Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.CS(O[CH2:23][C:24]([F:27])([F:26])[CH3:25])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:26][C:24]([F:27])([CH3:25])[CH2:23][O:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[CH:4][CH:3]=1
Reactant: CC(F)(F)COS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(F)(F)COc1ccc(CCNC(=O)OC(C)(C)C)cc1
Temperature: 115 °C
Reaction time: 3 h
Yield: 13.9 %

Procedure:
A mixture of tert-butyl 4-hydroxyphenethylcarbamate (700 g, 2.94 mmol), 2,2-difluoropropyl methanesulfonate (668 mg, 3.84 mmol) and cesium carbonate (1.92 g, 5.88 mmol) in DMF (5 mL) was stirred at 115° C. in a microwave reactor for 3 h. After cooling to room temperature, water was added and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum to give the crude product, which was purified by preparative thin layer chromatography (22% ethyl acetate in petroleum ether) to afford the title compound (130 mg, 0.41 mmol, 14% yield). MS (ESI) m/z 316.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][OH:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:26](Br)[CH3:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][O:23][CH2:26][CH3:27])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCBr
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(CO)nc3N21
Agent: [H-]
Agent: [Na+]
Product: CCOCc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
This compound was prepared in analogy to Example 15 intermediate c), from (4R,9aR)-6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester, sodium hydride and ethyl bromide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-])=O)=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8]>CO.[C].[Pd]>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1cc(F)ccc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a mixture of 5-fluoro-2-nitrobenzamide (17.5 g, 95.04 mmol, 1.00 equiv) and palladium carbon (10%) (1.75 g, 0.10 equiv) in methanol (150 mL). To the above H2 (enough) was introduced. The resulting solution was stirred for 2 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 12.0 g (82%) of 2-amino-5-fluorobenzamide as a white solid. MS (ESI) m/z 155 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]([S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]=[C:15]([CH2:17][CH2:18][C:19]([OH:21])=O)[N:16]=1)=[CH:8]2.[N:30]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>O.CN(C)C=O>[CH3:1][N:2]([S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]=[C:15]([CH2:17][CH2:18][C:19]([NH2:30])=[O:21])[N:16]=1)=[CH:8]2
Reactant: CN(c1cccc2cc(-c3nc(CCC(=O)O)cs3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cccc2cc(-c3nc(CCC(N)=O)cs3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 0.33 h
Yield: 36.4 %

Procedure:
To a mixture of 3-(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-4-yl)propanoic acid (0.11 g), 1H-1,2,3-benzotriazol-1-ol (40 mg) and N,N-dimethylformamide (6 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (57 mg) at room temperature. The mixture was stirred for 20 min, and 28% aqueous ammonia (0.08 mL) was added. The reaction mixture was stirred at room temperature for 1 hr, and water was added. The resulting crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (0.04 g, yield 36%) was obtained as colorless crystals from a fraction eluted with tetrahydrofuran-hexane (4:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 200-201° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:8][C:9]1[CH:15]=[C:14]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=[CH:12][C:10]=1[NH2:11])=[O:5])[CH3:2].[Cl:30][C:31]1[CH:32]=[C:33]2[CH2:45][CH2:44][C@@H:43]([CH2:46][C:47](O)=[O:48])[N:35]3[C:36](=[O:42])[C:37](=[O:41])[NH:38][C:39]([CH:40]=1)=[C:34]23>C(O)(=O)C.C(OCC)(=O)C>[Cl:30][C:31]1[CH:32]=[C:33]2[CH2:45][CH2:44][C@@H:43]([CH2:46][C:47](=[O:48])[NH:11][C:10]3[CH:12]=[CH:13][C:14]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:15][C:9]=3[CH2:8][CH2:7][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:35]3[C:36](=[O:42])[C:37](=[O:41])[NH:38][C:39]([CH:40]=1)=[C:34]23
Reactant: O=C(O)C[C@@H]1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23
Reactant: CCOC(=O)C(CCc1cc(CNC(=O)OC(C)(C)C)ccc1N)C(=O)OCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(CCc1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23)C(=O)OCC
Yield: 78.3 %

Procedure:
A procedure similar to that described in Example 18-6) was performed with 2-(3,3-diethoxycarbonylpropyl)-4-tert-butoxycarbonylaminomethylaniline (559 mg, 1.37 mmol) and (S)-9-chloro-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (445 mg, 1.51 mmol) to give 735 mg of the title compound after silica gel column chromatography with 0.3% acetic acid/ethyl acetate (78%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9](O)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[Pd]>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCC(O)c1cccc(F)c1F
Agent: [Pd]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CCCCCCc1cccc(F)c1F

Procedure:
Quantities: compound from Example 17 (52.6 g, 0.25 mol), phosphorus pentoxide (105 g, 0.74 mol) and 5% palladium-on-charcoal (5.8 g). The experimental procedure was as described in Example 22.
Reaction SMILES: Br([O-])(=O)=[O:2].[Na+].[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1>C(#N)C.O>[F:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]([OH:2])=[O:12])=[CH:9][CH:8]=1
Reactant: OCc1ccc(F)cc1
Reactant: [O-][Br+2]([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1ccc(F)cc1
Yield: 89.7 %

Procedure:
The separated catalyst was added to a fresh batch of sodium bromate (0.3 g) and 4-fluorobenzyl alcohol (0.256 g, 2 mmol) in acetonitrile:water (1:1, 10 ml). The above procedure was repeated to give 4-fluorobenzoic acid as a white solid (0.25 g, 88%).
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[N:6]1)[CH:2](C)C.Br[C:20]1[CH:38]=[CH:37][C:23]([C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][N:31]3[CH:34]=[CH:35][N:36]=[C:30]3[CH:29]=2)=[O:25])=[CH:22][CH:21]=1.Br[C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=C[CH:41]=1>>[N:36]1[CH:35]=[CH:34][N:31]2[CH:32]=[CH:33][C:28]([CH2:27][NH:26][C:24](=[O:25])[C:23]3[CH:37]=[CH:38][C:20]([C:46]4[CH2:45][CH2:43][N:44]([C:7]5[CH:8]=[CH:9][N:5]=[C:1]([CH3:2])[N:6]=5)[CH2:41][CH:40]=4)=[CH:21][CH:22]=3)=[CH:29][C:30]=12
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(Br)cc1
Reactant: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1ccc(Br)cc1
Product: Cc1nccc(N2CC=C(c3ccc(C(=O)NCc4ccn5ccnc5c4)cc3)CC2)n1

Procedure:
The title compound was prepared as described in Example 51A, substituting 2-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-1(2H)-yl)pyrimidine for 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 4-bromo-N-(imidazo[1,2-a]pyridin-7-ylmethyl)benzamide for 4-bromoaniline. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.07-8.95 (m, 1H), 8.78 (dd, J=7.0, 0.5 Hz, 1H), 8.28-8.16 (m, 2H), 8.00 (d, J=2.0 Hz, 1H), 7.97-7.87 (m, 2H), 7.80-7.74 (m, 1H), 7.63-7.54 (m, 2H), 7.40 (dd, J=7.0, 1.5 Hz, 1H), 7.04 (d, J=7.4 Hz, 1H), 6.41-6.31 (m, 1H), 4.66 (m, 2H), 4.47 (m, 2H), 4.10 (t, J=5.8 Hz, 2H), 2.77-2.64 (m, 2H), 2.55 (s, 3H); MS (ESI(+)) m/e 425 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:29])[C:19](=[O:28])[NH:20][N:21]=2)[C@@H:10]([CH3:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:29])[C:19](=[O:28])[NH:20][N:21]=2)[C@@H:10]([CH3:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1C(=O)NN=C2COc3ccc(C4=CCN(C(=O)OC(C)(C)C)C[C@@H]4C)cc3N21
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1C(=O)NN=C2COc3ccc([C@@H]4CCN(C(=O)OC(C)(C)C)C[C@@H]4C)cc3N21
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.7 %

Procedure:
A mixture of (R)-3-methyl-4-((R)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (isomer 1, SFC (Table 1, Method 42), Rt=8.561 min., 0.55 g, 1.333 mmol) and Pd/C (10%, 0.142 g) in MeOH (20 mL) was stirred under an atmosphere of H2 (1 atm) at ambient temperature for 3 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give (3R,4R)-3-methyl-4-((R)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.54 g, 98%) as a colorless solid. 1H NMR (CDCl3, 400 MHz) δ 8.35 (s, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 6.71 (s, 1H), 4.77 (q, J=6.8 Hz, 1H), 4.65-4.52 (d, J=13.2 Hz, 2H), 4.48-3.98 (m, 2H), 3.18-2.73 (m, 3H), 2.13-1.92 (m, 2H), 1.61 (brs, 1H), 1.55-1.48 (m, 13H), 0.76-0.67 (d, J=5.6 Hz, 3H). LC/MS (Table 1, Method 25), Rt=0.869 min.; MS m/z: 415 [M+H]+. SFC (Table 1, Method 45), Rt=4.910 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:47])[C@H:4]([CH2:43][CH2:44][S:45][CH3:46])[NH:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]2[CH2:19][CH:18]([O:20][Si](C(C)(C)C)(C)C)[CH2:17][N:16]2[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:9][C:8]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:47])[C@H:4]([CH2:43][CH2:44][S:45][CH3:46])[NH:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]2[CH2:19][CH:18]([OH:20])[CH2:17][N:16]2[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:9][C:8]=1[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC(=O)[C@@H]2CC(O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)cc1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC(=O)[C@@H]2CC(O)CN2C(=O)OC(C)(C)C)cc1-c1ccccc1
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of 1.82 g (2.65 mmol) of {4-[N-Boc-4-(t-butyldimethylsilyloxy)-prolinyl]amino-2-phenylbenzoyl}methionine methyl ester, prepared as in Example 169B, in 20 ml of THF was added 3 ml (3 mmol) of 1 M tetra-n-butylammonium fluoride in THF. The reaction mixture was stirred overnight, diluted with ethyl acetate, and washed 3 times with water. The combined aqueous washings were extracted 3 times with ethyl acetate. The combined organic fractions were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (ethyl acetate) to obtain 864 mg (57%) of [4-(N-Boc-4-hydroxyprolinyl)amino-2-phenylbenzoyl]methionine methyl ester as a white solid: mp 121-123° C. ; [α]25D−53.3 (c=0.43, CHCl3);
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]([NH:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:17])=[O:16])=[O:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])O.[Na+:25]>O>[C:1]([NH:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]([NH:12][CH2:13][CH2:14][S:15]([O-:18])(=[O:17])=[O:16])=[O:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Na+:25]
Reactant: CC(=O)Nc1ccc(OC(=O)NCCS(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc(OC(=O)NCCS(=O)(=O)[O-])cc1
Yield: 103.7 %

Procedure:
Sodium 2-((4-Acetamidophenoxy)carbonylamino)ethanesulfonic acid (12) was prepared following the General Procedure for the Preparation of Alkali Metal Salts (Procedure B). 4-Acetamidophenoxy)carbonylamino)ethanesulfonic acid (12a) (1.0 g, 3.3 mmol), dissolved in 5 mL of water, was reacted with 275 mg (3.27 mmol; 1.0 eq.) of sodium hydrogencarbonate (NaHCO3) dissolved in 2 mL of water. The mixture was frozen and the solvents lyophilized off to afford 1.10 g (˜quantitative yield) of the title compound (12) as a colorless solid. The material thus obtained was contaminated with some sodium chloride (NaCl) and other sodium salts. Rt=5.024 min. 1H NMR (300 MHz, D2O): δ=7.25 (d, J=9.0 Hz, 2H), 6.97 (d, J=8.7 Hz, 2H), 3.43 (t, J=6.6 Hz, 2H), 2.98 (t, J=6.9 Hz, 2H), 2.00 (s, 3H). LC/MS (ESI): m/z=303.0 [M+H]+, 626.8 [2M+Na]+, 602.8 [2M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:34][CH3:35])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:36].C1C=C(Cl)C=C(C(OO)=[O:45])C=1>ClCCl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:34]([CH3:35])=[O:45])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:36]
Reactant: CSc1nc(-c2cc(C(=O)Nc3nccs3)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.7 %

Procedure:
To the solution of 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide (262 mg, 0.50 mmol) in dichloromethane (10 mL) was added mCPBA (116 mg, 0.75 mmol). The reaction mixture was stirred at room temperature for 10 minutes. Then the reaction mixture was applied to flash chromatography to afford the titled compound 256 mg (95%). LC-MS m/z 541 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:17](OC)(=[O:20])[C:18]#[CH:19]>C(O)C>[O:20]=[C:17]1[CH:18]=[CH:19][N:6]2[C:2]([S:3][C:4]3[CH:10]=[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:7][C:5]=32)=[N:1]1
Reactant: CCOC(=O)Cc1ccc2nc(N)sc2c1
Reactant: C#CC(=O)OC
Solvent: CCO
Product: CCOC(=O)Cc1ccc2c(c1)sc1nc(=O)ccn12
Yield: 47.2 %

Procedure:
A stirred mixture of 5 g of ethyl 2-aminobenzothiazole-6-acetate [prepared according to Sawhney et al., Ind J. Chem., Vol. 16B p. 605 (1978)], 1.95 g of methyl propiolate and 30 ml of ethanol was heated under reflux for 2 hours and the mixture was allowed to cool. The crude product was collected and then recrystallized from n-butyl alcohol to obtain 2.88 g of ethyl 2-oxo-2H-pyrimido[2,1-b]benzothiazole-8-acetate as yellow needles (48% yield).
Reaction SMILES: [H-].[Na+].[C:3]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:8]=[CH:7][C:6]([C:9]([N:11]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[N:21][C:15]=3[NH:14][C:13]3[CH:22]=[CH:23][CH:24]=[CH:25][C:12]2=3)=[O:10])=[CH:5][CH:4]=1.[CH3:32]I>CCCCCC.ClCCl>[C:3]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:4]=[CH:5][C:6]([C:9]([N:11]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[N:21][C:15]=3[N:14]([CH3:32])[C:13]3[CH:22]=[CH:23][CH:24]=[CH:25][C:12]2=3)=[O:10])=[CH:7][CH:8]=1
Reactant: CI
Reactant: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2cccnc2Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Product: CN1c2ccccc2N(C(=O)c2ccc(-c3ccccc3)cc2)Cc2cccnc21
Reaction time: 1 h
Yield: 61.3 %

Procedure:
Sodium hydride (60% suspension, 0.10 g, 2.5 mmol) washed with hexane and dried under nitrogen, was suspended in dry N,N-dimethylformamide (15 mL). Following addition of 1,1′-biphenyl-4-yl-(5,11-dihydro-benzo[b]pyrido[2,3-e][1,4]diazepin-6-yl)-methanone of Example 4 (0.76 g, 2.0 mmol), methyl iodide (0.5 mL, 2.4 mmol) was added. After stirring for 1 hour, the reaction was quenched with water and extracted with dichloromethane The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give a yellow solid. Purification of the residue by flash chromatography using a solvent gradient from 25% to 35% of ethyl acetate in hexane gave a white foam which was redissolved in dichloromethane, concentrated in vacuo to a foam, then crystallized by sonication from ethyl acetate/hexane to provide the title compound (0.48 g, 61.3%) as a white solid, m.p. 220-223° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][N:11]([C:13]3[N:18]=[C:17]([C:19]([OH:21])=O)[CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9][C:7]=2[N:8]=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1>>[CH3:29][C:25]1[CH:24]=[C:23]([NH:22][C:19]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([N:11]3[CH2:10][CH2:9][C:7]4[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[CH2:12]3)[N:18]=2)=[O:21])[CH:28]=[CH:27][CH:26]=1
Reactant: CSc1ncc2c(n1)CCN(c1cccc(C(=O)O)n1)C2
Reactant: Cc1cccc(N)c1
Product: CSc1ncc2c(n1)CCN(c1cccc(C(=O)Nc3cccc(C)c3)n1)C2

Procedure:
In a manner similar to that described in Example 108, a mixture of 6-[2-(methylthio)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-yl]pyridine-2-carboxylic acid and m-toluidine were converted to the title compound.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].COC(C1NN=C(OCC2C(C3C=CC=CC=3)=NOC=2C)C=1)=O.[F:48][C:49]([F:53])([F:52])[CH2:50][NH2:51]>>[F:48][C:49]([F:53])([F:52])[CH2:50][NH:51][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)n[nH]1
Reactant: NCC(F)(F)F
Agent: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Product: Cc1onc(-c2ccc(F)cn2)c1COc1cc(C(=O)NCC(F)(F)F)[nH]n1
Yield: 21 %

Procedure:
As described for example 1b, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.3 mmol), instead of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester, was converted, using 2,2,2-trifluoroethylamine instead of morpholine, to the title compound (25 mg, 21%), which was obtained as a white solid. MS: m/e=400.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([N:22]([CH3:46])[CH:23]2[C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][C:26]=3[CH2:25][CH2:24]2)[N:33]=[C:32]([CH3:36])[N:31]([CH2:37][O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C:30]4=[O:45])[CH:19]=[CH:18][C:3]=1[C:4](OC1C(F)=C(F)C(F)=C(F)C=1F)=[O:5].[NH2:47][C@@H:48]([CH2:53][CH2:54][C:55]1[NH:59][N:58]=[N:57][N:56]=1)[C:49]([O:51][CH3:52])=[O:50]>>[F:1][C:2]1[CH:21]=[C:20]([N:22]([CH3:46])[CH:23]2[C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][C:26]=3[CH2:25][CH2:24]2)[N:33]=[C:32]([CH3:36])[N:31]([CH2:37][O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:41])[CH3:42])[C:30]4=[O:45])[CH:19]=[CH:18][C:3]=1[C:4]([NH:47][C@@H:48]([CH2:53][CH2:54][C:55]1[NH:59][N:58]=[N:57][N:56]=1)[C:49]([O:51][CH3:52])=[O:50])=[O:5]
Reactant: COC(=O)[C@@H](N)CCc1nnn[nH]1
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
Product: COC(=O)[C@H](CCc1nnn[nH]1)NC(=O)c1ccc(N(C)C2CCc3cc4nc(C)n(COC(=O)C(C)(C)C)c(=O)c4cc32)cc1F
Yield: 73 %

Procedure:
Using analogous procedures to those described in the second and third paragraphs of Example 12, 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 was reacted with methyl (2S)-2-amino-4-(tetrazol-5-yl)butyrate to give methyl (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}-4-(tetrazol-5-yl)butyrate in 73% yield which in turn was hydrolysed with aqueous sodium hydroxide solution to give (2S)-2-{o-fluoro-p-[N-methyl-N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]benzamido}-4-(tetrazol-5-yl)butyric acid in 81% yield, m.p. 203°-205° C.;
Reaction SMILES: [Mg].BrCCBr.[CH2:6]([O:8][CH:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)[CH3:10])[CH3:7].[Br:19][C:20]([CH2:22]Br)=[CH2:21]>C1COCC1>[CH2:6]([O:8][CH:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:22][C:20]([Br:19])=[CH2:21])[CH3:10])[CH3:7]
Reactant: CCOC(C)OCCCCCCBr
Reactant: C=C(Br)CBr
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: C=C(Br)CCCCCCCOC(C)OCC
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 75.5 %

Procedure:
A slurry of 5.6 g of magnesium turnings (230 mmol) in 100 ml of THF was treated with a small amount of 1,2-dibromoethane. 1-(1-Ethoxyethoxy)-6-bromohexane (38.5 g, 152 mmol) was fed slowly to the reaction mixture, maintaining the temperature at 40-50° C. At the end of the addition the reaction mixture was held 20 minutes, then transferred by cannula to solution of 33.4 g (167 mmol) of 2,3-dibromopropene in 25 ml of THF at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes, then stirred at room temperature for 15 minutes, then quenched with water. The reaction mixture was transferred into a separatory funnel. A small amount of 1 N HCl was added, the phases were separated, the ether phase was washed with water and brine, then dried over magnesium sulfate, filtered, and stripped to give 33.63 g of a yellow liquid which was used without further purification.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][O:11][C:12](=[O:51])[CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][C@@H:19]1[C@@H:23](/[CH:24]=[CH:25]/[C@@H:26]([O:36]C2CCCCO2)[C:27]([CH2:34]C)([CH2:32]C)[CH2:28][CH2:29][CH2:30][CH3:31])[C@H:22]([O:43]C2CCCCO2)[CH2:21][C@@H:20]1O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[CH3:10][O:11][C:12](=[O:51])[CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][C@@H:19]1[C@@H:23](/[CH:24]=[CH:25]/[C@@H:26]([OH:36])[C:27]([CH3:34])([CH3:32])[CH2:28][CH2:29][CH2:30][CH3:31])[C@H:22]([OH:43])[CH2:21][C@H:20]1[F:7]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCCCC(CC)(CC)[C@@H](/C=C/[C@@H]1[C@@H](CC/C=C\CCC(=O)OC)[C@@H](O)C[C@H]1OC1CCCCO1)OC1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCC(C)(C)[C@H](O)/C=C/[C@@H]1[C@@H](CC/C=C\CCC(=O)OC)[C@H](F)C[C@H]1O
Temperature: -70 °C
Reaction time: 3.5 h

Procedure:
0.56 ml of diethylaminosulfur trifluoride (DAST) is instilled in a solution of 2.05 g of (4Z,13E)-(9S,11R,15R)-9-hydroxy-16,16-diethyl-11,15-bis-(tetrahydropyran-2-yloxy)-4,13-prostadienoic acid methyl ester in 43 ml of methylene chloride and 1.1 ml of pyridine at -70° C. and stirred for 3.5 hours at -70° C. Then it is added to 200 ml of 5% sodium bicarbonate solution cooled to 0° C. and allowed to stir vigorously for 10 minutes. Then it is extracted several times with methylene chloride, the extract is washed with water, dried over MgSO4 and concentrated by evaporation in a vacuum. The residue is stirred for 24 hours at 20° C. with 60 ml of a mixture of acetic acid/water/tetrahydrofuran (65/35/10), concentrated by evaporation in a vacuum after addition of toluene and the raw product is purified by chromatography on silica gel with toluene/0-10% isopropanol. 306 mg of the title compound is obtained as oil.