Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:15]=O)[CH:11]=2)[CH2:6]1)=[O:4].[NH:19]1[CH2:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl>[N:19]1([CH2:15][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH2:6][N:5]([C:3](=[O:4])[C:2]([F:18])([F:17])[F:1])[CH2:14][CH2:13]3)[CH2:22][CH2:21][CH2:20]1
Reactant: O=Cc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2
Reactant: C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(N1CCc2cc(CN3CCC3)ccc2C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-(2,2,2-Trifluoro-acetyl)-1,2,3,4-tetrahydro-isoquinoline-6-carbaldehyde (7.776 mmol, 1 equiv.) and azetidine (9.331 mmol, 1.2 equiv.) were dissolved in 1,2-dichloroethane (37 ml), and the mixture was stirred for 10 minutes at 25° C. Sodium triacetoxyborohydride (10.89 mmol, 1.4 equiv.) was added, and the reaction mixture was stirred for 16 hours at 25° C. Saturated sodium hydrogen carbonate solution (50 ml) was then added, the phases were separated, and the aqueous phase was extracted with dichloromethane (4×20 ml). The combined organic phases were washed with saturated NaCl solution (1×50 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (ethyl acetate/dichloromethane/hexane/methanol/-ammonia (25% aq), 30:10:10:2:0.02). Yield: 1.55 g (67%)
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][CH2:21][CH2:22][NH2:23]>S([O-])([O-])(=O)=O.[Cu+2]>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([NH:23][CH2:22][CH2:21][O:20][CH3:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(n1)CCN(Cc1ccccc1)C2
Reactant: COCCN
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Product: COCCNc1ccc2c(n1)CCN(Cc1ccccc1)C2

Procedure:
Copper (II) sulphate (200 mg) was added to a solution of 6-benzyl-2-chloro-5,6,7,8-tetrahydro-[1,6]naphthyridine (4.5 g, 17.4 mmol)(see reference WO9830560 Example 33 b) in 2-methoxyethylamine and the mixture was heated under reflux for 20 hours. The mixture was evaporated under reduced pressure and the residue was partitioned between dichloromethane (100 ml) and water (50 ml). The aqueous phase was extracted with dichloromethane (2×50 ml) and the combined organic phases were dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using methanol in dichloromethane as eluant (gradient from 1:99 to 3:97) to give the title compound as an orange oil (1.32 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:43])[N:18]([C@H:29]3[CH2:34][CH2:33][C@H:32]([O:35][CH2:36][C:37](N(OC)C)=[O:38])[CH2:31][CH2:30]3)[C:19]3[N:20]([N:25]=[C:26]([CH3:28])[N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[CH2:44]([Mg]Br)[CH3:45].Cl>O1CCCC1>[CH3:28][C:26]1[N:27]=[C:19]2[N:18]([C@H:29]3[CH2:30][CH2:31][C@H:32]([O:35][CH2:36][C:37](=[O:38])[CH2:44][CH3:45])[CH2:33][CH2:34]3)[C:17](=[O:43])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]2[N:25]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2nc(C)nn12
Reactant: CC[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)CC)CC2)c2nc(C)nn12
Reaction time: 1 h

Procedure:
2-[(trans-4-{6-[(2′-Cyanobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide (0.3 g) was dissolved in tetrahydrofuran (10 mL), and ethylmagnesium bromide (3.0 M diethyl ether solution, 0.52 mL) was added at room temperature. The reaction mixture was stirred for 1 hr, 1 N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.34 g, 100%).
Reaction SMILES: C([O:4][C@@H:5]([C:7]1[N:12]=[C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:28]=[N:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[CH2:15][CH2:14]2)[CH:10]=[CH:9][N:8]=1)[CH3:6])(=O)C.O.[OH-].[Li+]>O1CCCC1.O.CO>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:27]=[CH:28][C:19]=1[N:16]1[CH2:15][CH2:14][N:13]([C:11]2[CH:10]=[CH:9][N:8]=[C:7]([C@H:5]([OH:4])[CH3:6])[N:12]=2)[CH2:18][CH2:17]1
Reactant: CC(=O)O[C@H](C)c1nccc(N2CCN(c3cnc4ccccc4n3)CC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)c1nccc(N2CCN(c3cnc4ccccc4n3)CC2)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90 %

Procedure:
To a solution of (R)-1-[4-(4-quinoxalin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl acetate (prepared according to the method of Example 1, Step A, 14.1 g, 37.2 mmol) in a 3:1:1 mixture of tetrahydrofuran/water/methanol (375 mL) was added lithium hydroxide hydrate (4.7 g, 112 mmol). This mixture was stirred at room temperature for 1 h 45 min, concentrated, and extracted with chloroform (6×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (2×; 2% methanol/chloroform) to give 11.3 g (90%) of the title compound as a pale yellow solid after tritration with hexanes. mp: 106.5-108° C.; 1H NMR (CDCl3, 250 MHz) δ8.62 (s, 1H), 8.26 (d, 1H), 7.92 (dd, 1H), 7.72 (dd, 1H), 7.61 (td, 1H), 7.44 (td, 1H), 6.45 (d, 1H), 4.75 (m, 1H), 3.95-3.85 (c, 8H), 1.54 (d, 3H); MS (CI/NH3) 337 (MH+); [α]D +15.3 (c 2.3, MeOH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[F:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[N:48]=[C:49]=[S:50].NC(N)=S>>[F:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[NH:48][C:49]([N:27]1[C:17]2[N:18]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:20]=[C:15]([C:12]3[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=4)[CH2:30][C:31]4[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=4)=[N:14][CH:13]=3)[C:16]=2[CH2:29][CH2:28]1)=[S:50]
Reactant: Fc1ccccc1N=C=S
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Agent: NC(N)=S
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=S)Nc3ccccc3F)cn2)cc1
Yield: 117 %

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (80.0 mg, 0.148 mmol) and 2-fluorophenyl isothiocyanate (54.6 μl, 0.445 mmol) instead of o-tolyl isothiocyanate, thiourea was formed in the same manner as Example 1-D-210, to obtain a crude product of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carbothioic acid (2-fluoro-phenyl)-amide as a brown solid (120 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-222) as a yellow powder (54.5 mg, 80%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=3)[S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[C:37]3[CH:43]=[CH:42][NH:41][C:38]3=[N:39][CH:40]=2)O1>>[CH3:20][S:17]([C:13]1[CH:12]=[C:11]([C:9]2[S:8][C:6]3[N:7]=[C:2]([C:35]4[CH:36]=[C:37]5[CH:43]=[CH:42][NH:41][C:38]5=[N:39][CH:40]=4)[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:5]=3[N:10]=2)[CH:16]=[CH:15][CH:14]=1)(=[O:19])=[O:18]
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: CS(=O)(=O)c1cccc(-c2nc3c(N4CCOCC4)nc(Cl)nc3s2)c1
Product: CS(=O)(=O)c1cccc(-c2nc3c(N4CCOCC4)nc(-c4cnc5[nH]ccc5c4)nc3s2)c1
Yield: 43.6 %

Procedure:
5-Chloro-2-(3-methanesulfonyl-phenyl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine (80 mg) was reacted with 54 mg of 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine via General Procedure A. The product was purified by reverse phase HPLC to yield 41.8 mg of 109. MS (Q1) 493.2 (M)+.
Reaction SMILES: CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.C(P(CCCC)CCCC)CCC.[CH2:30]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][C:45]=1[NH:51][C:52](=O)[CH2:53][NH:54][CH2:55][CH2:56][OH:57])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CCOC(C)=O>[ClH:50].[CH2:30]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][C:45]=1[N:51]1[CH2:52][CH2:53][NH:54][CH2:55][C:56]1=[O:57])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(CNCCO)Nc1cc(Cl)ccc1-c1ccccc1OCc1ccccc1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: CCOC(C)=O
Product: Cl
Product: O=C1CNCCN1c1cc(Cl)ccc1-c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of di-tert-butylazodicarboxylate (5.557 g, 24.1 mmol) in 20 mL of EtOAc at 0° C. was added tributylphosphine (6.013 mL, 24.1 mmol) dropwise. After 10 minutes, a solution of the product from Step D (6.8548 g, 16.09 mmol) in 10 mL of EtOAc was added dropwise over 15 minutes, and the reaction was allowed to warm to room temperature. After one hour, the solution was poured into EtOAc, washed with sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product mixture was taken up in 30 mL of ether, 1N HCl/Ether was added (17 mL), and the solution was concentrated in vacuo. This was stirred in 50 mL of cold isopropanol over an ice bath for 30 minutes, and the resulting slurry was filtered and rinsed with cold isopropanol. The filtered solid was dried in vacuo next to P2O5 to provide the titled product as a white solid.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][N:7]2[CH:11]=[C:10]([C:12]3[C@H:13]([CH3:26])[C@@H:14]4[C@@H:21]([C@H:22]([OH:24])[CH3:23])[C:20](=[O:25])[N:15]4[C:16]=3[C:17]([O-:19])=[O:18])[S:9][C:8]=12)(=[O:3])[CH3:2].[Na+].[C:28]([O:34][CH2:35]I)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:4]1[N:5]=[CH:6][N:7]2[CH:11]=[C:10]([C:12]3[C@H:13]([CH3:26])[C@@H:14]4[C@@H:21]([C@H:22]([OH:24])[CH3:23])[C:20](=[O:25])[N:15]4[C:16]=3[C:17]([O:19][CH2:35][O:34][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[O:18])[S:9][C:8]=12)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ncn2cc(C3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1ncn2cc(C3=C(C(=O)OCOC(=O)C(C)(C)C)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Reaction time: 1.5 h

Procedure:
To a solution of 38.1 mg of sodium (1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate in 3 ml of DMF was added 0.021 ml of pivaloyloxymethyl iodide under the atmosphere of argon at −30° C., and the mixture was stirred for 1.5 hours. The reaction mixture was diluted with 20 ml of ethyl acetate and washed with 20 ml of semi-saturated aqueous saline. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to a volume of 3 ml. The residue thus obtained was purified by column chromatography on silica gel (dichloromethane:methanol=20:1) and on Sephadex LH-20 (chloroform:methanol=1:1) in this sequence to give 35.8 mg of the title compound.
Reaction SMILES: C[Al](C)C.[F:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[OH:13][C@@H:14]([CH2:19][O:20][C@H:21]([CH3:34])[CH2:22][O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[C:15](OC)=[O:16]>C1(C)C=CC=CC=1>[F:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:15](=[O:16])[C@@H:14]([OH:13])[CH2:19][O:20][C@@H:21]([CH3:34])[CH2:22][O:23][Si:24]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:26])[CH3:27])[CH:31]([CH3:32])[CH3:33])=[N:10][CH:11]=1
Reactant: COC(=O)[C@@H](O)CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C
Reactant: Nc1ccc(F)cn1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)[Si](OC[C@H](C)OC[C@H](O)C(=O)Nc1ccc(F)cn1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 75.1 %

Procedure:
Trimethylaluminium (5.98 mL, 11.96 mmol) was added to 5-fluoropyridin-2-amine (1.340 g, 11.96 mmol) in toluene (20 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (S)-Methyl 2-hydroxy-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanoate (Intermediate AU5) (2 g, 5.98 mmol) in toluene (6 mL) was added and the reaction was allowed to warm to room temperature and then refluxed for 6 hours. The reaction mixture was allowed to cool and concentrated in vacuo. The residue was neutralised with citric acid (1M, aq) and then diluted with water (25 mL) and extracted with EtOAc (2×50 mL). The combined organics were washed with brine (20 mL), then dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 30 to 50% EtOAc in isohexane to afford the product (1.863 g, 75%).
Reaction SMILES: O1[C:6](=[O:7])[CH2:5][O:4][CH2:3][C:2]1=[O:8].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=1[CH3:17].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>C(OC)(C)(C)C.O>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:2](=[O:8])[CH2:3][O:4][CH2:5][C:6]2=[O:7])=[CH:12][C:11]=1[CH3:17]
Reactant: O=C1COCC(=O)O1
Reactant: Cc1cc(N)ccc1Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: COC(C)(C)C
Solvent: O
Product: Cc1cc(N2C(=O)COCC2=O)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
[1,4]Dioxane-2,6-dione (312 mg, 2.69 mmol) was added to a solution of 4-bromo-3-methyl-phenylamine (500 mg, 2.69 mmol) in tBuOMe (7.0 ml), and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. Acetic anhydride (4.0 ml, 42.3 mmol) and sodium acetate (35 mg, 0.427 mmol) were added to the resulting residue, and the mixture was heated with stirring at 60° C. for three hours. Water was added to the reaction solution, and collection by filtration and trituration with water gave 4-(4-bromo-3-methyl-phenyl)-morpholine-3,5-dione (577 mg, 73%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[CH2:10][C:11]1([C:16]([OH:18])=O)[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20]CN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.C[C:50]1[CH:51]=[C:52]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH:53]=[CH:54][C:55]=1[CH2:56][C@@H:57]([C:59]1[NH:63][N:62]=[N:61][N:60]=1)[NH2:58]>CN(C=O)C.CCOC(C)=O>[CH3:20][C:68]1[CH:69]=[C:64]([C:52]2[CH:51]=[CH:50][C:55]([CH2:56][C@H:57]([NH:58][C:16]([C:11]3([CH2:10][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15]3)=[O:18])[C:59]3[NH:63][N:62]=[N:61][N:60]=3)=[CH:54][CH:53]=2)[CH:65]=[CH:66][CH:67]=1
Reactant: O=C(CC1(C(=O)O)CCCC1)OCc1ccccc1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1cc(-c2ccccc2)ccc1C[C@H](N)c1nnn[nH]1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2ccc(C[C@H](NC(=O)C3(CC(=O)OCc4ccccc4)CCCC3)c3nnn[nH]3)cc2)c1
Reaction time: 0.5 h

Procedure:
To a solution of 1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxylic acid (150 mg, 0.572 mmol) in DMF (3 mL) were added EDC-HCl (110 mg, 0.572 mmol), HOAt (62.3 mg, 0.423 mmol) and triethylamine (0.133 mL, 0.953 mmol) at room temperature. After being stirred for 0.5 hours, (S)-2-(3-methylbiphenyl-4-yl)-1-(1H-tetrazol-5-yl)ethanamine (106 mg, 0.381 mmol) was added and stirred for 2 hours. The reaction mixture was diluted with EtOAc and washed with saturated NH4Cl aqueous solution and brine. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel flash column chromatography (10% MeOH in DCM/DCM) to give (S)-benzyl 2-(1-(2-(3′-methylbiphenyl-4-yl)-1-(1H-tetrazol-5-yl)ethylcarbamoyl)cyclopentyl)acetate. LCMS (condition A): 524 (M+1); retention time=1.82 min.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[C:6](=O)(O)[O-].[Na+].[OH:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=C(N[N+]([O-])=O)[N:13]=1>O>[OH:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:2]([N:3]([CH3:6])[O:4][CH3:5])[N:13]=1
Reactant: O=C([O-])O
Reactant: Cc1cc(O)nc(N[N+](=O)[O-])n1
Reactant: CNOC
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CON(C)c1nc(C)cc(O)n1

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (7.7g) in water (40 ml) was added, firstly, sodium bicarbonate (6.5 g) and, secondly, 4-hydroxy-6-methyl-2-nitraminopyrimidine (10.8 g) and the resultant mixture was heated at 100°C for 2 hours. After filtering hot to remove traces of insoluble material the filtrate was cooled and extracted with chloroform (12 × 25 ml). The extracts were dried over anhydrous sodium sulphate and the solvent evaporated. The residual solid was recrystallised twice from benzene to yield 4-hydroxy-6-methyl-2(N-methyl-N-methoxyamino) pyrimidine having a melting point of 128°-129°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10][CH:11]([C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23])[CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:30]1([C:36]2[O:37][C:38]([C:43]([F:46])([F:45])[F:44])=[C:39]([CH2:41]O)[N:40]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:30]1([C:36]2[O:37][C:38]([C:43]([F:46])([F:45])[F:44])=[C:39]([CH2:41][O:18][C:17](=[O:19])[C:16]3[CH:20]=[CH:21][C:13]([CH2:12][CH:11]([S:10][CH2:9][CH2:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:27])[Cl:28])=[O:23])=[CH:14][CH:15]=3)[N:40]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: OCc1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: O=C(O)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OCc1nc(-c2ccccc2)oc1C(F)(F)F)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
To a solution of 4-[2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-2-(2,2,2-trichloro-ethoxy-carbonyl)-ethyl]-benzoic acid (278 mg, 0.58 mmol) and (2-phenyl-5-trifluoromethyl-oxazol-4-yl)-methanol (155 mg, 0.64 mmol) in anhydrous DCM (20 mL) was first added EDCxHCl (144 mg, 0.75 mmol) then DMAP (1.0 mg, 0.006 mol) under nitrogen atmosphere at 0° C. After complete addition the cooling bath was removed and the reaction mixture was stirred at ambient temperature until no starting material was left. The mixture was diluted with water and aq. HCl (2N) and extracted with DCM. The combined organic layers were dried (MgSO4) and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography using n-heptane/EtOAc 4:1 as the eluent to afford the final product as an oil (289 mg, 56.6%). 1H NMR (400 MHz, CDCl3): δ 8.02 (d, 2H), 7.93 (d, 1H), 7.40-7.47 (m, 2H), 7.19-7.29 (m, 4H), 7.02 (dt, 2H), 6.89 (dt, 2H), 5.34 (d, 2H), 4.64 (q, 2H), 3.50 (dd, 1H), 3.18-3.24 (dd, 1H), 2.73-2.98 (m, 5H), 1.1 (s, 2H). Mass Spectrum: M−H+ 703.91.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[S:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.[CH2:26]1[O:38][C:37]2[CH:36]=[C:35]3[C:30]([CH2:31][CH2:32][NH:33][CH2:34]3)=[CH:29][C:28]=2[O:27]1>C(#N)C>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([CH:7]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:33]2[CH2:32][CH2:31][C:30]3[CH:29]=[C:28]4[O:27][CH2:26][O:38][C:37]4=[CH:36][C:35]=3[CH2:34]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: c1c2c(cc3c1OCO3)CNCC2
Reactant: COc1ccc(C(CCCCCBr)Sc2ccc(C)cc2)cc1OC
Solvent: CC#N
Product: COc1ccc(C(CCCCCN2CCc3cc4c(cc3C2)OCO4)Sc2ccc(C)cc2)cc1OC
Yield: 91.7 %

Procedure:
The procedure of Example 46 is repeated using 3.67 g of 4-[6-bromo-1-[(4-methylphenyl)thio]hexyl]-1,2-dimethoxybenzene in 40 mL of acetonitrile and 2.65 g of 6,7-methylenedioxy-1,2,3,4-tetrahydroiso quinoline. This affords 4.13 g of the desired product as a yellow gum. MS(CI): m/z 520(M+H+). Calcd for C31H37NO4S 7/8H2O: C=69.53, H=7.15, N=2.57, S=5.84 Found C=69.54, H=7.30, N=2.62, S=5.98
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([NH2:15])=[O:14])=[CH:10][CH:11]=2)[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:5]=1[CH2:24][CH2:25][CH3:26])(=O)[CH3:2].Cl.[NH2:28][OH:29].C([O-])(=O)C.[Na+]>C(O)C>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)[C:4]([C:1](=[N:28][OH:29])[CH3:2])=[C:5]1[CH2:24][CH2:25][CH3:26]
Reactant: NO
Reactant: CCCc1c(C(C)=O)c2ccc(C(N)=O)cc2n1Cc1ccccc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCc1c(C(C)=NO)c2ccc(C(N)=O)cc2n1Cc1ccccc1Cl
Temperature: 100 °C
Yield: 86.1 %

Procedure:
To a suspension of 3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxamide (36.5 mg) in ethanol (5 ml) was added hydroxylamine hydrochloride (70 mg) and sodium acetate (200 mg), and the mixture was heated in a sealed tube at 100° C. The reaction was evaporated in vacuo, then the residue was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 1-(2-chlorobenzyl)-3-(1-hydroxyiminoethyl)-2-propylindole-6-carboxamide (32.7 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:21]([O-])=O.[CH:24]1([C:27]2[N:32]=[C:31]([CH:33]=O)[CH:30]=[CH:29][CH:28]=2)[CH2:26][CH2:25]1.S(S([O-])=O)([O-])=O.[Na+].[Na+].O>C(O)C>[CH:24]1([C:27]2[N:32]=[C:31]([C:33]3[NH:1][C:2]4=[N:7][C:6]([N:8]5[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]6[CH2:20][CH2:19][CH2:18][CH2:17]6)=[O:15])[CH2:9]5)=[CH:5][CH:4]=[C:3]4[N:21]=3)[CH:30]=[CH:29][CH:28]=2)[CH2:26][CH2:25]1
Reactant: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1[N+](=O)[O-]
Reactant: O=Cc1cccc(C2CC2)n1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C([C@@H]1CCCN(c2ccc3nc(-c4cccc(C5CC5)n4)[nH]c3n2)C1)N1CCCC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 18.6 %

Procedure:
To a solution of (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (250 mg, 0.711 mmol) in ethanol (15 mL) was added 6-cyclopropylpicolinaldehyde (0.137 g, 0.974 mmol), sodium dithionite (536 mg, 2.96 mmol) and water (2 mL). The reaction mixture was stirred for 16 h at 100° C. in a sealed tube. The mixture was cooled, and the solvent was removed under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via preparative TLC eluting with 4% methanol in dichloromethane to afford the title compound (55 mg, 17%). MS (ES+APCI) (M+H) 417.2; LCMS retention time 1.944 (Method F). 1H NMR (300 MHz, CDCl3) δ 1.00-1.09 (m, 2H), 1.09-1.16 (m, 2H), 1.63-1.74 (m, 1H), 1.81-2.14 (m, 7H), 2.62-2.76 (m, 1H), 2.99 (dd, 1H), 3.08-3.21 (m, 1H), 3.44-3.55 (m, 3H), 3.58-3.70 (m, 1H), 4.35 (d, 1H), 4.48 (d, 1H), 6.71 (d, 1H), 7.19 (d, 1H), 7.66 (t, 1H), 7.87 (d, 1H), 8.04 (d, 1H), 10.18 (br s, 1H).