Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]2[NH:7][N:6]=[CH:5][C:4]=2[C:3]=1[C:12]([O:14][CH3:15])=[O:13].F[B-](F)(F)F.[CH3:21][O+](C)C>C(OCC)(=O)C>[Br:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:21])[N:7]=2)[C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: C[O+](C)C
Reactant: COC(=O)c1c(Br)c(Cl)cc2[nH]ncc12
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Br)c(Cl)cc2nn(C)cc12
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of methyl 5-bromo-6-chloro-1H-indazole-4-carboxylate (390 mg, 1.35 mmol) in ethyl acetate (27 mL) was added trimethyloxonium tetrafluoroborate (260 mg, 1.76 mmol) at room temperature, and the mixture was stirred for 2 hr. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane=10/90→40/60) to give the title compound (336 mg, yield 82%).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[C:8]([F:15])[CH:7]=1.[Cl:16][CH2:17][CH2:18]Cl>>[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](=[O:11])[CH2:18][CH2:17][Cl:16])=[C:8]([F:15])[CH:7]=1
Reactant: ClCCCl
Reactant: O=C(Cl)c1ccc(Br)cc1F
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCl)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a stirred suspension of aluminum trichloride (153 g, 1.15 mol) in DCE (1000 mL) was added a solution of 144b (271 g, 1.14 mol) in DCE (1000 mL) at 0° C. See FIG. 3. Ethylene gas was bubbled through the dark suspension for 3 h until the acid chloride was consumed. The reaction mixture was then stirred at RT overnight, cooled to 0° C., and quenched with 4M HCl (500 mL). The organic phase was separated and washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by column chromatography (PE/EA=30 to 10:1) to give 1-(4-bromo-2-fluorophenyl)-3-chloropropan-1-one 144c (210 g, 68%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:8][N:9]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:19]([F:28])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])[CH:16]=3)[NH:11][C:10]2=[O:29])[CH:2]=1.[H-].[Na+].[C:32](OC(=O)C)(=[O:34])[CH3:33]>CC(N(C)C)=O>[C:32]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([C:19]([F:28])([C:24]([F:25])([F:26])[F:27])[C:20]([F:22])([F:21])[F:23])=[CH:14][CH:13]=2)[CH2:18][N:9]([N:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:10]1=[O:29])(=[O:34])[CH3:33]
Reactant: O=C1Nc2ccc(C(F)(C(F)(F)F)C(F)(F)F)cc2CN1N=Cc1cccnc1
Reactant: CC(=O)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)N1C(=O)N(N=Cc2cccnc2)Cc2cc(C(F)(C(F)(F)F)C(F)(F)F)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
In 10 ml of dimethylacetamide was dissolved 0.84 g (1.8 mmol) of 3-(3-pyridylmethylideneamino)-3,4-dihydro-6-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-2(1H)-quinazolinone, and to the resulting solution was added 0.09 g (2.3 mmol) of sodium hydride (purity: 62.4%). The reaction was carried out at room temperature for 30 minutes, after which 0.25 g (2.4 mmol) of acetic anhydride was added and the reaction was carried out for 4 hours. After completion of the reaction, the reaction solution was poured into ice water and the desired compound was extracted with ethyl acetate (20 ml×3). The extract solution was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated in vacuo. The crude product thus obtained was purified by silica gel column chromatography (ethyl acetate−methanol=10:1) to obtain 0.78 g of the desired compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:14])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].[CH3:15][N:16]([CH:18](OC)OC)[CH3:17]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](/[CH:14]=[CH:15]/[N:16]([CH3:18])[CH3:17])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(SC)nc1C
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(SC)nc1/C=C/N(C)C
Yield: 61.9 %

Procedure:
4-Methyl-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester 3 (18.0 g, 84.8 mmol) was dissolved in DMF (50 mL), N,N-Dimethylformamidedimethylacetal (22.5 mL, 170 mmol) and stirred at reflux for 3 hours. Then mixture was concentrated, the residue was dissolved in TCM, washed with water, dried, filtered, and concentrated. The product was purified by crystallization from ether to yield in a colorless solid (14.0 g, 52.5 mmol, 62%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:10]=[O:11])=[C:5]([Cl:9])[C:6]=1[C:7]#[N:8].ClCC(O)=C(C#N)C#N.C(#N)CC#N.ClCC(Cl)=O.[NH4+]=S.NC1SC=C(O)C=1C#N.P(Cl)(Cl)(Cl)=O.[CH3:47][N:48]([CH3:51])[CH:49]=O>C(N(CC)CC)C>[Cl:9][C:5]1[C:6]([C:7]#[N:8])=[C:2]([N:1]=[CH:47][N:48]([CH3:51])[CH3:49])[S:3][C:4]=1[CH:10]=[O:11]
Reactant: N#Cc1c(N)sc(C=O)c1Cl
Reactant: CN(C)C=O
Agent: N#CC(C#N)=C(O)CCl
Agent: N#Cc1c(O)csc1N
Agent: O=C(Cl)CCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: N#CCC#N
Solvent: CCN(CC)CC
Product: CN(C)C=Nc1sc(C=O)c(Cl)c1C#N

Procedure:
The preparation of 2-amino-4-chloro-3-cyano-5-formylthiophene is known from EP-A-No. 193 885, according to which the intermediate triethylamine salt of 3-chloro-1,1-dicyano-2-hydroxy-1-propene is prepared from malononitrile, chloroacetyl chloride, and triethylamine and cyclized with ammonium sulfide to 2-amino-3-cyano-4-hydroxythiophene, which is then treated with a mixture of N,N-dimethylformamide and phosphoryl chloride; the N'-(4-chloro-3-cyano-5-formyl-2-thienyl)-N,N-dimethylformamidine that is formed is isolated and then hydrolyzed with formic acid, giving the required product. However, it has been found that the yield of 2-amino-4-chloro-3-cyano-5-formylthiophene obtained by this process is unsatisfactory.
Reaction SMILES: [CH2:1]([C@@H:7]1[CH2:16][CH2:15][C:14]2[CH:13]=[C:12]([CH:17]3[CH2:21][CH2:20][C:19](=O)[CH2:18]3)[CH:11]=[CH:10][C:9]=2[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl-].[NH4+:24].[C-:25]#[N:26].[Na+].N>CO.ClCCl>[NH2:24][C:19]1([C:25]#[N:26])[CH2:20][CH2:21][CH:17]([C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][C@H:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:16][CH2:15][C:14]=3[CH:13]=2)[CH2:18]1
Reactant: [NH4+]
Reactant: [C-]#N
Reactant: CCCCCC[C@@H]1CCc2cc(C3CCC(=O)C3)ccc2C1
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCCCCC[C@@H]1CCc2cc(C3CCC(N)(C#N)C3)ccc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3-((R)-6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentanone (I-8E, 5.96 g, 19.97 mmol), ammonium chloride (5.34 g, 100 mmol), sodium cyanide (4.89 g, 100 mmol), 7 M methanol solution of ammonia (28.5 ml, 200 mmol), and dichloromethane (15 mL) was stirred at room temperature for 1 day. Additional 7 M methanol solution of ammonia (15 mL) was added. The mixture was stirred at room temperature for 1 day and then concentrated. The residue was partitioned between ethyl acetate (70 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was separated and extracted with ethyl acetate (3×50 mL). The combined ethyl acetate solutions were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-amino-3-((R)-6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentanecarbonitrile as a semi-solid. The semi-solid material was mixed with a mixture of concentrated hydrochloric acid (56 ml, 1843 mmol), water (28 ml, 1554 mmol), acetic acid (35 ml), and dioxane (35 ml). The mixture was stirred at 100° C. under nitrogen for 10 h and then concentrated to give a solid. The solid was dissolved in methanol (20 mL) and mixed with toluene (20 mL). The mixture was concentrated to dryness. This drying procedure was repeated one more time to give a dry solid. The solid was dissolved in anhydrous methanol (300 mL). Thionyl chloride (11.66 mL, 160 mmol) was added dropwise at 0° C. under nitrogen. The reaction mixture was stirred at 70° C. for 7 h before being concentrated. The residue was made basic with saturated aqueous sodium bicarbonate solution (100 mL) and some potassium carbonate solid and extracted with ethyl acetate (100 mL, 3×30 mL). The combined ethyl acetate extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Flash chromatography purification (80 g silica gel column, gradient elution from 20 to 100% ethyl acetate in hexanes) afforded methyl 1-amino-3-((R)-6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentanecarboxylate (5.7 g, 15.94 mmol) as a liquid. LC/MS M+1=358.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:21][C:22]1[CH:23]=[N:24][NH:25][CH:26]=1.C(N(CC)CC)C.O>C(Cl)Cl>[I:21][C:22]1[CH:23]=[N:24][N:25]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:26]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Ic1cn[nH]c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Ic1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reaction time: 8 h
Yield: 26.4 %

Procedure:
Trityl chloride (885 mg, 3.2 mmol) was added to a stirred cold (0-5° C.) solution of 4-iodo pyrazole (513 mg, 2.6 mmol) and triethylamine (401 mg, 0.55 mL, 0.4 mmol) in DCM (10 mL). Stirring was continued at room temperature overnight. Cold water was then added and the product was extracted with DCM and the organic layer was washed with sat. sodium bicarbonate solution followed by brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using neutral alumina and 2% EtOAc in Hexane as eluent) to afford 300 mg (26% yield) of 4-iodo-1-trityl-1H-pyrazole.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Br[C:9]1[N:10]=[CH:11][S:12][CH:13]=1>Cl>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:9]2[N:10]=[CH:11][S:12][CH:13]=2)[CH2:7]1
Reactant: C[C@@H]1CNCCN1
Reactant: Brc1cscn1
Agent: Cl
Product: C[C@@H]1CN(c2cscn2)CCN1
Temperature: 25 °C
Reaction time: 18 h
Yield: 8.9 %

Procedure:
10.0 g (100 mmol) (R)-2-methylpiperazine were fused at 100° C. 2.7 g (16.8 mmol) 4-bromothiazol was added in portions to this fusion over a period of 2 h. Stirring was subsequently performed for 18 h at 100° C. After cooling to RT, the residue was received in 10% aq. hydrochloric acid and washed with AE. Alkalic adjustment was subsequently performed with a 10% aq. NaOH sol. (pH>12) and extracted with DCM. The organic phase was dried over MgSO4, filtered and concentrated in a vacuum. CC (SiO2, DCM/MeOH 9:1) was performed with the residue, whereby 277 mg (1.5 mmol, 9%) (R)-4-(3-methylpiperazine-1-yl)thiazol was obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[C@H:10]([CH3:11])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:12][C:13]1[CH:38]=[CH:37][C:16]([CH2:17][N:18]([CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:19]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>C(#N)C.O>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[C:19]([N:21]2[CH2:22][CH2:23][N:24]([C:2]3[C:3]4[C@H:10]([CH3:11])[CH2:9][CH2:8][C:4]=4[N:5]=[CH:6][N:7]=3)[CH2:25][CH2:26]2)=[O:20])=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)NCCN(Cc1ccc(Cl)cc1)C(=O)N1CCNCC1
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)N(CCNC(=O)OC(C)(C)C)Cc4ccc(Cl)cc4)CC3)c21
Temperature: 80 °C
Yield: 30.2 %

Procedure:
(R)-4-Chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (46 mg, 0.27 mmol, 1.1 eq.) was added to a solution of the tert-butyl 2-(N-(4-chlorobenzyl)piperazine-1-carboxamido)ethylcarbamate (100 mg, 0.25 mmol) and Hunig's base (0.1 mL, 0.75 mmol, 3 eq.) in acetonitrile (3 mL). The resulting mixture was heated to 80° C. overnight. The reaction mixture was diluted with H2O and extracted with DCM, dried and concentrated to yield (R)-tert-butyl 2-(N-(4-chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxamido)ethylcarbamate (40 mg, 30%). MS (ESI) m/e (M+H+) 529.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:26]([O:59][CH3:60])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:57][CH3:58])[C@@H:36]([CH3:56])[C:37]([NH:39][C@H:40](/[CH:48]=[CH:49]/[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12].O=[CH:66][CH2:67][CH2:68][C:69]([OH:71])=[O:70].C([BH3-])#N.[Na+].O1CCOCC1>O1CCOCC1.O>[C:69]([CH2:68][CH2:67][CH2:66][N:9]([CH3:8])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:26]([O:59][CH3:60])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:57][CH3:58])[C@@H:36]([CH3:56])[C:37]([NH:39][C@H:40](/[CH:48]=[CH:49]/[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH:11]([CH3:13])[CH3:12])([OH:71])=[O:70]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](/C=C/c1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Reactant: O=CCCC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](/C=C/c1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C

Procedure:
15.5 mg (10 μmol) of N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S,3E)-1,4-diphenylbut-3-en-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetate were dissolved in 1.0 ml of dioxane/water and, analogously to the preparation of Intermediate 61, reacted with 15% aqueous solution of 4-oxobutanoic acid in the presence of sodium cyanoborohydride. After lyophilization from dioxane, 10.3 mg (68% of theory) of the title compound were obtained in the form of a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:26]([OH:28])=[CH:25][CH:24]=[CH:23][C:22]=4[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[C:29]([O:34][CH3:35])(=[O:33])[C@H:30]([CH3:32])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][C@H:30]([CH3:32])[C:29]([O:34][CH3:35])=[O:33])[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1
Reactant: COC(=O)[C@H](C)O
Reactant: Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
DTAD (11.48 g, 49.9 mmol) was added portion-wise to an ice-cooled solution of 4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-ol (7.36 g, 20 mmol), (S)-methyl lactate (2.29 ml, 24 mmol) and triphenylphosphine (13.1 g, 49.9 mmol) in DCM (200 ml). The mixture was stirred at room temperature for 1 hour. The mixture was extracted with 2N hydrochloric acid (2×50 ml). The hydrochloric layers were combined and washed with DCM. The pH of the solution was adjusted to pH 9 by slow addition of concentrated aqueous ammonia while cooling. This aqueous solution was extracted with DCM (2×100 ml). These DCM layers were combined, washed with water and brine and dried over MgSO4. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 4% methanol in DCM) to give methyl (2R)-2-[(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate as a yellowish solid (7.35 g, 80%); NMR Spectrum (CDCl3) 1.80 (d, 3H), 3.85 (s, 3H), 5.15 (q, 1H), 5.76 (s, 2H), 6.79 (d, 1H), 6.85 (d, 1H), 7.18 (m, 1H), 7.43 (d, 1H), 7.50 (d, 1H), 7.63-7.54 (m, 2H), 7.70 (dd, 1H), 8.11 (s, 1H), 8.38 (s, 1H), 8.59 (br d, 1H), 8.63 (s, 1H); Mass spectrum MH+ 455.
Reaction SMILES: ClC1C=CC=CC=1C[O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16][CH2:17]C(C)(C)C(O)=O)=[CH:14][N:15]=1.Br[CH2:37][C:38]1[C:39]2[CH:46]=[C:45]([Cl:47])[CH:44]=[CH:43][C:40]=2[S:41][CH:42]=1.C([O:50][C:51](=[O:60])CSC1SC(N)=NC=1)C>>[Cl:47][C:45]1[CH:44]=[CH:43][C:40]2[S:41][CH:42]=[C:38]([CH2:37][O:5][CH2:6][CH2:7][N:8]([C@H:25]3[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]3)[C:9](=[O:24])[NH:10][C:11]3[S:12][C:13]([S:16][CH2:17][C:51]([OH:60])=[O:50])=[CH:14][N:15]=3)[C:39]=2[CH:46]=1
Reactant: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: CCOC(=O)CSc1cnc(N)s1
Reactant: Clc1ccc2scc(CBr)c2c1
Product: C[C@H]1CC[C@H](N(CCOCc2csc3ccc(Cl)cc23)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 3-{2-[3-[2-(2-chloro-benzyloxy)-ethyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid using 3-bromomethyl-5-chloro-benzo[b]thiophene and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[Cl:19][C:20]1[CH:35]=[CH:34][C:23]2[NH:24][C@@H:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:26][O:27][C:22]=2[CH:21]=1.[O:36]=[C:37]1[NH:42][C:41]2[CH:43]=[C:44]([C:47](O)=[O:48])[CH:45]=[CH:46][C:40]=2[O:39][CH2:38]1.CCN(C(C)C)C(C)C>C(OC(C)=O)CCC.CCOC(C)=O>[Cl:19][C:20]1[CH:35]=[CH:34][C:23]2[N:24]([C:47]([C:44]3[CH:45]=[CH:46][C:40]4[O:39][CH2:38][C:37](=[O:36])[NH:42][C:41]=4[CH:43]=3)=[O:48])[C@@H:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:26][O:27][C:22]=2[CH:21]=1
Reactant: CCOC(=O)C[C@H]1COc2cc(Cl)ccc2N1
Reactant: O=C1COc2ccc(C(=O)O)cc2N1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCOC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H]1COc2cc(Cl)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 140 °C
Reaction time: 24 h
Yield: 82.8 %

Procedure:
T3P (50% solution in EtOAc, 146 g, 230 mmol) was added into a solution of ethyl [(3S)-7-chloro-3,4-dihydro-2H-1,4-benzoxazin-3-yl]acetate (Intermediate 20a, 29.4 g, 115 mmol) in n-BuOAc (100 mL), 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (22.7 g, 118 mmol) and DIPEA (44.5 g, 345 mmol) at 20° C. The resulting mixture was stirred at 140° C. for 24 h. The reaction mixture was cooled and diluted with of EtOAc (500 mL). The resulting mixture was washed with 200 mL of saturated sodium bicarbonate, 200 mL of 1 M citric acid and 200 mL of 1 M HCl. The organic phase was dried over anhydrous Na2SO4, filtered and evaporated to dryness. The residue was applied onto a silica gel column and eluted with EtOAc/PE (1/10 to 1/1). The pure fraction was concentrated in vacuo to afford the title compound (41 g, 83%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[Li]CCCC.[Cl:12][C:13]1[N:18]=[C:17]([Cl:19])[CH:16]=[CH:15][N:14]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1.CCOCC>[Cl:12][C:13]1[N:18]=[C:17]([Cl:19])[CH:16]=[C:15]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[Cl:1])[N:14]=1
Reactant: Clc1ccsc1
Reactant: Clc1ccnc(Cl)n1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Clc1cc(-c2sccc2Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-chlorothiophene (384 mg, 3.0 mmol) in THF (6 mL) at −78° C. was added n-BuLi (1.6 M, 2 mL) and the resulting mixture stirred for 45 minutes. The resulting product was added to a solution of 2,4-dichloropyrimidine (430 mg, 2.9 mmol) in ether (10 mL) at −30° C. and the resulting mixture stirred for 30 minutes, then warmed up to 0° C. and stirred for another 30 minutes. DDQ (700 mg, 3 mmol) was added and the resulting mixture was stirred overnight, then filtered through Celite®. The filtrate was concentrated and the residue was purified by silica gel column (EtOAc/hexanes, 1:5) to yield a white solid.
Reaction SMILES: C(C1C=C(C=CC=1CC)C(C1C=CC=CC=1)=O)C.[CH2:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH3:28])[CH3:20].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][C:43]=1[O:44][CH3:45])[C:38](Cl)=[O:39]>>[CH2:19]([C:21]1[CH:26]=[C:25]([C:38](=[O:39])[C:37]2[CH:41]=[CH:42][C:43]([O:44][CH3:45])=[C:35]([O:34][CH3:33])[CH:36]=2)[CH:24]=[CH:23][C:22]=1[CH2:27][CH3:28])[CH3:20]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CCc1ccccc1CC
Agent: CCc1ccc(C(=O)c2ccccc2)cc1CC
Agent: [Al+3]
Agent: [Cl-]
Product: CCc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1CC

Procedure:
3′,4′-Diethyl-3,4-dimethoxybenzophenone was prepared analogously to 3,4-diethylbenzophenone using diethylbenzene (2.5 mL, 15 mmol), aluminum chloride (2.2 g, 16.5 mmol) and 3,4-dimethoxybenzoyl chloride (3 g, 15 mmol) with a reaction time of 3 hours at reflux. The crude product was purified by flash column chromatography (silica gel, 1.5% ethyl acetate/hexane) to afford 0.84 g (20%) of the product as an orange solid: mp 60–61° C.; 1H NMR (CDCl3) δ 7.74–7.15 (m, 5H), 7.00–6.80 (m, 1H) 3.96 (s, 3H) 3.94 (s, 3H), 2.93–2.60 (m, 4H), 1.43–1.15 (m, 6H); 13C NMR (CDCl3) δ 195.5, 152.7, 148.8, 146.3, 141.7, 135.9, 130.6, 129.8, 128.0, 127.7, 125.1, 112.2, 109.7, 56.0, 25.6, 25.4, 15.1, 15.0; Anal. Calcd for C19H22O3. Theoretical: C, 76.48; H, 7.43. Found: C, 76.53; H, 7.34.
Reaction SMILES: [Cl:1][C@@H:2]1[CH2:15][C@@H:14]([O:16]C2CCCCO2)[C@H:13](/[CH:23]=[CH:24]/[C@@H:25]([O:33]C2CCCCO2)[CH:26]([CH3:32])[CH2:27]/[CH:28]=[C:29](\[Cl:31])/[CH3:30])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]>C(O)(=O)C.O.O1CCCC1>[Cl:1][C@@H:2]1[CH2:15][C@@H:14]([OH:16])[C@H:13](/[CH:23]=[CH:24]/[C@@H:25]([OH:33])[CH:26]([CH3:32])[CH2:27]/[CH:28]=[C:29](\[Cl:31])/[CH3:30])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: C/C(Cl)=C/CC(C)[C@@H](/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@H](Cl)C[C@H]1OC1CCCCO1)OC1CCCCO1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: C/C(Cl)=C/CC(C)[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@H](Cl)C[C@H]1O
Yield: 59.1 %

Procedure:
Under argon, 427 mg of (5Z,13E,18Z)-(8R,9R,11R,12R,15S,16RS)-9,19-dichloro-16-methyl-11,15-bis(tetrahydropyran-2-yloxy)-5,13,18-prostatrienoic acid was stirred at room temperature for 16 hours with 9 ml of a mixture of acetic acid/water/tetrahydrofuran (65/35/10). The mixture was then evaporated under vacuum and the residue purified by column chromatography on silica gel with hexane/20-80% ethyl acetate, thus producing 180 mg of the title compound.