Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](=[C:3]([C:10](=O)[C@@H:11]([C@@H:13]1[C@@H:16]([C@H:17]([OH:19])[CH3:18])[C:15](=[O:20])[NH:14]1)[CH3:12])[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])=[N-].C([S:25][C@@H:26]1[CH2:30][N:29]([C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32])[C@H:28]([CH2:37][CH2:38][N:39]2[C:43]([CH2:44][OH:45])=[CH:42][N:41]=[CH:40]2)[CH2:27]1)(=O)C>>[CH2:34]([O:33][C:31]([N:29]1[CH2:30][C@@H:26]([S:25][C:10]2[C@H:11]([CH3:12])[C@H:13]3[N:14]([C:15](=[O:20])[C@@H:16]3[C@H:17]([OH:19])[CH3:18])[C:3]=2[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])[CH2:27][C@H:28]1[CH2:37][CH2:38][N:39]1[C:43]([CH2:44][OH:45])=[CH:42][N:41]=[CH:40]1)=[O:32])[CH:35]=[CH2:36]
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CCn1cncc1CO
Reactant: C=CCOC(=O)C(=[N+]=[N-])C(=O)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CCn3cncc3CO)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 59.6 %

Procedure:
Allyl (4R)-2-diazo-4-[(2R,3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (709 mg) and (2R,4S)-4-acetylthio-1-allyloxycarbonyl-2-[2-(5-hydroxymethylimidazol-1-yl) ethyl]pyrrolidine (849 mg) were reacted in substantially the same manner as that of Example 2-3) to give allyl (4R,5S,6S)-3-[(2R,4S)-1-allyloxycarbonyl-2-{2-(5-hydroxymethylimidazol-1-yl)ethyl}pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (802 mg) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)=[O:5])[CH3:2].Cl[CH2:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=1.[I-:26].[Na+]>C(#N)C>[I-:26].[CH2:1]([O:3][C:4]([N+:6]1[CH:10]=[CH:9][N:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)n1ccnc1
Reactant: CCOC(=O)COc1ccc(CCl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc(Cn2cc[n+](C(=O)OCC)c2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
1.4 g of 1-ethoxycarbonylimidazole, 2.5 g of ethyl 4-chloromethylphenoxyacetate and 1.7 g of sodium iodide were added to 5 ml of dry acetonitrile, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the insoluble materials were filtered off and the filtrate was concentrated under reduced pressure. The residue was triturated with an adequate amount of dry diethyl ether, the resulting powder was collected by filtration and dried to obtain 4.6 g of 1-ethoxycarbonyl-3-(4-ethoxycarbonylmethoxybenzyl)imidazolium iodide (quantitative yield). Colorless hygroscopic amorphous.
Reaction SMILES: C[CH2:2][CH2:3][CH:4]([OH:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:14]CCCC(O)CCCCCCC.CCCCCC(O)CCCCCC.CC(O)CCCCCCCCCCCC>>[CH3:2][CH2:3][CH:4]([OH:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:14]
Reactant: CCCCCCCC(O)CCCC
Reactant: CCCCCCCCC(O)CCC
Agent: CCCCCCC(O)CCCCC
Agent: CCCCCCCCCCCCC(C)O
Product: CCCCCCCCCC(O)CC

Procedure:
4-dodecanol; 5-dodecanol; 6-dodecanol; 2-tetradecanol;
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:6]=2[N:7]=1.O.[CH3:20][N:21]1C(=O)CCC1>>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][CH3:20])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1Cl)CC2
Reactant: CN1CCCC1=O
Solvent: O
Product: CNc1nc(Cl)nc2c1CCC2c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of Preparation AR [2,4-dichloro-7-(2-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine] (900 mg, 3.00 mmol) in NMP (Volume: 3.00E+04 μl) was added 2 M monomethanamine (7525 μl, 15.05 mmol). The resulting reaction mixture was stirred at RT for 1 h. Water was added (120 ml) to the mixture and stirred for 30 min. The mixture was filtered to get light green solid which was dried to get 2-chloro-7-(2-chlorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (713 mg, 2.424 mmol, 81% yield). LC-MS (M+H)+=295.9. 1H NMR (400 MHz, CD3OD) δ 7.50-7.39 (m, 1H), 7.34-7.19 (m, 2H), 7.04-6.90 (m, 1H), 4.86-4.72 (m, 1H), 3.07 (s, 3H), 2.90-2.67 (m, 3H), 2.11-1.91 (m, 1H).
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:28]([C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH2:40])(=[O:39])=[O:38])=[CH:33][CH:32]=1)([O-:30])=[O:29]>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:40][S:37]([C:34]3[CH:33]=[CH:32][C:31]([N+:28]([O-:30])=[O:29])=[CH:36][CH:35]=3)(=[O:38])=[O:39])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 4-nitrobenzenesulfonamide in accordance with Procedure 1, Method A described hereinabove. Yield (32%); 1H NMR (d6-DMSO) δ 8.33 (d, J=8.8 Hz, 2H), 8.08 (d, J=8.8 Hz, 2H), 7.38–7.07 (m, 13H), 6.82 (d, J=8.0 Hz, 2H), 6.35 (d, J=15.7 Hz, 1H), 2.35 (q, J=7.3 Hz, 2H), 0.81 (t, J=7.3 Hz, 3H); APcI m/z: 538 (M+).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=[O:2].C(S(N)(=O)=O)(CC)C.[CH2:21]1[CH2:31][CH2:30][N:29]2[C:24](=N[CH2:26][CH2:27][CH2:28]2)C[CH2:22]1>C1COCC1.C(Cl)Cl>[C@@:30]12([OH:2])[N:29]([CH3:24])[C@@H:28]([CH2:27][CH2:26]1)[CH2:22][CH2:21][CH2:31]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C1CCC2=NCCCN2CC1
Agent: CCC(C)S(N)(=O)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1[C@@H]2CCC[C@@]1(O)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 195.7 %

Procedure:
In a 100 mL round-bottomed flask (RBF) was added carboxylic acid 1 (575 mg, 1.291 mmol) and 1,1′-carbonyldiimidazole (460 mg, 2.84 mmol) in THF (15 mL) to give a yellow solution. The mixture was stirred at room temperature under nitrogen for 1 hour then heated to 70° C., in an oil bath, for 90 minutes. The mixture was cooled and sec-butyl sulfonamide (921 mg, 6.71 mmol) in 4 mL of THF was added along with neat DBU (0.389 mL, 2.58 mmol). The RBF was returned to the oil bath and heated overnight at 70° C. The reaction mixture was transferred to a separatory funnel, diluted with 100 mL of DCM, washed ×3 with 100 mL of 0.5 M HCl, then with 100 mL of H2O, and finally saturated NaCl. The organic mixture was dried over MgSO4, filtered and concentrated to give 713 mgs of the desired acylsulfonamide 2 as a yellow solid (96% yield) which was placed under vacuum overnight. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10μ, C18, 4.6×30 mm column, using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min., a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min., a hold time of 1 min., and an analysis time of 3 min. where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. 1H NMR (500 MHz, CD3OD): δ ppm 0.84-0.92 (m, 3 H), 1.03 (t, J=7.32 Hz, 3 H), 1.23 (m, 1 H), 1.28-1.44 (m, 7 H), 1.58 (m, 1 H), 1.72 (m, 2 H), 1.85 (m, 1 H), 1.95-2.07 (m, 3 H), 2.17 (m, 1 H), 2.78 (m, 1 H), 3.69 (m, 2 H), 3.83-3.91 (m, 3 H), 7.02 (s, 1 H), 7.11 (m, 1 H), 7.47 (d, J=7.63 Hz, 1 H), 7.74 (m, 3 H), 8.25 (s, 1 H). LC/MS: m/z 565.22, Rf 2.192 min., 97.5% purity.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([NH2:7])=[N:4][CH:3]=1.[CH:8]1[C:21]2[CH:20]([C:22](Cl)=[O:23])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[O:13][C:12]=2[CH:11]=[CH:10][CH:9]=1>>[CH3:1][C:2]1[O:6][C:5]([NH:7][C:22]([CH:20]2[C:21]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[O:13][C:14]3[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:23])=[N:4][CH:3]=1
Reactant: Cc1cnc(N)o1
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Product: Cc1cnc(NC(=O)C2c3ccccc3Oc3ccccc32)o1

Procedure:
The title compound, white solid, m.p. 217-220° C. and MS: m/e=306.1 (M+) was prepared in accordance with the general method of example 44a from 5-methyl-oxazol-2-ylamine [Ber. 95, 2419(1962)] and 9-xanthene-carboxylic acid chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([NH2:26])=[N:23][C:22]=1[CH3:27])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([NH:26][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:23][C:22]=1[CH3:27])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)c2ccc(Cl)cc2)sc1C(=O)NCc1ccccc1
Yield: 23 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 4-chlorobenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 23% yield; 1H NMR (CDCl3, 300 MHz) δ 7.84 (d, J=8.5 Hz, 2H), 7.45 (d, J=8.5 Hz, 2H), 7.32-7.24 (m, 5H), 6.02 (s, 1H), 5.27 (s, 2H), 2.01 (s, 3H); MS (ES+) m/z 386.1 (M+1).
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH:5]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])(=[O:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH:5]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCOc1ccccc1C1Sc2ccccc2N1C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N1c2ccccc2SC1c1ccccc1OCCCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To the solution of 7.71 g of 3-acetyl-2-[2-[3-(ethoxycarbonyl)-propoxy]phenyl]benzothiazoline in 50 ml of methanol, 2N-sodium hydroxide solution is added and the reaction mixture is stirred for 2 hours at room temperature. Methanol is removed off in vacuo. The residue is acidified with 2N-hydrochloric acid to give 5.72 g (80%) of the titled compound.
Reaction SMILES: [Li]CCCC.CCCCCC.[CH3:12][C:13]1[CH:17]=[CH:16][N:15]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:14]=1.CO[B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1>C1COCC1>[CH3:12][C:13]1[CH:17]=[C:16]([B:26]2[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]2)[N:15]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:14]=1
Reactant: Cc1ccn(C2CCCCO2)n1
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(B2OC(C)(C)C(C)(C)O2)n(C2CCCCO2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-methylpyrazole (3.0 g, 35.4 mmol), 3,4-dihydro-2H-pyrane (4.97 mL, 53.2 mmol) and TFA (0.02 mL, 0.260 mmol) was stirred at 85° C. for 6 h under an argon atmosphere. The RM was cooled to RT and NaH 60% in mineral oil (0.061 g, 1.524 mmol) was and the RM was stirred for 10 min. The RM was purified by bulb-to-bulb distillation to give 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (b.p. 150-170° C./12 mbar). A solution of n-BuLi in n-hexane (3.38 mL of 1.6 M, 5.41 mmol) was added dropwise over 10 min to a solution of 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (1.0 g, 5.41 mmol) in THF (12 mL) at −70° C. under a nitrogen atmosphere and The RM was stirred for 10 min and then treated dropwise with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.898 g, 5.69 mmol) and stirred at −70° C. for 1 h. The RM was allowed to warm to RT, treated with n-hexane and the product was filtered, dissolved in water (10 mL) and acidified to pH 6 with aqueous citric acid (10%). The water was evaporated off under reduced pressure and the aqueous residue extracted with EtOAc, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the title product as a yellow resin. UPLC-MS (Condition 3) tR=0.56 min, m/z=211.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:30][CH2:31][NH:32][C:33](=[O:35])[CH3:34])([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:19][C:18]2=[O:36])[CH3:16])=[CH:11][CH:10]=1.[H-].[Na+].I[CH3:40]>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:30][CH2:31][N:32]([CH3:40])[C:33](=[O:35])[CH3:34])([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:19][C:18]2=[O:36])[CH3:16])=[CH:11][CH:10]=1
Reactant: CC(=O)NCC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(C)CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 14.6 %

Procedure:
A solution of N-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)acetamide (60 mg, 0.121 mmol) in tetrahydrofuran anhydrous (5 mL) was added sodium hydride (15 mg, 0.605 mmol) at 0° C. and then stirred for 30 minutes at the same temperature. Iodomethane (86 mg, 0.605 mmol) was then added to the above mixture. The reaction mixture was stirred at rt for a further 8 h. The reaction mixture was poured into ice/water and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated to afford the residue, which was purified by TLC and separated by preparative HPLC to give N-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)-N-methylacetamide (9 mg, 15%). LC-MS Method 3 tR=1.43, min, m/z=511; 1H NMR (CDCl3): 1.26 (m, 1H), 1.56 (m, 3H), 1.96 (m, 1H), 2.04 (m, 3H), 2.22 (m, 4H), 2.83 (m, 1H), 2.94 (m, 3H), 3.36 (m, 1H), 5.69 (m, 1H), 6.87 (m, 2H), 7.04 (m, 4H), 7.26 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1.[H-].[Na+].[CH3:16]I.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH3:16])=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1
Reactant: CI
Reactant: CS(=O)(=O)c1cc(Br)ccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCc1ccc(Br)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
To a solution of (4-bromo-2-methanesulfonyl-phenyl)-methanol (preparation 112) (500 mg, 1.89 mmol) in DMF (10 mL) was added NaH (226 mg, 5.66 mmol, 60% in oil) at room temperature. After stirring at room temperature for 30 minutes, to above mixture was added MeI (230 mg, 10 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 hrs. TLC (petroleum ether:EtOAc 1:1) showed the reaction was complete. Then the mixture was poured into H2O (10 mL) and extracted with EtOAc (50 mL×3), washed with brine (10 mL×3), dried over sodium sulfate, concentrated in vacuo to give the residue, which was purified by a Biotage silica gel cartridge (petroleum ether/EtOAc 1:1, Rf˜0.5) to give the title compound (200 mg, 40%) as yellow oil.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([NH:9][C:10]([C:12]1[C:13]2[CH2:14][C@@H:15]3[CH2:27][C@@H:16]3[C:17]=2[N:18]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][N:21]=2)[N:19]=1)=[O:11])[C:5]([F:8])([CH3:7])[CH3:6].[BH4-].[Na+].Cl>O1CCOCC1.O>[F:8][C:5]([CH3:7])([CH3:6])[CH:4]([NH:9][C:10]([C:12]1[C:13]2[CH2:14][C@@H:15]3[CH2:27][C@@H:16]3[C:17]=2[N:18]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][N:21]=2)[N:19]=1)=[O:11])[CH2:3][OH:2]
Reactant: COC(=O)C(NC(=O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@@H]1C[C@H]21)C(C)(C)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(F)C(CO)NC(=O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@@H]1C[C@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-{[(1aS,5aS)-2-(4-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-3-fluoro-3-methyl-butyric acid methyl ester (171 mg, 0.420 mmol) was dissolved in dioxane (3 mL) and water (2 mL). Sodium borohydride (63.6 mg, 1.681 mmol) was added slowly at 0° C. The reaction mixture was stirred at room temperature overnight, neutralized with 1 N HCl solution, then extracted with ethyl acetate. The combined organics were washed with water, dried over anhydrous Na2SO4, filtered then concentrated. The residue was purified by column chromatography to give the title compound as a white foam. LCMS m/z=379.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.45-0.50 (m, 1H), 1.23-1.30 (m, 1H), 1.47 (d, J=22.1 Hz, 3H), 1.53 (d, J=21.7 Hz, 3H), 2.22-2.30 (m, 1H), 2.33-2.40 (m, 1H), 2.78-2.85 (m, 1H), 2.88-3.05 (m, 2H), 3.90-4.00 (m, 2H), 4.11-4.25 (m, 1H), 7.22 (dd, J=5.3 and 1.8 Hz, 1H), 7.36 (d, J=9.3 Hz, 1H), 7.97 (d, J=1.4 Hz, 1H), 8.35 (d, J=5.3 Hz, 1H).
Reaction SMILES: [N:1]1[C:2](=[O:9])[NH:3]C(=O)C(=O)C=1.C(O[C:13]([C:15]1([C:40]([O:42]CC)=O)[CH2:19][CH2:18][C:17](=[O:20])[N:16]1[C:21]1[CH:22]=[N:23][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][N:35]3[CH:39]=[CH:38][CH:37]=[N:36]3)=[CH:30][CH:29]=2)=[CH:25][CH:26]=1)=[O:14])C.NC(N)=O>[O-]CC.[Na+].C(O)C>[N:35]1([CH2:34][C:31]2[CH:30]=[CH:29][C:28]([O:27][C:24]3[N:23]=[CH:22][C:21]([N:16]4[C:15]5([C:13](=[O:14])[NH:3][C:2](=[O:9])[NH:1][C:40]5=[O:42])[CH2:19][CH2:18][C:17]4=[O:20])=[CH:26][CH:25]=3)=[CH:33][CH:32]=2)[CH:39]=[CH:38][CH:37]=[N:36]1
Reactant: O=C1N=CC(=O)C(=O)N1
Reactant: CCOC(=O)C1(C(=O)OCC)CCC(=O)N1c1ccc(Oc2ccc(Cn3cccn3)cc2)nc1
Agent: CC[O-]
Agent: NC(N)=O
Agent: [Na+]
Solvent: CCO
Product: O=C1NC(=O)C2(CCC(=O)N2c2ccc(Oc3ccc(Cn4cccn4)cc3)nc2)C(=O)N1

Procedure:
Following the procedure for pyrimidinetrione formation outlined in Example 1, reaction of 5-oxo-1-[6-(4-pyrazol-1-ylmethyl-phenoxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.2 g, 0.4 mmol) with urea (0.074 g, 1.2 mmol) in 1.2 mL of 1M sodium ethoxide in ethanol afforded 6 mg of 1-[6-(4-Pyrazol-1-ylmethyl-phenoxy)-pyridin-3-yl]-1,7,9-triaza-spiro[4.5]decane-2,6,8,10-tetraone as a colorless solid. 1H NMR (CD3OD, 500 MHz): 7.99 (d, 1H, J=2.5 Hz), 7.72 (m, 2H), 7.53 (d, 1H, J=2.5 Hz), 7.29 (d, 2H, J=8.5 Hz 7.10 (d, 2H, J=8.5 Hz), 6.97 (d, 1H, J=8.5 Hz), 6.35 (t, 1H, J=2.0 Hz), 5.38 (s, 2H), 2.75 (m, 2H), 2.65 (m, 2H) ppm. MS (APCl, m/z): 447.2 [M+H]+.
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:4]([CH2:14][OH:15])[CH2:3]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[F:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@@H:4]([CH2:14][O:15][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@@H]1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@@H]1COS(C)(=O)=O
Temperature: 2.5 °C

Procedure:
7.5 3.2 g of tert-butyl (2R,4S)-4-fluoro-2-hydroxymethylpyrrolidine-1-carboxylate are dissolved in 50 ml of CH2Cl2 with stirring, 3.1 ml of triethylamine are added, the mixture is cooled to 0-5° C., and a solution of 1.4 ml of methane-sulfonyl chloride in 10 ml of CH2Cl2 is subsequently added dropwise. The mixture is subsequently stirred at RT for 4 h. After aqueous work-up, the 4.1 g of tert-butyl (2R,4S)-4-fluoro-2-methanesulfonyloxymethylpyrrolidine-1-carboxylate) obtained are reacted further directly.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH2:21]([NH2:24])[CH2:22][CH3:23].O>CN1C(=O)CCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:24][CH2:21][CH2:22][CH3:23])[CH:3]=1
Reactant: CCCN
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCNc1cc(Br)ccc1[N+](=O)[O-]
Reaction time: 14 h
Yield: 95.2 %

Procedure:
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (0.5 g, 2.29 mmol) and diisopropyl ethyl amine (1.38 mL, 3.44 mmol) in NMP (5 mL) was added propylamine (0.22 mL, 2.7 mmol). The solution was stirred for 14 h to which was slowly added H2O (5 mL). The resulting yellow precipitate was filtered, washed with 2 mL of water, subjected to high vacuum for drying for 14 h to furnish 5-bromo-2-nitro-N-propylbenzenamine (520 mg, 2.18 mmol), 92% yield, which was used without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][C:16]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([Cl:30])[CH:23]=3)=[C:17]([CH3:19])[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCC(C2SC(CCl)=C(C)N=2)CC1)=O)(C)(C)C.ClC1C=C(O)C=CC=1C#N.FC(F)(F)C(O)=O>ClCCl>[Cl:30][C:24]1[CH:23]=[C:22]([O:21][CH2:20][C:16]2[S:15][C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:18][C:17]=2[CH3:19])[CH:27]=[CH:26][C:25]=1[C:28]#[N:29]
Reactant: Cc1nc(C2CCN(C(=O)OC(C)(C)C)CC2)sc1COc1ccc(C#N)c(Cl)c1
Agent: Cc1nc(C2CCN(C(=O)OC(C)(C)C)CC2)sc1CCl
Agent: N#Cc1ccc(O)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(C2CCNCC2)sc1COc1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
4.5 g 4-[5-(3-Chloro-4-cyano-phenoxymethyl)-4-methyl-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (derived from 4-(5-Chloromethyl-4-methyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and commercially available 2-Chloro-4-hydroxy-benzonitrile according to the method described in Example 1) was dissolved in 100 ml dichloromethane. 20 ml trifluoroacetic acid were added and the reaction mixture stirred at room temperature for one hour. The solvent was removed in vacuo and the residue was dissolved in 200 ml ethyl acetate, washed three times with saturated NaHCO3 solution and then dried over MgSO4. The solvent was removed in Vacuo to obtain 3.5 g 2-Chloro-4-(4-methyl-2-piperidin-4-yl-thiazol-5-ylmethoxy)-benzonitrile as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16](=[O:33])[C@@H:17]([NH:25]C(=O)OC(C)(C)C)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:25][C@@H:17]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:4]1[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)[CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:33]
Reactant: Cc1cc(-c2cc(Cl)cc(NC(=O)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)c2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cc(Cl)cc(NC(=O)[C@@H](N)Cc3ccccc3)c2)ccn1
Reaction time: 3 h
Yield: 98.1 %

Procedure:
2-methylpyridin-4-ylboronic acid (327 mg, 2.39 mmol), (S)-tert-butyl 1-(3-bromo-5-chlorophenylamino)-1-oxo-3-phenylpropan-2-ylcarbamate (542 mg, 1.19 mmol), tetrakis(triphenylphosphine)palladium (345 mg, 0.30 mmol), cesium fluoride (544 mg, 3.58 mmol) were added to a vial then DME (4778 μl, 1194 μmol) was added and the mixture was heated to 85° C. for 8 h. The reaction was loaded and purified on Phenomenex Geminni C18 HPLC 50 mm×250 mm running ACN/Water/0.1% TFA in a linear gradient. The fractions containing the desired product were combined and concentrated to afford tert-butyl (S)-1-(3-chloro-5-(2-methylpyridin-4-yl)phenylamino)-1-oxo-3-phenylpropan-2-ylcarbamate (367 mg, 66% yield). tert-butyl (S)-1-(3-chloro-5-(2-methylpyridin-4-yl)phenylamino)-1-oxo-3-phenylpropan-2-ylcarbamate (367 mg, 0.78 mmol) was dissolved in DCM (3 mL) and TFA (1 mL) add stirred for 3 h. The solution was concentrated to afford (2S)-2-amino-N-(3-chloro-5-(2-methylpyridin-4-yl)phenyl)-3-phenylpropanamide (280 mg, 99%).
Reaction SMILES: [CH:1]1([O:6][CH2:7][CH2:8][NH2:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:10][C:11]1[N:15]2[N:16]=[C:17](F)[CH:18]=[CH:19][C:14]2=[N:13][CH:12]=1>>[Br:10][C:11]1[N:15]2[N:16]=[C:17]([NH:9][CH2:8][CH2:7][O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:18]=[CH:19][C:14]2=[N:13][CH:12]=1
Reactant: NCCOC1CCCC1
Reactant: Fc1ccc2ncc(Br)n2n1
Product: Brc1cnc2ccc(NCCOC3CCCC3)nn12
Yield: 69 %

Procedure:
The 2-(cyclopentyloxy)ethanamine was reacted with 3-bromo-6-fluoroimidazo[1,2-b]pyridazine, using the amine displacement conditions described in example 5.6.42, part A to afford 69% product.