Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[O:3][C:4](=[O:11])[C@@H:5]([CH2:7][C:8](O)=[O:9])[NH2:6].Cl.[NH2:13][OH:14].C(N(CC)CC)C>CO>[CH2:7]([C:8]([NH:13][OH:14])=[O:9])[CH:5]([NH2:6])[C:4]([OH:3])=[O:11]
Reactant: NO
Reactant: CCOC(=O)[C@H](N)CC(=O)O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: NC(CC(=O)NO)C(=O)O
Reaction time: 48 h
Yield: 50 %

Procedure:
0.1 mole of D-aspartic acid β-ethyl ester is dissolved in 200 ml of methanol, 0.2 mole of hydroxylamine hydrochloride is then added and the mixture is stirred until complete dissolution occurs. 0.4 mole of triethylamine is added and stirring is continued at room temperature for about 48 hr. The precipitate formed is collected on a filter. This crude product is recrystallized by dissolution in water, then diluted in absolute ethanol. This solution is kept at +4° C. for 12 hr. The crystals are filtered, washed with absolute ethanol and air-dried. This reaction yields 50 to 70% of D-Aspartic acid β-Hydroxamate.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([Br:11])=[CH:9][CH:10]=1)=O.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([NH2:20])=[O:19].C([O-])(O)=O.[Na+]>CCOC(C)=O>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:20]=[C:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)[O:19][CH:2]=2)=[CH:6][N:7]=1
Reactant: O=C(CBr)c1ccc(Br)nc1
Reactant: NC(=O)c1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Brc1ccc(-c2coc(-c3ccccn3)n2)cn1
Yield: 10 %

Procedure:
A mixture of 2-bromo-1-(6-bromopyridin-3-yl)ethanone from Step A (2.3 g, 8.25 mmol) and pyridine-2-carboxamide (1 g, 8.25 mmol) was melted at 85°. Heating was continued until the mixture reached 140° at which point the product solidified. Ice, EtOAc and sat aq NaHCO3 were added. The aqueous layer was then back extracted with EtOAc/THF (3:1). Pooled organics were dried over MgSO4, filtered, concentrated, and purified on silica gel to afford 250 mg (10% yield) of 2-bromo-5-(2-pyridin-2-yl-1,3-oxazole-4-yl)pyridine. LC/MS: m/e 302.0 (M+H).
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([CH2:23][CH2:24][C:25](OCC)=O)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH2:30]C)[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.ClC1C2C(=CC=C(CC)C=2)[N:37]=C(N2CC3C=CC=CC=3S(=O)(=O)CC2)C=1.C(#N)C=C>>[O:32]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([CH2:23][CH2:24][C:25]#[N:37])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:30])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: CCc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: CCOC(=O)CCc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(CC)cc12
Solvent: C=CC#N
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(CCC#N)c2c1

Procedure:
The title compound was prepared in analogy to ethyl 3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-ethylquinolin-4-yl]propanoate in Example 95 in Scheme 46 by using 4-(4-chloro-6-ethylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and acrylonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([NH:20][NH2:21])=[O:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[C:24]([N:28]=[C:29]=S)[CH:23]=1.CCN=C=NCCCN(C)C.CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]3[O:19][C:29]([NH:28][C:24]4[CH:23]=[C:22]([CH3:31])[CH:27]=[CH:26][CH:25]=4)=[N:21][N:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: Cc1cccc(N=C=S)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(Nc2nnc(-c3ccc4nc(-c5c(Cl)cccc5Cl)[nH]c4c3)o2)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (150 mg, 0.466 mmol) in DMF (3 mL) add m-tolyl isothiocyanate (69 uL, 0.512 mmol) and stir for 3.5 hr. Add EDCI (179 mg, 0.932 mmol) and heat to 80° C. for 1 hr. Upon cooling to room temp dilute the reaction with EtOAc (75 mL) and extract with water (15 mL). Evaporate the organic phase and recrystallize from toluene/EtOAc. Suspend the solid in 1 N NaOH. Collect the solid wash with water and Et2O to afford the title compound as a white solid: 1H NMR (400 MHz, MeOD) ppm 2.38 (s, 3 H) 6.90 (d, J=7.58 Hz, 1 H) 7.26 (t, J=7.77 Hz, 1 H) 7.37 (d, J=1.77 Hz, 1 H) 7.43 (s, 1 H) 7.56-7.65 (m, 3 H) 7.82 (d, J=8.59 Hz, 1 H) 8.01 (dd, J=8.53, 1.33 Hz, 1 H) 8.27 (s, 1H); MS m/z=436.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:10]3[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:9]=3[NH:8][C:5]2=[N:6][CH:7]=1.[OH-].[K+].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1>CN1C(=O)CCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:10]3[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:9]=3[N:8]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([C:19]([F:29])([F:18])[F:28])=[CH:25][CH:24]=3)[C:5]2=[N:6][CH:7]=1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: Cc1cnc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cnc2c(c1)c1c(n2CCc2ccc(C(F)(F)F)nc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.4 %

Procedure:
To a stirred solution of 3,6-dimethyl-6,7,8,9-tetrahydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridine (201 mg, 1.0 mmol) in NMP (3 mL) was added powdered KOH (392 mg, 7.0 mmol). After stirring for 10 min at RT, 2-(trifluoromethyl)-5-vinylpyridine (346 mg, 2.0 mmol) was added to the reaction mixture and stirring continued for another 3 h. The progress of reaction was monitored by TLC and NMR. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The organic layer was washed with water (5×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 3,6-dimethyl-9-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-6,7,8,9-tetrahydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridine (80 mg). 1H NMR (CDCl3, TFA salt) δ (ppm): 8.38 (s, 1H), 8.0 (s, 1H), 7.5 (d, 2H), 7.4 (d, 1H), 4.4 (t, 2H), 3.58 (s, 2H), 3.2 (t, 2H), 2.68 (t, 2H), 2.5 (t, 2H), 2.47 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][CH:19]=1>C(#N)C>[CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][CH:19]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(CCO)cc1
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Solvent: CC#N
Product: O=C(Nc1ccc(CCO)cc1)c1cc(NC2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and 2-(4-aminophenyl)ethanol (Fluka), the title compound was obtained as a white solid after trituration in acetonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][N:9]=1)=[O:6].[CH3:22][O:23][C:24](=[O:37])[CH2:25][CH2:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([CH:34]=O)=[C:29]([CH3:36])[CH:28]=1.OOS([O-])=O.[K+].O>CN(C=O)C>[CH3:22][O:23][C:24](=[O:37])[CH2:25][CH2:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([C:34]2[NH:1][C:2]3[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]4[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[CH:11]=[CH:10][N:9]=4)[CH:18]=[CH:19][C:20]=3[N:21]=2)=[C:29]([CH3:36])[CH:28]=1
Reactant: Nc1ccc(C(=O)Nc2nccc3ccccc23)cc1N
Reactant: COC(=O)CCc1cc(C)c(C=O)c(C)c1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1cc(C)c(-c2nc3ccc(C(=O)Nc4nccc5ccccc45)cc3[nH]2)c(C)c1
Reaction time: 1 h

Procedure:
A solution of 3,4-diamino-N-isoquinolin-1-yl-benzamide (200 mg) and 3-(4-formyl-3,5-dimethylphenyl)-propionic acid methyl ester (189 mg) (from Example 6-17) in 5 mL DMF/0.5 mL water was stirred at ambient temperature for 15 min then oxone (292 mg) was added and stirring was continued for 1 h. Water was added and the mixture was extracted with EtOAc. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography using 5% MeOH/methylene chloride as eluent to give 3-{4-[6-(Isoquinolin-1-ylcarbamoyl)-1H-benzoimidazol-2-yl]-3,5-dimethylphenyl}-propionic acid methyl ester. MS (ESI)m/z 479.1 (M+H), retention time=1.33 min, Method 10.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN(CCN(C)C)C.Cl.C1C[O:36][CH2:35]C1>CN(C=O)C>[Si:5]([O:8][CH2:9][CH2:10][C:11]1[C:12]([O:17][CH3:18])=[C:13]([CH:14]=[CH:15][CH:16]=1)[CH:35]=[O:36])([C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:6])[CH3:7]
Reactant: C1CCOC1
Reactant: COc1ccccc1CCO[Si](C)(C)C(C)(C)C
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: COc1c(C=O)cccc1CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl(2-methoxyphenethoxy)dimethylsilane [Aromatic Intermediate 26, step a] (2.0 g), as a solution in THF (1 mL), was added dropwise over 5 min to a stirred solution of butyllithium (2.5M in hexanes, 4.5 mL) and TMEDA (1.7 mL) in tetrahydrofuran (20 mL) at 0° C. The resulting mixture was stirred for 4 hours, and then DMF (2.9 mL) was added. The mixture was stirred for a further 30 min and allowed to warm to RT. The reaction was poured into aqueous HCl (0.5M, 20 mL) and extracted with ether (2×50 mL). The u) combined organic solutions were washed with water (50 mL) and brine (50 mL), dried over magnesium sulphate, filtered and evaporated. The resulting gum was purified by silica gel chromatography eluting with isohexane to 4:1 isohexane:ethyl acetate gradient to give the titled compound as a clear oil. Yield 0.40 g.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[C@H:4]([N+:14]([O-])=O)[C@@H:3]1[CH3:17].C(O)(=O)C>CO.[Zn]>[CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[C@H:4]([NH2:14])[C@@H:3]1[CH3:17]
Reactant: Cc1ccccc1[C@@H]1CN(C)[C@@H](C)[C@H]1[N+](=O)[O-]
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccccc1[C@@H]1CN(C)[C@@H](C)[C@H]1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
(2R,3R,4S)+(2S,3S,4R)-1,2-dimethyl-3-nitro-4-(o-tolyl) pyrrolidine (28 mg, 0.12 mmol) was dissolved in 1 ml MeOH and Acetic Acid (2.0 ml) and charged with ZINC (39.1 mg, 0.598 mmol). The reaction was allowed to stir overnight at rt. The solution was filtered through celite and concentrated in vacuo. The residue was dissolved in 2 mL MeOH and desalted on ps-bicarb. The solvents were removed in vacuo to afford (2R,3R,4S)+(2S,3S,4R)-1,2-dimethyl-4-(o-tolyl)pyrrolidin-3-amine (17 mg, 0.08 mmol, 70% yield). LC/MS M+H 205.2
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[C:13]([O:17][C:18]([N:20]1[CH2:23][CH:22]([CH2:24][C:25]([OH:27])=O)[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].O[N:29]=[C:30]([C:32]1[CH:33]=[CH:34][C:35]([CH3:50])=[C:36]([NH:38][C:39]([C:41]2[N:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]3=[N:43][CH:42]=2)=[O:40])[CH:37]=1)[NH2:31].O>CN1C(=O)CCC1>[N:43]1[CH:42]=[C:41]([C:39]([NH:38][C:36]2[CH:37]=[C:32]([C:30]3[N:29]=[C:25]([CH2:24][CH:22]4[CH2:21][N:20]([C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])[CH2:23]4)[O:27][N:31]=3)[CH:33]=[CH:34][C:35]=2[CH3:50])=[O:40])[N:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=12
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)O)C1
Reactant: Cc1ccc(C(N)=NO)cc1NC(=O)c1cnc2ccccn12
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc(-c2noc(CC3CN(C(=O)OC(C)(C)C)C3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 125 °C
Reaction time: 0.33 h

Procedure:
Carbonyl diimidazole (CDI) (52.0 mg, 0.32 mmol) was added to a stirred solution of 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)acetic acid (69.0 mg, 0.32 mmol) in NMP (1.0 mL). After 20 minutes, N-(5-(N′-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (9) (49.5 mg, 0.16 mmol) was added in one portion and the resulting solution was stirred for 30 minutes before it was heated at 125° C. for 15 minutes in a microwave reactor. The reaction mixture was added dropwise to water (20 mL) with stirring. The precipitate was filtered and dried to give tert-butyl 3-((3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)methyl)azetidine-1-carboxylate (54). MS m/z 489.2 (M+1)+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](#[N:12])[CH2:10]O>>[CH2:1]([NH:8][CH2:10][C:9]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: N#CCO
Product: N#CCNCc1ccccc1
Reaction time: 3 h

Procedure:
Benzyl amine (10.7 grams, 0.1 mole) was added to 8.2 g (0.1 mole) of a 70% aqueous solution of glycolonitrile, HOCH2CN, in a round-bottom flask. The exothermic reaction mixture was stirred for 3 hours with no external heating. The desired product was not recovered.
Reaction SMILES: [CH2:1]1COCC1.[CH:6]1[C:18]2[N:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][C:28]([N:31]5[C:43]6[CH:42]=[C:41]([C:44]7[CH:51]=[CH:50][C:47]([CH:48]=O)=[CH:46][CH:45]=7)[CH:40]=[CH:39][C:38]=6[C:37]6[C:32]5=[CH:33][CH:34]=[CH:35][CH:36]=6)=[CH:27][CH:26]=4)=[CH:21][CH:20]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.C(C1C=CC(C2N=C(C3C=CC(C(C)(C)C)=CC=3)N=C(C3C=CC(C4C=CC(C=C)=CC=4)=CC=3)N=2)=CC=1)(C)(C)C.BrC1C=C(Br)C=C(Br)C=1I>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl>[CH:6]1[C:18]2[N:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][C:28]([N:31]5[C:43]6[CH:42]=[C:41]([C:44]7[CH:51]=[CH:50][C:47]([CH:48]=[CH2:1])=[CH:46][CH:45]=7)[CH:40]=[CH:39][C:38]=6[C:37]6[C:32]5=[CH:33][CH:34]=[CH:35][CH:36]=6)=[CH:27][CH:26]=4)=[CH:21][CH:20]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: C1CCOC1
Reactant: O=Cc1ccc(-c2ccc3c4ccccc4n(-c4ccc(-c5ccc(-n6c7ccccc7c7ccccc76)cc5)cc4)c3c2)cc1
Agent: Brc1cc(Br)c(I)c(Br)c1
Agent: C=Cc1ccc(-c2ccc(-c3nc(-c4ccc(C(C)(C)C)cc4)nc(-c4ccc(C(C)(C)C)cc4)n3)cc2)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: C=Cc1ccc(-c2ccc3c4ccccc4n(-c4ccc(-c5ccc(-n6c7ccccc7c7ccccc76)cc5)cc4)c3c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
0.86 g (0.00767 mol) of potassium tert-butoxylate and 2.55 g (0.00714 mol) of methyltriphenylphosphonium bromide are initially introduced. The apparatus is cooled to 0° C., and the solids are dissolved using 15 ml of THF (abs.). The mixture is stirred for 30 min, while, in a second apparatus, 2.31 g (0.0039 mol) of 4-[9-(4′-carbazol-9-ylbiphenyl-4-yl)-9H-carbazol-2-yl]benzaldehyde is weighed out and dissolved using 25 ml of THF. At 0° C., solution 2 is added to solution 1 and stirred for a further 1.5 h. The mixture is taken up in CH2Cl2 and washed by shaking three times with water. The combined organic phases are dried over magnesium sulfate, filtered off and evaporated to dryness. Column chromatography with toluene give 2.1 g (93%) of clean substance.
Reaction SMILES: [S:1](=[O:29])(=[O:28])([O:3][C:4]1[CH:21]=[CH:20][C:19]2[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C@@H:13]([C:22](=[O:27])[NH:23][CH2:24]CC)[CH2:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=1)[NH2:2].S(=O)(=O)(OC1C=CC2[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)C(C(=O)NC)=CC4)CCC=2C=1)N>>[S:1](=[O:28])(=[O:29])([O:3][C:4]1[CH:21]=[CH:20][C:19]2[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C@@H:13]([C:22](=[O:27])[NH:23][CH3:24])[CH2:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=1)[NH2:2]
Reactant: CCCNC(=O)[C@H]1CC[C@H]2[C@@H]3CCc4cc(OS(N)(=O)=O)ccc4[C@H]3CC[C@]12C
Agent: CNC(=O)C1=CC[C@H]2[C@@H]3CCc4cc(OS(N)(=O)=O)ccc4[C@H]3CC[C@]12C
Product: CNC(=O)[C@H]1CC[C@H]2[C@@H]3CCc4cc(OS(N)(=O)=O)ccc4[C@H]3CC[C@]12C

Procedure:
In similar manners to those described for the synthesis of compound 7, compound 29f was prepared from compound 11f. FAB-MS m/z 393 (M+H)+; 1H NMR (270 MHz, DMSO-d6) δ 0.60 (s, 3H, CH3), 2.59 (d, 3H, J=3.6 Hz, NHCH3), 6.96 (d, 1H, J=2.3 Hz, ArH), 7.01 (dd, 1H, J=2.3, 8.6 Hz, ArH), 7.34 (d, 1H, J=8.6 Hz, ArH), 7.29 (m, 1H, NHCH3), 7.87 (s, 2H, NH2).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[O:9][CH:8]([C:14]([F:17])([F:16])[F:15])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]2)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:27](Br)[CH3:28].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[O:9][CH:8]([C:14]([F:15])([F:16])[F:17])[C:7]([C:18]([O:20][CH2:27][CH3:28])=[O:19])=[CH:6]2)[CH3:2]
Reactant: CCBr
Reactant: CCc1cc2c(cc1O)OC(C(F)(F)F)C(C(=O)O)=C2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2cc(CC)c(O)cc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
To a solution of 0.3 g (1.04 mmol) of 6-ethyl-7-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid in 5 mL of anhydrous dimethylformamide was added 255 mg (0.78 mmol) of cesium carbonate in one portion, followed by addition of 103 uL (1.7 mmol) of ethyl bromide. The reaction was stirred at room temperature overnight. The reaction was added to 100 mL of ethyl acetate. The organic phase was washed with brine three times, and dried over anhydrous magnesium sulfate. After removing the volatiles, the residue was purified by silica chromatography with EtOAc/hexane (3:7) to afford 0.21 g (67%) of a light yellow solid: 1H NMR (CDCl3/400 MHz) 7.68(s, 1H), 7.00(s, 1H), 6.42(s, 1H), 5.63 (q, J=7.2 Hz, 1H), 5.38(s, 1H), 4.28(m, 2H), 2.54(q, J=7.2 Hz, 2H), 1.31(t, J=7.2 Hz, 3H), 1.20(t, J=7.6 Hz, 3H), MS (ESI+) 317 (M+1, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[CH2:22][C@@H:21]([CH2:23][C:24]([O:26]CC)=[O:25])[C:20]4[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=4[CH2:18][C:17]=3[CH:33]=2)[CH:3]=1.O[Li].O.C1COCC1>O>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[CH2:22][C@@H:21]([CH2:23][C:24]([OH:26])=[O:25])[C:20]4[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=4[CH2:18][C:17]=3[CH:33]=2)[CH:3]=1
Reactant: CCOC(=O)C[C@@H]1Cc2ccc(OCCCNc3cc(N)ccn3)cc2Cc2ccccc21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccnc(NCCCOc2ccc3c(c2)Cc2ccccc2[C@H](CC(=O)O)C3)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.9 %

Procedure:
A mixture of ethyl (S)-10,11-dihydro-3-[3-(4-aminopyridin-2-ylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate (2.4 g, 5 mmole), LiOH.H2O (0.3 g, 7 mmole), THF (30 mL), and H2O (10 mL) was stirred at RT for 48 hr, then was concentrated. The residue was diluted with H2O and extracted with Et2O. The Et2O layers were discarded. The aqueous layer was stirred with gentle warming under vacuum to remove residual organic solvents, then was filtered. The resulting aqueous solution was stirred at RT while the pH was slowly and carefully adjusted to 5.5-6.0 with 1.0 N HCl The mixture was stirred for 0.5 hr, then the solid was collected by suction filtration and washed with plenty of H2O. Drying in high vacuum at 60° C. gave the title compound (1.0 g, 42%) as a glassy solid: MS (ES) m/e 417.7 (M+H)+. Anal. Calcd for C25H27N3O3 1.4 HCl (468.554): C, 64.08; H, 6.11; N, 8.97. Found: C, 64.16; H, 6.20; N, 8.71.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[N:17]=[C:11]3[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][N:3]=1.[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[N:25][N:26]([CH3:31])[C:27]=1[C:28](O)=[O:29])=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[N:25][N:26]([CH3:31])[C:27]=1[C:28](=[O:29])[NH:16][C:13]1[CH:14]=[CH:15][N:10]2[N:9]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=3)[N:17]=[C:11]2[CH:12]=1)=[O:22])[CH3:19]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Reactant: Nc1ccn2nc(-c3ccnc(F)c3)nc2c1
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3ccnc(F)c3)nc2c1
Yield: 65.6 %

Procedure:
The product was prepared in the same manner as described in example 44d using 2-(2-fluoropyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine (0.5 g, 2.18 mmol) and 4-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (519 mg, 2.62 mmol) as starting materials. The reaction affords 5-[2-(2-fluoro-pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl]-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (585 mg, 65.5%) as white solid. mp.: 220-230° C., MS: m/z=410.0 (M+H+).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C@H:20]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:21]([N:23]([CH3:25])[CH3:24])=[O:22].CO>CCCCCCC>[CH3:24][N:23]([CH3:25])[C:21]([CH:20]([NH:19][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:22]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CN(C)C(=O)[C@H](N)c1ccccc1
Agent: Cl
Solvent: CCCCCCC
Solvent: CO
Product: CN(C)C(=O)C(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)c1ccccc1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42 a) and (αR)-α-amino-N,N-dimethyl-benzeneacetamide hydrochloride (1:1) (CAN 129157-29-5) as starting materials. Racemization occurred during the synthesis and the product was isolated by chiral chromatography on Reprosil Chiral NR using heptane/20% ethanol as eluent. The (+)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 394.2120 (M+H)+, αD20 (MeOH)=+44.4°.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:27]=[CH:28][CH:29]=1
Reactant: COc1cc2c(=O)[nH]c3nccc(Cl)c3c2cc1OC
Reactant: COc1cccc(N)c1
Product: COc1cccc(Nc2ccnc3[nH]c(=O)c4cc(OC)c(OC)cc4c23)c1
Yield: 6.2 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 212 using Compound 211 (50 mg, 0.17 mmol) and 3-methoxyaniline (27 mg, 0.22 mmol) to provide 214 (4 mg, 6% yield) as a white solid. LC-MS (M+H=378, obsd.=378).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][N:6]=[N:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9].N1C(C)=CC=CC=1C.O([Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])S(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH:29]([Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[O:1][CH2:2][C:3]1[S:7][N:6]=[N:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9])([CH3:31])[CH3:30]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: COC(=O)c1nnsc1CO
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)c1nnsc1CO[Si](C(C)C)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 86.4 %

Procedure:
To a solution of methyl 5-(hydroxymethyl)-1,2,3-thiadiazole-4-carboxylate (1.22 g, 0.007 mol) in DCM (20 mL) at 0° C. was added 2,6-lutidine (2.0 mL, 0.018 mol) followed by triisopropylsilyl triflate (2.4 mL, 0.0091 mol). The solution was stirred at 0° C. for 5 minutes. The reaction was then concentrated and purified by flash chromatography to give the desired product (2.0 g, 87%). 1H NMR (400 MHz, CDCl3): δ□; MF=C14H26N2O3SSi; LCMS calculated for C14H27N2O3SSi (M+H)+: m/z 331.1.