Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:28][C:29]1[C:34]([F:35])=[C:33]([F:36])[CH:32]=[CH:31][C:30]=1[S:37](Cl)(=[O:39])=[O:38]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:11][N:10]=[CH:9][N:8]=1)[S:37]([C:30]1[CH:31]=[CH:32][C:33]([F:36])=[C:34]([F:35])[C:29]=1[F:28])(=[O:39])=[O:38]
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1F
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(F)c2F)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution of N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (3.0 g, 12 mmol) in tetrahydrofuran (50 mL) at −78° C. was added lithium bis(trimethylsilyl)amide (1 M solution in tetrahydrofuran, 15.5 mL, 15.5 mmol). The reaction mixture was allowed to warm to ambient temperature. After 1 h, the reaction mixture was cooled to −78° C. and 2,3,4-trifluorobenzene-1-sulfonyl chloride (1.8 mL, 12 mmol) was added. After 2 further lithium bis(trimethylsilyl)amide (1 M solution in tetrahydrofuran, 2.4 mL, 2.4 mmol) and 2,3,4-trifluorobenzene-1-sulfonyl chloride (0.3 mL, 2.4 mmol) were added. After 1 h, the reaction mixture was allowed to warm to ambient temperature, diluted with ethyl acetate (150 mL), washed with saturated ammonium chloride (2×125 mL) and brine (2×125 mL), dried over sodium sulfate and concentrated in vacuo. The residue was triturated with methanol to afford N-(2,4-dimethoxybenzyl)-2,3,4-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as a pale yellow solid in 67% yield (3.5 g).
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[C:10](Cl)(Cl)=[S:11].[CH:14]([Cl:17])(Cl)Cl>>[Cl:17][C:14]1[CH:7]=[CH:8][C:2]([C:3]2[C:4]([F:9])=[C:5]([N:6]=[C:10]=[S:11])[CH:7]=[CH:8][CH:2]=2)=[CH:3][CH:4]=1
Reactant: ClC(Cl)Cl
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(Cl)cc1F
Product: Fc1c(N=C=S)cccc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 75 parts of chloroform and 100 parts of ice and 15 parts of 4-chloro-2-fluoroaniline, 14.2 parts of thiophosgene were added dropwise over 15 min. After allowing the warm to room temperature and stirring overnight, the phases were separated. The aqueous phase was extracted with 50 parts of chloroform. The organic phases were combined, dried with anhydrous sodium sulfate and evaporated at 300 mm.Hg and 25° to yield 21.3 parts of 4-chlorophenyl-2-fluorophenyl isothiocyanate as a yellow oil with a nD25 of 1.6343.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=1)=O.O=[C:19]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21]>CC(O)C.O.O.[Na+].Cl[Au-](Cl)(Cl)Cl>[F:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:19]([CH:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:28])[CH3:26])[CH3:21])[C:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)=[C:9]2[C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Cc1ccccn1
Reactant: Cc1cccnc1C(=O)c1cc(F)ccc1N
Agent: Cl[Au-](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cc1cccnc1-c1c(-c2ccccn2)c(C(C)NC(=O)OC(C)(C)C)nc2ccc(F)cc12
Reaction time: 48 h

Procedure:
A solution of (2-amino-5-fluorophenyl)(3-methylpyridin-2-yl)methanone (0.29 g, 1.26 mmol), (S)-tert-butyl 3-oxo-4-(pyridin-2-yl)butan-2-ylcarbamate (0.366 g, 1.386 mmol), and sodium tetrachloroaurate(iii) dihydrate (0.025 g, 0.063 mmol) in 2-propanol (5.0 mL) was stirred at 80° C. for 24 h under an argon atmosphere, then at room temperature for an additional 48 h. The solution was purified by silica gel column chromatography eluting with a gradient of 10-40% EtOAc in hexane to afford tert-butyl 1-(6-fluoro-4-(3-methylpyridin-2-yl)-3-(pyridin-2-yl)quinolin-2-yl)ethylcarbamate as a dark solid: LC-MS (ESI) m/z 459.2 [M+H]+.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[C:2]#[CH:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23](I)[CH:22]=1)=[O:19].C(N(CC)CC)C>CN(C=O)C.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.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[NH:17][C:18]([NH:20][C:21]1[CH:22]=[C:23]([C:3]#[C:2][C:1]([NH2:5])=[O:4])[CH:24]=[CH:25][CH:26]=1)=[O:19]
Reactant: O=C(Nc1cccc(I)c1)Nc1cc(C(F)(F)F)ccc1F
Reactant: C#CC(N)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)C#Cc1cccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.5 %

Procedure:
To a mixture of propynoic acid amide (41.4 mg, 0.60 mmol), 1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-(3-iodophenyl)urea (169.7 mg, 0.40 mmol), triethylamine (0.167 mL, 1.2 mmol), dichlorobis(triphenylphosphine)palladium(II) (22.5 mg, 0.032 mmol), and triphenylphosphine (5.2 mg, 0.020 mmol) in 3.0 mL DMF (degassed) was added copper(I)iodide (7.6 mg, 0.04 mmol) and the reaction stirred at rt for 15 hours. The reaction was partitioned between EtOAc and H2O/brine mixture. The EtOAc layer was washed 3 times with H2O/brine mixture, then brine, dried with anhydrous Na2SO4 and rotary evaporated to a solid. The solid was triturated with hot MeOH and then triturated with hot EtOAc to give the title compound as a light tan solid (107.4 mg, 74%). 1H NMR (DSMO-d6) δ: 9.33 (s, 1H), 8.95 (d, J=2.1 Hz, 1H), 8.60 (dd, J=7.3, 2.1 Hz, 1H), 8.17 (br. s., 1H), 7.87 (s, 1H), 7.67 (br. s., 1H), 7.37-7.55 (m, 4H), 7.17-7.25 (m, 1H)
Reaction SMILES: O.[OH-].[Li+].[CH3:4][N:5]([CH3:26])[S:6]([N:9]1[CH:13]=[C:12]([CH2:14][C:15]([CH3:19])([CH3:18])[CH2:16][CH3:17])[N:11]=[C:10]1[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])(=[O:8])=[O:7]>O.CO.C1COCC1>[CH3:26][N:5]([CH3:4])[S:6]([N:9]1[CH:13]=[C:12]([CH2:14][C:15]([CH3:19])([CH3:18])[CH2:16][CH3:17])[N:11]=[C:10]1[CH2:20][CH2:21][C:22]([OH:24])=[O:23])(=[O:7])=[O:8]
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(CCC(=O)OC)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(CCC(=O)O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of lithium hydroxide monohydrate (182 mg, 4.3 mmol) in water (1.5 mL) was added to a solution of methyl 3-[1-[(dimethylamino)sulfonyl]-4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]propanoate (for synthesis see intermediate 25) (500 mg, 1.4 mmol) in methanol (1.6 mL) and THF (1.6 mL). After stirring at rt overnight, the reaction mixture was concentrated and 2M hydrochloric acid was added. The resulting reaction mixture was concentrated to dryness to afford the title compound, which was used without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[C:12]([CH2:14][OH:15])[N:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1)=[CH2:2].[CH2:16]([Zn]CC)C.ICI>C1(C)C=CC=CC=1.CCCCCC>[CH:1]1([C:3]2[CH:4]=[C:5]([N:9]3[CH:13]=[C:12]([CH2:14][OH:15])[N:11]=[CH:10]3)[CH:6]=[CH:7][CH:8]=2)[CH2:16][CH2:2]1
Reactant: CC[Zn]CC
Reactant: C=Cc1cccc(-n2cnc(CO)c2)c1
Solvent: CCCCCC
Solvent: ICI
Solvent: Cc1ccccc1
Product: OCc1cn(-c2cccc(C3CC3)c2)cn1
Temperature: 20 °C
Reaction time: 12 h
Yield: 93 %

Procedure:
Under an Ar atmosphere, a mixture of [1-(3-vinyl-phenyl)-1H-imidazol-4-yl]-methanol (0.10 g, 0.5 mmol) in toluene (20 ml) was successively treated with diethylzinc (3.8 ml of a 1.1 M solution in hexane, 4.2 mmol) and diiodomethane (6.6 g, 25 mmol). The resulting mixture was stirred at 20° C. for 12 h. The preciptate was filtered and stirred for 30 min with AcOEt and saturated aqueous NH4Cl solution. The organic phase was separated, dried (Na2SO4) and concentrated to yield the title compound as a yellow oil (0.10 g, 93%). MS: m/e=215 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:7]([NH:8][C:9](=[O:12])[CH2:10]Br)=[C:6]([Br:13])[CH:5]=[C:4]([CH3:14])[N:3]=1.[OH:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[C:7]([NH:8][C:9](=[O:12])[CH2:10][N:21]2[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][OH:15])[CH2:19][CH2:20]2)=[C:6]([Br:13])[CH:5]=[C:4]([CH3:14])[N:3]=1
Reactant: Cc1cc(Br)c(NC(=O)CBr)c(Br)n1
Reactant: OCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(Br)c(NC(=O)CN2CCN(CCO)CC2)c(Br)n1
Yield: 82.6 %

Procedure:
N-[2,4-Dibromo-6-methylpyridin-3-yl]-2-bromoacetamide (1.4 g, 37.3 mmol) was dissolved in acetonitrile (60 mL). 1-(2-Hydroxyethyl)piperazine (0.58 g, 4.48 mmol) was added to the solution with stirring and cooling with ice, and then potassium carbonate (37.5 g, 0.271 mol) was added thereto. The temperature of the mixture was elevated to room temperature, and the mixture was stirred for 24 hours. After completion of reaction, the solvent was removed under reduced pressure. Chloroform and water was added to the residue, and the organic layer was collected from the mixture. The aqueous layer was further extracted with chloroform and the two organic layers were combined together. The combined organic layer was washed with saturated brine, dried over sodium sulfate anhydrate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (developer: ammonia-saturated methanol/chloroform=1/20), to thereby obtain 1.613 g of N-[2,4-dibromo-6-methylpyridin-3-yl]-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide as an amorphous (yield: 99%).
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9].N1C=CC=CC=1.O>CC(OC)(C)C>[CH3:6][O:5][C:3](=[O:4])[C:2]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7]
Reactant: CC(C)(C)O
Reactant: COC(=O)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: COC(C)(C)C
Product: COC(=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of methyl chlorooxoacetate in TBME (1 mmol/ml) was added at 0-5° C. tert-butanol (1.5 equiv.), followed by dropwise addition of pyridine (1.5 equiv.). The resulting mixture was stirred at room temperature for 20 h. Water (15 vol.) was added, the mixture was extracted with TBME twice. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum to give a colorless oil.
Reaction SMILES: C(Cl)(Cl)[Cl:2].[S:5]1[C:9]2[CH:10]=[CH:11][C:12]([NH:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[C:19]([CH2:29]Cl)[CH:18]=3)=[O:16])=[CH:13][C:8]=2[N:7]=[CH:6]1.[NH:31]1[CH2:36][CH2:35][CH:34]([C:37]([NH2:39])=[O:38])[CH2:33][CH2:32]1.Cl>C(OCC)(=O)C.C(O)C>[ClH:2].[S:5]1[C:9]2[CH:10]=[CH:11][C:12]([NH:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[C:19]([CH2:29][N:31]4[CH2:36][CH2:35][CH:34]([C:37]([NH2:39])=[O:38])[CH2:33][CH2:32]4)[CH:18]=3)=[O:16])=[CH:13][C:8]=2[N:7]=[CH:6]1
Reactant: O=C(Nc1ccc2scnc2c1)c1ccc(-c2ccccc2)c(CCl)c1
Reactant: ClC(Cl)Cl
Reactant: NC(=O)C1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: NC(=O)C1CCN(Cc2cc(C(=O)Nc3ccc4scnc4c3)ccc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 10 ml of chloroform were added 250 mg of N-1,3-benzothiazol-5-yl-2-(chloromethyl)biphenyl-4-carboxamide and 169 mg of piperidine-4-carboxamide, followed by 3 days of stirring at room temperature. The reaction solvent was removed by evaporation under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform:methanol) to obtain a yellow foamy substance. Thereto were added 2 ml of ethanol and 1 ml of a 4M ethyl acetate solution of hydrochloric acid, followed by removal of the solvent under reduced pressure. The residue was crystallized (ethanol:water:ethyl acetate) to obtain 205 mg of 1-({4-[(1,3-benzothiazol-5-ylamino)carbonyl]biphenyl-2-yl}methyl)piperidine-4-carboxamide hydrochloride.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][CH:15]=3)[CH2:10][CH2:9]2)C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH2:6][CH2:7][N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:12][CH2:13]1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCC(c2c[nH]c3ccccc23)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCN1CCC(c2c[nH]c3ccccc23)CC1
Yield: 91.1 %

Procedure:
A mixture of 1-(2-phthalimidoethyl)-4-(3-indolyl)piperidine (6.3 g) and hydrazine monohydrate (2.2 g) in ethanol (250 ml) was refluxed for 70 minutes. After cooling, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was treated with 5% sodium hydroxide solution (300 ml) and extracted with ethyl acetate (300 ml). The organic layer was washed with a saturated sodium chloride solution and dried over magnesium sulfate. The evaporation of solvent gave 1-(2-aminoethyl)-4-(3-indolyl)piperidine (3.74 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:14]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]=2)(=[O:17])=[O:16])=[CH:13][C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=1.[C:31](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.[Cl:47]CCCl>ClCCl>[ClH:47].[CH3:2][O:3][C:4]1[C:14]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]=2)(=[O:17])=[O:16])=[CH:13][C:7]2[CH2:8][CH2:9][N:10]([CH3:31])[CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: ClCCCl
Reactant: COc1cc2c(cc1S(=O)(=O)c1cccc(Oc3ccccc3)c1)CCNCC2
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2c(cc1S(=O)(=O)c1cccc(Oc3ccccc3)c1)CCN(C)CC2
Reaction time: 18 h

Procedure:
A mixture of E1 hydrochloride salt (0.2 g, 0.5 mmol), sodium triacetoxyborohydride (400 MG), aqueous formaldehyde (0.5 mL, 37%), and 1,2-dichloroethane (10 mL containing 0.5 mL triethylamine) was stirred for 18 h then diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium hydrogen carbonate (100 mL), dried (MgSO4), and evaporated to give the title compound E2 isolated as the hydrochloride salt from ether (0.3 g). MH+ 423. 1H NMR δ (CDCl3) 2.39 (3H, s), 2.60 (4H, m), 2.97 (4H, m), 3.70 (3H, s), 6.65 (1H, s), 6.99 (2H, d), 7.20 (2H, m), 7.38 (3H, m), 7.63 (2H, m), 7.81 (1H, s).
Reaction SMILES: N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.[CH3:28][C:29]1[CH:33]=[CH:32][O:31][C:30]=1[C:34]([OH:36])=O.C(N(C(C)C)CC)(C)C.[CH3:46][O:47][C:48]1[CH:49]=[C:50]([NH:58][C:59]2[N:60]=[CH:61][C:62]3[CH2:68][NH:67][CH2:66][CH2:65][C:63]=3[N:64]=2)[CH:51]=[C:52]([O:56][CH3:57])[C:53]=1[O:54][CH3:55]>CN(C=O)C.CCOC(C)=O>[CH3:28][C:29]1[CH:33]=[CH:32][O:31][C:30]=1[C:34]([N:67]1[CH2:66][CH2:65][C:63]2[N:64]=[C:59]([NH:58][C:50]3[CH:49]=[C:48]([O:47][CH3:46])[C:53]([O:54][CH3:55])=[C:52]([O:56][CH3:57])[CH:51]=3)[N:60]=[CH:61][C:62]=2[CH2:68]1)=[O:36]
Reactant: COc1cc(Nc2ncc3c(n2)CCNC3)cc(OC)c1OC
Reactant: Cc1ccoc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc3c(n2)CCN(C(=O)c2occc2C)C3)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.3 %

Procedure:
A solution of (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium-hexafluorophosphate (0.035 g, 0.079 mmol) in anhydrous DMF (2 mL) was treated sequentially with 3-methylfuran-2-carboxylic acid (0.013 g, 0.103 mmol) and diisopropylethylamine (0.035 mL, 0.159 mmol). The reaction mixture was allowed to stir for 30 minutes at room temperature. After 30 minutes, N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, Intermediate 1 (0.025 g, 0.079 mmol) was added to the reaction mixture. The reaction was allowed to stir for 3 hours at room temperature. The reaction mixture was then diluted with EtOAc and washed three times with brine. The combined aqueous layers were then washed twice with EtOAc. The organic layers were combined, dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The crude product was then purified over silica using a MeOH/CHCl3 gradient affording the final product in 47.3% yield (0.014 g, 0.037 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31](F)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.CS(CCN)(=O)=[O:37].[CH3:42][CH2:43][N:44](C(C)C)C(C)C>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:33]=[CH:32][C:31]([NH:44][CH2:43][CH2:42][OH:37])=[N:30][CH:29]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CS(=O)(=O)CCN
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(F)nc4)ccc2OCC3)c(F)c1
Solvent: CN1CCCC1=O
Product: OCCNc1ccc(-c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)cn1
Temperature: 150 °C
Yield: 14 %

Procedure:
2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (470 mg, 1.0 mmol), from the procedure for 249, 2-Methanesulfonyl-ethylamine (147 mg, 1.2 mmol), DIPEA (340 mg, 3 mmol) and NMP (4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 150° C. for 120 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give (68.9 mg, yield: 14%). 1HNMR (DMSO-d6, 400 MHz): δ8.63 (s, 1H), 8.30 (s, 1H), 7.90-7.85 (m, 2H), 7.70-7.70 (m, 2H), 7.41-7.38 (m, 2H), 7.19 (s, 2H), 6.90-6.88 (m, 1H), 6.63 (d, J=8.8 Hz, 1H), 4.75 (s, 1H), 4.29 (s, 2H), 3.56-3.55 (m, 2H), 3.40-3.38 (m, 2H), 3.15 (s, 2H). ESI-MS: m/z=519 [M+H+]
Reaction SMILES: CS[C:3]1[C:4]2[NH:11][N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[NH2:16].Cl.N1C=CC=CC=1>CN1CCCC1=O.C(OCC)(=O)C>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:3]2[C:4]3[NH:11][N:10]=[CH:9][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: CSc1ncnc2cn[nH]c12
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Fc1cccc(COc2ccc(Nc3ncnc4cn[nH]c34)cc2Cl)c1
Temperature: 120 °C
Reaction time: 10 h
Yield: 66 %

Procedure:
A mixture of 7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (known compound from literature: J. Am. Chem. Soc., 1956, 78, 2418) (150 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (227 mg) and pyridine hydrochloride (156 mg) in 1-methyl-2-pyrrolidone (3 mL) was stirred at 120° C. for 10 hrs. After the completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane/ethyl acetate=1/3→1/10) to give the title compound (220 mg, yield 61%) as a pale-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:12]([O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH2:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c(OCc2ccccc2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 2-amino-3-nitro-phenol (1.54 g, 0.01 mol), benzyl bromide (1.71 g, 0.01 mol) and K2CO3 (1.54 g, 0.011 mol) in DMF (5.0 mL) was stirred at room temperature. After 20 h, reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL×3). Combined organic layers were washed with 2N NaOH (20 mL×3), water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate and concentrated to afford 2-Benzyloxy-6-nitro-phenylamine, I-107 (2.01 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17](O)=[O:18].[CH:20]([NH:23][NH:24][C:25]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)=[O:26])([CH3:22])[CH3:21].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([N:23]([CH:20]([CH3:22])[CH3:21])[NH:24][C:25]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)=[O:26])=[O:18]
Reactant: CC(C)NNC(=O)c1cccs1
Reactant: Cc1cccc(-c2ccccc2CCC(=O)O)c1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2ccccc2CCC(=O)N(NC(=O)c2cccs2)C(C)C)c1C
Yield: 50.8 %

Procedure:
A solution of 3-(2′,3′-dimethyl-biphenyl-2-yl)-propionic acid (207 mg, 0.81 mmoles) and thiophene-2-carboxylic acid N′-isopropyl-hydrazide (150 mg, 0.81 mmoles) in DMF (8 mL) was treated with triethylamine (0.34 mL, 2.44 mmoles), HOBT (132 mg, 0.98 mmoles) and EDCI (156 mg, 0.98 mmoles) at room temperature for 48 h. The reaction mixture was partitioned between 1N HCl and dichloromethane. The organic layer was washed successively with 1N NaOH and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product (173 mg, 51%). LC-MS m/e 421.46 (M+H+)
Reaction SMILES: [OH:1][CH:2]([CH:4]1[CH:7]([C:8]#[C:9][Si](C)(C)C)[NH:6][C:5]1=[O:14])[CH3:3].[F-].[Cs+]>O1CCCC1.CO.O>[OH:1][C@@H:2]([C@H:4]1[C@@H:7]([C:8]#[CH:9])[NH:6][C:5]1=[O:14])[CH3:3]
Reactant: CC(O)C1C(=O)NC1C#C[Si](C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C#C[C@H]1NC(=O)[C@H]1[C@@H](C)O
Temperature: 60 °C
Yield: 27.3 %

Procedure:
A cis/trans mixture (1.0 g) of 3-(1-hydroxyethyl)-4-trimethylsilylethynyl-2-azetidinone is dissolved in a mixture of tetrahydrofuran (10 ml) and methanol (5 ml), and a solution of cesium fluoride (0.2 g) in water (2 ml) is added to the solution. The mixture is stirred at 60° C. for an hour and concentrated under reduced pressure and the residue is extracted with ethyl acetate (20 ml) and tetrahydrofuran (20 ml). The extract is dried over magnesium sulfate, concentrated under reduced pressure and crystallized from ethyl acetate to give 0.18 g of cis-3-[(R)-1-hydroxyethyl]-4-ethynyl-2-azetidinone.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]([CH3:10])[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[P:11](Cl)(Cl)(=[O:23])[O:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]=1[O:12][P:11](=[N:2][C@@H:3]([CH3:10])[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5])=[O:23]
Reactant: CC(C)OC(=O)[C@H](C)N
Reactant: Cl
Reactant: O=P(Cl)(Cl)Oc1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)[C@H](C)N=[P+]([O-])Oc1c(Cl)ccc2ccccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
(S)-isopropyl 2-aminopropanoate hydrochloride (Oakwood, 1.28 g, 7.64 mmol) and naphthalen-1-yl phosphorodichloridate (2 g, 7.66 mmol) was suspended in anhydrous DCM (35 mL). The reaction was cooled to −78° C. Triethylamine (1.55 g, 2.13 mL, 15.3 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 1 h, then warmed up to room temperature and stirred for 5 h. The solvent was removed, and the residue was washed with dry ethyl ether and filtered. The filtrate was concentrated to give crude (2S)-isopropyl 2-(chloro(naphthalen-1-yloxy)phosphorylamino)propanoate as a light yellow oil (2.5 g, 92%) and used without further purification.