Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[S:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[SH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH:14]1[CH:15]=[C:10]([S:9][CH:2]2[S:6][C:5](=[O:7])[NH:4][C:3]2=[O:8])[N:11]=[CH:12][CH:13]=1
Reactant: Sc1ccccn1
Reactant: O=C1NC(=O)C(Br)S1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1NC(=O)C(Sc2ccccn2)S1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.5 %

Procedure:
To a solution of 5-bromo-thiazolidine-2,4-dione (28.24 g, 0.144 mol) and 2-mercaptopyridine [(II), 16.0 g, 0.144 moll] in dry THF (200 mL) at -78° C. was added lithium bis(trimethylsilyl)amide (1.0M in hexanes, 317 mL, 0.317 mol) dropwise over a 40 min period. After 30 min. the reaction mixture was warmed to room temperature. After an additional 3 hr, 10% HC1 was added to pH=1. The layers were separated and the aqueous phase was extracted with ethyl acetate (2×500 mL). The combined organic phase was washed with water (500 mL), brine (500 mL), dried (MgSO4) and concentrated to provide the title compound as a green solid (30.45 g, 93%): mp 118°-120 ° C.; NMR (DMSO, d 6): δ 12.35 (s, 1H, NH), 8.39 (d, J=5.3 Hz, 1H, PyrH), 7.69 (dd, J=7.3, 8.3 Hz, 1H, PryH), 7.42 (d, J=8.3 Hz, 1H, PyrH), 7.19 (dd, J=5.3,7.3 Hz, 1H, PyrH), 6.31 (s, 1H, CH), MS(EI): 226 (MI, 12%), 155 (10%), 79 (100%); Anal. (C8H6N2O2S2): C,H,N.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.Br[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cc(Br)ccc1OCc1ccccc1

Procedure:
4-bromo-2-fluorophenol (2.557 g, 13.39 mmol) and (bromomethyl)benzene (1.590 ml, 13.39 mmol) in DMF (20 ml) were treated with K2CO3 (3.70 g, 26.8 mmol) overnight. The reaction was then diluted with ethyl acetate and washed with water. The organic layer was dried over Na2SO4 and concentrated to provide the title compound. LCMS (APCI) m/e 282 (M+H).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:34](=[O:35])[N:6]2[C:7]([C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])=[C:8](OP(OC3C=CC=CC=3)(OC3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@@H:5]12)[CH3:3].[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([SH:47])[CH2:44][C@H:43]1[CH2:48][CH:49]1[CH2:53][N:52]([C:54]([O:56][CH2:57][CH:58]=[CH2:59])=[O:55])[C@H:51]([C:60](=[O:63])[NH:61][CH3:62])[CH2:50]1)=[O:41])[CH:37]=[CH2:38].C(N(CC)C(C)C)(C)C>>[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([S:47][C:8]2[C@H:9]([CH3:10])[C@@H:5]3[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:34](=[O:35])[N:6]3[C:7]=2[C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])[CH2:44][C@H:43]1[CH2:48][CH:49]1[CH2:53][N:52]([C:54]([O:56][CH2:57][CH:58]=[CH2:59])=[O:55])[C@H:51]([C:60](=[O:63])[NH:61][CH3:62])[CH2:50]1)=[O:41])[CH:37]=[CH2:38]
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CC1C[C@@H](C(=O)NC)N(C(=O)OCC=C)C1
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@H]2[C@@H]([C@@H](C)O)C(=O)N12
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CC3C[C@@H](C(=O)NC)N(C(=O)OCC=C)C3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 66.4 %

Procedure:
The same procedure as in Example 8-1 was carried out by using allyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-diphenoxyphosphoryloxy-1-carbapen-2-em-3-carboxylate (204 mg, 0.41 mmol), (2R,4S)-N-allyloxycarbonyl-2-[(2S)-N-allyloxycarbonyl-2-(methylcarbamoyl)pyrrolidin-4-ylmethyl]-4-mercaptopyrrolidine (168 mg, 0.41 mmol) and N,N-diisopropylethylamine (71 μl, 0.41 mmol) to obtain allyl (1R,5S,6S)-2-[(2R,4S)-N-allyloxycarbonyl-2-[(2S)-N-allyloxycarbonyl-2-(methylcarbamoyl)pyrrolidin-4-ylmethyl]pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (180 mg, yield: 67%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]>>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][CH2:12][N:7]4[C@H:6]4[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:16][C@@H:5]34)[CH:10]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: COc1ccc(B(O)O)cc1OC
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CC3)cc1OC

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl (6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and corresponding 3,4-dimethoxyphenyl boronic acid (182 mg, 1.0 mmol) to afford after chromatographic purification the title compound (92 mg, 42%). 1H NMR (CDCl3, 300 MHz) δ7.15 (s, 1H), 7.11 (s, 1H), 7.01-7.04 (m, 2H), 6.89 (d, 1H, J=8.0 Hz), 4.02-4.10 (m, 1H), 3.92 (d, 6H, J=8.1 Hz), 3.64-3.78 (m, 1H), 2.82-3.52 (m, 8H), 1.82-1.90 (m, 2H), 1.49 (s, 9H) ppm. MS-ApCI: 437 [M+H+].
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[N:24]1[CH:25]=[CH:26][C:21]([NH:20][C:17]([CH:14]2[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:16][CH2:15]2)=[O:19])=[CH:22][CH:23]=1
Reactant: Nc1ccncc1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccncc1)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 4 h
Yield: 89.9 %

Procedure:
In DMF (5 mL), 1-[(benzyloxy)carbonyl]-4-piperidinecarboxylic acid (P. E. Maligres et al., Tetrahedron, 53:10983 (1997)) (1.00 g, 3.80 mmol), 4-aminopyridine (572 mg, 6.08 mmol), EDC (801 mg, 4.18 mmol), and HOAt (569 mg, 4.18 mmol) were combined and aged under N2 for 4 h. The reaction was partitioned between sat. NaHCO3 and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×). The combined organics were washed with water and brine then dried over Na2SO4, filtered and concentrated under reduced pressure, affording 1.16 g of benzyl 4-[(4-pyridinylamino)carbonyl]-1-piperidinecarboxylate as a yellow oil which was used without further purification.
Reaction SMILES: C1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2C=C1)[CH2:7]3.[C:11]([O:18]C=C)(=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[C:11]([O:18][C:6]12[CH2:7][CH:8]([CH2:4][CH2:5]1)[CH:9]=[CH:10]2)(=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: C=COC(=O)CCCCC
Product: CCCCCC(=O)OC12C=CC(CC1)C2
Temperature: 160 °C
Reaction time: 30 h
Yield: 25 %

Procedure:
Vinyl hexanoate (100 ml) and dicyclopentadiene (15 ml) were brought to reflux under nitrogen (160° C.). Over a period of 24-36 h, a further 9 additions (each 15 ml) of dicyclopentadiene were made, and heating under reflux continued. During this time, the temperature of the boiling liquid increased until after the last addition it was about 205° C. Excess starting materials were then allowed to distil off. After cooling of the mixture to 50° C., methanol (200 ml) was added and the precipitate allowed to form and settle, cooling to 20° C. The ester solution was decanted off and the precipitate washed with a further batch of methanol (100 ml). The methanol solutions were combined and evaporated under reduced pressure at 40-50° C. to yield about 114 g crude norbornenyl hexanoate (estimated molar yield 25% based on the vinyl hexanoate). This material was suitable for biotransformation.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([CH3:9])[C:6](=[O:8])[CH:7]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(OCC)(=O)C>[CH3:9][C:5]1[CH:4]=[C:3]([OH:10])[C:2]([CH3:1])=[CH:7][C:6]=1[OH:8]
Reactant: CC1=CC(=O)C(C)=CC1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc(O)c(C)cc1O

Procedure:
2,5-Dimethylbenzoquinone (5 g) in ethyl acetate was shaken with an aqueous solution of sodium hydrosulfite. The organic layer was separated, washed, dried and evaporated to yield 2,5-dimethylhydroquinone. To a solution of 2,5-dimethylhydroquinone (5 g), prepared as described above, and 3-methyl-2-buten-1-ol (3.1 g) in dioxane (20 mL) was added BF3-ether (4.5 mL) at room temperature under nitrogen. The solution was stirred at room temperature for one hour, extracted with ethyl acetate, washed with water and dried. The mixture containing starting material and alkylated product was hydrogenated in methanol (100 mL) with 5 drops of concentrated HCl in the presence of Pd/C (10%, 200 mg) at60 psi for 18 hours. Workup and chromatography (silica gel hexane-ethyl acetate 5% to 12%) gave 2 g of the desired product, 2,5-dimethyl-3-(3-methyl-butyl)-hydroquinone.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[CH:23][C:22]=3[O:34][CH3:35])=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl.C([O:43]CC)C.CCCCCC>CC(C)=O>[CH3:35][O:34][C:22]1[CH:23]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH:25]=[CH:26][C:21]=1[C:19]([N:10]1[C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH2:13][N:14]2[C:5]([C:3]([OH:4])=[O:43])=[CH:6][CH:7]=[C:8]2[CH2:9]1)=[O:20]
Reactant: COc1cc(-c2ccccc2C)ccc1C(=O)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Reactant: CCOCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: COc1cc(-c2ccccc2C)ccc1C(=O)N1Cc2ccc(C(=O)O)n2Cc2ccccc21
Reaction time: 8 h

Procedure:
To a solution of 2,2,2-trichloro-1-{10-[(3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Step E (1.6 g, 2.9 mmol) in acetone (20 mL) was added 2.5 N sodium hydroxide (2.3 mL, 5.8 mmol). After stirring overnight, the reaction was acidified with 2 N hydrochloric acid (3.2 mL, 6.4 mmol) then concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The layers were separated, and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown solid. Trituration with diethyl ether/hexane provided 1.2 g of desired product as an off-white solid, m.p. 201–204° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]([OH:12])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[CH3:29]O>>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10]([O:12][CH3:29])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1ccc(OCc2ccccc2)c(OC2CCCC2)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OCc2ccccc2)c(OC2CCCC2)c1

Procedure:
A solution of 3-cyclopentyloxy-4-benzyloxybenzoic acid (5.1 g; that is prepared as described in Reference Example 38) in methanol (150 mL) and concentrated sulfuric acid (1 mL) is heated at reflux for 6 hours, and then it is cooled and concentrated in vacuo. The resulting residue is treated with ethyl acetate (150 mL) and saturated aqueous sodium bicarbonate solution (50 mL). The organic layer is collected, dried and evaporated. The resulting oil is subjected to flash chromatography on silica gel, using a mixture of ethyl acetate and pentane (1:4 v/v) as eluent, to give methyl 3-cyclopentyloxy-4-benzyloxybenzoate (4.8 g), in the form of a white solid, m.p. 58-59° C.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]([OH:16])=[O:15])=[N:10][N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=3)[C:8]2=[O:27])=[CH:4][CH:3]=1.[CH:30](O)([CH3:32])[CH3:31]>S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]([O:16][CH:30]([CH3:32])[CH3:31])=[O:15])=[N:10][N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=3)[C:8]2=[O:27])=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1cccc(-n2nc(C(=O)O)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Reactant: CC(C)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)Nc1cccc(-n2nc(C(=O)OC(C)C)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Temperature: 80 °C
Yield: 30 %

Procedure:
According to Scheme 7 Step 5: A mixture of 4-(4-chlorobenzyl)-2-(3-acetamidophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 7.6 (100 mg, 0.24 mmol), isopropylalcohol (3 mL) and sulfuric acid (2 drops) was heated at 80° C. for 20 hours. The reaction mixture was diluted with a saturated solution of NaHCO3 (50 mL) and the aqueous layer was extracted twice with DCM (50 mL). The organic layers were combined and selectively dried over MgSO4, filtered and concentrated under reduced pressure to afford a brown solid. The crude solid was purified by flash chromatography with silica gel (Merck Flashmart prepacked column 7 g SiO2) using CH2Cl2/MeOH 98/2 as eluant to afford isopropyl 4-(4-chlorobenzyl)-2-(3-acetamidophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate (33 mg, 30%) as a beige solid.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)[CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.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>[CH2:15]([NH:14][C:12]([NH:11][C:8]1[S:9][C:10]2[C:2]([C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)=[CH:3][C:4]([N:17]3[CH:21]=[CH:20][CH:19]=[N:18]3)=[CH:5][C:6]=2[N:7]=1)=[O:13])[CH3:16]
Reactant: OB(O)c1cccnc1
Reactant: CCNC(=O)Nc1nc2cc(-n3cccn3)cc(Br)c2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-n3cccn3)cc(-c3cccnc3)c2s1
Temperature: 120 °C
Yield: 24.5 %

Procedure:
To a solution of 1-(7-bromo-5-pyrazol-1-yl-benzothiazol-2-yl)-3-ethyl-urea (0.27 g, 0.74 mmol) in DMF: H2O (2:1, 15 mL) was added 3-pyridyl boronic acid (0.11 g, 0.88 mmol) and K3PO4 (0.17 g, 0.81 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was then degassed for half an hour followed by the addition of bis(triphenylphosphine)palladium(II) dichloride (0.077 g, 0.11 mmol). The reaction mixture was then again degassed for half an hour and heated at 120° C. for 2 h under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), DMF was distilled off; water was added to the reaction mixture and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The crude residue was purified over silica gel (230-400 M) using EtOAc-Hexane (70:30) to provide the title compound (0.066 g, 22%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([O:14]C)=[O:13])[O:10][CH:11]=2)=[CH:5][CH:4]=[N:3]1.[OH-].[Na+]>O1CCCC1>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[O:10][CH:11]=2)=[CH:5][CH:4]=[N:3]1
Reactant: COC(=O)c1cc(-c2ccnn2C)co1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1nccc1-c1coc(C(=O)O)c1
Yield: 46.7 %

Procedure:
A solution of methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (124 mg, 0.60 mmol) in 6N sodium hydroxide (2.0 ml, 12.0 mmol) and tetrahydrofuran (3.0 ml) was stirred at 70° C. in a sealed tube for 2 h. The resulting solution was cooled and then partitioned between H2O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated affording 4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid (54 mg, 0.28 mmol, 47% yield) as a white solid: LCMS (ES) m/e 192 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[C:4]([NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:3]=1>CC(O)=O>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][CH2:10][C:9]1[N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:4]2[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][C:5]=2[N:8]=1
Reactant: COc1cccc(OCC(=O)Nc2ccc(O)cc2NCC(C)C)c1
Solvent: CC(=O)O
Product: COc1cccc(OCc2nc3ccc(O)cc3n2CC(C)C)c1
Yield: 70.9 %

Procedure:
A solution of 65a (5.5 g, 0.016 mol) in AcOH (50 mL) was heated at 100° C. for 1 hr. The reaction mixture was then concentrated in vacuo. The residue was dissolved in CH2Cl2 (100 mL), washed with saturated NaHCO3 (2×75 mL) and brine (75 mL), filtered through phase separation filter paper, and concentrated in vacuo to give a solid. The solid was triturated with EtOAc (35 mL), collected, and dried to give 3.7 g (71%) of 66a. HPLC analysis showed a purity of 80%. The solid was chromatographed on 75 g silica gel with 25 g of anhydrous sodium sulfate on top packed with hexanes. The column was eluted with 50 mL portions of 10% EtOAc in hexanes for fractions 1-4, 25% EtOAc in hexanes for fractions 5-8, and 50% EtOAc in hexanes for fractions 9-28. The pure product was eluted in fractions 15-20 (HPLC analysis) to give 3.2 g (61%) of 66a as a white solid. HPLC analysis showed a purity of 97%. 1H NMR (60 MHz, CDCl3): δ 7.7 (d, 1H), 7.4-6.4 (m, 6H), 6.8 (br s, 1H), 5.0 (s, 2H), 4.1 (d, 2H), 3.7 (s, 3H), 2.5-1.6 (m, 1H), 1.0 (d, 6H) ppm.
Reaction SMILES: [CH3:1][CH:2]([C:6](O)=O)[C:3]([OH:5])=[O:4].[CH3:9][NH:10][CH3:11].C=O>O>[CH3:9][N:10]([CH3:11])[CH2:6][CH:2]([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CNC
Reactant: CC(C(=O)O)C(=O)O
Agent: C=O
Solvent: O
Product: CC(CN(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In 1.0 ml of water was dissolved 1.5 g of methylmalonic acid, after which 1.26 g of a 50% aqueous dimethylamine solution and 0.96 ml of a 37% aqueous formaldehyde solution were added with stirring at 0° C., and the resulting mixture was stirred at 0° to 5° C. for 3 hours and then at 80° C. for 30 minutes.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[C:7]([CH2:12][C:13]#[CH:14])[CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[OH:16][C:17]1[CH:26]=[C:25](I)[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[OH:16][C:17]1[CH:26]=[C:25]([C:14]#[C:13][CH2:12][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[O:5][CH2:4][CH2:3][C:2]3([CH3:15])[CH3:1])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: C#CCc1cccc2c1OCCC2(C)C
Reactant: COC(=O)c1ccc(I)cc1O
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CCc2cccc3c2OCCC3(C)C)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.18 g (5.9 mmol) of 3-(4,4-dimethylchroman-8-yl)-1-propyne, 1.60 g (5.9 mmol) of methyl 2-hydroxy-4-iodobenzoate and 60 ml of triethylamine are introduced into a three-necked flask under argon. The reaction mixture is degassed by sparging with nitrogen, 332 mg (0.46 mmol) of bis(triphenylphosphine) palladium(II) chloride and 134 mg of copper iodide are introduced and the mixture is stirred at room temperature for eight hours. The reaction mixture is evaporated to dryness, the residue is taken up in ethyl acetate and hydrochloric acid (1N), and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue is purified by chromatography on a silica column eluted with heptane. After evaporating the solvents, an oil, which slowly crystallizes, is obtained and is recrystallized from heptane. 1.00 g (50%) of methyl 2-hydroxy-4-[3-(4,4-dimethylchroman-8-yl)prop-1-ynyl]benzoate is collected in the form of a white solid with a melting point of 92-93° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[Br:13][C:14]1[CH:19]=[CH:18][C:17](O)=[CH:16][CH:15]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:1][CH2:2][CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[CH:16][CH:15]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CN(CCO)C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(CCOc1ccc(Br)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.5 eq), 4-bromophenol (1.0 eq) and PPh3 (1.5 eq) in anhydrous THF under nitrogen was added DIAD (1.5 eq) dropwise at 0° C. The reaction was stirred at rt. for 48 h., quenched with water, and extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography to give the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([OH:21])=O)=[CH:5]2.S(Cl)(Cl)=O.[NH3:26]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([NH2:26])=[O:21])=[CH:5]2
Reactant: N
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Yield: 29.1 %

Procedure:
A suspension, stirred at 20° C., of 2 g (6.96 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid, prepared according to the protocol described in step 1.1, in 80 ml of dry toluene is admixed with 5.08 ml (69.62 mmol) of thionyl chloride. The reaction mixture is stirred at reflux for 2 hours and then concentrated under reduced pressure. The resulting product is taken up in 10 ml of dichloromethane and this solution is poured dropwise into a solution of 9.12 ml (69.62 mmol) of 30% aqueous ammonia. The reaction mixture is stirred at 20° C. for 14 hours. After this time a solid is recovered by filtration and triturated in 50 ml of diisopropyl ether. Filtration and drying under reduced pressure give 0.58 g of expected product.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][C:8]1[C:9](=[N:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:10]([NH2:13])=[N:11][N:12]=1>CN(C=O)C>[NH2:13][C:10]1[C:9](=[N:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:8]([CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[N:12][N:11]=1
Reactant: NCC1=NN=C(N)C1=NNc1cccc(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Product: CS(=O)(=O)NCC1=NN=C(N)C1=NNc1cccc(F)c1
Yield: 52 %

Procedure:
Methanesulfonyl chloride was reacted with 5-(aminomethyl)-4-(3-fluorophenylhydrazono)-3-amino-4H-pyrazole (60 mg, 0.25 mmole) in DMF at ambient temperature to yield 43 mg (52%) of the title compound. 1H NMR (ppm, 300 MHz, DMSO-d6) δ 11.49 (br s, 1H), 7.20-7.50 (m, 3H), 6.70-7.10 (m, 2H), 6.45 (br s, NH2), 4.40 (d, 2H), 2.79 (s, 3H, CH3).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.[CH3:12][O:13][C:14](=[O:21])[CH2:15][C:16](=O)[CH2:17][O:18][CH3:19]>>[CH3:12][O:13][C:14]([C:15]1[C:3]([C:4]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=2)=[N:2][O:1][C:16]=1[CH2:17][O:18][CH3:19])=[O:21]
Reactant: O/N=C(\Cl)c1ccc(F)cc1
Reactant: COCC(=O)CC(=O)OC
Product: COCc1onc(-c2ccc(F)cc2)c1C(=O)OC
Yield: 74 %

Procedure:
As described for Example 36c, (E)- and/or (Z)-N-hydroxy-4-fluoro-benzenecarboximidoyl chloride (12.1 g, 70 mmol) was converted, using 4-methoxy-3-oxo-butyric acid methyl ester instead of acetylacetone to the title compound (13.8 g, 74%) which was obtained as a light yellow solid. MS: m/e=266.0 [M+H]+.