Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([OH:27])[C@@H:17]([CH2:28][CH:29]=O)[CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]1(C)C=CC=CC=1>N1C=CC=CC=1.C1COCC1.[CH3-].C[Al+]C.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Cl-].[Ti+3]>[CH2:28]([C@@H:17]1[CH2:16][C@H:15]2[C@H:14]3[C@H:23]([CH2:22][CH2:21][C@:19]2([CH3:20])[C@H:18]1[OH:27])[C:24]1[CH:25]=[CH:26][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][C:11]=1[CH2:12][CH2:13]3)[CH:29]=[CH2:31]
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1C[C@H](CC=O)[C@@H]2O
Reactant: Cc1ccccc1
Agent: [Ti+3]
Agent: C[Al+]C
Agent: [CH3-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=CC[C@@H]1C[C@H]2[C@@H]3CCc4cc(OCc5ccccc5)ccc4[C@H]3CC[C@]2(C)[C@H]1O
Temperature: -78 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
A solution of 5.3 mg (0.013 mmol) of 27 in anhydrous toluene (99.7 μL), pyridine (1 μL) and THF (33 μL) was stirred at −78° C. as 0.0156 mmol of Tebbe reagent (31 μL of a 0.5 M solution in toluene) was added by syringe. Reaction was stirred at −78° C. for 2 h, allowed to stir at 40° C. for 2 h then at 0° C. for 1 h. Reaction was quenched with 15% NaOH (25 μL), allowed to stir for ½ h, warmed to rt and passed through a 1″ plug of Celite. The filter was washed with EtOAc and the filtrate was concentrated in vacuo. Purification of the residue on a 1×17 cm column of silica gel using hexanes/EtOAc (2:1) followed by hexanes/EtOAc (4:1) gave 1.3 mg (25%) of 28 as a clear colorless oil and 1.8 mg (34%) of recovered 27. Data for 28: TLC, T-6, Rf0.76. 1H NMR (500 MHz, CDCl3) δ 0.83 (s, 3H, H-18), 2.86 (m, 2H, H-6), 3.33 (d, 1H, J=7.4 Hz, H-17α), 5.03-5.12 (m, 2H,═CH2), 5.04 (s, 2H, benzylic), 5.85-5.93 (m, 1H, —CH═CH2), 6.72 d, 1H, J=2.6 Hz, H-4), 6.79 (dd, 1H, J=8.7, 2.6 Hz, H-2), 7.21 (d, 1H, J=8.7 Hz, H-1), 7.31-7.44 (m, 5H, Ar—H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[OH:12].[Cl:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:15]=1[C:16](Cl)=[O:17].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>CC(N(C)C)=O.O>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[O:12][C:16](=[O:17])[C:15]1[C:14]([Cl:13])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:23]
Reactant: Nc1cccc2c(O)ccnc12
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1cccc2c(OC(=O)c3c(Cl)cccc3Cl)ccnc12
Reaction time: 1 h
Yield: 38.5 %

Procedure:
A mixture of 8-amino-4-hydroxyquinoline (300 mg), 2,6-dichlorobenzoyl chloride (432 mg), triethylamine (569 mg) and catalytic amount of dimethylaminopyridine in dimethylacetamide (3 ml) was stirred for 1 hour under ice-cooling. To the mixture was added water (3 ml) and the resulting precipitate was collected by filtration. The residue was suspended in hot ethanol (10 ml) with stirring. The resulting precipitate was collected by filtration, and the residue was purified by flash chromatography (ethyl acetate-dichloromethane) to give 8-amino-4-(2,6-dichlorobenzoyloxy)quinoline (240 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:37])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[C:20](=[O:29])[C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=1>>[CH3:9][O:10][C:11](=[O:37])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[C:30]3[C:35](=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)/[C:21](=[C:22](\[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)/[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:20]2=[O:29])[CH:13]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2cccc(F)c2)c1
Reactant: Clc1ccc(I)cc1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(Cl)cc3)c3ccc(F)cc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-4-iodo-benzene (commercially available) and 3-{[(3-fluoro-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 3.90 (s, 3H), 4.96 (s, 2H), 6.48 (d, 1H), 7.10 (d, 1H), 7.19 (d, 1H), 7.31-7.50 (m, 11H), 7.94 (d, 1H), 7.98 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH3:19][C:20]1[C:25]([CH2:26]Br)=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=1[CH2:26][N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[CH:17][C:5]=2[C:1]([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2C)CCCC1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.4 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (870 mg, 3.58 mM), a-bromo-o-xylene (662 mg, 3.58 mM), and potassium carbonate (500 mg, 3.61 mM) in 20 mL DMF was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate, washed with H2O and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated to afford 1.21 g (98%) of the 9-[(2-methylphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a dark oil. 1H NMR (DMSO-d6) δ7.5-7.2 (m, 4H), 7.15 (t, 1H, J=8 Hz), 7.0 (t, 1H, J=8 Hz), 6.15 (d, 1H, J=8 Hz), 5.55 (s, 2H), 3.85 (s, 3H), 2.6 (m, 2H), 2.4 (m, 2H), 2.4 (s, 3H), and 2.1 (m, 2H). IR (CHCl3, cm−1) 3010, 2952, 1724, 1671, 1653, 1604, 1460, 1444, 1290, 1174, and 1122. MS (ES) m/e 348.5.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12](=[O:21])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:22]I.[OH-].[K+]>O1CCCC1>[CH3:22][N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12](=[O:21])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CI
Reactant: CCCCCCCNC(=O)Oc1ccc2c(c1)CCCN2
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)Oc1ccc2c(c1)CCCN2C
Temperature: 36 °C
Reaction time: 5 h

Procedure:
A mixture of heptyl-carbamic acid-1, 2, 3, 4-tetrahydro-quinolin-6-yl ester (0.58 g., 2 mmol), methyl iodide (0.224 ml, 3.6 mmol) and pulverized potassium hydroxide (0.16 g., 2 mmol) in dry tetrahydrofuran (10 ml) was stirred for 5 hours at room temperature (36° C.). The reaction mixture was concentrated under vaccum, diluted with water (5 ml), extracted with ether (3×5 ml), dried over sodium sulphate and the combined ether fractions were concentrated under vaccum. The residue was then chromatographed on deactivated silica gel (water: silica gel=12.88, v/w) using dichloromethane: hexane (20:80) as eluant to give 2n; yield: 0.36 g. (59.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=[O:17])[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:4]([CH3:18])[CH:3]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.C([BH3-])#N.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C(O)(=O)C>[CH:12]1([CH2:11][C:10]([NH:9][C:5]2[C:4]([CH3:18])=[CH:3][C:2]([NH:1][CH2:25][C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:29])[F:30])=[CH:28][CH:27]=3)=[CH:7][C:6]=2[CH3:8])=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1cc(N)cc(C)c1NC(=O)CC1CCCC1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: Cc1cc(NCc2ccc(C(F)(F)F)cc2)cc(C)c1NC(=O)CC1CCCC1
Temperature: 150 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
N-(4-Amino-2,6-dimethyl-phenyl)-2-cyclopentyl-acetamide (207 mg) and 4-trifluoromethyl-benzaldehyde (125 uL) were dissolved in acetonitrile (2 mL) and heated to 150° C. for 5 minutes in a sealed microwave process vial. Sodium cyanoborohydride (0.7 M in methanol, 5 mL) and acetic acid (500 uL) were added and the reaction mixture was stirred at 25° C. for 16 hours. Aqueous sodium carbonate (10%, 25 mL) was added, and the product was collected by filtration to furnish 0.31 g (91% yield) of the title compound as a white solid. LC-MS (m/z) 405 (MH+); tR=3.19, (UV, ELSD) 97%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.19 (m, 2H), 1.51 (m, 2H), 1.60 (m, 2H), 1.75 (m, 2H), 1.96 (s, 6H), 2.22 (m, 3H), 4.34 (d, 2H), 6.18 (t, 1H), 6.25 (s, 2H), 7.55 (d, 2H), 7.67 (d, 2H), 8.76 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:45])[CH2:14][CH2:15][N:16]([C:23]([C:25]1[CH:44]=[CH:43][C:28]2[N:29]([CH3:42])[C:30]([CH2:32][NH:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=3)=[N:31][C:27]=2[CH:26]=1)=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(C)(C)C.C(=O)([O-])[O-].[NH4+:51].[NH4+]>Cl.C(O)C>[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([CH2:14][CH2:15][N:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23]([C:25]1[CH:44]=[CH:43][C:28]2[N:29]([CH3:42])[C:30]([CH2:32][NH:33][C:34]3[CH:39]=[CH:38][C:37]([C:40](=[NH:41])[NH2:51])=[CH:36][CH:35]=3)=[N:31][C:27]=2[CH:26]=1)=[O:24])=[O:45]
Reactant: [NH4+]
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCC(=O)NCCCCNC(=O)OC(C)(C)C)c3ccccc3)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)NCCCCN)c3ccccc3)ccc21
Temperature: 25 °C

Procedure:
The product of 1f (4.81 mmol) was dissolved in a saturated solution of HCl in ethanol (250 mL), the mixture stirred at room temperature over night and then evaporated to dryness at 30° C. The remaining raw material was dissolved in 200 mL dry ethanol, then ammonium carbonate (48.1 mmol) was added and the mixture stirred at room temperature over night. After evaporation of the solvent the remaining raw material was triturated with ca. 5 mL ethanol, the undissolved material separated by filtration and the solvent evaporated at 30° C. The product was then dissolved in 30 mL water, the solution stirred with ca. 2 g charcoal, filtered and evaporated to dryness.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][S:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:17])=[O:16])[C:3]=1[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1.C(O)(=O)C[C:35](CC(O)=O)([C:37](O)=[O:38])[OH:36]>C(O)CO.O>[OH:36][CH2:35][CH2:37][O:38][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][S:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:17])=[O:16])[C:3]=1[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: Cc1ccc(-c2c(Cl)nc(-c3ccncc3)nc2NS(=O)(=O)CCc2ccccc2)cc1
Solvent: O
Solvent: OCCO
Product: Cc1ccc(-c2c(NS(=O)(=O)CCc3ccccc3)nc(-c3ccncc3)nc2OCCO)cc1
Temperature: 11 °C
Reaction time: 72 h

Procedure:
2-Phenyl-ethanesulfonic acid (6-chloro-2-pyridin-4-yl-5-p-tolyl-pyrimidin-4-yl)-amide (480 mg) was added to a solution of K-tert. butylate (580 mg) in ethylene glycol (5 ml). The mixture was stirred at 11° C. for 72 h before it was diluted with water (100 ml), acidified with 10% aq. citric acid (13 ml). The resulting precipitate was collected, washed with water and diethyl ether and dried to give 2-phenyl-ethanesulfonic acid [6-(2-hydroxy-ethoxy)-2-pyridin-4-yl-5-p-tolyl-pyrimidin-4-yl]-amide as a beige powder. LC-MS: tR=4.17 min, [M+1]+=491.24, [M−1]−=489.08.
Reaction SMILES: C([O:5][C:6](=[O:38])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:19]2[N:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:31]([N:18]([C:19]1[N:20]=[CH:21][C:22]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[CH:23][N:24]=1)[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:38])=[O:5])[S:12][CH:13]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(N2CCOCC2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 46.9 %

Procedure:
2-[(4-{2-[Heptyl(5-morpholin-4-ylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (710 mg) obtained in Example 442-2 was dissolved in dichloromethane (4 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (at this time point, the object product had been extracted in the ethyl acetate layer). The ethyl acetate layer was washed with aqueous 10% citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (300 mg) as a white solid.
Reaction SMILES: CN1C(N)=NC(=O)C1.[CH:9]1[C:14]([OH:15])=[CH:13][C:12]2[C:16]([CH2:19][CH2:20][NH2:21])=[CH:17][NH:18][C:11]=2[CH:10]=1.O.OS(O)(=O)=O.C(N1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43])(OCC)=O.C(=O)([O-])[O-].[K+].[K+]>O>[OH:15][C:14]1[CH:13]=[C:12]2[C:11](=[CH:10][CH:9]=1)[NH:18][CH:17]=[C:16]2[CH2:19][CH2:20][N:21]1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43]
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NCCc1c[nH]c2ccc(O)cc12
Agent: CN1CC(=O)N=C1N
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccc(O)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 954.3 %

Procedure:
To a suspension of serotonin creatinine sulfate monohydrate (5 g, 12.333 mmol) in water (80 mL) were added N-carbethoxyphthalimide (2.84 g, 1.30 mmol) and potassium carbonate (3.54 g, 24.6 mmol). The resulting mixture was stirred at room temperature for 4 hours. The precipitate was filtered, washed with water and dried to give the title compound (3.8 g, 100%) as a yellow solid. 1H NMR (CD3SOCD3, 300 MHz) δ: 10.52 (s, 1H), 8.64 (s, 1H), 7.87-7.83 (A2B2 system, 4H), 7.12 (d, J=8.6 Hz, 1H), 7.08 (broad s, 1H), 6.89 (broad s, 1H), 6.60 (broad d, J=8.6 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.Br[C:36]1[CH:37]=[CH:38][C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([C:36]3[CH:37]=[CH:38][C:39](=[O:43])[N:40]([CH3:42])[CH:41]=3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1
Reactant: Cn1cc(Br)ccc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Yield: 37.2 %

Procedure:
A mixture of (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (1.7 g, 3.7 mmol) and 5-bromo-1-methylpyridin-2(1H)-one (816 mg, 4.4 mmol), Pd(Ph3P)2Cl2 (200 mg), and aq Cs2CO3 solution (4 mL, 2M) in 1,4-dioxane (30 mL) was stirred and heated to reflux for 2 h. When the reaction was over, the mixture was washed with water and extracted with EtOAc, and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give crude product, which was purified by preparative TLC to give (R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (614 mg, 37%). LC-MS Method 2 tR=1.075 min, m/z=447.1; 1H NMR (CDCl3): δ=1.38 (m, 1H), 1.47 (d, 3H), 1.73 (m, 2H), 1.98 (m, 2H), 2.20 (m, 1H), 2.31 (m, 2H), 2.94 (m, 1H), 3.51 (m, 2H), 3.56 (s, 3H), 5.63 (m, 1H), 6.67 (m, 1H), 6.87 (m, 2H), 7.05 (m, 2H), 7.31-7.41 (m, 6H), 7.48 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1[Cl:12].CN(C(OC)[O:17]C)C>CN(C=O)C.CN(C=O)C.O>[Cl:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]([CH:11]=[O:17])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 140 °C
Reaction time: 14 h
Yield: 23 %

Procedure:
A mixture of 1,2-dichloro-4-methyl-5-nitrobenzene (2 g, 9.71 mmol) and DMF-DMA (3 g, 25.2 mmol) in DMF (50 mL) was stirred at 140° C. for 14 h. The dark solution was cooled to 0° C., and then added to a solution of NaIO4 (10.8 g, 50.5 mmol) in DMF/water (1:4, 25 mL) at 0° C. After stirring at room temperature for 8 h, the mixture was filtered and the cake was rinsed with ethyl acetate. The filtrate was diluted with ethyl acetate and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether=1:20) to afford the desire product (480 mg, 23% yield, 2 steps)
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[CH2:23]([O:25][C:26]1[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH:31]=1)[CH3:24].CN(C)C=O.[H-].[Na+]>O>[CH2:23]([O:25][C:26]1[CH:27]=[CH:28][C:29]([O:37][CH2:2][C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[CH:5][CH:4]=2)=[C:30]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH:31]=1)[CH3:24]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOc1ccc(O)c(CC(=O)OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c(CC(=O)OC)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.4 %

Procedure:
To a mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.72 g), methyl 2-(5-ethoxy-2-hydroxyphenyl)acetate (0.40 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60%, oil, 0.08 g) under ice-cooling and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration of the organic layer, the residue was subjected to silica gel column chromatography to give methyl 2-[5-ethoxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate as an oil (0.56 g, 60%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:19][O:20][C:21]1[N:26]=[CH:25][C:24]([CH2:27][N:28]2[CH:32]=[C:31]([C:33](OCC)=[O:34])[C:30]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[N:29]2)=[CH:23][CH:22]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:10][C:9]=1[CH2:19][O:20][C:21]1[N:26]=[CH:25][C:24]([CH2:27][N:28]2[CH:32]=[C:31]([CH2:33][OH:34])[C:30]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[N:29]2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)nc2)nc1-c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CO)c(-c3ccccc3)n2)cn1
Reaction time: 2 h
Yield: 89 %

Procedure:
Lithium aluminium hydride (300 mg) was added gradually to a solution of ethyl 1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-3-phenyl-1H-pyrazole-4-carboxylate (1.56 g) in tetrahydrofuran (70 ml) at 0° C., which was stirred for 2 hours. Sodium sulfate-decahydrate (3.40 g) was added to the reaction mixture, and the precipitate was filtered. The filtrate was concentrated, and residue was subjected to silica gel column chromatography to obtain 1-(6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-3-phenyl-1H-pyrazol-4-ylmethanol (1.27 g, yield 89%) as a colorless oily substance from the fraction eluted with acetone-hexane (2:3, volume ratio).
Reaction SMILES: N([O-])=O.[Na+].[Br:5][C:6]1[CH:7]=[CH:8][C:9](N)=[N:10][C:11]=1[F:12].S(=O)(=O)(O)[OH:15]>O>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([OH:15])=[N:10][C:11]=1[F:12]
Reactant: O=S(=O)(O)O
Reactant: Nc1ccc(Br)c(F)n1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(Br)c(F)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 925.6 %

Procedure:
A solution of sodium nitrite (21.67 g, 314.13 mmol) in water (150 mL) was added dropwise to a stirred mixture of 5-bromo-6-fluoropyridin-2-amine (50 g, 261.78 mmol) and sulphuric acid (1.2 mL, 22.51 mmol) in water (750 mL) at 0-5° C. The resulting suspension was stirred for 48 h at ambient temperature then the precipitate collected by filtration, washed with water (200 mL) and dried under vacuum to afford the desired material (40.0 g, 80%) as a pale yellow solid, which was used without further purification. NMR Spectrum: 1H NMR (300 MHz, DMSO-d6) δ 6.55 (1H, d), 8.00 (1H, t), 11.71 (1H, bs). Mass Spectrum: m/z (ES+)[M+H]+=192.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([N:7]1[CH2:11][C:10]2[CH2:12][N:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[CH2:14][C:9]=2[CH2:8]1)=[O:6].[CH:30]1([CH2:35][CH2:36][NH2:37])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:30]1([CH2:35][CH2:36][NH:37][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([N:13]3[CH2:14][C:9]4[CH2:8][N:7]([C:5](=[O:6])[C:4]5[CH:24]=[CH:25][CH:26]=[CH:27][C:3]=5[C:2]([F:29])([F:1])[F:28])[CH2:11][C:10]=4[CH2:12]3)=[N:16][CH:17]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=C(O)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Reactant: NCCC1CCCC1
Product: O=C(NCCC1CCCC1)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Yield: 34 %

Procedure:
6-[5-(2-Trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]nicotinic acid (50 mg, 0.124 mmol) was reacted with cyclopentylethylamine analogously to example 3d. Yield: 34%, M+H+: 499.28.
Reaction SMILES: [PH:1](=[O:4])([OH:3])[OH:2].[CH2:5]([C:7]([CH2:35][CH3:36])([CH:9](Br)[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:8])[CH3:6].[N-:37]=[N+:38]=[N-:39].[Na+].CN(C)C=O>C1OCCOCCOCCOCCOC1.O>[PH:1](=[O:2])([OH:4])[OH:3].[CH2:5]([C:7]([CH2:35][CH3:36])([CH:9]([N:37]=[N+:38]=[N-:39])[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:8])[CH3:6]
Reactant: [N-]=[N+]=[N-]
Reactant: CCC(C)(CC)C(Br)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C1COCCOCCOCCOCCO1
Agent: O=[PH](O)O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)(CC)C(N=[N+]=[N-])c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 100 °C
Yield: 65.3 %

Procedure:
A mixture of diethyl 3-bromo-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.05 g, prepared as described in Example 29), sodium azide (0.60 g), 15-Crown-5 (0.02 g), water (1.2 ml) and N,N-dimethylformamide (10 ml) was heated at 100° C. for five hours, cooled, poured into water, and extracted with ethyl acetate. The extracts were washed with water and brine, dried over magnesium sulphate, and evaporated under reduced pressure. The residue was chromatographed on silica, using dichloromethane-ethanol (49:1) as eluant, to give diethyl 3-azido-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.64 g, m.p. 82-84° C.). NMR (CDCl3): δ 1.3(6H,dt), 1.6-2.0(2H,m), 2.2-2.3(2H,m), 4.1(4H,m), 4.65(1H,t), 7.1(6H,m), 7.3(9H,m), 8.0(1H,s). M/S: MH+ 531.