Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[OH:30])[C:23]([NH:25][NH2:26])=[O:24].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CCOC(C)=O.C1COCC1>[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[OH:30])[C:23]([NH:25][NH:26][C:12](=[O:14])[C@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:18])[C@H:15]([OH:17])[CH3:16])=[O:24]
Reactant: NNC(=O)c1ccc(O)c(Cl)c1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(O)c(Cl)c2)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: -20 °C
Reaction time: 1 h
Yield: 53.3 %

Procedure:
To a 50 mL round bottom flask was added (2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (1.00 g, 3.73 mmol, 1.0 equiv.) and anhydrous THF (18.7 mL). After the flask was flushed with nitrogen, 3-chloro-4-hydroxybenzoic hydrazide (766 mg, 4.11 mmol, 1.1 equiv.) was added. The stirring solution was cooled to −20° C., and 1-hydroxybenzotriazole (HOBt) (555 mg, 4.11 mmol, 1.1 equiv.) was added in one portion, followed by 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (EDC) (1.79 g, 9.33 mmol, 2.5 equiv.) and then triethylamine (TEA) (2.08 mL, 14.9 mmol. 4.0 equiv.). The solution was stirred at −20° C. for 1 h and gradually warmed to room temperature overnight. The contents of the flask were filtered over Celite® in a ground glass fritted funnel to remove solids formed during the reaction. The solution was diluted with 50 mL of EtOAc. The EtOAc solution was washed with 5% citric acid solution (w/v) (2×50 mL), distilled water (2×50 mL), and brine (1×50 mL). The organic layer was dried over Na2SO4 and then concentrated in vacuo to yield a light yellow solid. The product was purified via automated flash chromatography (0→50% EtOAc/hexanes→100% EtOAc, 24 g of silica gel; TLC Rf=0.38, 100% EtOAc, vanillin stain) to provide the desired product as an off-white solid (870 mg, 53% yield). Other data: 1H NMR (400 MHz, acetone-d6, δ in ppm) 7.96 (d, J=2.2 Hz, 1H), 7.79 (dd, J=2.19, 8.49 Hz, 1H), 7.53 (d, J=8.65 Hz, 1H), 7.105 (d, J=8.5 Hz, 1H), 6.72 (d, J=8.65 Hz, 1H), 5.58 (d, J=7.18 Hz, 1H), 4.22 (m, 1H), 4.11 (dd, J=5.13, 7.18 Hz, 1H), 2.35 (s, 3H), 1.37 (d, J=6.45 Hz, 3H); LRMS (ESI−) exact mass calcd for C19H18Cl2N4O4 [M]+437.28, found 438.1.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=O.S(O)(O)(=O)=O.[CH3:21][S:22][C:23](=[NH:25])[NH2:24].[O-]CC.[Na+]>C(O)C>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:25]=[C:23]([S:22][CH3:21])[N:24]=1
Reactant: CSC(=N)N
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccn1
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CSc1nc(-c2ccccn2)cc(C(F)(F)F)n1
Temperature: 25 °C
Yield: 16.8 %

Procedure:
To a solution of 4,4,4-trifluoro-1-(pyridin-2-yl)butane-1,3-dione (1.0 g, 4.6 mmol) in ethanol (10 mL) was added 2-methyl-2-thiopseudourea sulfate (0.64 g, 4.6 mmol), followed by sodium ethoxide (3.0 mL of 21 wt. % solution in ethanol, 9 mmol). The mixture was heated at reflux for 9 h, then cooled to room temperature and extracted with EA. The EA was washed with water and the solvent removed under reduced pressure. The crude product was purified by column chromatography, eluting with 49:1 chloroform/MeOH, to give 4-trifluoromethyl-2-methylthio-6-(pyridin-2-yl)pyrimidine (0.21 g, 17% yield) as an off-white solid.
Reaction SMILES: COC1C=CC(C[N:8]2[N:14]=[C:13]([C:15]3[CH:38]=[CH:37][C:18]4[N:19]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]6[CH2:36][CH2:35][O:34][CH2:33][CH2:32]6)=[CH:24][CH:23]=5)[O:21][C:17]=4[CH:16]=3)[CH:12]3[CH:10]([CH2:11]3)[C:9]2=[O:39])=CC=1.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[Na+].[Na+]>>[N:31]1([CH2:30][CH2:29][O:28][C:25]2[CH:24]=[CH:23][C:22]([C:20]3[O:21][C:17]4[CH:16]=[C:15]([C:13]5[CH:12]6[CH:10]([CH2:11]6)[C:9](=[O:39])[NH:8][N:14]=5)[CH:38]=[CH:37][C:18]=4[N:19]=3)=[CH:27][CH:26]=2)[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1
Reactant: COc1ccc(CN2N=C(c3ccc4nc(-c5ccc(OCCN6CCOCC6)cc5)oc4c3)C3CC3C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C1NN=C(c2ccc3nc(-c4ccc(OCCN5CCOCC5)cc4)oc3c2)C2CC12

Procedure:
107 mg (194 μmol) 3-(4-methoxy-benzyl)-5-{2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzoxazol-6-yl}-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one and 2 ml TFA are stirred in the microwave for 30 min at 150° C. The reaction mixture is made basic with 10% sodium carbonate solution, the precipitate formed is filtered off and the residue is purified on silica gel (eluant: DCM/methanol/ammonia).
Reaction SMILES: Cl.C(O[C:5](=[O:9])[CH2:6][NH:7][CH3:8])C.[Cl:10][C:11]1[C:19]2[O:18][CH:17]([CH3:20])[CH2:16][C:15]=2[C:14]([N:21]=[C:22]=[O:23])=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:10][C:11]1[C:19]2[O:18][CH:17]([CH3:20])[CH2:16][C:15]=2[C:14]([N:21]2[C:5](=[O:9])[CH2:6][N:7]([CH3:8])[C:22]2=[O:23])=[CH:13][CH:12]=1
Reactant: CC1Cc2c(N=C=O)ccc(Cl)c2O1
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1Cc2c(N3C(=O)CN(C)C3=O)ccc(Cl)c2O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.30 g of sarcosine ethyl ester hydrochloride was added over 5 minutes to a mixture of 2.10 g of 34A, 1.52 g of triethylamine and 60 mL of methylene chloride, under nitrogen at 25°-30° C. The mixture was stirred at room temperature for 24 hours, then diluted with 100 mL of methylene chloride, washed with water, then brine, dried (MgSO4) and stripped of solvent. The residue was dissolved in 70 mL of a 1:1 v:v mixture of ethanol and 2N hydrochloric acid. The solution was refluxed for 4 hours, the resulting mixture was stirred at room temperature overnight, stripped of volatiles, diluted with water and extracted with methylene chloride. The extract was dried (MgSO4) and stripped of solvent. The residue was purified by flash chromatography over silica gel with a 1:2 v:v mixture of hexane and ethyl acetate as eluent to give the title compound, as a glass/sticky solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]([Cl:19])[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[O:20]1[CH2:25][CH2:24][CH:23]([CH:26]2[CH2:29][NH:28][CH2:27]2)[CH2:22][CH2:21]1>>[Cl:19][C:8]1[N:9]=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:11]2[N:12]=[C:3]([CH2:2][N:28]3[CH2:29][CH:26]([CH:23]4[CH2:24][CH2:25][O:20][CH2:21][CH2:22]4)[CH2:27]3)[CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(CBr)ccc2n1
Reactant: C1CC(C2CNC2)CCO1
Product: Clc1nc(N2CCOCC2)c2nc(CN3CC(C4CCOCC4)C3)ccc2n1

Procedure:
4-(6-(Bromomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine 7 (0.34 g) was reacted with 3-(tetrahydro-2H-pyran-4-yl)azetidine via General Procedure B to produce crude 4-(2-chloro-6-((3-(tetrahydro-2H-pyran-4-yl)azetidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)morpholine
Reaction SMILES: [C:1](Cl)(=O)C.[CH3:5][C:6]1[CH:7]=[C:8]([CH2:25][C:26]([OH:28])=[O:27])[CH:9]=[C:10]([CH3:24])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH:21]([CH3:23])[CH3:22])[CH:14]=1>CO>[CH3:5][C:6]1[CH:7]=[C:8]([CH2:25][C:26]([O:28][CH3:1])=[O:27])[CH:9]=[C:10]([CH3:24])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH:21]([CH3:23])[CH3:22])[CH:14]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(Oc2c(C)cc(CC(=O)O)cc2C)cc1C(C)C
Solvent: CO
Product: COC(=O)Cc1cc(C)c(Oc2ccc(OC)c(C(C)C)c2)c(C)c1
Temperature: 25 °C
Yield: 46.9 %

Procedure:
To a stirred cold solution of methanol (15 mL) and acetyl chloride (3 mL, 86.0 mmol) at 0° C. was added dropwise a solution of 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)phenylacetic acid (0.7 g, 4.3 mmol) in methanol (5 mL). The reaction mixture was heated under reflux for 5 h and cooled to room temperature. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (100 mL). The organic solution was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was triturated with hexane, filtered and dried under reduced pressure to afford methyl 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)phenylacetate as a yellow solid (0.69 g, 95%): 1H NMR (300 MHz, CDCl3): δ 7.02 (s, 2 H), 6.82 (d, J=2.7 Hz, 1 H), 6.66 (d, J=8.7 Hz, 1 H), 6.38 (dd, J=3.3, 8.7 Hz, 1 H), 3.79 (s, 3 H), 3.75 (s, 3 H), 3.60 (s, 2 H), 3.28-3.25 (m, 1 H), 2.14 (s, 6 H), 1.20 (d, J=7.2 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate-hexanes (1:1); Rf=0.6.
Reaction SMILES: N1C(C)=CC=CC=1C.[Br:9][C:10]1[CH:11]=[C:12]([N+:20]([O-:22])=[O:21])[C:13]([O:18][CH3:19])=[C:14]([CH:17]=1)[CH2:15]O.[Br-:23].[Li+].CS(OS(C)(=O)=O)(=O)=O>O1CCCC1>[Br:9][C:10]1[CH:11]=[C:12]([N+:20]([O-:22])=[O:21])[C:13]([O:18][CH3:19])=[C:14]([CH:17]=1)[CH2:15][Br:23]
Reactant: [Br-]
Reactant: COc1c(CO)cc(Br)cc1[N+](=O)[O-]
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: COc1c(CBr)cc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 118.6 %

Procedure:
2,6-Lutidine (10.5 mL) was added to a stirring solution of 5-bromo-2-methoxy-3-nitrobenzyl alcohol (13.6 g) and lithium bromide (11.75 g) in anhydrous tetrahydrofuran (200 mL) at 0° C. A solution of methanesulfonic anhydride (11.8 g) in anhydrous tetrahydrofuran (20 mL) was added dropwise. The resulting mixture was left to stir at room temperature for 16 h. It was partitioned between diethyl ether (250 mL) and saturated sodium hydrogen carbonate (150 mL). The organic layer was dried (sodium sulfate) and evaporated in vacuo. Silica gel chromatography of the crude residue eluting with diethyl ether in petroleum ether gave the title compound (20 g) as an amber oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([NH:12][CH3:13])=[CH:7][C:6]=1[N:14]1[CH2:19][CH2:18][CH:17]([C:20]([F:23])([F:22])[F:21])[CH2:16][CH2:15]1)[CH3:2].[C:25]([O:29][C:30](=[O:44])[NH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([N:40]=[C:41]=S)[C:34]=1[Cl:43])([CH3:28])([CH3:27])[CH3:26].CC(C)N=C=NC(C)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:6]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]([F:22])([F:21])[F:23])[CH2:16][CH2:15]2)=[CH:7][C:8]2[N:12]([CH3:13])[C:41]([NH:40][C:35]3[C:36]([Cl:39])=[CH:37][CH:38]=[C:33]([CH2:32][NH:31][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:44])[C:34]=3[Cl:43])=[N:11][C:9]=2[CH:10]=1)=[O:24])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reactant: CCOC(=O)c1cc(N)c(NC)cc1N1CCC(C(F)(F)F)CC1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2nc(Nc3c(Cl)ccc(CNC(=O)OC(C)(C)C)c3Cl)n(C)c2cc1N1CCC(C(F)(F)F)CC1

Procedure:
The title compound is prepared in analogy to 1e from ethyl-2-[4-trifluoromethyl-piperidinyl]-4-methylamino-5-amino-benzoate (compound 52b, 4.31 g, 12.5 mmol), (2,4-dichloro-3-isothiocyanato-benzyl)-carbamic acid tert-butyl ester (compound B; 4.16 g, 12.5 mmol), DIC (2.17 mL, 15.4 mmol) and DMF (50 mL). Yield: 6.9 g. HPLC Rt=1.49 min (method A). MS m/z: 644 [M+H]+.
Reaction SMILES: N(C(C)C)(C(C)C)CC.[Cl:10][C:11]1[C:12]([CH:17]([NH2:34])[C:18]2[CH:27]=[C:26]3[C:21]([CH:22]=[CH:23][C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:25]3)=[CH:20][CH:19]=2)=[N:13][CH:14]=[CH:15][N:16]=1.[CH:35]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:10][C:11]1[C:12]([CH:17]([NH:34][C:39]([CH:35]2[CH2:38][CH2:37][CH2:36]2)=[O:40])[C:18]2[CH:27]=[C:26]3[C:21]([CH:22]=[CH:23][C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:25]3)=[CH:20][CH:19]=2)=[N:13][CH:14]=[CH:15][N:16]=1
Reactant: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Reactant: O=C(Cl)C1CCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl)C1CCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of NEt(iPr)2 (150 μL, 111 mg, 0.861 mmol), DMAP (5 mg, 0.04 mmol), and C-(3-chloropyrazin-2-yl)-C-(2-phenylquinolin-7-yl)-methylamine (202 mg, 0.583 mmol) in dry CH2Cl2 (5 mL), cooled by ice/water, is added cyclobutanecarbonyl chloride (75 μL, 78 mg, 0.66 mmol), then the cooling bath is removed, and the reaction mixture is stirred at rt for 3 h. Water is added, the layers are separated, and the aqueous layer is extracted with CH2Cl2 (3×15 mL). The combined CH2Cl2 layers are washed with water, saturated NaHCO3 solution, and brine, dried over MgSO4, filtered and concentrated to give crude material as yellow foam, which is used for the next step without purification. 1H NMR (CDCl3, 400 MHz) δ 1.81-1.90 (m, 1H), 1.90-2.02 (m, 1H), 2.11-2.23 (m, 2H), 2.23-2.35 (m, 2H), 3.12 (quint, J=8.4 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.43-7.48 (m, 1H), 7.48-7.54 (m, 2H), 7.73 (dd, J=2.0, 8.4 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.90 (d, J=0.8 Hz, 1H), 8.07-8.12 (m, 2H), 8.19 (d, J=8.4 Hz, 1H), 8.38 (d, J=2.4 Hz, 1H), 8.58 (d, J=2.4 Hz, 1H). MS (ES+): m/z 429.0/431.0 (38/13) [MH+], 469.8/471.8 (6/2) [MH++MeCN]. HPLC: tR=3.6 min (MicromassZQ, polar—5 min).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][C:29]=1[F:37])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH3:38][C@H:39](O)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].N(C(OCC)=O)=NC(OCC)=O>C1COCC1.ClCCl>[CH2:20]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([O:34][C@H:39]([CH3:38])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:33])=[CH:30][C:29]=1[F:37])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: CCCCCC[C@H](C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCC[C@@H](C)OC(=O)c1ccc(OCc2ccccc2)c(F)c1

Procedure:
Triphenylphosphine (7.92 g, 30 mmol) in THF (40 ml) was added dropwise to a stirred solution of compound 11 (7.00 g, 28 mmol), (S)-(+)-octan-2-ol (3.66 g 28 mmol) and diethyl azodicarboxylate (4.87 g, 28 mmol) in THF (100 ml). The reaction solution was left stirring under nitrogen until completion [reaction monitored by TLC (dichloromethane, silica)]. Upon completion, the solvent was removed in vacuo to yield a colourless solid which was purified by column chromatography (dichloromethane) on silica to yield a colourless oil. Yield 10.01 g (99%), [α]D=−22.4° at 25° C.
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:28])([F:27])[C:9]1[CH:26]=[CH:25][C:12]([O:13][CH:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17][NH:16][CH2:15]2)=[CH:11][CH:10]=1.C(N(CC)CC)C.[C:36]1([CH2:42][C:43](Cl)=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)(Cl)Cl>[C:36]1([CH2:42][C:43]([N:16]2[CH2:15][CH:14]([O:13][C:12]3[CH:25]=[CH:26][C:9]([C:8]([F:7])([F:27])[F:28])=[CH:10][CH:11]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17]2)=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: FC(F)(F)c1ccc(OC2CNCCc3ccccc32)cc1
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Cc1ccccc1)N1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled solution of 2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine of Example 1 (5.8 g. 0.019 mole) and triethylamine (2.3 g, 0.023 mole) in chloroform (75 ml) was slowly dropped phenylacetyl chloride (3.5 g. 0.023 mole) in chloroform (10 ml). After stirring at ambient temperature overnight the reaction mixture was concentrated to an oil. The oil was dissolved in ether, then washed with water, dilute HCl (10%), again with water and dried (saturated NaCl, anhydrous MgSO4). The solution was filtered, concentrated to an oil which was extracted with boiling hexanes and then concentrated to an oil (6.8 g, 84%). A sample was distilled to yield an oil of 3-phenylacetyl-2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine, 240°-250° C./0.1 mm.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][CH:6]=[C:5]([C:8]([O:10]C)=O)[CH:4]=1.C[O-].[Na+].[CH3:15][NH:16][CH3:17]>CO>[OH:1][CH2:2][C:3]1[S:7][CH:6]=[C:5]([C:8]([N:16]([CH3:17])[CH3:15])=[O:10])[CH:4]=1
Reactant: CNC
Reactant: COC(=O)c1csc(CO)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN(C)C(=O)c1csc(CO)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of methyl 5-(hydroxymethyl)-3-thiophenecarboxylate (3 g), sodium methoxide (0.2 g) and excess anhydrous dimethylamine in dry methanol (20 ml) was stirred for 24 h at ambient temperature. The solvent was removed in vacuo, water was added and the product was extracted with ethyl acetate. The organic extract was evaporated to leave an oily residue which was chromatographed on silica with ethyl acetate-light petroleum 40°-60°; (1:1) to give the title compound (1.3 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]=[C:4]([S:15][CH3:16])[N:3]=1.O.[NH2:18][NH2:19]>CO>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([NH:18][NH2:19])[N:5]=[C:4]([S:15][CH3:16])[N:3]=1
Reactant: NN
Reactant: CSc1nc(Cl)c(-c2ccccc2)c(Cl)n1
Solvent: O
Solvent: CO
Product: CSc1nc(Cl)c(-c2ccccc2)c(NN)n1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a cold (ice bath) stirred solution of 25 g (0.09 mole) of 4,6-dichloro-2-methylthio-5-phenylpyrimidine in 250 ml of methanol was added slowly 10 g (0.2 mole) of hydrazine hydrate. After one hour the mixture was allowed to warm to about 20° C., and was then stirred at 20° C. for about 16 hours. The precipitate was separated by filtration to provide 4-chloro-6-hydrazino-2-methylthio-5-phenylpyrimidine. Recrystallization twice from hexanes/cyclohexane provided white crystals, m.p. 134°-135° C. Analysis: Calculated for C11H11ClN4S: %C, 49.5; %H, 4.15; % N, 21.0; Found: %C, 49.4; %H, 4.0; %N, 20.9.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[OH:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21]CC)=[O:20]>CC(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][CH2:18][C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)CBr
Reactant: Oc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)COc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
The mixture of 2-benzothiazolol (320 mg, 2.1 mmol), potassium carbonate (910 mg, 6.6 mmol), ethyl bromoacetate (500 mg, 3.0 mmol) and acetone (25 ml) was refluxed for 15 h. After cooling, the mixture was filtered to remove potassium carbonate. The filtrate was concentrated under reduced pressure. To this residue, 10 ml of dioxane and 14 ml 5% sodium hydroxide solution were added. After the mixture was stirred at room temperature overnight, it was acidified with hydrochloric acid to pH 1, and then extracted three times with ethyl acetate (20 ml each). Organic phases were combined, washed with water and brine, dried over magnesium sulfate, filtered, and then evaporated in vacuo. The residue was recrystallized from ethanol and petroleum ether to give 290 mg benzothiazole-2-oxyacetic acid as white crystals, mp 168-170° C.
Reaction SMILES: C(OC([NH:11][C@@H:12]1[C:15](=[O:16])[NH:14][C@@H:13]1[CH2:17][N:18]1[N:22]=[C:21]([CH2:23][NH:24][C:25](=[N:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[N:26]([CH2:34][CH:35]2[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36]2)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:20]=[N:19]1)=O)C1C=CC=CC=1.[H][H]>CCO.CO.[Pd]>[NH2:11][C@@H:12]1[C:15](=[O:16])[NH:14][C@@H:13]1[CH2:17][N:18]1[N:22]=[C:21]([CH2:23][NH:24][C:25](=[N:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[N:26]([CH2:34][CH:35]2[CH2:36][N:37]([C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[CH2:38]2)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:20]=[N:19]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N=C(NCc1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)n1)N(CC1CN(C(=O)OC(C)(C)C)C1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)N=C(NCc1cnn(C[C@H]2NC(=O)[C@H]2N)n1)N(CC1CN(C(=O)OC(C)(C)C)C1)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of tert-butyl 3-((3-((2-(((2R,3S)-3-(((benzyloxy)carbonyl)amino)-4-oxoazetidin-2-yl)methyl)-2H-1,2,3-triazol-4-yl)methyl)-1,2-bis(tert-butoxycarbonyl)guanidino)methyl)azetidine-1-carboxylate (390 mg, 0.526 mmol) in EtOH (10 mL) and MeOH (10.00 mL) was added Pd/C (5%, 112 mg, 53 μmol) and hydrogen baloon after evacuation and backfilled with H2. After 1 h, the reaction mixture was filtered over celite pad, and the filtrate was concentrated in vacuo to afford title compound (302 mg, 95%). The crude residue was used as such in the following step. LCMS: Rt=0.74 min, m/z=608.4 (M+1) Method 2m_acidic.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[S:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)C)(C)(C)C.C(OCC)C.Cl>CO>[F:17][C:15]1[CH:14]=[CH:13][C:12]([S:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)=[C:11]([CH2:10][CH2:9][NH:7][CH3:6])[CH:16]=1
Reactant: CN(CCc1cc(F)ccc1Sc1c[nH]c2ccccc12)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CNCCc1cc(F)ccc1Sc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
{2-[5-Fluoro-2-(1H-indol-3-ylsulfanyl)-phenyl]-ethyl}-methyl-carbamic acid tert-butyl ester (99 mg, 0.24 mmol) is dissolved in methanol (1.5 mL) and diethyl ether saturated with hydrochloric acid (0.5 mL) is added. The mixture is stirred at ambient temperature for 2 hours and concentrated in vacuo. Water (5 mL) is added to the remanence and the mixture is basified by addition of aqueous ammonia (25%). The aqueous fraction is extracted with ethyl acetate (3×10 mL). The combined organic fractions are dried (MgSO4) and concentrated in vacuo. The product is purified by preparative HPLC or silica gel chromatography eluting with ethyl acetate-ethanol-triethyl amine (100:5:5) to give 62 mg (83%) of the title compound.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.IC1C=CC([N+]([O-])=O)=CC=1>>[N+:33]([C:30]1[CH:29]=[CH:28][C:27]([C:24]2[O:23][C:22]([C:9](=[O:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:26][CH:25]=2)=[CH:32][CH:31]=1)([O-:35])=[O:34]
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(-c2ccc([N+](=O)[O-])cc2)o1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: O=[N+]([O-])c1ccc(I)cc1
Product: O=C(CCCCCCc1ccccc1)c1ncc(-c2ccc([N+](=O)[O-])cc2)o1
Yield: 100 %

Procedure:
2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)-5-(4-nitrophenyl)oxazole. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (90 mg, 0.136 mmol) and 1-iodo-4-nitrobenzene following General Procedure A. Flash chromatography (5-10% EtOAc/hexanes) yielded the title compound as a yellow oil (67 mg, 100%): 1H NMR (CDCl3, 500 MHz) δ 8.28 (d, 2H, J=9.0 Hz), 7.78 (d, 2H, J=9.0 Hz), 7.48 (s, 1H), 7.27-7.24 (m, 2H), 7.17-7.15 (m, 3H), 4.87 (t, 1H, J=6.0 Hz), 2.59 (t, 2H, J=7.8 Hz), 2.00-1.88 (m, 2H), 1.67-1.58 (m, 2H), 1.40-1.34 (m, 6H), 0.91 (s, 9H), 0.11 (s, 3H), 0.01 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 166.6, 149.0, 147.1, 142.6, 133.7, 128.3, 128.2, 125.5, 125.1, 124.4, 124.3, 68.6, 36.3, 35.8, 31.3, 29.1, 25.6, 25.6, 25.0, 18.1, −5.0, −5.1.