Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[OH-:7].[K+].[S:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[C:11]([CH2:18][OH:19])=[N:10]1>O>[S:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[C:11]([C:18]([OH:7])=[O:19])=[N:10]1
Reactant: OCc1nsc2ncccc12
Reactant: [OH-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1nsc2ncccc12
Reaction time: 0.08 h
Yield: 42 %

Procedure:
Potassium permanganate (2.25 mmol) and potassium hydroxide (1.79 mmol) were added to a solution of isothiazolo[5,4-b]pyridin-3-ylmethanol (1.08 mmol) in water (4 mL) and the resulting solution was allowed to react for 3 h at rt. The reaction mixture was filtered through Celite and was extracted with ethyl acetate (3×10 mL). The pH of the combined aqueous layers was adjusted to 2 by the addition of 0.6 M hydrochloric acid. The slurry was stirred for 5 min and the solids were collected by filtration to provide isothiazolo[5,4-b]pyridine-3-carboxylic acid in 42% yield as a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6](=[O:28])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][N:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)[CH:17]=4)[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:31][N:32]1[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]1.[ClH:45]>C(Cl)Cl.O1CCOCC1>[ClH:45].[ClH:45].[ClH:45].[OH:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6](=[O:28])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][N:22]5[CH2:23][CH2:24][O:25][CH2:26][CH2:27]5)[CH:17]=4)[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:31][N:32]1[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ccc(OCCN5CCOCC5)cc24)C3=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1/C(=C/c2c[nH]c3ccc(OCCN4CCOCC4)cc23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A solution of tert-butyl (Z)-4-[(6-hydroxy-2-{[5-(2-morpholinoethoxy)-1H-indol-3-yl]methylene}-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.076 g, 0.013 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 1 hour. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was suspended in methylene chloride and thereby washed to obtain (Z)-6-hydroxy-2-{[5-(2-morpholinoethoxy)-1H-indol-3-yl]methylene}-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one trihydrochloride (0.048 g, 60%).
Reaction SMILES: F[C:2]1[C:11]2[C:10](=[O:12])[O:9][C:8](=[O:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.N[C:15]1C=CC=C(C)C=1C(O)=O>>[CH3:15][C:2]1[C:11]2[C:10](=[O:12])[O:9][C:8](=[O:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cccc(F)c2c(=O)o1
Reactant: Cc1cccc(N)c1C(=O)O
Product: Cc1cccc2[nH]c(=O)oc(=O)c12

Procedure:
Prepared analogously to Compound 27E replacing 2-amino-6-fluorobenzoic acid with 2-amino-6-methylbenzoic acid. 1H NMR (DMSO-d6, 500 MHz) δ 2.32 (s, 3H), 7.09 (m, 1H), 7.21-7.25 (m, 1H), 7.51-7.61 (m, 1H), 11.65 (br.s, 1H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9](Cl)=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14])(=[O:3])[CH3:2].[O:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([C:30]2[CH:31]=[CH:32][O:28][CH:29]=2)=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14])(=[O:3])[CH3:2]
Reactant: OB(O)c1ccoc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1c(C)ccnc1Cl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1c(C)ccnc1-c1ccoc1

Procedure:
By carrying out the operation analogously to example 1, starting from 2-chloro-4-methyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to preparation VI, and 3-furanboronic acid, the desired product is obtained in the form of an ecru solid (yield=77%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=2)=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:22]([C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[Cl:19])=[O:23])=[N:16][CH:17]=2)=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1
Reactant: Cc1nc2cc(Cl)c(-c3ccc(N)nc3)cc2o1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cc(Cl)c(-c3ccc(NC(=O)c4ccccc4Cl)nc3)cc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
To a solution of 5-(5-chlorob-2-methylenzoxazol-6-yl)-2-pyridylamine (36) (19 mg, 0.073 mmol) and 2 mg DMAP in 2 ml DCM was added 2-chlorobenzoyl chloride (19 μl, 0.14 mmol) followed by addition of DIEA (64 μl). The resulting solution was stirred at r.t. for overnight. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (140 μl) at r.t. for 1 h before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished 20.6 mg 37 as pale yellow solid. (yield: 71%).
Reaction SMILES: [C:1]([C@@H:4]1[C:8]([CH3:10])([CH3:9])[S:7][CH2:6][N:5]1C(OC(C)(C)C)=O)(=[O:3])[NH2:2].[ClH:18]>O1CCOCC1>[ClH:18].[CH3:9][C:8]1([CH3:10])[S:7][CH2:6][NH:5][C@@H:4]1[C:1]([NH2:2])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CSC(C)(C)[C@H]1C(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)SCN[C@@H]1C(N)=O

Procedure:
In analogy to the procedure described in Example 82 a), (R)-tert-butyl 4-carbamoyl-5,5-dimethylthiazolidine-3-carboxylate was treated with a 4 M solution of HCl in dioxane to give the title compound as yellow solid which was sufficiently pure to be used in the next step; MS (EI): m/e=161.2 [(M-Cl)H+].
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])#[N:2].C([Sn]([N:26]=[N+:27]=[N-:28])(CCCC)CCCC)CCC.Cl>C1(C)C=CC=CC=1.CCOCC>[NH:26]1[C:1]([CH2:3][C:4]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:5])=[N:2][N:28]=[N:27]1
Reactant: N#CCC(=O)Nc1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=C(Cc1nnn[nH]1)Nc1ccccc1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
A solution of 2-cyano-acetanilide (0.801 g, 5.0 mmol) and tri-n-butyltin azide (2.05 mL, 7.5 mmol) in anhydrous toluene (10 mL) was heated at reflux for 48 hrs. The mixture was allowed to cool to room temperature and treated with 2.0 N HCl in Et2O (5.0 mL). The resulting precipate was collected by suction, washed with hexane and dried in vacuo to give 2-(1H-tetrazol-5-yl)acetanilide (0.917 g, 90%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28]>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[N:3]=1
Reactant: NCCCCCCCCN
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Solvent: CCO
Product: NCCCCCCCCNc1nc(N)nc2c1ncn2[C@H]1C=C[C@@H](CO)C1
Yield: 42.8 %

Procedure:
A solution of (±)-(cis)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (272 mg, 1.00 mmol) and 1,8-diaminooctane (1.44 g, 10 mmol) in absolute ethanol (15 mL) was refluxed under nitrogen for 1.5 hours. The solution was concentrated, cooled, and the resulting precipitate filtered and crystallised from i-propanol to give title compound as white solid (160 mg, 42%), m.p. 125-127° C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)[CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13].[C:27](Cl)(Cl)=[S:28]>C(Cl)(Cl)Cl>[CH2:8]([C@H:14]1[CH2:15][CH2:16][C@H:17]([C:20]2[CH:21]=[CH:22][C:23]([N:24]=[C:27]=[S:28])=[CH:25][CH:26]=2)[CH2:18][CH2:19]1)[CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13]
Reactant: S=C(Cl)Cl
Reactant: C=CCCCC[C@H]1CC[C@H](c2ccc(N)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CCCCC[C@H]1CC[C@H](c2ccc(N=C=S)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.36 ml of triethylamine in 15 ml of chloroform was treated dropwise at -10° C. with a solution of 2.18 g of p-[trans-4-(5-hexenyl)cyclohexyl]aniline in 20 ml of chloroform. After 5 minutes the mixture was treated with a solution of 690 μl of thiophosgene in 10 ml of chloroform, warmed to room temperature and stirred for 2 hours. Thereafter, the reaction mixture was partitioned between water and chloroform. The organic phase was dried over magnesium sulphate and concentrated. Chromatographic separation on 140 g of silica gel using ethyl acetate/petroleum ether (vol. 5:95) and subsequent crystallization from 80 ml of methanol and low temperature filtration gave 1.24 g of p-[trans-4-(5-hexenyl)cyclohexyl]phenylisothiocyanate (purity 100%) as a milky liquid of m.p. (C-N) 15.2° C. and cl.p. (N-I) 46.1° C.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[CH:14]=[C:13]([I:15])[CH:12]=[C:11]([Cl:16])[N:10]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[Cl:16][C:11]1[N:10]=[C:9]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:14]=[C:13]([I:15])[CH:12]=1
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Product: Clc1cc(I)cc(N2CCOCC2)n1
Temperature: 100 °C

Procedure:
To a solution of triethylamine (1.0 equiv.) and 2,6-dichloro-4-iodopyridine (1.0 equiv.) at RT was added morpholine (1.0 equiv) in one portion, the resulting mixture was then heated in an oil bath at 100° C. for 18 hours. LCMS analysis indicated the formation of the desired product (M+H=324.9/326.8, Rt=0.98 min). Water was then added, and the mixture was extracted with ethyl acetate, and the combined extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was chromatographed via ISCO to yield 4-(6-chloro-4-iodopyridin-2-yl)morpholine as a light brown solid (63%). LCMS (m/z) (M+H)=324.9/326.8, Rt=0.98 min.
Reaction SMILES: Cl.Cl.Cl.Cl.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C@H:12]([C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)[CH2:18][CH2:17]1)=[O:15])[NH2:13].[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38](O)=[O:39])[CH:36]=2)[CH:31]=[CH:30]1>>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38]([NH:13][C@@H:12]([C:14]([N:16]3[CH2:17][CH2:18][N:19]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:20][CH2:21]3)=[O:15])[CH2:11][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=3)=[O:39])[CH:36]=2)[CH:31]=[CH:30]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: CN1CCC(N2CCN(C(=O)[C@H](N)Cc3ccccn3)CC2)CC1
Agent: Cl
Product: CN1CCC(N2CCN(C(=O)[C@@H](Cc3ccccn3)NC(=O)c3ccc4cc[nH]c4c3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the titled compound was prepared from 1-[β-(2-pyridinyl)-D-alanyl]-4-(1-methylpiperidin-4-yl)piperazine tetrahydrochloride and indole-6-carboxylic acid (62%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35]>C1COCC1>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[C:13]3[CH:12]=[CH:11][C:10](=[O:31])[N:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[C:14]=3[N:15]=[C:16]([NH:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])[N:17]=2)=[C:20]([CH3:26])[CH:21]=1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CC(C)(N)CO
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(NC(C)(C)CO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 72 h

Procedure:
The product of Example 48 (200 mg, 0.45 mmol) and 95% 2-amino-2-methyl-1-propanol (94 mg, 1 mmol) were dissolved in THF (10 ml) and stirred under Ar at 50° for 3 days. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography eluted with 0-15% EtOAc/CH2Cl2 gave the title compound as a off-white amorphous solid. mp 99-105° C., LC MS m/z=455 (MH+) Retention time=2.19 min.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH2:16][CH3:17])[C:8]=2[N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:33])([CH3:32])[CH3:31]>CN(C)C=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:33])([CH3:32])[CH3:31])[C:10](=[O:15])[N:9]([CH2:16][CH3:17])[C:8]=2[N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cnc2c1c(=O)[nH]c(=O)n2CC
Reactant: CC(C)(O)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1cnc2c1c(=O)n(CCCCCC(C)(C)O)c(=O)n2CC

Procedure:
4.7 g of 7-butyl-3-ethylxanthine, 2.8 g of potassium carbonate, and 4.4 g of 1-bromo-6-hydroxy-6-methylheptane are stirred in 100 ml of dimethylformamide at 120° C. for 7 hours. The mixture is filtered hot with suction, the filtrate is concentrated under reduced pressure, the residue is taken up in chloroform, washed first with 2 N sodium hydroxide solution and then with water until neutral and dried over sodium sulphate, the solvent is distilled off under reduced pressure whereupon an oily crude product in virtually quantitative yield is obtained which can advantageously be purified by filtration over a silica gel column using a chloroform/methanol (10:1) mixture as mobile phase, followed by a final recrystallization from diisopropylether with addition of petroleum ether.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][CH:3]=1.Cl[C:20]1[CH:21]=[C:22]2[N:29]([CH3:30])[C@@H:28]([CH3:31])[CH2:27][N:23]2[C:24](=[O:26])[N:25]=1>>[CH3:30][N:29]1[C:22]2[N:23]([C:24](=[O:26])[N:25]=[C:20]([O:16][CH2:15][C:12]3[CH:13]=[CH:14][C:7]([O:6][C:5]4[CH:17]=[CH:18][C:2]([F:1])=[CH:3][CH:4]=4)=[C:8]([CH:11]=3)[C:9]#[N:10])[CH:21]=2)[CH2:27][C@@H:28]1[CH3:31]
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(F)cc1
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4ccc(F)cc4)c(C#N)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 2-(4-fluorophenoxy)-5-(hydroxymethyl)benzonitrile and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([C@@H:24]([NH:38][C:39](=[O:55])[O:40][CH2:41][C:42]1([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:31])[C:13](=[O:23])[NH:14][C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16].C(N(CC)CC)C>ClCCl>[N:32]1([C:30]([NH:29][CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]([NH:38][C:39](=[O:55])[O:40][CH2:41][C:42]2([CH2:48][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]2)[C:12](=[O:11])[C:13](=[O:23])[NH:14][C@@H:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16])=[O:31])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: C[C@@H](NC(=O)C(O)[C@H](CCCCNC(=O)N1CCOCC1)NC(=O)OCC1(Cc2ccccc2)CCCCC1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@@H](NC(=O)C(=O)[C@H](CCCCNC(=O)N1CCOCC1)NC(=O)OCC1(Cc2ccccc2)CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
To a −60° C. solution of 0.034 mL (0.39 mmol) of oxalyl chloride in 1 mL of dichloromethane was added 0.055 mL (0.78 mmol) of dimethylsulfoxide, dropwise. A solution of 110 mg (0.177 mmol) of (1-benzylcyclohexyl)methyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)-5-[(4-morpholinylcarbonyl)amino]pentylcarbamate in 1 mL of dichloromethane was added dropwise and the reaction stirred for 10 min before 0.12 mL (0.89 mmol) of triethylamine was added dropwise. The reaction was let warm to room temperature and stirred for 15 min before being applied directly to a silica gel column eluting with 3:7 acetone:dichloromethane to afford 90 mg (82%) of (1-benzylcyclohexyl)methyl(1S)-5-[(4-morpholinylcarbonyl)amino]-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate. 1H NMR (300 MHz, 80° C., DMSO-d6) δ 8.91 (m, 1H), 7.15-7.38 (m, 11H), 6.30 (m, 1H) 5.01 (qnt, J=7 Hz, 1H), 4.85 (m, 1H), 3.63-3.72 (m, 2H), 3.54 (t, J=5 Hz, 4H), 3.26 (t, J=5 Hz, 4H), 3.04 (m, 2H), 2.66 (s, 2H), 1.316-1.714 (m, 19H). ES-LCMS m/z 643 (M+Na). HRMS C35H48N4O6 m/z 621.3652 (M+H)Cal; 621.3641 (M+Na)Obs.
Reaction SMILES: [C:1]([CH:4]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2].[Br:14]Br>C(Cl)(Cl)Cl>[Br:14][CH2:2][C:1]([CH:4]([CH2:10][CH:11]([CH3:12])[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:3]
Reactant: CCOC(=O)C(CC(C)C)C(C)=O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(CC(C)C)C(=O)CBr
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A solution comprised of ethyl 2-acetyl-4-methylpentanoate (1.86 gm, 10 mmol) in chloroform (20 mL) was cooled to 0° C. and treated with bromine (0.6 mL, 11.0 mmol in 10 mL chloroform). The mixture was stirred for approximately 12 hours and then concentrated to provide ethyl 2-bromoacetyl-4-methylpentanoate as a crude product.
Reaction SMILES: ClC1C=CC=CN=1.N1CC(NC(=O)OC(C)(C)C)C1.Cl[C:21]1[C:22]([N:31]2[CH2:34][CH:33]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:32]2)=[N:23][CH:24]=[C:25](C(F)(F)F)[CH:26]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:21][C:22]=1[N:31]1[CH2:34][CH:33]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:32]1
Reactant: CC(C)(C)OC(=O)NC1CN(c2ncc(C(F)(F)F)cc2Cl)C1
Agent: CC(C)(C)OC(=O)NC1CNC1
Agent: Clc1ccccn1
Product: CC(C)(C)OC(=O)NC1CN(c2ccccn2)C1

Procedure:
The title compound was prepared from 2-chloropyridine and tert-butyl azetidin-3-ylcarbamate in a similar manner as described for tert-butyl {1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]azetidin-3-yl}carbamate. 1H NMR (500 MHz CDCl3): δ 1.46 (s, 9H), 3.76-3.80 (m, 2H), 4.31-4.35 (m, 2H), 4.63 (bs, 1H), 5.10 (bs, 1H), 6.29 (d, 1H), 6.61-6.64 (m, 1H), 7.43-7.47 (m, 1H), 8.14-8.16 (m, 1H); 13C NMR (125 MHz CDCl3): δ 28.58, 41.79, 58.58, 80.22, 106.36, 113.48, 137.37, 148.42, 155.24, 160.66; Mass Spectrum: M+H+ 250.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Br:22])[CH:21]=1)[C:10]([CH3:24])([CH3:23])[CH:9]2O)=[O:5])[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Br:22])[CH:21]=1)[C:10]([CH3:23])([CH3:24])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cncc(Br)c1)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cncc(Br)c1)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 28.6 %

Procedure:
To a mixture of 2-(5-bromo-pyridin-3-yl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (16 g, 39.5 mmol) and triethylsilane (40 mL) at 25° C. was added trifluoroacetic acid (20 mL) dropwise. The resulting mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (2×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(30% ethyl acetate/hexanes) to afford 2-(5-bromo-pyridin-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (4.4 g, 28%) as a yellow solid: LC/MS m/e calcd for C19H21BrN2O2 (M+H)+: 390.30, observed: 390.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[C:10]([O:15][CH2:16][CH2:17][CH3:18])(=[O:14])[C:11]([CH3:13])=O>>[CH2:16]([O:15][C:10](=[O:14])[C@H:11]([CH3:13])[NH:5][C:4]1[CH:3]=[C:2]([Cl:1])[CH:8]=[C:7]([Cl:9])[CH:6]=1)[CH2:17][CH3:18]
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CCCOC(=O)C(C)=O
Product: CCCOC(=O)[C@H](C)Nc1cc(Cl)cc(Cl)c1

Procedure:
Following General Procedure A above and using 3,5-dichloroaniline (Aldrich) and n-propyl pyruvate (which can be prepared by following General Procedure O above using n-propanol in place of iso-butanol), the title compound could be prepared.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[S:14][CH2:13][C:12]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[N:11]2[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:5]([CH2:24][CH3:25])[CH:4]=1)#N.CC(C[AlH]CC(C)C)C.CC[O:37]C(C)=O>C1(C)C=CC=CC=1>[CH2:24]([C:5]1[CH:4]=[C:3]([CH:1]=[O:37])[CH:8]=[CH:7][C:6]=1[N:9]=[C:10]1[S:14][CH2:13][C:12]2([CH2:18][CH2:17][CH2:16][CH2:15]2)[N:11]1[CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH3:25]
Reactant: CCc1cc(C#N)ccc1N=C1SCC2(CCCC2)N1C1CCCC1
Reactant: CCOC(C)=O
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CCc1cc(C=O)ccc1N=C1SCC2(CCCC2)N1C1CCCC1
Temperature: -78 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
2-(4-Cyano-2-ethylphenylimino)-3-thia-1-azaspiro[4.4]nonane was prepared in a manner analogous to Method C2a and the thiazolidine was alkylated in a manner analogous to Method D2b to give 2-(4-cyano-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. To a solution of 2-(4-cyano-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane (0.21 g, 0.60 mmol) in anh. toluene (20 mL) at −78C. was added DIBAL (1.0M in toluene, 1.20 mL, 1.20 mmol). The reaction mixture was stirred at −78° C. for 3 h, then EtOAc (3 mL) was added at −78° C., stirring was continued for 0.5 h, and wet silica gel (5% water, 2 g) was added. The reaction mixture was warmed to room temp., stirred for 3 h, then filtered through a pad of through Celite®. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative TLC (30% EtOAc/hex) to give 2-(2-ethyl-4-formylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane as a white solid (0.16 g, 75%): mp 104-105° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[N:5]=[C:4]([CH3:14])[N:3]=1.[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>>[Cl:13][C:10]1[S:9][C:8]([C:6]2[N:5]=[C:4]([CH3:14])[N:3]=[C:2]([NH:20][C:19]3[CH:21]=[CH:22][C:16]([F:15])=[CH:17][CH:18]=3)[N:7]=2)=[CH:12][CH:11]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cc1nc(Cl)nc(-c2ccc(Cl)s2)n1
Product: Cc1nc(Nc2ccc(F)cc2)nc(-c2ccc(Cl)s2)n1
Yield: 24 %

Procedure:
4-(5-chlorothiophen-2-yl)-N-(4-fluorophenyl)-6-methyl-1,3,5-triazin-2-amine was prepared using 2-chloro-4-(5-chlorothiophen-2-yl)-6-methyl-1,3,5-triazine and 4-fluoroaniline by the method described for Step 3 of EXAMPLE 1 (13 mg, 24% yield). MW=320.77. 1H NMR (300 MHz, CDCl3) δ 7.93 (d, J=4.2 Hz, 1H), 7.64 (dd, J=9, 4.8 Hz, 2H), 7.11 (t, J=8.7 Hz, 2H), 7.01 (d, J=4.2 Hz, 1H), 2.55 (s, 3H).