Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:36])[CH2:28][S:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:36])[CH2:28][S:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:13]=2)[N:6]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: [N-]=[N+]=NCCNC(=O)CSc1ccccc1
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2cn(CCNC(=O)CSc3ccccc3)nn2)nc1N

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.112 g, 0.405 mmol) was reacted with N-(2-azidoethyl)-2-(phenylthio)acetamide (0.096 g, 0.405 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(2-(phenylthio)acetamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.45 (s, 1H0, δ 7.19 (m, 5H), δ 7.13 (s, 1H), δ 6.43 (s, 1H), δ 6.13 (bs, 2H0, δ 4.29 (s, 2H), δ 3.68 (s, 2H), δ 3.57 (s, 2H), δ 2.56 (s, 2H), δ 2.35 (s, 2H), δ 1.52 (m, 15H) ppm; 13C NMR (75 MHz, CDCl3) δ 187.8, 172.0, 169.1, 162.4, 156.9, 135.0, 129.5, 128.3, 126.8, 121.8, 85.00, 49.4, 39.9, 37.4, 29.4, 28.9, 28.4, 28.2, 27.6, 25.6 ppm; HRMS (ESI) calcd for C25H35N7O3S (M+) 513.2522. found 513.2522, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-2-(phenylthio)acetamide hydrochloride (0.133 g, 73% yield). 1H NMR (300 MHz, CD3OD) δ 8.47 (s, 1H), δ 7.30 s, 4H), δ 7.19 (s, 1H), δ 6.58 (s, 1H), δ 4.66 (s, 2H), δ 3.76 (s, 2H), δ 3.64 (s, 2H), δ 2.84 (s, 2H), δ 2.34 (s, 2H), δ 1.73 (s, 2H), δ 1.64 (s, 2H), δ 1.26 (s, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 170.9, 159.3, 158.9, 147.2, 135.6, 128.1, 128.9, 127.6, 126.6, 108.7, 108.6, 52.-, 39.1, 37.5, 37.2, 36.6, 36.1, 30.8, 28.1, 27.9, 27.7, 24.2, 23.7, 23.6 ppm; HRMS (ESI) calcd for C20H27N7OS (M+) 413.1998. found 413.1991.
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16].[Br:21][C:22]1[C:27]([C:28]([OH:30])=[O:29])=[C:26](F)[C:25]([F:32])=[C:24]([F:33])[CH:23]=1>C1COCC1>[Br:21][C:22]1[C:27]([C:28]([OH:30])=[O:29])=[C:26]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[Cl:13])[C:25]([F:32])=[C:24]([F:33])[CH:23]=1
Reactant: Nc1ccccc1Cl
Reactant: O=C(O)c1c(Br)cc(F)c(F)c1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1c(Br)cc(F)c(F)c1Nc1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
To a solution of i-Pr2NH (5.83 mL, 41.2 mmol) in THF (16 mL) at 0° C. was added n-BuLi (16.4 mL, 41.1 mmol, 2.5 M solution in hexanes). After stirring for 15 minutes, the reaction mixture was cooled to −78° C. 2-Chloroaniline (2.89 mL, 27.5 mmol) was added. After vigorous stirring for 10 minutes, a solution of 6-bromo-2,3,4-trifluorobenzoic acid (3.51 g, 13.8 mmol) in THF (4 mL) was added. The reaction mixture was warmed to room temperature and stirred for 2 hours at room temperature. The reaction mixture was concentrated, treated with 10% aqueous HCl (15 mL) until the aqueous phase was acidic, and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that was triturated three times with boiling CH2Cl2 to afford the desired product (3.18 g, 64%).
Reaction SMILES: [S:1]1(=[O:8])(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][NH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:19][C:20]1[CH:47]=[CH:46][C:23]([CH2:24][N:25]2[C:30](=[O:31])[C:29]3[C:32]([O:41][CH3:42])=[C:33]4[C:38](=[O:39])[N:37]([CH3:40])[CH2:36][CH2:35][N:34]4[C:28]=3[C:27]([CH:43](Cl)[CH3:44])=[N:26]2)=[CH:22][CH:21]=1>CN(C=O)C.C1COCC1>[F:19][C:20]1[CH:47]=[CH:46][C:23]([CH2:24][N:25]2[C:30](=[O:31])[C:29]3[C:32]([O:41][CH3:42])=[C:33]4[C:38](=[O:39])[N:37]([CH3:40])[CH2:36][CH2:35][N:34]4[C:28]=3[C:27]([CH:43]([N:2]3[CH2:3][CH2:4][CH2:5][CH2:6][S:1]3(=[O:8])=[O:7])[CH3:44])=[N:26]2)=[CH:22][CH:21]=1
Reactant: COc1c2n(c3c(C(C)Cl)nn(Cc4ccc(F)cc4)c(=O)c13)CCN(C)C2=O
Reactant: O=S1(=O)CCCCN1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1c2n(c3c(C(C)N4CCCCS4(=O)=O)nn(Cc4ccc(F)cc4)c(=O)c13)CCN(C)C2=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a cold (0° C.) solution of 1,2-thiazinane 1,1-dioxide (32 mg, 0.24 mmol) in anhydrous DMF (2 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (0.18 mL, 1M) was added. After stirred at room temperature for 20 minutes, solid 2-(4-fluorobenzyl)-10-methoxy-4-(1-chloroethyl)-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (50 mg. 0.12 mmol) was added and the reaction mixture was stirred at room temperature overnight. The product mixture was concentrated under vacuum. The residue was partitioned between dichloromethane and dilute hydrochloric acid. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to afford the title compound. ES MS M+1=518
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH2:14][NH:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[O:17])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].C(O)(=O)C.CO>[C:26]1([C:11]2([CH2:14][NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[O:17])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1ccccc1C(=O)NCC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccccc1C(=O)NCC1(c2ccccc2)CCNCC1

Procedure:
A mixture of 1.3 g (3.1 mmol) of 1-N-Benzyl-4-phenyl-4-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)piperidine (Example 1), 100 mg of Pearlman's catalyst (palladium hydroxide on carbon, purchased from Aldrich Chemical Co., Milwaukee, Wis.) and 3 drops of acetic acid in 20 mL of methanol was stirred in a hydrogen atmosphere (50 psi) for 18 hr. The reaction mixture was filtered and the filtrate was concentrated to afford the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:23]([C:27]([NH:29][CH2:30][C:31]4([OH:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:28])=[C:22]([Cl:39])[CH:21]=[CH:20][C:19]=3[N:18]=2)[CH2:13]1)(C(C)(C)C)(C)C.Cl>O1CCCC1>[Cl:39][C:22]1[CH:21]=[CH:20][C:19]2[N:18]=[C:17]([N:14]3[CH2:15][CH2:16][C@H:12]([NH:11][CH2:10][CH2:9][OH:8])[CH2:13]3)[CH:26]=[CH:25][C:24]=2[C:23]=1[C:27]([NH:29][CH2:30][C:31]1([OH:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:28]
Reactant: CC(C)(C)[Si](C)(C)OCCN[C@H]1CCN(c2ccc3c(C(=O)NCC4(O)CCCCCC4)c(Cl)ccc3n2)C1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(NCC1(O)CCCCCC1)c1c(Cl)ccc2nc(N3CC[C@H](NCCO)C3)ccc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.8 %

Procedure:
To a solution of 2-{(3S)-3-[(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)amino]pyrrolidin-1-yl}-6-chloro-N-[(1-hydroxycycloheptyl)methyl]quinoline-5-carboxamide (26.0 g) in tetrahydrofuran (125 ml) was added hydrogen chloride (50 ml, 4M in dioxane) dropwise over ten minutes with ice bath cooling to maintain the internal temperature below 30° C. The mixture was stirred at room temperature for 2.5 hours before being concentrated in vacuo. The crude product was redissolved in MeOH (30 ml) and purified by chromatography (SiO2, 1:4:95-1:10:89 7M N3 in methanol:methanol:dichloromethane as gradient elution). The pure fractions were concentrated in vacuo (20.1 g) and then slurried in acetonitrile:methanol (99:1, 400 ml total volume) for 18 hours before being filtered and washed with acetonitrile (30 ml). The solid was dried in vacuo to afford the title compound as a colourless solid (18.5 g).
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[CH:19]=[C:18]([Cl:20])[C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[NH:25][C:26](=O)[CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[CH:9][CH:8]=1)(=O)C.[OH-].[Na+]>C(O)C>[Cl:20][C:18]1[C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]2[N:25]=[C:26]([CH2:27][CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=3)[N:13]([C:10]3[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][OH:4])=[CH:8][CH:9]=3)[C:14]=2[CH:19]=1
Reactant: CC(=O)OCCc1ccc(Nc2cc(Cl)c(C(F)(F)F)cc2NC(=O)CCCc2ccncc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCCc1ccc(-n2c(CCCc3ccncc3)nc3cc(C(F)(F)F)c(Cl)cc32)cc1
Temperature: 40 °C
Reaction time: 7 h
Yield: 54.4 %

Procedure:
A mixture of 2-(4-{[5-chloro-2-{[4-(4-pyridinyl)butanoyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate (step 3, 220 mg, 0.42 mmol) and 2N NaOH (15 ml) in ethanol (20 ml) was stirred at 40° C. for 7 h. The solvent was removed and the residue was added water (50 ml). The mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with brine (50 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with dichloromethane:methanol (20:1) to afford 105 mg (54%) of the title compound as pale brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:12][C:23](=[O:24])[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cccc(OCc2ccccc2)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3-benzyloxyaniline (0.999 g, 5.01 mmol) in DCM (10 mL) was added pyridine (1.22 ml, 15.03 mmol) and phenyl chloroformate (0.68 ml, 5.51 mmol) dropwise (Exotherm!). The reaction was then allowed to stir at room temperature for 2 hours. The reaction mixture was then partitioned between DCM and 1M HCl, extracted twice, combined organics passed through phase separating cartridge and filtrate evaporated to dryness to give an orange solid. This was then triturated in 10% ethyl acetate/hexanes, filtered and dried to give the product, phenyl [3-(benzyloxy)phenyl]carbamate, as beige solid (1.209 g, 3.78 mmol, 75% yield).
Reaction SMILES: N[C@@H:2]([CH3:6])[C:3]([OH:5])=[O:4].N([O-])=O.[Na+]>C(O)(=O)C>[C:3]([O:5][C@H:2]([CH3:6])[C:3]([OH:5])=[O:4])(=[O:4])[CH3:2]
Reactant: C[C@H](N)C(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)O[C@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.8 %

Procedure:
To a solution of (S)-2-aminopropanoic acid (60 g, 0.67 mol) in acetic acid (400 ml) was added NaNO2 (93 g, 1.34 mol) several portions at 0° C. After addition, the mixture was stirred at room temperature for 4 hours. After removed the acetic acid, water added and then extracted with ether. The organic phase was collected, dried, concentrated to afford (R)-2-acetoxypropanoic acid (30 g, 35%). 1H NMR (400 MHz, CDCl3) δ ppm, 11.70 (s, 2H), 5.02-5.07 (q, 1H), 2.07 (s, 3H), 1.46-1.52 (d, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([F:16])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[F:18][C:19]([F:38])([F:37])[O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[C:28][CH2:29][CH2:30][CH2:31]OS(C)(=O)=O)=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:31][CH2:30][CH2:29][C:28]#[C:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][C:19]([F:18])([F:37])[F:38])=[CH:22][CH:23]=2)=[C:11]([F:16])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)c(F)c1
Reactant: CS(=O)(=O)OCCCC#Cc1ccc(OC(F)(F)F)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCCC#Cc2ccc(OC(F)(F)F)cc2)c(F)c1

Procedure:
In analogy to the procedure described in example 20A], 2-(3-fluoro-4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester (example 32E]) and methanesulfonic acid 5-(4-trifluoromethoxy-phenyl)-pent-4-ynyl ester (example 1G]) yielded the title compound as brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][N:30]=1.[N:35]1C=CC=CC=1>C(Cl)Cl.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:35][C:31]2[N:32]=[CH:33][CH:34]=[CH:29][N:30]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: c1ccncc1
Reactant: Nc1ccncn1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ncccn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 143, 50 mg, 0.15 mmol) in methylene chloride (1.5 mL) was treated with N,N-dimethylformrnamide (1 drop) and then cooled to 0° C. The reaction mixture was then treated dropwise with a 2M solution of oxalyl chloride in methylene chloride (0.11 mL, 0.23 mmol) and stirred at 0° C. for 30 min. The reaction mixture was then treated with a solution of 4-aminopyrimidine (29 mg, 0.30 mmol) and pyridine (0.06 mL, 0.76 mmol) in tetrahydrofuran (2.5 mL). The resulting reaction mixture was allowed to warm to 25° C. where it was stirred for 16 h. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 20/80 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrimidin-2-yl-propionamide (47 mg, 76%) as a white foam: EI-HRMS m/e calcd for C19H22ClN3O3S (M+) 407.1070, found 407.1080.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:23])[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=3[CH3:22])[C:6]=2[CH:5]=[C:4]([NH2:24])[CH:3]=1.Br[CH2:26][CH2:27][O:28][CH2:29][CH2:30]Br.CCN(C(C)C)C(C)C>C(O)CO.O>[Br:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:23])[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:21])[F:20])[C:13]=3[CH3:22])[C:6]=2[CH:5]=[C:4]([N:24]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:3]=1
Reactant: Cc1c(Cn2c(C)nc3c(Br)cc(N)cc32)cccc1C(F)(F)F
Reactant: BrCCOCCBr
Solvent: OCCO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cn2c(C)nc3c(Br)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Temperature: 100 °C
Reaction time: 20 h
Yield: 79.4 %

Procedure:
A mixture of 7-bromo-2-methyl-3-(2-methyl-3-(trifluoromethyl)benzyl)-3H-benzo[d]imidazol-5-amine (45 g, 113 mmol), 1-bromo-2-(2-bromoethoxy)ethane (39 g, 169 mmol) and DIPEA (21 g, 169 mmol) in ethylene glycol (700 mL) was stirred at 100° C. for 20 h. It was cooled to rt, and diluted with water (300 mL) and extracted with DCM (300 mL×4). The combined organic layers were washed with brine, dried over sodium sulphate and evaporated. The residue was combined with previous batch prepared similarly and purified by column chromatography (eluted with petroleum ether/ethyl acetate=1/1) to give the product (42 g, 55%) as a yellow solid; LC/MS: MS (ES+) m/e 468 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 2.36 (s, 3H), 2.53 (s, 3H), 3.06 (t, J=4.5 Hz, 4H), 3.70 (t, J=4.5 Hz, 4H), 5.53 (s, 2H), 6.32 (d, J=7.8 Hz, 1H), 6.99 (d, J=1.5 Hz, 1H), 7.10 (d, J=1.5 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:20][O:21][N:22]=[C:23]([Cl:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:9][C:29]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:23]([Cl:30])=[N:22][O:21][CH3:20]
Reactant: CN(C)C=O
Reactant: Oc1cccc(Cl)c1
Reactant: CON=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: CON=C(Cl)c1ccccc1COc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 91.2 %

Procedure:
3-Chlorophenol (3.09 g, 0.024 mol), N,N-dimethylformamide (20 ml) and potassium carbonate (4.15 g, 0.03 mol) were added to 2-chloromethyl-(α-methoxyiminobenzyl chloride (4.36 g, 0.02 mol), and the mixture was stirred at room temperature for 4 days. After completion of the reaction, ether (250 ml) was added, and the mixture was washed with brine (200 ml) twice. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(3-chlorophenoxymethyl)-α-methoxyiminobenzyl chloride (5.66 g, 91.2%) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:13][C@@H:14]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=1)[C@H:15]([OH:25])[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].O>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH:14]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[CH:15]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:22])[CH3:23])([CH3:19])[CH3:20])[O:25][CH2:10][C:9]1=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](O)[C@@H](CN(Cc1ccccc1)C(=O)CCl)c1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC1OCC(=O)N(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
To a solution of N-benzyl-N-[(2R,3S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(3,4-dichlorophenyl)-3-hydroxybutyl]-2-chloroacetamide (4.13 g) in THF (100 mL) was added sodium tert-butoxide (897 mg) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.52 g).
Reaction SMILES: C(N(CC)CC)C.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13](Cl)=O.Cl.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([NH:28][NH2:29])=[N:20][N:19]=1>O1CCOCC1>[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2=[N:28][N:29]=[C:13]([C:9]3[O:8][CH:12]=[CH:11][CH:10]=3)[N:20]2[N:19]=1
Reactant: O=C(Cl)c1ccco1
Reactant: NNc1nnc(Cl)c2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Clc1nn2c(-c3ccco3)nnc2c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.2 %

Procedure:
Triethylamine (1.46 ml, 10.5 mmol) and 2-furoyl chloride (1.03 ml, 10.4 mmol) were added to a stirred solution of 1-chloro-4-hydrazinophthalazine hydrochloride (2.0 g, 8.7 mmol) in dioxane (200 ml) at room temperature under nitrogen. The mixture was stirred at room temperature for 2 h and then heated at reflux for 6 h. The mixture was cooled to room temperature, the solvent evaporated in vacuo and the residue partitioned between dichloromethane (800 ml) and water (200 ml). The organic layer was separated, washed further with water (4×200 ml) and brine (x 1), dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica gel, eluting with a 0.5-2% methanol/dichloromethane gradient, to afford the title-product (0.665 g, 28%); 1H NMR (250 MHz, CDCl3) 6.68 (1H, q, J=1.7 Hz, Ar—H), 7.56 (1H, m, Ar—H), 7.73 (1H, m, Ar—H), 7.91 (1H, m, Ar—H), 8.05 (1H, m, Ar—H), 8.31 (1H, d, J=7.5 Hz, Ar—H), 8.76 (1H, m, Ar—H).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([OH:34])=O)[CH:25]=[CH:26][CH:27]=1>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]2[C:32](=[O:34])[C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[CH2:29][CH2:28][C:24]=2[CH:23]=1
Reactant: COc1cccc(CCc2ccccc2C(=O)O)c1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1ccc2c(c1)CCc1ccccc1C2=O
Temperature: 80 °C
Yield: 100 %

Procedure:
To 5 g of phosphorous pentoxide was added 50 ml of methane sulphonic acid. The mixture was heated to 80° C. for 1 hour. The reaction mixture was brought down to 40° C. and 3 g (11.7 mmol) of 2 was added as solid. The mixture was heated at 40° C. for 1 hour and cooled down to room temperature. The reaction mixture was poured into 300 ml of ice/water and extracted with 200 ml of ethyl acetate. The organic layer was washed with 2×150 ml of water, 2×150 ml of saturated NaHCO3 and 100 ml of water. The resulting organic layer was dried (Na2SO4) and concentrated to give 2.6 g (11.7 mmol, 94%) of 3 as off-white powder.
Reaction SMILES: ClC(OC(Cl)C)=O.C([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[N:25][CH:24]=[C:23]([Cl:27])[N:22]=2)[CH:17]([CH2:28][CH3:29])[CH2:16]1)C1C=CC=CC=1>ClCCl>[Cl:27][C:23]1[N:22]=[C:21]([N:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH:17]2[CH2:28][CH3:29])[CH:26]=[N:25][CH:24]=1
Reactant: CCC1CN(Cc2ccccc2)CCN1c1cncc(Cl)n1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: CCC1CNCCN1c1cncc(Cl)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1-Choroethyl chloroformate (4.16 g, 29.1 mmol) was added dropwise under 2 h to a stirred solution of the product obtained in step 2 above (6.15 g, 19.4 mmol) in dry dichloromethane (75 mL) at 0° C. After being stirred at room temperature for 15 h, the reaction mixture was concentrated in vacuo and methanol was added. The mixture was heated at reflux for 2 h and concentrated. The residue was dissolved in CHCl3 and passed through a short (4 cm) plug of silica gel using CHCl3/MeOH (8:2) as eluent. Solvents were evaporated off and the residue was purified by chromatography on silica gel (12×5 cm) using CHCl3/MeOH/Et3N (95:5:0.2) as eluent. This provided 1.9 g (43%) of the title compound as an oil. MS m/z 226/228 (M)+ (35Cl/37Cl-isotope pattern). HRMS m/z calcd for C10H15ClN4 (M)+ 226.0985, found 226.0986.
Reaction SMILES: [F:1][CH:2]([F:7])[C:3](OC)=[O:4].[CH2:8]([CH2:10][NH2:11])[OH:9].ClCCl>C(#N)C>[NH3:11].[F:7][CH:2]([F:1])[C:3]([NH:11][CH2:10][CH2:8][OH:9])=[O:4]
Reactant: COC(=O)C(F)F
Reactant: NCCO
Solvent: ClCCl
Solvent: CC#N
Product: N
Product: O=C(NCCO)C(F)F
Yield: 195.7 %

Procedure:
Methyl difluoroacetate (5 g, 45 mmol) in acetonitrile (50 ml) was reacted with ethanolamine (2.66 ml, 45.4 mmol) at ambient temperature for 24 hours. The solvent was evaporated and the residual oil was purified by chromatography on silica gel, eluting with dichloromethane:methanol (96:4) then dichloromethane:methanolic ammonia (94:6) to yield 2,2-difluoro-N-(2-hydroxyethyl)acetamide (6.18 g, 98% yield):