Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:22])[S:3]([C:6]1[CH:21]=[CH:20][C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[CH2:14][C:8]=2[CH:7]=1)(=[O:5])=[O:4].[BH4-].[Na+]>O1CCOCC1.O>[CH3:1][N:2]([CH3:22])[S:3]([C:6]1[CH:21]=[CH:20][C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[CH:13]([OH:15])[CH2:14][C:8]=2[CH:7]=1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)c1ccccc1S2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN(C)S(=O)(=O)c1ccc2c(c1)CC(O)c1ccccc1S2
Temperature: 40 °C
Reaction time: 4 h

Procedure:
14 g of 10,11-dihydro-2-dimethylsulphamoyl-dibenzo[b,f]-thiepin-10-one in 200 ml of dioxane are treated with 3.5 g of sodium borohydride in 15 ml of water and the mixture is stirred at 40° C for 4 hours. The mixture is evaporated under reduced pressure and the residue taken up in ethyl acetate and water. The organic phase is washed with water, dried and evaporated. 10,11-dihydro-2-dimethylsulphamoyl-dibenzo[b,f]-thiepin-10-ol is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:3]=1[CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N+:7]=1[O-:12].ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:3]=1[CH2:4][S:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N+:7]=1[O-:12])=[O:27]
Reactant: Cc1cc(C)c(CSc2cccc[n+]2[O-])c(C)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c(CS(=O)c2cccc[n+]2[O-])c(C)c1

Procedure:
To a mixture of 7.8 g (0.03 mole) of 2-(2,4,6-trimethylbenzylthio)-pyridine-N-oxide in 50 ml of chloroform were added, with stirring at less than 10° C., a mixture of 6 g (0.03 mole) of metachloroperbenzoic acid (85%) in 100 ml of chloroform. The mixture was stirred overnight at room temperature. The mixture was then washed with saturated sodium bicarbonate solution, the chloroform layer was separated and dried over sodium sulfate. The sodium sulfate was filtered off and the chloroform solution evaporated to leave a residue, which was crystallized from ethanol. The product was filtered off, and air-dried, melting point 164–166° C., yield 7.2 g. C, H, N, calculated for C15H17NO2S: % C=65.43, % H=6.22; % N=5.09. Found: % C=66.22; % H=6.63; % N=5.13.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH:18]([OH:22])[CH2:19][O:20][CH3:21])[C:12](=[O:23])[N:11]([CH3:24])[C:10]=3[N:9]=[C:8]2[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:36])([F:35])[F:34])[CH:27]=2)=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][C:18](=[O:22])[CH2:19][O:20][CH3:21])[C:12](=[O:23])[N:11]([CH3:24])[C:10]=3[N:9]=[C:8]2[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:36])([F:34])[F:35])[CH:27]=2)=[CH:37][CH:38]=1
Reactant: COCC(O)Cn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Solvent: CS(C)=O
Solvent: CC(=O)OC(C)=O
Product: COCC(=O)Cn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.1 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-1-(2-hydroxy-3-methoxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (40 mg, 0.072 mmol, example 7f) in methyl sulfoxide (4 mL) was added acetic anhydride (37 mg, 0.363 mmol) dropwise. Then the mixture was stirred at 25° C. for 16 h. The mixture was partitioned between ethyl acetate and water and the organic phase was washed with brine, dried over sodium sulfate, filtered and was concentrated to give crude product. This crude material was further purified preparative HPLC to give 7-(4-chlorobenzyl)-1-(3-methoxy-2-oxopropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (12 mg, 30.2%) as white solid. 1H-NMR (CD3OD) δ 7.56-7.52(t, 1H), 7.42-7.39(d, 2H), 7.36-7.31(m, 4H), 7.24-7.22(d, 1H), 5.45(s, 2H), 4.92(s, 2H), 4.24(s, 2H), 3.46(s, 3H), 3.39(s, 3H). LCMS retention time 3.210 min; LCMS MH+ 553.
Reaction SMILES: [NH2:1][C:2]1([C:8]#[C:9][C:10]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH:22]4[CH2:27][C:26]([CH3:29])([CH3:28])[NH:25][C:24]([CH3:31])([CH3:30])[CH2:23]4)[N:16]=3)=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[H][H]>CO.[Pd]>[NH2:1][C:2]1([CH2:8][CH2:9][C:10]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH:22]4[CH2:23][C:24]([CH3:31])([CH3:30])[NH:25][C:26]([CH3:29])([CH3:28])[CH2:27]4)[N:16]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(C#CC4(N)CCCCC4)s3)n2)CC(C)(C)N1
Agent: [Pd]
Solvent: CO
Product: CC1(C)CC(Nc2nccc(-c3ccc(CCC4(N)CCCCC4)s3)n2)CC(C)(C)N1

Procedure:
Compound of Example 78 (2.5 g, 5.7 mmol) was dissolved in 200 ml MeOH and 0.8 g palladium on charcoal 10% were added. Hydrogenation was performed at room temperature and 1 bar hydrogen pressure for 8 hours. Afterwards the mixture was filtered through Hyflo and evaporated. The crude was purified by chromatography on silicagel (DCM/MeOH/ammonia:85/15/1.5). Yield: 1.6 g (64%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH:16]([CH2:19][C:20]([OH:22])=O)[NH:15][C:14]3=[O:23])[CH:10]=[N:9]2)=[C:5]([CH3:24])[O:4][N:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH:16]([CH2:19][C:20]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:22])[NH:15][C:14]3=[O:23])[CH:10]=[N:9]2)=[C:5]([CH3:24])[O:4][N:3]=1
Reactant: Nc1ccccc1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(CC(=O)O)C2=O)cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1cc(N2C(=O)NC(CC(=O)Nc3ccccc3)C2=O)cn1
Temperature: 65 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
3-(1-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,5-dioxoimidazolidin-4-yl)acetic acid (example 10-44) (100 mg, 0.3 mmol), aniline (33 mg, 0.36 mmol), Pybop (187 mg, 0.36 mmol) and triethyl ammine (0.05 mL, 0.36 mmol) were mixed in DMF (1 mL). The reaction stirred at 65° C. for 4 hours. The reaction was allowed to cool to room temperature and then diluted with ethyl aceate (2 mL). The organic phase was washed with saturated sodium bicarbonate solution (2×, 2 mL) and then with saturated NaCl solution (1 ml). The organic phase was extracted, dried over anhydrous Na2SO4, and filtered. The crude product was re-suspended in MeOH (1 mL) and purified by reversed phase HPLC (5-95% acetonitrile in H2O; 16 minute gradient). The pure fractions were combined and solvent was removed on the rotovap to afford 2-(1-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,5-dioxoimidazolidin-4-yl)-N-phenylacetamide as a white solid (50%). 1H NMR (CDCl3, 400 MHz): δ 2.18 (s, 3H), 2.40 (s, 3H), 2.72 (m, 1 H), 3.14-3.13 (d, 1H, J=4 Hz), 4.54-4.51 (d, J=8 Hz 1H), 5.04 (s, 2H), 6.53 (bs, 1H), 7.15-7.13 (m, 1H), 7.33-7.22 (m, 2H), 7.47-7.45 (d, J=8 Hz, 2H), 7.78 (bs, 1H), 7.09 (s, 1H), 8.05 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.75 μM.
Reaction SMILES: [SH:1][C:2]1[C:3]2[C:13](=[O:14])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11](=[O:21])[N:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:4]=2[N:5]([CH3:9])[C:6](=[O:8])[N:7]=1.[CH3:28]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].CI>O>[CH3:9][N:5]1[C:4]2[N:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11](=[O:21])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:13](=[O:14])[C:3]=2[C:2]([S:1][CH3:28])=[N:7][C:6]1=[O:8]
Reactant: Cn1c(=O)nc(S)c2c(=O)n(-c3ccccc3)c(=O)n(-c3ccccc3)c21
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: CSc1nc(=O)n(C)c2c1c(=O)n(-c1ccccc1)c(=O)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
To crude 5-mercapto-8-methyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyrimidine-2,4,7-trione 24 (100 mg) obtained in Step 5 was added N,N-dimethylformamide (0.5 ml). Under a nitrogen atmosphere, potassium carbonate (44 mg) and methyl iodide 25 (20 μl) were successively added, and the mixture was stirred at room temperature for 3 hrs. Water was added, and the mixture was extracted with chloroform. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=4:1→3:1) to give 8-methyl-5-methylsulfanyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyrimidine-2,4,7-trione 26 (91 mg, yield 89%) as brown crystals.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:4]([OH:9])=[N:5][CH:6]=[CH:7][CH:8]=1.[I:12]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>CC#N.CN(C=O)C>[I:12][C:7]1[CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[C:4]([OH:9])=[N:5][CH:6]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ncccc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Oc1ncc(I)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
3-trifluoromethyl-2-pyridinol (25 g, 153.3 mmol) is dissolved in anhydrous CH3CN (150 mL) and DMF (150 mL). N-iodosuccinimide (34.5 g, 153 mmol) is then added. The reaction mixture is stirred at 80° C. for 2 hours and cooled to room temperature. Aqueous 1 M NaHCO3 (150 mL) is then added to the cooled mixture. After stirring for 5 min, the solvents are evaporated to dryness. Water is added and the aqueous phase is extracted (×2) with dichloromethane. The organic phase is then evaporated and the desired product is recrystallized in water to afford 36.2 g (81%) of a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11](O)[CH2:10][C@@:9]1([C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH2:14][CH2:15][CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.F.F.F.C(N(CC)CC)C.C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([F:27])[CH2:10][C@:9]1([C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH2:14][CH2:15][CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC[C@]1(C(=O)c2ccc(Cl)c(Cl)c2)CC(O)CN1C(=O)OC(C)(C)C
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC[C@@]1(C(=O)c2ccc(Cl)c(Cl)c2)CC(F)CN1C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 99.5 %

Procedure:
To a stirred solution of (R)-2-(3,4-dichloro-benzoyl)-4-hydroxy-2-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.222 g, 0.554 mmol) in THF (3 mL) at ambient temperature under nitrogen was added perfluorobutanesulfonyl fluoride (0.195 mL, 1.11 mmol), triethylamine trihydrofluoride (0.181 mL, 1.11 mmol) and triethylamine (0.46 mL, 3.32 mmol). The reaction mixture was stirred for 18 hours, then filtered through a pad of silica, washed with EtOAc, and concentrated in vacuo to give (S)-2-(3,4-dichloro-benzoyl)-4-fluoro-2-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.222 g, 0.551 mmol, 99%) as a yellow foam that was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[C:4]([CH3:10])[CH:3]=1.[F:11][CH:12]([F:16])[C:13](O)=O.CCOCC>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]2[N:6]([C:13]([CH:12]([F:16])[F:11])=[N:9][N:8]=2)[N:7]=1
Reactant: Cc1cc(Cl)nnc1NN
Reactant: O=C(O)C(F)F
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1cc(Cl)nn2c(C(F)F)nnc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a beige suspension of 6-chloro-3-hydrazinyl-4-methylpyridazine (step 195.1) (22.44 g, 127 mmol) in dioxane (250 mL) was added difluoroacetic acid (Aldrich) (9.40 mL, 146 mmol) and the reaction mixture was stirred at rt for 5 min, then heated-up to 120° C. for 2.5 hr. With heating the suspension turned into a red-orange solution. The reaction mixture was cooled to rt. Et2O (80 mL) was added and the suspension was stirred for 2 hours at 0° C. Precipitated solids were isolated by filtration, suspended in hexanes and filtered again. After repeated washings with hexanes the tittle compound was obtained as an orange solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][C@@:11]([CH2:17][CH3:18])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[F:21][C:22]([F:36])([F:35])[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH2:17]([C@@:11]1([C:14]([N:32]2[CH2:33][CH2:34][N:29]([C:25]3[CH:24]=[C:23]([C:22]([F:36])([F:21])[F:35])[CH:28]=[CH:27][N:26]=3)[CH2:30][CH2:31]2)=[O:16])[CH2:12][CH2:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]1)[CH3:18]
Reactant: CC[C@@]1(C(=O)O)CC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: FC(F)(F)c1ccnc(N2CCNCC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
To a solution of (1R,3S)-3-[(tert-butoxycarbonyl)amino]-1-ethylcyclopentanecarboxylic acid (0.30 g, 1.2 mmol) and 1-[4-(trifluoromethyl)pyridin-2-yl]piperazine dihydrochloride (0.39 g, 1.3 mmol) in DMF (10 mL) under N2 was added triethylamine (0.65 mL, 4.7 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.663 g, 1.75 mmol). After being stirred at room temperature overnight, the reaction was quenched with saturated NaHCO3 and extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered, concentrated and purified by flash column chromatography to yield the desired product (400 mg, 72.9%). MS calculated for C23H34F3N4O3: (M+H) 471.3; found 371.2 (M+H-Boc).
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:46][CH2:47][C:48]1[C:49]([OH:56])=[N:50][C:51]([CH3:55])=[CH:52][C:53]=1[CH3:54]>ClCCl>[OH:56][C:49]1[C:48]([CH2:47][NH:46][C:14]([C:11]2[CH:12]=[N:13][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:9][CH:10]=2)=[O:16])=[C:53]([CH3:54])[CH:52]=[C:51]([CH3:55])[N:50]=1
Reactant: O=C(O)c1cnc(Oc2ccccc2)nc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2cnc(Oc3ccccc3)nc2)c(O)n1
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
A solution of 2-phenoxypyrimidine-5-carboxylic acid (300 mg, 1.4 mmol) in dichloromethane (15.0 mL) was added N-hydroxybenzotriazole (270 mg, 2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (384 mg, 2 mmol), triethylamine (202 mg, 2 mmol). Then the mixture was stirred for 30 minutes, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (270 mg, 2 mmol) was added and the mixture was stirred at room temperature 24 hours. The mixture was washed with water (50 mL), and extracted with dichloromethane (2*50 mL). The combined organic phase was separated, dried over sodium sulphate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, methanol/dichloromethane=1:20, 1% NH3) to afford N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-phenoxypyrimidine-5-carboxamide (200 mg, 46%) as white solid. LRMS (M+H+) m/z: calcd 350.14. found 350. HPLC purity (214 nm): 100%. 1H NMR (300 MHz, CD3OD): δ 8.93 (s, 2H), 7.46-7.16 (m, 5H), 6.10 (s, 1H), 4.48 (s, 2H), 2.35 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: C([O-])(=[O:3])C.[Cs+].Cl[CH2:7][C:8]1[NH:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][C:12]3[CH2:21][CH2:20][CH2:19][C:13]=3[CH:14]=2)[N:9]=1>CN(C=O)C>[OH:3][CH2:7][C:8]1[NH:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][C:12]3[CH2:21][CH2:20][CH2:19][C:13]=3[CH:14]=2)[N:9]=1
Reactant: O=c1[nH]c(CCl)nc2cc3c(cc12)CCC3
Reactant: CC(=O)[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1[nH]c(CO)nc2cc3c(cc12)CCC3
Temperature: 40 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
A solution of caesium acetate (14.4 g, 75.2 mmol) in dry DMF (40 ml) was heated to 60° C. under argon for 30 min. The mixture was cooled to 40° C. and a suspension of 2chloromethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4-one (L. Skelton, V. Bavetsias, A. Jaclinan, WO 00/050417-A1; 2.2 g, 9.4 mmol) in dry DA (60 ml) was added via a cannula. The mixture was heated to 80° C. under argon for 16 h. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was suspended in water (50 ml) and MeOH (20 ml). The pH was adjusted to 12.5 with 1M sodium hydroxide solution and the brown suspension was stirred for 2 h at room temperature. The insoluble brown solid was removed by filtration and the resulting solution was acidified to pH 5 with 1M hydrochloric acid. The precipitate was collected by filtration, washed with acidified water and dried in vacuo over P2O5 to yield the product as a pale yellow solid (1.17 g, 58%); m.p. 205-210° C.; 1H NMR (DMSO-d6) δ 2.07 (quin, J=7.4 Hz, 2H, 7-H), 2.98 (q, J=6.95 Hz, 4H, 6-H and 8-H), 4.38 (s, 2H, 2-CH2), 7.46 (s, 1H, 9-H), 7.92 (s, 1H, 5-H); MS (FAB-m/z): Found 217 [(M+H)+, 100%]; RRMS: measured 217.0977; calculated for C12H13N2O2 (M+H)+: 217.0977.
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([OH:15])=[O:14])=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.[CH2:17]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH:33]N)[C:28]=2[F:35])=[CH:23][CH:22]=1)[CH2:18][CH2:19][CH3:20].C(C1C=CC(B(O)O)=CC=1)CCC>>[CH2:17]([C:21]1[CH:22]=[CH:23][C:24]([C:27]2[C:28]([F:35])=[C:29]3[C:30]([C:3]4[CH2:4][CH2:5][CH2:6][C:7]5[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][C:8]=5[C:2]=4[NH:33]3)=[CH:31][CH:32]=2)=[CH:25][CH:26]=1)[CH2:18][CH2:19][CH3:20]
Reactant: O=C(O)c1ccc2c(c1)CCCCC2=O
Reactant: CCCCc1ccc(-c2cccc(NN)c2F)cc1
Agent: CCCCc1ccc(B(O)O)cc1
Agent: Cl
Product: CCCCc1ccc(-c2ccc3c4c([nH]c3c2F)-c2ccc(C(=O)O)cc2CCC4)cc1
Yield: 34 %

Procedure:
The title material is prepared in 34% yield by reacting 5-Oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acid (J. Org. Chem. 1962, 27(1), p 70-76) and (4′-Butyl-2-fluoro-biphenyl-3-yl)-hydrazine hydrochloride (prepared as in example 69, steps 1 and 2 except using 4-n-butylphenylboronic acid as the coupling partner) in an analogous manner to example 1, step 3 except that purification is accomplished by reverse phase mass triggered HPLC: 1H NMR (Acetone-d6) δ 10.72 (bs, 1H), 8.09 (d, 1H), 7.99 (d, 1H), 7.92 (s, 1H), 7.58 (d, 2H), 7.45 (d, 1H), 7.31 (d, 2H), 7.17 (dd, 1H), 3.18 (t, 2H), 3.10-3.04 (m, 2H), 2.72 (t, 2H), 2.22-2.14 (m, 2H), 1.73-1.64 (m, 2H), 1.45-1.38 (m, 2H), 0.96 (t, 3H); LC/MS calculated for [M+H]+ C28H26FNO2: 428.2, found: 428.2.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[C:18]([OH:19])=[C:17]([Br:20])[CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].CN(C)C=O.Br[CH2:27][CH:28]1[CH2:31][CH2:30][CH2:29]1>O>[Br:7][C:8]1[C:18]([O:19][CH2:27][CH:28]2[CH2:31][CH2:30][CH2:29]2)=[C:17]([Br:20])[CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: BrCC1CCC1
Reactant: CCOC(=O)c1ccc(Br)c(O)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(Br)c(OCC2CCC2)c1Br
Temperature: 125 °C

Procedure:
2.990 g (21.60 mmol) of potassium carbonate and 3.050 g (9.40 mmol) of ethyl 2,4-dibromo-3-hydroxybenzoate were introduced into 50 ml of N,N-dimethylformamide. 1.401 g (9.40 mmol) of bromomethylcyclobutane were added at room temperature and the mixture was heated for 6 hours at 120-130° C. The mixture was subsequently poured into water and extracted with diethyl ether. The combined organic phases were washed with water, dried over Na2SO4 and evaporated completely on a rotary evaporator. Drying in an oil-pump vacuum gave ethyl 2,4-dibromo-3-cyclobutylmethoxybenzoate as brown oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH:12]=[CH:11][CH:10]=[N:9][C:7]=2[N:8]=1.CCN(C(C)C)C(C)C.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[O:13]=[C:5]1[NH:4][C:3]([CH2:2][NH:1][S:32]([CH2:31][CH2:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[F:23])(=[O:33])=[O:34])=[N:8][C:7]2[N:9]=[CH:10][CH:11]=[CH:12][C:6]1=2
Reactant: NCc1nc2ncccc2c(=O)[nH]1
Reactant: O=S(=O)(Cl)CCc1ccccc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]c(CNS(=O)(=O)CCc2ccccc2F)nc2ncccc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 12.1 %

Procedure:
To an ice cooled suspension of 2-aminomethyl-3H-pyrido[2,3-d]pyrimidin-4-one (example 84.3; 50 mg, 0.28 mmol) in CH2Cl2 (2 ml) were added DIPEA (0.10 ml, 0.58 mmol) and 2-(2-fluoro-phenyl)-ethanesulfonyl chloride (78 mg, 0.35 mmol). The reaction mixture was stirred for 3 hours at 0° C. Unreacted 2-aminomethyl-3H-pyrido[2,3-d]pyrimidin-4-one was filtered off, the filtrate was evaporated to dryness and chromatographed (silica gel, EtOAc) to yield 2-(2-fluoro-phenyl)-ethanesulfonic acid (4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-ylmethyl)-amide (12 mg, 0.034 mmol; 12%) as a white solid. MS (m/e): 363.1 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:7][C@H:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]([NH:11][CH2:12][CH2:13][C:14](O)=[O:15])=[O:10])=[O:5])[CH3:2].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:1]([O:3][C:4]([C@@H:6]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:7][C@H:8]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:9]([NH:11][CH2:12][CH2:13][C:14]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:15])=[O:10])=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)NCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)NCCC(=O)N1CCOCC1

Procedure:
Similarly to the procedure described in example 6, condensation of N-[4-ethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyryl]-3-aminopropionic acid with morpholine in the presence of dicyclohexylcarbodiimide yields N-[N'-(4-ethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyryl)-3-aminopropionyl]-morpholine as an oil; NMR (CDCl3) δ7.28 and 7.22 (s, 10H), 5.74 (t, 1H, J=7 Hz), 4.03 (q, 2H, J=8 Hz), 1.08 (t, 3H, J=8 Hz).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:28])[C:19]2[N:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].Cl[CH2:30][C:31](Cl)=[O:32].[H-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[C:31](=[O:32])[CH2:30][O:28][CH:18]([C:19]3[N:20]=[C:21]([C:24]([F:26])([F:27])[F:25])[S:22][CH:23]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)COc1ccc(CC(C)N2CC(c3csc(C(F)(F)F)n3)OCC2=O)cc1

Procedure:
Prepared by analogy to Example 74a by reaction of N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine (diastereomer B), chloroacetyl chloride and sodium hydride, and purification of the base on a silica gel column using toluene/ethyl acetate=6:4 as eluant.