Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:16]#[N:17])[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:25])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:16]#[N:17])[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[Br:25]
Reactant: N#CC1(c2ccc(N)cc2)CCS(=O)(=O)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: N#CC1(c2ccc(N)c(Br)c2)CCS(=O)(=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A solution of 4-(4-amino-phenyl)-1,1-dioxo-hexahydro-1λ6-thiopyran-4-carbonitrile (114 mg, 0.455 mmol, as prepared in the previous step) in CH2Cl2 (15 mL) was cooled to 0° C., treated with solid NBS (77.0 mg, 0.433 mmol), and stirred at that temperature for 30 min. The mixture was diluted with CH2Cl2 (20 mL) and washed with satd aq NaHCO3 (1×20 mL). The aqueous layer was extracted with CH2Cl2 (1×20 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 50% EtOAc-hexane afforded the title compound (136 mg, 90%) as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 7.53 (d, 1H, J=2.0 Hz), 7.23 (dd, 1H, J=8.4, 2.0 Hz), 6.79 (d, 1H, J=8.0 Hz), 4.40-4.15 (br s, 2H), 3.60-3.45 (m, 2H), 3.26-3.11 (m, 2H), 2.78-2.63 (m, 2H), 2.51-2.38 (m, 2H).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:13][CH2:12][CH2:11][CH2:10][O:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=1
Reactant: ClCCCBr
Reactant: Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(OCCCCl)cc1
Yield: 102 %

Procedure:
A mixture of 27 g (0.25 mole) of p-cresol, 78.7 g (0.5 mole) of 1-bromo-3-chloropropane and 103.7 g (0.75 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 24 hr. The reaction mixture was cooled, filtered and concentrated in vacuo at 90° C. to give 47.1 g of an oil residue. The oil was subjected to vacuum distillation to give 39.3 g (85%) of clear oil, bp 85°-90° C. at 0.1 mm Hg.
Reaction SMILES: [Cl:1][CH:2]([NH:4][C:5](Cl)=[O:6])[CH3:3].C(N=C=O)=C>ClC1C2C(=CC=CC=2)C=CC=1>[CH:2]([N:4]=[C:5]=[O:6])=[CH2:3].[Cl:1][CH:2]([N:4]=[C:5]=[O:6])[CH3:3]
Reactant: CC(Cl)NC(=O)Cl
Agent: C=CN=C=O
Solvent: Clc1cccc2ccccc12
Product: CC(Cl)N=C=O
Yield: 92 %

Procedure:
30 parts of 1-chloroethylcarbamyl chloride are dissolved in 100 parts by volume of 1-chloronaphthalene and a solution of 16 parts of vinyl isocyanate in 20 parts by volume of 1-chloronaphthalene is added to the mixture in the course of 0.3 hour at 2° C. 12.5 parts (8% of theory) of vinyl isocyanate and 43 parts (92% of theory) of 1-chloroethyl isocyanate are obtained, the determinations being carried out by gas chromatography.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[C@@H:30]12[CH2:36][N:35]([C:37]3[S:38][C:39]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[C:40]([CH3:42])[N:41]=3)[C@@H:34]1[CH2:33][CH2:32][NH:31]2.[Cl:48][C:49]1[N:50]=[C:51]([C:56](O)=[O:57])[NH:52][C:53]=1[CH2:54][CH3:55]>CC(N(C)C)=O.ClCCl.C(OCC)(=O)C>[Cl:48][C:49]1[N:50]=[C:51]([C:56]([N:31]2[CH2:32][CH2:33][C@@H:34]3[C@H:30]2[CH2:36][N:35]3[C:37]2[S:38][C:39]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[C:40]([CH3:42])[N:41]=2)=[O:57])[NH:52][C:53]=1[CH2:54][CH3:55]
Reactant: CCOC(=O)c1sc(N2C[C@H]3NCC[C@H]32)nc1C
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCOC(=O)c1sc(N2C[C@@H]3[C@H]2CCN3C(=O)c2nc(Cl)c(CC)[nH]2)nc1C
Temperature: 25 °C
Reaction time: 19 h
Yield: 68.6 %

Procedure:
WSC hydrochloride (377 mg, 1.97 mmol), 1-hydroxybenzotriazole (97 mg, 0.72 mmol) and N-methylmorpholine (0.14 mL, 1.31 mmol) were added to a mixed solution of ethyl 2-[(1R,5R)-2,6-diazabicyclo[3.2.0]hept-6-yl]-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (236c) (175 mg, 0.66 mmol) and 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (137 mg, 0.79 mmol) in DMA/dichloromethane (4 mL/4 mL), and the mixture was stirred at room temperature for 19 hours. The reaction solution was diluted with ethyl acetate, and then the mixture was washed with 5% saline and dried over anhydrous magnesium sulfate. Following filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=2/1) to obtain 192 mg of the title compound as a milk white solid (69%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:42][N:43]([CH2:60][CH2:61][C:62]1[S:63][CH:64]=[CH:65][CH:66]=1)[C:44](=[O:59])[C@H:45]([NH:57][CH3:58])[CH2:46][C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=1.C(N(C(C)C)C(C)C)C>ClCCl.CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:11]1[CH:19]=[CH:18][CH:17]=[C:13]([C:14](=[O:16])[N:57]([CH3:58])[C@@H:45]([C:44](=[O:59])[N:43]([CH3:42])[CH2:60][CH2:61][C:62]2[S:63][CH:64]=[CH:65][CH:66]=2)[CH2:46][C:47]2[CH:56]=[CH:55][C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[CH:48]=2)[CH:12]=1)[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(NC(=O)OC(C)(C)C)c1cccc(C(=O)O)c1
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCc1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)OC(C)(C)C)c1cccc(C(=O)N(C)[C@H](Cc2ccc3ccccc3c2)C(=O)N(C)CCc2cccs2)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 97.4 %

Procedure:
3-(1-(t-Butyloxycarbonylamino)ethyl)benzoic acid (217 mg, 0.82 mmol) was dissolved in dichloromethane (5 ml) and N,N-dimethylformamide (3 ml). 1-Hydroxy-7-azabenzotriazole (111 mg, 0.82 mmol) was added. The solution was cooled to 0° C. N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (157 mg, 0.82 mmol) was added. A solution of (2R)-N-Methyl-2-(methylamino)-3-(2-naphthyl)-N-(2-(2-thienyl)ethyl)propionamide (288 mg, 0.82 mmol) in dichloromethane (3 ml) was added. Ethyldiisopropylamine (0.14 ml, 0.82 mmol) was added. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (80 ml) and washed with 10% sodium hydrogen sulfate solution (50 ml). The aqueous phase was extracted with ethyl acetate (2×40 ml). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (50 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silcia (110 g), using ethyl acetate/heptane 1:1 as eluent, to give 479 mg of (1-(3-(N-methyl-N-((1R)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)phenyl)ethyl)carbamic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[CH3:27][N:28]([CH3:42])[CH2:29][CH2:30][NH:31][S:32]([C:35]1[S:39][C:38]([NH2:40])=[N:37][C:36]=1[CH3:41])(=[O:34])=[O:33]>>[CH3:27][N:28]([CH3:42])[CH2:29][CH2:30][NH:31][S:32]([C:35]1[S:39][C:38]([NH:40][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:14])=[N:37][C:36]=1[CH3:41])(=[O:34])=[O:33]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1nc(N)sc1S(=O)(=O)NCCN(C)C
Product: Cc1nc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)NCCN(C)C

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-dimethylamino-ethyl)-amide (example B.15) according to general procedure II.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([O:24][CH3:25])[CH:3]=1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:28]3[CH2:29][CH2:30][O:26][C:27]3=[O:31])=[CH:3][C:4]=2[O:24][CH3:25])=[O:9])[CH2:11][CH2:12]1
Reactant: O=C1NCCO1
Reactant: COc1cc(Br)ccc1C(=O)N1CCN(c2ccc(C)cc2C)CC1
Product: COc1cc(N2CCOC2=O)ccc1C(=O)N1CCN(c2ccc(C)cc2C)CC1
Yield: 50 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methoxyphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (807 mg) described in Preparation Example 5 and oxazolidin-2-one (174 mg), the title compound (409 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[C:25]([CH3:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([N:33]4[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[N:34]4)[N:21]=3)[CH2:16][CH:15]2[C:41](=[O:50])[N:42]([CH2:44][CH2:45][CH2:46][CH2:47][CH:48]=[CH2:49])[CH3:43])=[O:13])[CH2:8][CH:7]1C=C)=[O:5])[CH3:2]>CC(C)OC1C(C=[Ru](Cl)([P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)Cl)=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]12[CH2:7][CH:8]1[CH:49]=[CH:48][CH2:47][CH2:46][CH2:45][CH2:44][N:42]([CH3:43])[C:41](=[O:50])[CH:15]1[CH:14]([CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[C:25]([CH3:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([N:33]4[CH:37]=[CH:36][C:35]([CH:38]([CH3:39])[CH3:40])=[N:34]4)[N:21]=3)[CH2:16]1)[C:12](=[O:13])[NH:11]2)=[O:5])[CH3:2]
Reactant: C=CCCCCN(C)C(=O)C1CC(Oc2nc(-n3ccc(C(C)C)n3)nc3c(C)c(OC)ccc23)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Agent: CC(C)Oc1ccccc1C=[Ru](Cl)(Cl)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Product: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3nc(-n4ccc(C(C)C)n4)nc4c(C)c(OC)ccc34)CC1C(=O)N2
Temperature: 80 °C

Procedure:
A solution of the diene (144) (230 mg, 0.335 mmol) and Hoveyda-Grubbs 1st generation catalyst (60.8 mg, 0.101 mmol) in dried and degassed 1,2-dichloroethane (230 mL) was heated at 80° C. under nitrogen for 18 h. Then, the solvent was evaporated and the residue purified by silica gel chromatography (ether) to give the target compound, m/z=659 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:9].[CH:10](O)=[O:11]>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:10]=[O:11])=[CH:4][C:3]=1[Cl:9]
Reactant: O=CO
Reactant: Nc1ccc(Br)c(Cl)c1
Product: O=CNc1ccc(Br)c(Cl)c1

Procedure:
A mixture of 60.7 g of 4-bromo-3-chloroaniline and 300 ml of 97% formic acid was refluxed for four hours. The resulting mixture was poured over ice and filtered. The solid was washed with water and recrystallized from 3/1 v/v ether/hexane to give N-(4-bromo-3-chlorophenyl)formamide (4A), as a tan solid, mp: 110°-113° C.
Reaction SMILES: [C:1]1([C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH2:10]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]([O:17]C1C=CC(C(=O)C)=CC=1)([CH3:16])[CH3:15]>CCOC(C)=O>[CH:14]([O:17][C:4]1[CH:3]=[CH:2][C:1]([C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH3:10])=[CH:6][CH:5]=1)([CH3:16])[CH3:15]
Reactant: CCC(=O)CC(=O)c1ccccc1
Reactant: CC(=O)c1ccc(OC(C)C)cc1
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)c1ccc(OC(C)C)cc1

Procedure:
The title compound was prepared (as described above for Intermediate 16) from 2.42 g of 4′-isopropoxyacetophenone and 2.65 mL of EtOAc to yield 2.25 grams of Intermediate 29: TLC analysis: Rf=0.73 (2/1, hexanes/EtOAc); 1H NMR (400 MHz, CDCl3, enol form) δ7.84 (d, 2H, J=8.9), 6.9 (d, 2H, J=9.0), 6.1 (s, 1H), 4.62 (hept, 1H, J=6.0), 2.16 (s, 3H), 1.36 (d, 6H, J=6.0).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][OH:14])=[C:11]([C:15]([N:17]([CH2:39][CH:40]([CH3:42])[CH3:41])[C@H:18]2[CH2:23][C@@H:22]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])[CH2:21][N:20]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:19]2)=[O:16])[N:10]=[N:9]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:55][O:56][CH2:57][CH2:58]O>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][O:14][CH2:58][CH2:57][O:56][CH3:55])=[C:11]([C:15]([N:17]([CH2:39][CH:40]([CH3:42])[CH3:41])[C@H:18]2[CH2:23][C@@H:22]([C:24]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[O:25])[CH2:21][N:20]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:19]2)=[O:16])[N:10]=[N:9]1
Reactant: CC(C)CN(C(=O)c1nnn(-c2ccccc2F)c1CO)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: COCCO
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COCCOCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
tert-Butyl (3S,5R)-3-[{[1-(2-fluorophenyl)-5-(hydroxymethyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (510 mg) and triethylamine (365 μl) were dissolved in THF (8 ml), and methanesulfonyl chloride (110 μl) was added under ice-cooling. The mixture was stirred at 0° C. for 3 hr, 2-methoxyethanol (200 mg) was added and the mixture was stirred at room temperature for 14 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (491 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)O)=[CH:4][C:3]=1[F:15].C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:4][C:3]=1[F:15]
Reactant: OC(c1ccc(Br)c(F)c1)c1nccs1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(Cc2nccs2)ccc1Br

Procedure:
A solution of (4-Bromo-3-fluoro-phenyl)-thiazol-2-yl-methanol (3.4 g, 12.6 mmol), TFA (25 mL), and Triethylsilane (10 mL, 63 mmol), were refluxed overnight. The reaction was then concentrated under vacuum, and purified by silica gel chromatography (gradient elution 10–40% Ethylacetate/Hexanes). Yield 1.96 g, 61%.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[F:16][C:17]1[CH:36]=[C:35]([N:37]([CH3:61])[CH:38]2[C:42]3[CH:43]=[C:44]4[C:49](=[CH:50][C:41]=3[CH2:40][CH2:39]2)[N:48]=[C:47]([CH3:51])[N:46]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C:45]4=[O:60])[CH:34]=[CH:33][C:18]=1[C:19](OC1C(F)=C(F)C(F)=C(F)C=1F)=[O:20].CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl>CN(C=O)C.CO.O>[F:16][C:17]1[CH:36]=[C:35]([N:37]([CH3:61])[CH:38]2[C:42]3[CH:43]=[C:44]4[C:49](=[CH:50][C:41]=3[CH2:40][CH2:39]2)[N:48]=[C:47]([CH3:51])[N:46]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:56])([CH3:57])[CH3:58])[C:45]4=[O:60])[CH:34]=[CH:33][C:18]=1[C:19]([NH:1][C@@H:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4])=[O:20]
Reactant: N[C@H](C(=O)O)c1ccc(CC(=O)O)cc1
Reactant: Cc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(N(C)c1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(F)c1)CC3
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(N(C)c1ccc(C(=O)N[C@H](C(=O)O)c2ccc(CC(=O)O)cc2)c(F)c1)CC3
Temperature: 25 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
To a solution of (S)-α-amino-p-carboxymethylphenylacetic acid (0.1 g, 0.48 mmol) and pentafluorophenyl o-fluoro-p-[N-methyl-N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]-benzoate (0.213 g, 0.4 mmol), prepared as described in Example 2, in 5 ml of DMF was added bistrimethyl silyl acetamide (BSA) (0.194 g, 0.96 mmol). After stirring under N2 for 20 minutes N-methylmorpholine was added (0.081 g, 0.8 mmol) followed by N-hydroxybenzotriazole (HOBT) (0.01 g). The reaction mixture was stirred at room temperature for 4 hours and evaporated to dryness. The solid obtained by trituration with ether and filtration was resuspended in a mixture of methanol/water (2 ml) and the pH adjusted to 2.5 with 2N HCl . The resulting precipitate was filtered off, washed with water and dried to give (2S)-2-{o-fluoro-p-[N-methyl-N-((6RS)-2-methyl-3-pivaloyloxymethyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]-benzamido}-2-[p-(carboxymethyl)phenyl]acetic acid (140 mg, 64%) as a yellow solid;
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:9]=[C:10]([CH:14]3[N:18]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[N:17]=[C:16]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])[CH2:15]3)[CH:11]=[CH:12][CH:13]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH:41]1([S:44](Cl)(=[O:46])=[O:45])[CH2:43][CH2:42]1>ClCCl>[CH:41]1([S:44]([N:5]2[CH2:4][CH2:3][N:2]([C:8]3[CH:9]=[C:10]([CH:14]4[N:18]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=5[F:26])[N:17]=[C:16]([C:27]([F:33])([F:32])[C:28]([F:29])([F:30])[F:31])[CH2:15]4)[CH:11]=[CH:12][CH:13]=3)[CH2:7][CH2:6]2)(=[O:46])=[O:45])[CH2:43][CH2:42]1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cccc(N3CCNCC3)c2)c(F)c1
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(C1CC1)N1CCN(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.9 %

Procedure:
5-[3-(Piperazin-1-yl)-phenyl]-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (100.0 mg, 0.2 mmol) prepared in Step 1 of Example 96, triethylamine (143.0 uL, 1.02 mmol) and cyclopropanesulfonyl chloride (43.0 mg, 0.30 mmol) were added to dichloromethane (2.0 mL). The reaction mixture was stirred at room temperature for 18 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 80.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]([CH2:17][C:18]([N:20]([N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)[CH3:21])=[O:19])[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[NH:12][N:11]=[CH:10]2)[CH3:2].FC(F)(F)S(O[CH2:38][CH:39]([F:41])[F:40])(=O)=O>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]([CH2:38][CH:39]([F:41])[F:40])[N:11]=[CH:10]2)[CH2:17][C:18]([N:20]([N:22]1[CH2:23][C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30]1)[CH3:21])=[O:19])[CH3:2]
Reactant: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc2cn[nH]c2cc1C
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Product: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc2cnn(CC(F)F)c2cc1C
Yield: 70.3 %

Procedure:
Using the compound (767 mg, 1.82 mmol) of Example 241, step B and 2,2-difluoroethyl trifluoromethanesulfonate (534 mg, 2.49 mmol), and according to the method of Example 241, step C, the title compound (621 mg, yield 70%) was obtained as a colorless amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[I-].[K+].Br[CH:14]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[CH:21][CH:20]=1)[C:15]([O:17][CH3:18])=[O:16]>O1CCCC1>[CH3:18][O:17][C:15](=[O:16])[CH:14]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[CH:21][CH:20]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: COC(=O)C(Br)c1ccc(OCCOc2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(OCCOc2ccc(Cl)cc2)cc1
Yield: 98.5 %

Procedure:
As described in Example 5, a mixture of 2.52 g of p-chlorophenol, 0.785 g of 60% sodium hydride-oil dispersion, 3.60 g of potassium iodide and 7.8 g of methyl bromo{p-[2-(p-chlorophenoxy)ethoxy]phenyl}acetate in 70 ml of tetrahydrofuran are refluxed for 18 hours and worked up to give 8.6 g of oil. The oil is triturated with hexane to give 6.9 g of tan crystals. Two recrystallizations from methanol gives the product as white crystals, mp 97°-112° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][CH3:6].C(=O)=O.[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[C:18](F)[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22]>CN(C=O)C.C(OCC)(=O)C>[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[C:18]([O:7][CH2:3][CH2:4][CH2:5][CH3:6])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22]
Reactant: COC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CCCCO
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOc1ccc([N+](=O)[O-])c(C(=O)OC)c1

Procedure:
Sodium hydride (302.4 mg) was added to a solution of 1-butanol (0.634 mL) in DMF (15 mL). The reaction mixture was stirred until there was no further evolution of CO2 and then 5-fluoro-2-nitrobenzoic acid methyl ester (1.15 g) was added and the mixture was stirred at room temperature overnight. The reaction was then mixed with ethyl acetate, washed with 10% sodium bicarbonate and 10% citric acid solution, dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC. The product with the molecular weight of 253.26 (C12H15NO5) was obtained in this way; MS (ESI): 254 (M+H+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:12](=[O:29])[C@@H:13]([NH:21]C(=O)OC(C)(C)C)[CH2:14][C:15]3[N:19]([CH3:20])[CH:18]=[N:17][CH:16]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.Cl.C(N(CC)CC)C.[C:42]([CH2:46][C:47](Cl)=[O:48])([CH3:45])([CH3:44])[CH3:43]>ClCCl.O1CCOCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:12](=[O:29])[C@@H:13]([NH:21][C:47](=[O:48])[CH2:46][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:14][C:15]3[N:19]([CH3:20])[CH:18]=[N:17][CH:16]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CC(C)CN(Cc1ccc2occc2c1)C(=O)[C@H](Cc1cncn1C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)CN(Cc1ccc2occc2c1)C(=O)[C@H](Cc1cncn1C)NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of compound 17 (320 mg, 0.70 mmol) in dichloromethane (4 ml) was added 4N HCl in dioxane (4 ml). The mixture was stirred for 1 hr at room temperature and concentrated in vacuo. To a solution of the resulting material were added triethylamine (293 μl, 0.49 mmol) and tert-butylacetyl chloride (117 μl, 0.84 mmol). After 30 min, water (10 ml) was added to quench the reaction. The aqueous phase was extracted with dichloromethane (5 ml) and the organic layer was washed with brine (10 ml), dried over anhydrous MgSO4 and concentrated in vacuo. The crude material was purified by preparative TLC (10% MeOH in dichloromethane) to provide compound 69 (220 mg, 70%) as a white solid. [M+H]+ 453.3, HPLC purity: 99%.