Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[C@@H]1(N)CCCC[C@H]1N.I[C:18]1[CH:19]=[C:20]([CH3:25])[CH:21]=[C:22]([CH3:24])[CH:23]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31]>[Cu]I.O1CCOCC1>[CH3:24][C:22]1[CH:23]=[C:18]([N:26]2[CH2:30][CH2:29][CH2:28][C:27]2=[O:31])[CH:19]=[C:20]([CH3:25])[CH:21]=1
Reactant: O=C1CCCN1
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(C)cc(N2CCCC2=O)c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 98.1 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (2.0 mg, 0.0105 mmol, 1.0 mol %), K3PO4 (450 mg, 2.12 mmol), evacuated and backfilled with argon. trans-1,2-Cyclohexanediamine (13 μL, 0.108 mmol, 10 mol %), 5-iodo-m-xylene (150 μL, 1.04 mmol), 2-pyrrolidinone (94 μL, 1.24 mmol) and dioxane (1.0 mL) were added under argon. The Schlenk tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 24 h. The resulting pale yellow suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×20 cm; hexane-ethyl acetate 3:2; 20 mL fractions). Fractions 12-23 provided 193 mg (98% yield) of the product as white crystals. 1H NMR (400 MHz, CDCl3): δ 7.23 (s, 2H), 6.82 (s, 1H), 3.85 (t, J=7.1 Hz, 2H), 2.61 (t, J=8.1 Hz, 2H), 2.34 (s, 6H), 2.16 (tt, J=8.1, 7.1 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 174.1, 139.2, 138.4, 126.3, 118.0, 49.1, 32.8, 21.5, 18.1. IR (neat, cm−1): 1692, 1596, 1480, 1393, 1333, 1247, 852. Anal. Calcd for C12H15NO: C, 76.16; H, 7.99. Found: C, 76.06; 8.06.
Reaction SMILES: O.[NH2:2][NH2:3].C([C:6]1([O:15][CH3:16])[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH2:7]1)C.O>C(O)C>[CH3:16][O:15][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:2][NH2:3])=[O:11])=[CH:8][CH:7]=1
Reactant: CCC1(OC)C=CC(C(=O)O)=CC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=O)NN)cc1
Yield: 64.5 %

Procedure:
303 g of hydrazine hydrate was added to a solution of 150 g of p-ethylanisic acid in 300 ml of ethanol, followed by heat-refluxing for 20 hours. After the reaction, the reaction mixture was poured into 1.5 liters of iced water to precipitate a crystal. The crystal was recrystallized from ethanol to obtain 88.2 g of 4-methoxybenzohydrazide.
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([CH2:21][O:22][CH3:23])[C:10]([CH:19]=O)=[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)[C:6]2=[CH:5][CH:4]=1)[CH3:2].C1(P(=[CH:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([CH2:21][O:22][CH3:23])[C:10](/[CH:19]=[CH:43]/[C:44]([O:46][CH2:47][CH3:48])=[O:45])=[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)[C:6]2=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCc1ccc2c(-c3cncc(C)c3)c(C=O)c(COC)nn12
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1c(COC)nn2c(CC)ccc2c1-c1cncc(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
A mixture of 7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carbaldehyde (48 mg) and ethyl (triphenylphosphoranylidene)acetate (56.8 mg) in THF (3 mL) was stirred at ambient temperature for 2 hours. After evaporation of solvent, the residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (5:1-2:1) to give ethyl (2E)-3-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]acrylate as a yellow powder (30 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>ClCCl>[C:26]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])(=[O:28])[CH3:27]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cccc(C=O)c1

Procedure:
3-Hydroxybenzaldehyde (10 g., 81.88 mmol) was dissolved in 150 ml dichloromethane under argon. Triethylamine (17.12 ml, 0.123 mol) and dimethylaminopyridine (5 mg.) were added, and the resulting stirred solution was treated with acetic anhydride (8.5 ml, 90 mmol). After stirring for fifteen hours, the reaction mixture was transferred to a separatory funnel using an additional 50 ml dichloromethane. The organic layer was washed with water (2×100 ml) and concentrated to give a light brown oil weighing 14.85 g. Plug filtration through silica gel using dichloromethane furnished 13.3 g (quant.) of a light orange oil which was shown by NMR and IR to be pure enough for use in subsequent reactions (see Tables 3 and 7). ##STR34##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:11]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)(=[O:13])[CH3:12]
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc([N+](=O)[O-])cn1

Procedure:
2-Amino-5-nitropyridine was treated with acetic anhydride in dry pyridine in the presence of 4-dimethylaminopyridine at room temperature for 24 hrs under argon. The solvent was removed by rotary evaporation. The residue was dissolved in CH2Cl2, and ether was added to form a solid. The white solid was collected and dried giving 2-acetamido-5-nitropyridine. Hydrogenation of this material using 10%Pd on C in MeOH at room temperature under atmospheric pressure gave 2-acetamido-5-aminopyridine.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH:11]=[CH:12][N:13]2[CH2:17]CCC2)[C:3]=1C#N.Cl.[OH2:19]>>[Cl:10][C:8]1[CH:7]=[C:6]2[C:3](=[C:2]([Cl:1])[N:9]=1)[C:17](=[O:19])[NH:13][CH:12]=[CH:11]2
Reactant: N#Cc1c(C=CN2CCCC2)cc(Cl)nc1Cl
Reactant: O
Agent: Cl
Product: O=c1[nH]ccc2cc(Cl)nc(Cl)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension 2,6-dichloro-4-(2-(pyrrolidin-1-yl)vinyl)nicotinonitrile (2 g, 7.457 mmol) in 6 mL of conc-HCl is stirred at 60° C. for 6 hours and stirred at room temperature for 1 hour. The reaction mixture is added to 50 mL of water and the precipitate is collected by filtration and washed with water and ether to give 1.4 g of 6,8-dichloro-2,7-naphthyridin-1(2H)-one as a crude product (pale yellow solid). The dichloro compound was used for the reaction transformations without any further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH3:16])=[N:13]2)=[CH:8][CH:7]=1.[Se](=O)=[O:18]>O1CCOCC1.O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH:16]=[O:18])=[N:13]2)=[CH:8][CH:7]=1
Reactant: O=[Se]=O
Reactant: COCCOc1ccc2ccc(C)nc2c1
Solvent: C1COCCO1
Solvent: O
Product: COCCOc1ccc2ccc(C=O)nc2c1
Yield: 68.3 %

Procedure:
To a solution of 7-(2-methoxyethoxy)-2-methylquinoline (0.16 g, 0.76 mmol) in dioxane (15 mL) and water (0.15 mL) was added selenium dioxide (0.10 g, 0.91 mmol) and the resultant mixture heated at reflux for 2 hours. The cooled reaction mixture was filtered through a plug of Celite® to remove solids, rinsing with dichloromethane. The filtrate was concentrated under reduced pressure and purified by normal phase chromatography on silica gel (10-20% ethyl acetate/hexanes) to afford the title compound (0.12 g, 70%).
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[N:24][CH:25]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[N:24][CH:25]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(F)cc3c2C)C2CCCCC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)nc2)C2CCCCC2)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a mixture of ethyl 3-{[(5-{[cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}pyridin-2-yl)carbonyl]amino}propanoate (361 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (324 mg, 95%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:23][C:24]1([F:38])[CH2:27][N:26]([C:28](=[O:37])[CH2:29][O:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:25]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:38][C:24]1([F:23])[CH2:27][N:26]([C:28](=[O:37])[CH2:29][O:30][CH:31]2[CH2:36][CH2:35][N:34]([C:4]([C:3]3[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=3[F:1])[CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[NH:14][N:13]=3)=[O:6])[CH2:33][CH2:32]2)[CH2:25]1
Reactant: O=C(COC1CCNCC1)N1CC(F)(F)C1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1)N1CC(F)(F)C1
Reaction time: 1 h
Yield: 17.7 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.2 g, 0.67 mmol), 1-(3,3-difluoroazetidin-1-yl)-2-(piperidin-4-yloxy)ethanone (88) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (0.215 g, 0.67 mmol) were dissolved in DMF (10 mL), to this was added DIPEA (0.117 mL, 0.67 mmol) and the reaction was stirred for 1 hour. The solvent was evaporated to dryness and the gum was dissolved in acetonitrile (4 mL). The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compounds were evaporated to dryness to afford 4-(3-(4-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethoxy)piperidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (89) as a white solid (0.061 g, 17.7% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.67-1.48 (2H, m), 1.86-1.75 (1H, m), 2.01-1.89 (1H, m), 3.19-3.06 (1H, m), 3.56-3.39 (2H, m), 3.66-3.57 (1H, m), 4.17-3.95 (3H, m), 4.28 (2H, s), 4.39-4.33 (2H, m), 4.62-4.57 (2H, m), 7.02 (1H, t), 7.31-7.26 (2H, m), 7.79-7.70 (3H, m), 8.48-8.46 (1H, m), 10.53 (1H, s) m/z (LC-MS, ESI+), RT=1.83 (M+H 515). and 2-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperidin-4-yloxy)acetic acid (90) as a white solid (0.016 g, 5.50%); 1H NMR (400.132 MHz, CDCl3) δ 1.68-1.60 (1H, m), 1.84-1.71 (2H, m), 2.05-1.96 (1H, m), 3.16-3.04 (1H, m), 3.53-3.45 (2H, m), 3.78-3.68 (1H, m), 4.23-4.04 (3H, m), 4.32-4.28 (2H, m), 7.07-7.02 (1H, m), 7.30-7.24 (2H, m), 7.86-7.74 (3H, m), 8.47-8.42 (1H, m), 11.12 (1H, s) COOH missing; m/z (LC-MS, ESI+), RT=0.91 (M+H 440).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH2:14]1[O:24][C:23]2[C:16](=[C:17]([CH:20]=[CH:21][CH:22]=2)[CH:18]=[O:19])[O:15]1>CC(C)=O>[CH2:14]1[O:24][C:23]2[C:16](=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]([OH:3])=[O:19])[O:15]1
Reactant: O=Cc1cccc2c1OCO2
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cccc2c1OCO2
Reaction time: 4 h
Yield: 1805.8 %

Procedure:
Freshly prepared Jones reagent (0.2 mmol) was added dropwise (until a brown color persisted in the reaction) to a solution of 2-methylenedioxybenzaldehyde (1.0 g, 6.67 mmol) in 10 mL of acetone at 0° C. The reaction was completed after 4 hours at 0° C., and it was poured onto ethyl ether (20 mL). The ether solution was then washed with brine and extracted with 1N NaOH solution. The NaOH extract was acidified with concentration HCl, and product was extracted out with ether (3×10 mL). Ether layers were combined, dried, and evaporated to give 0.6 g pure product; this compound was used for the next step without further purification (54%). M+167.0
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH3:31])[C:15](=[O:30])[C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:17]=1.C([O-])([O-])=O.[K+].[K+].[CH:38]1(Br)[CH2:41][CH2:40][CH2:39]1.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[CH:38]1([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:31])[C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:19]=[C:18]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:17]=2)[CH2:41][CH2:40][CH2:39]1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccccc1O
Reactant: BrC1CCC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccccc1OC1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
To a solution N-(4-(2-hydroxyphenyl)pyridin-3-yl)-N-methyl-3-(methylsulfonyl)-5-(trifluoromethyl)benzamide (100 mg, 222 μmol, example 263, intermediate a) in DMF (2 mL) was added K2CO3 (61.4 mg, 444 μmol) and cyclobutylbromide (33.0 mg, 244 μmol). The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was stirred for 18 hours at 80° C. The reaction mixture was poured on 30 mL 10% aqueous NaHCO3 solution and 30 mL EtOAc and the layers were separated. The aqueous layer was extracted a second time with 30 mL EtOAc. The organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). A second purification step using preparative HPLC (Gemini NX column) with a gradient of MeOH:water (containing 0.05% formic acid) (80:20 to 98:2) furnished the desired compound as a colorless foam (39 mg, 35%). MS (ESI): m/z=505.141 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[N:4]=1.C([O-])([O-])=O.[K+].[K+].[F:19][C:20]1[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[C:21]=1[CH2:22][N:23]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[S:26](=[O:34])(=[O:33])[N:25](CCC2C(C)=NOC=2C)[C:24]1=[O:44]>CN(C=O)C>[F:19][C:20]1[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[C:21]=1[CH2:22][N:23]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[S:26](=[O:34])(=[O:33])[N:25]([CH2:2][C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH3:12])[N:4]=2)[C:24]1=[O:44]
Reactant: Cc1noc(C)c1CCN1C(=O)N(Cc2c(F)cccc2F)c2ccccc2S1(=O)=O
Reactant: Cn1nc(CCl)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nc(CN2C(=O)N(Cc3c(F)cccc3F)c3ccccc3S2(=O)=O)c2ccccc21

Procedure:
The title compound (11 mg, 0.02 mmol) was prepared from (IntE3) (50 mg, 0.154 mmol), 3-(chloromethyl)-1-methyl-1H-indazole (69.6 mg, 0.39 mmol), KI (5.1 mg, 0.03 mmol) and K2CO3 (53.3 mg, 0.39 mmol) in DMF (3 mL) in a CEM Discover microwave reactor (100° C., 1 h) using the methods of (120).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:18][CH2:19][NH2:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:27][C:28]([F:34])([F:33])[CH2:29][C:30](O)=[O:31]>>[F:27][C:28]([F:34])([F:33])[CH2:29][C:30]([NH:20][CH2:19][CH2:18][CH:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:31]
Reactant: O=C(O)CC(F)(F)F
Reactant: NCCC(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Product: O=C(CC(F)(F)F)NCCC(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Yield: 97 %

Procedure:
Prepared from 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenylpropan-1-amine (25 mg, 0.05 mmol) and 3,3,3-trifluoropropionic acid using General Coupling Method A to give 24 mg (97%) of 3,3,3-trifluoro-N-(3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenylpropyl)propanamide. MS found: (M+H)+=456.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5](=[O:10])[O:6][CH:7]([CH3:9])[CH3:8].[CH3:11][C:12]([CH3:23])=[CH:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>>[CH3:11][C:12]([CH3:23])=[CH:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:2][CH2:3][NH:4][C:5](=[O:10])[O:6][CH:7]([CH3:9])[CH3:8])=[CH:20][CH:21]=1
Reactant: CC(C)=CCOc1ccc(O)cc1
Reactant: CC(C)OC(=O)NCCCl
Product: CC(C)=CCOc1ccc(OCCNC(=O)OC(C)C)cc1

Procedure:
Following the procedures of Example 1, isopropyl 2-chloroethylcarbamate is prepared and is then reacted with 4-(3-methyl-2-butenoxy)phenol to give isopropyl N-{2-[4-(3-methyl-2-butenoxy)phenoxy]ethyl}carbamate, MS m/e 307 (M+).
Reaction SMILES: O[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:34]>>[Cl:34][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][N:4]=1
Reactant: OCc1cc(-c2ccccc2)on1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: ClCc1cc(-c2ccccc2)on1
Yield: 58 %

Procedure:
3-Hydroxymethyl-5-phenylisoxazole (2.10 g, 12 mmol) was refluxed with triphenylphosphine (3.14 g, 12 mmol) in carbon tetrachloride (40 ml) overnight. After cooling the solvent was removed under reduced pressure and the residue taken up in ether, the solution filtered and concentrated to give an oil. This material was filtered through a plug of silicagel (5 g, ether-hexane 1:1) to remove triphenylphosphine oxide then crystallised to give the title compound (1.33 g, 6.9 mmol, 58%); m.p. 48°-9° C.; νmax (CHCl3) 3000, 1610, 1590, 1570, 1450, 1265, 945, 690 cm-1 ; δH (CDCl3) 4.55 (2H, s, CH2Cl), 6.55 (1H, s, CH-het) 7.2-8.0 (5H, m, Ph).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[N:13]1[CH:18]=[CH:17][C:16]([S:19][CH2:20][C:21]([OH:23])=O)=[CH:15][CH:14]=1.FC(F)(F)C([O-])=O.[NH2:31][C@@H:32]1[C:39](=[O:40])[N:38]2[C@@H:33]1[S:34][CH2:35][C:36](/[CH:44]=[C:45]1/[C:46](=[O:68])[N:47]([CH2:50][C:51]3[CH:56]=[CH:55][N+:54]([CH2:57][C:58](=[O:67])[NH:59][C:60]4[CH:65]=[CH:64][C:63]([OH:66])=[CH:62][CH:61]=4)=[CH:53][CH:52]=3)[CH2:48][CH2:49]/1)=[C:37]2[C:41]([OH:43])=[O:42]>CN(C)C(=O)C>[OH:66][C:63]1[CH:62]=[CH:61][C:60]([NH:59][C:58]([CH2:57][N+:54]2[CH:55]=[CH:56][C:51]([CH2:50][N:47]3[CH2:48][CH2:49]/[C:45](=[CH:44]\[C:36]4[CH2:35][S:34][C@H:33]5[N:38]([C:39](=[O:40])[C@H:32]5[NH:31][C:21](=[O:23])[CH2:20][S:19][C:16]5[CH:15]=[CH:14][N:13]=[CH:18][CH:17]=5)[C:37]=4[C:41]([O-:43])=[O:42])/[C:46]3=[O:68])=[CH:52][CH:53]=2)=[O:67])=[CH:65][CH:64]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(Cc4cc[n+](CC(=O)Nc5ccc(O)cc5)cc4)C3=O)CS[C@H]12
Reactant: O=C(O)CSc1ccncc1
Agent: O=C([O-])C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Product: O=C(C[n+]1ccc(CN2CC/C(=C\C3=C(C(=O)[O-])N4C(=O)[C@@H](NC(=O)CSc5ccncc5)[C@H]4SC3)C2=O)cc1)Nc1ccc(O)cc1

Procedure:
With 70.0 mg (0.43 mmol) 1,1′-carbonyldiimidazole, 72.8 mg (0.43 mmol) (pyridin-4-ylsulfanyl)-acetic acid and 232.8 mg (0.36 mmol) (E)-(6R,7R)-7-amino-3-[1-[1-[(4-hydroxy-phenylcarbamoyl)-methyl]-pyridin- 1-ium-4-ylmethyl]-2-oxo-pyrrolidin-3 -ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo [4.2.0]oct-2-ene-2-carboxylate trifluoroacetate in 4 ml ml N,N-dimethylacetamide. The brown solid was purified by column chromatography on MCI gel (75-150μ, Mitsubishi Kasei Corporation) with a gradient of water: acetonitrile (1:0, 4:1, 3:1, 2:1, 1:1). The organic solvent was stripped off at a rotary evaporator and the aqueous phase was freeze-dried.
Reaction SMILES: [OH:1][N:2]1[NH:6][N:5]=[CH:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1>CO>[OH:1][N:2]1[NH:6][N:5]=[CH:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1
Reactant: ON1NN=CN1c1ccc(OCc2ccccc2)cc1
Solvent: CO
Product: Oc1ccc(N2C=NNN2O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 100 mL recovery flask was added 4-(2-hydroxytetrazol-1-yl)-1-benzyloxybenzene 52 (515 mg, 1.92 mmol, 1.0 eq.) and CH3OH (20 mL). The solution was purged with N2 upon which 10% Pd/C (50 mg) was added. The flask was sealed and fitted with a balloon filled with H2. The reaction was stirred overnight at room temperature. The reaction was filtered through a pad of Celite and concentrated to give an off-white solid which was used in subsequent reactions without further purification (300 mg, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13](C3C([N+]([O-])=O)=C(S([O-])(=O)=O)C=CC=3)[CH2:12]2)=[O:10])=[C:4]([C:36](=[O:43])[NH:37][CH:38]([CH:40]2[CH2:42][CH2:41]2)[CH3:39])[CH:3]=1.C(O)(=O)C.[BrH:48].C(OCC)(=O)C.[OH-].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13]([Br:48])[CH2:12]2)=[O:10])=[C:4]([C:36](=[O:43])[NH:37][CH:38]([CH:40]2[CH2:42][CH2:41]2)[CH3:39])[CH:3]=1
Reactant: Br
Reactant: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(c2cccc(S(=O)(=O)[O-])c2[N+](=O)[O-])=NN1c1ncccc1Cl)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(Br)=NN1c1ncccc1Cl)C1CC1
Reaction time: 1 h

Procedure:
400 mg of 5-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenylcarbamoyl)-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazol-3-yl2-nitrobenzene sulfonate was dissolved in 0.7 mL of acetic acid, and 0.3 mL of a 33 mass % hydrogen bromide acetic acid solution was dropwise added, followed by stirring for about one hour. After completion of the reaction, ethyl acetate, water and 2 mL of 1 N sodium hydroxide were added, followed by stirring and extraction with ethyl acetate. Then, concentration under reduced pressure was carried out to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/2) to obtain 310 mg of the desired product in a paste form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8]/[C:9]/2=[N:12]\[OH:13])=[CH:5][CH:4]=1.CCN(CC)CC.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:21][S:22]([O:13]/[N:12]=[C:9]1\[CH2:8][CH2:7][C:6]2[C:10]\1=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:24])=[O:23]
Reactant: COc1ccc2c(c1)/C(=N/O)CC2
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)/C(=N/OS(C)(=O)=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 7750 %

Procedure:
To the solution of intermediate 16 (6.6 g, 37.2 mmol) in CH2Cl2 (120 mL) was added Et3N (20.6 mL, 149 mmol), DMAP (455 mg, 3.73 mmol) and MsCl (4.35 mL, 55.87 mmol). The mixture was stirred at rt overnight. The reaction mixture was washed successively with water, saturated aq NH4Cl, brine, dried over anhydrous MgSO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel column (elution with PE/CH2Cl2=1:1) to give (E)-6-methoxy-2,3-dihydro-1H-inden-1-one O-methylsulfonyl oxime (intermediate 17) (736 g, 82%) as a white solid.