:36]([C:41]([O:43][CH3:44])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39].Cl.C1CCC(N=C=NC2CCCCC2)CC1>C(OCC)(=O)C>[NH:16]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[C@H:17]([C:22]([NH:35][C@H:36]([C:41]([O:43][CH3:44])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39])=[O:24])[CH2:18][CH:19]([CH3:20])[CH3:21]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
4-Methylmorpholine (12.62 g, 124.8 mmol), Boc-Leucine monohydrate (29.92, 120.0 mmol) and HOBt (1.62 g, 12.0 mmol) were added to a solution of H-Leu-OMe.HCl (21.80 g, 120.0 mmol) in ethyl acetate (205 g). A solution of DCC (29.71 g, 144.0 mmol) in ethyl acetate (25.0 g) was added at 0 to 5° C. over 30 min and the resulting mixture was stirred over 2 h at a maximum temperature of 20° C. The resulting urea was removed by filtration and washed with ethyl acetate and the combined organic filtrate was extracted with successive portions of 5% aq. K2CO3 and 5% aq. KHSO4. The organic layer was dried (MgSO4), concentrated in vacuo, and the residual solid was recrystallized from petroleum ether (bp 100-125° C.) to give Boc-Leu-Leu-OMe (38.6 g, 89.8%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[CH:9]1([N+:15]#[C-:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:17][N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=O>Cl(O)(=O)(=O)=O>[CH:9]1([NH:15][C:16]2[N:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[N:7][C:2]3=[N:1][C:23]=2[C:19]2[N:18]([CH3:17])[CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: [C-]#[N+]C1CCCCC1
Reactant: Cc1ccnc(N)n1
Reactant: Cn1cccc1C=O
Agent: [O-][Cl+3]([O-])([O-])O
Product: Cc1ccn2c(NC3CCCCC3)c(-c3cccn3C)nc2n1

Procedure:
Compound (38) was prepared according to the general synthesis instructions from 1.0 ml of 2-amino-4-methylpyrimidine solution (0.1 M, DCM), 0.575 ml of cyclohexyl isocyanide solution (0.2 M, DCM), 0.500 ml of N-methylpyrrole-2-carbaldehyde solution (0.3 M, DCM), and 10 μl of perchloric acid (w=20%).
Reaction SMILES: C(O[C:6](=[O:25])[NH:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]1[S:15][C:16]2[N:17]=[CH:18][N:19]=[C:20]([O:23][CH3:24])[C:21]=2[N:22]=1)=[O:12])(C)(C)C.FC(F)(F)C(O)=O.COC1C2N=C(NC(N3CCC(N)C3)=O)SC=2N=CN=1.[F:53][C:54]1[CH:62]=[CH:61][C:57](C(Cl)=O)=[CH:56][C:55]=1[C:63]([F:66])([F:65])[F:64]>C(Cl)Cl>[F:53][C:54]1[CH:62]=[CH:61][C:57]([C:6]([NH:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]2[S:15][C:16]3[N:17]=[CH:18][N:19]=[C:20]([O:23][CH3:24])[C:21]=3[N:22]=2)=[O:12])=[O:25])=[CH:56][C:55]=1[C:63]([F:64])([F:65])[F:66]
Reactant: COc1ncnc2sc(NC(=O)NCCNC(=O)OC(C)(C)C)nc12
Reactant: O=C(Cl)c1ccc(F)c(C(F)(F)F)c1
Agent: COc1ncnc2sc(NC(=O)N3CCC(N)C3)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ncnc2sc(NC(=O)NCCNC(=O)c3ccc(F)c(C(F)(F)F)c3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.9 %

Procedure:
A solution of {2-[3-(7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-ureido]-ethyl}-carbamic acid tert-butyl ester (170 mg, 0.46 mmol) was treated with trifluoroacetic acid (80 μL, 0.57 mmol). The reaction was stirred at 25° C. for 1 h. The reaction was then concentrated in vacuo, triturated with diethyl ether, collected by filtration and dried in vacuo. A portion of the resulting trifluoroacetic acid salt of 3-amino-pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (88 mg, 0.23 mmol) in methylene chloride at 25° C. was treated with 4-fluoro-3-(trifluoromethyl)benzoyl chloride (70 mL, 0.46 mmol). The resulting solution was stirred at 25° C. overnight. Flash chromatography (Merck Silica gel 60, 230-400 mesh, gradient elution 3:1 ethyl acetate/hexanes to 100% ethyl acetate) afforded 4-fluoro-N-{2-[3-(7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-ureido]-ethyl}-3-trifluoromethyl-benzamide (25 mg, 11.8%) as a white solid; ES-HRMS m/e calcd for C17H14F4N6O3S (M+H)+ 459.0857, found 459.0862.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1Br)[CH3:2].C([Sn](CC[CH2:43][CH3:44])(CCCC)/C=C/[Sn](CCCC)(CCCC)CCCC)CCC.[I:45]I>C1(C)C=CC=CC=1.C(OCC)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1/[CH:44]=[CH:43]/[I:45])[CH3:2]
Reactant: CCOC(=O)CCCOc1ccccc1Br
Reactant: II
Reactant: CCCC[Sn](/C=C/[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCOc1ccccc1/C=C/I
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
861 mg of 4-(2-bromophenoxy)-butyric acid ethyl ester and 4.8 g of (E)-1,2-bis-(tri-n-butylstannyl)-ethylene (50%) are dissolved in 11 ml of toluene, mixed with 70 mg of tetrakis-(triphenylphosphine)-palladium and heated with stirring and under argon atmosphere for 1 hour to 120° C. (bath temperature). After cooling to room temperature, the reaction mixture is diluted with 9 ml of diethyl ether and mixed at 0° C. with a solution of 1.53 g of iodine in 7 ml of diethyl ether. The mixture is stirred for 2 hours at 0° C. and allowed to stand overnight in a refrigerator. The batch is concentrated by evaporation and the residue is chromatographed on silica gel with n-hexane/ethyl acetate=95/5. 810 mg of 4-[2-[(E)-2-iodovinyl]-phenoxy]-butyric acid ethyl ester is obtained as an oily crude product, which is further reacted without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[C:13](Cl)(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[OH-].[Na+].Cl>O.C(O)(C)C>[C:13]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Temperature: 11.5 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
L-Arginine (1106 g) was added with isopropyl alcohol (6919 g) and water (2964 g), and added dropwise simultaneously with lauroyl chloride (1522 g, Nippon Oil & Fats Co., Ltd.) and 27 wt % NaOH aqueous solution over 2 hours with stirring, while pH and reaction temperature were maintained at 10.5 to 11.5 and 10 to 13° C., respectively. After ripening for 1 hour, the reaction mixture was warmed to 50° C. and adjusted to pH 3.8 with addition of concentrated hydrochloric acid for complete dissolution of the reaction product. Then, the reaction mixture was adjust to pH 6.0 with addition of 27 wt % NaOH aqueous solution to deposit crystals, and the slurry was gradually cooled to 10° C. with stirring. After cooling to 10° C., the slurry was washed with water (10 kg) and isopropyl alcohol (4.4 kg), and the crystals obtained were dried under reduced pressure to give scaly crystals of Nα-mono-lauroyl-L-arginine (2081 g, yield: 92.3%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][P:6]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])=[O:7])C.[Br:17]C[C@H](O)CO.CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Br:17][CH2:16][C@H:15]1[CH2:1][O:3][C@H:4]([CH2:5][P:6]([O:8][CH2:9][CH3:10])([O:11][CH2:12][CH3:13])=[O:7])[O:14]1
Reactant: CCOC(CP(=O)(OCC)OCC)OCC
Reactant: OC[C@@H](O)CBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOP(=O)(C[C@H]1OC[C@H](CBr)O1)OCC
Temperature: 25 °C
Yield: 96.7 %

Procedure:
To a solution of diethylphosphonoacetaldehyde diethylacetal (4.20 g, 16.5 mmol) and (2R)-3-bromo-1,2-propanediol (example 90) (3.00 g, 19.4 mmol, 1.2 eq.) in toluene (30 mL) was added PTSA (few crystals). The mixture was stirred at reflux for 50 hr. After, the solution was cooled to room temperature, and a saturated solution of sodium bicarbonate was added, and the aqueous phase was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure. The crude material was pure by TLC and NMR, and gave 5.06 g of the compound in a 97% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH:27]=[CH:28][C:29]([OH:31])=[CH:30][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[CH2:32]1[O:34][C@H:33]1[CH2:35][OH:36].C(N(CC)CC)C>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH:27]=[CH:28][C:29]([O:31][CH2:32][C@@H:33]([OH:34])[CH2:35][OH:36])=[CH:30][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: OC[C@H]1CO1
Reactant: Oc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC[C@H](O)COc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 80 °C
Reaction time: 15 h
Yield: 40.2 %

Procedure:
To a solution of 4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)[1]benzothieno[2,3-d]pyrimidin-7-ol (30 mg, 0.07 mmol) in EtOH (1.0 mL) was added (S)-(−)-glycidol (5 mg, 0.07 mmol, 1.0 equiv) and triethylamine (0.34 mg, 0.0035 mmol, 0.05 equiv) under nitrogen. The reaction mixture was stirred at 80° C. for 15 h and then was cooled to rt. The solvent was removed in vacuo. The crude material was purified by preparative HPLC to give (2S)-3-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)[1]benzothieno[2,3-d]pyrimidin-7-yl]oxy}propane-1,2-diol as a white solid (14.8 mg, 40%). 1H-NMR (CD3OD) δ 8.45 (s, 1H), 8.32 (d, J=8.9 Hz, 1H), 7.73 (d, J=2.7 Hz, 1H), 7.61 (d, J=2.2 Hz, 1H), 7.46 (dd, J=2.7, 9.0 Hz, 1H), 7.40 (m, 1H), 7.30 (d, J=7.8 Hz, 1H), 7.25 (dd, J=2.3, 9.0 Hz, 2H), 7.16 (d, J=9 Hz, 1H), 7.05 (td, 1H), 5.22 (s, 2H), 4.20 (m, 1H), 4.11 (m, 1H), 4.04 (m, 1H), 3.72 (m, 2H), LCMS RT=3.36 min, [M+H]+=526.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[C:16]1[CH2:20][CH2:19][CH2:18][C:17]=1B(O)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27]([C:29]1[CH:34]=[N:33][CH:32]=[C:31](Cl)[N:30]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1[CH:34]=[N:33][CH:32]=[C:31]([C:17]2[CH2:18][CH2:19][CH2:20][C:16]=2[C:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:30]=1)=[O:28])[CH3:25]
Reactant: CCOC(=O)c1cncc(Cl)n1
Reactant: Cc1ccc(OCc2ccccc2)c(C2=C(B(O)O)CCC2)c1
Product: CCOC(=O)c1cncc(C2=C(c3cc(C)ccc3OCc3ccccc3)CCC2)n1

Procedure:
Prepared by general procedure C(iii) but using 2-[2-(benzyloxy)-5-methylphenyl]cyclopentene-1-boronic acid instead of 2-(2-benzyloxy-5-chlorophenyl)cyclopentene-1-boronic acid and 6-chloropyrazine-2-carboxylic acid ethyl ester instead of 2-chloropyrimidine-4-carboxylic acid methyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][CH:9]1[C:21]([OH:23])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:31]=[C:30]([I:32])[CH:29]=[CH:28][C:26]=1[NH2:27].CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@@H:9]1[C:21](=[O:23])[NH:27][C:26]1[CH:28]=[CH:29][C:30]([I:32])=[CH:31][C:25]=1[F:24])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Nc1ccc(I)cc1F
Reactant: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)Nc1ccc(I)cc1F
Yield: 91.3 %

Procedure:
4-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (0.673 g, 1.94 mmol), 2-fluoro-4-iodoaniline (0.46 g, 1.94 mmol), EEDQ (0.575 g, 2.32 mmol) and triethylamine (0.408 mL, 2.91 mmol) were heated at reflux in CHCl3 (10 mL) for 22 h. The solution was concentrated and resulting oil partitioned between EtOAc and water. The organic layer was washed with brine and dried over MgSO4. The product was purified by mplc to produce the product as a clear oil (1.0 g, 90% ). MS: APCI (AP−): 563.2 (M)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[OH:12])=O.C=O.[CH:23]([NH2:25])=O>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:25]=[CH:23][O:12][C:11]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20]
Reactant: NC=O
Reactant: O=C(c1ccc(Cl)cc1Cl)C(O)c1ccc(Cl)cc1Cl
Agent: C=O
Solvent: O
Product: Clc1ccc(-c2ncoc2-c2ccc(Cl)cc2Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
A mixture of (+/−)-2,2′,4,4′-tetrachlorobenzoin (1.0 gm, 2.9 mmol) from Step A and paraformaldehyde (0.70 gm, 24 mmol) in formamide (20 mL) was heated to 200–210° C. for 3 hr. The reaction was cooled to rt, diluted with water, and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by flash chromatography, eluting first with 10% ethyl acetate in hexanes to afford 4,5-di-(2,4-dichlorophenyl)oxazole as a higher Rf byproduct and then with 75% ethyl acetate in hexanes to elute the title compound as an oil. HPLC/MS: 357 (M+1), 359 (100%, M+3), 361 (M+5); Rt=2.72 min.