Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]([CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH:15]=O.[C:24](#[N:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH3:13][N:14]1[C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:31]=[CH:15]1
Reactant: CN(C=O)Cc1ccncc1
Reactant: N#Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cn1cnc(-c2ccccc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of di-iso-propyl-amine (11.2 mL, 79.9 mmol ) in 150 mL of THF at −78° C. was added n-butyllithium (31.9 mL of 2.5 M solution, 79.9 mmol). To the resulting mixture was added a solution of N-methyl-N-[4-picolyl]formamide (10 g, 66.5 mmol) in THF. The resulting orange-brown solution was stirred at −78° C. for 20 min, at which time benzonitrile (13.6 mL, 133 mmol) was added. The resulting dark brown mixture was allowed to warm to rt and stirred for 1 h, heated to reflux for 4 h, and then cooled to rt and partitioned between CH2Cl2 and H2O. The organic extract was washed with aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 50:1 CH2Cl2/MeOH. The title compound was obtained as a light tan solid (5.83 g, 37%): mp 158-159° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Mg].II.[C:13]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19])#[N:14].Cl>O1CCCC1>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:18]([C:17]1[CH:16]=[C:15]([CH:23]=[CH:22][CH:21]=1)[C:13]#[N:14])=[O:19]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: COc1ccccc1Br
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)c1cccc(C#N)c1
Temperature: -75 °C
Yield: 79 %

Procedure:
30 g (0.16 mol) of 2-bromoanisole are added dropwise to a mixture of 3.85 g (0.16 mol) of magnesium, containing a crystal of iodine, in 75 ml of anhydrous tetrahydrofuran and the reaction mixture is then refluxed for 1 hour. The resulting solution is then added dropwise to a solution of 26.48 g (0.16 mol) of 3-cyanobenzoyl chloride in 75 ml of anhydrous tetrahydrofuran, cooled to -75° C. The temperature is allowed to rise to 20° C., the reaction medium is hydrolyzed with a 1N aqueous solution of hydrochloric acid and the expected product is then extracted with ethyl acetate. The organic phase obtained is washed with water, dried over magnesium sulfate and then evaporated under reduced pressure. 30 g of the expected product (yield: 80%) are obtained in the form of crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22]([CH3:51])=[C:23]([C:42]([O:49][CH3:50])=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46])[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:29]([CH:33]=1)[C:30](O)=[O:31]>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22]([CH3:51])=[C:23]([C:42]([O:49][CH3:50])=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46])[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:29]([CH:33]=1)[C:30]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:31]
Reactant: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
Morpholine (0.451 g, 5.17 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.49 g, 7.76 mmol) were added to a methylene chloride solution (80 ml) of 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoic acid (1.17 g, 2.59 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=50:1) to obtain the titled compound (1.27 g, 2.59 mmol, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH2:15])[CH:6]=[C:7]([O:12][CH3:13])[C:8]=1[CH2:9][CH2:10][CH3:11].Br[C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=1[F:25]>>[CH3:13][O:12][C:7]1[CH:6]=[C:5]([CH:14]=[CH:15][C:21]2[C:22]([F:23])=[CH:17][C:18]([F:25])=[CH:19][C:20]=2[F:24])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[CH2:9][CH2:10][CH3:11]
Reactant: Fc1cc(F)c(Br)c(F)c1
Reactant: C=Cc1cc(OC)c(CCC)c(OC)c1
Product: CCCc1c(OC)cc(C=Cc2c(F)cc(F)cc2F)cc1OC
Yield: 58 %

Procedure:
This compound was synthesized from (3,5-dimethoxy-4-1-propylphenyl)ethene and 1-bromo-2,4,6-trifluorobenzene in 58% yield in the same procedure as described in preparation of 31B. 1HNMR (CDCl3, ppm): δ 1.32 (d, J=7.0 Hz, 6H), 3.62 (qint, J=7.1 Hz, 1H), 3.89 (s, 6H), 6.73 (s, 2H), 6.79-7.55 (m, 4H).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([CH2:9][OH:10])[O:6][N:5]=1)(=[O:3])[NH2:2].N1C=CC=CC=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:19]>ClCCl>[C:18](=[O:19])([O:20][C:21]1[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=1)[O:10][CH2:9][C:7]1[O:6][N:5]=[C:4]([C:1](=[O:3])[NH2:2])[CH:8]=1
Reactant: NC(=O)c1cc(CO)on1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: NC(=O)c1cc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)on1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2.0 g (14.07 mmol) of 3-carbamoylisoxazol-5-ylmethanol, 1.71 ml (21.11 mmol) of pyridine and 0.17 g (1.41 mmol) of N,N-dimethylaminopyridine in 15 mL of dichloromethane, cooled to about 0° C., are added portionwise 2.84 g (14.07 mmol) of 4-nitrophenyl chloroformate. The medium is kept stirring at 0° C. for 1 hour and then at room temperature for 1 hour.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:40]1[CH:41]=[C:42]([C:45](=[O:49])[CH:46]([CH3:48])[CH3:47])[S:43][CH:44]=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18]([C:40]4[CH:41]=[C:42]([C:45](=[O:49])[CH:46]([CH3:48])[CH3:47])[S:43][CH:44]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CC(C)C(=O)c1cc(Br)cs1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C(=O)C(C)C)c4)cc23)CC1
Reaction time: 0.33 h

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (50 mg, 0.11 mmol) in dioxane (3 mL) and H2O (1 mL) was added potassium carbonate (89.8 mg, 0.66 mmol), 1-(4-bromo-2-thienyl)-2-methyl-1-propanone (87 mg, 0.33 mmol) and tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.012 mmol). The reaction was run in a microwave for 20 min at 150° C. followed by an aqueous work-up with EtOAd and H2O. The reaction was then concentrated and treated with 1 N NaOH and extracted with EtOAc. The compound was purified by flash chromatography using DCM and MeOH to give 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(2-methylpropanoyl)-3-thienyl]-1H-indole-7-carboxamide.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8].C(N(CC)CC)C.[F:16][C:17]1[CH:18]=[N:19][C:20]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([S:33][CH3:34])[CH:28]=2)=[C:21]([CH:25]=1)[C:22](O)=[O:23].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:16][C:17]1[CH:18]=[N:19][C:20]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([S:33][CH3:34])[CH:28]=2)=[C:21]([CH:25]=1)[C:22]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[OH:8])=[O:23]
Reactant: N[C@H]1CCCC[C@H]1O
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@@H]2CCCC[C@@H]2O)c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 58 %

Procedure:
cis-2-Amino-cyclohexane-1-ol (85 mg, 0.56 mmol) and triethylamine (225 μl, 1.61 mmol) were dissolved in dimethylformamide (225 μl) and a solution of 5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (150 mg, 0.54 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (113 mg, 0.59 mmol) and 1-hydroxybenzotriazole (80 mg, 0.59 mmol) in dimethylformamide (5 ml) was added. The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between 0.5N HCl (10 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (2×10 ml). The combined organic phases were washed with brine (10 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with pentane:ethyl acetate (70:30, by volume). The product was triturated with pentane (3 ml) to give 5-fluoro-N-[cis-2-hydroxy-cyclohexyl]-2-(3-methylsulfanyl-phenoxy)-nicotinamide (118 mg) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:29][CH2:30][C:31]#[CH:32]>CCCCCCC.C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:32]#[C:31][CH2:30][CH2:29][CH2:28][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2nn(Cc3ccccc3)c3ccccc23)cc1
Reactant: C#CCCCc1ccccc1
Solvent: ClCCl
Solvent: CCCCCCC
Product: C(#Cc1nn(Cc2ccccc2)c2ccccc12)CCCc1ccccc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 1-benzyl-1H-indazol-3-yl ester and pent-4-ynyl-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 1:1; yield (87.5 mg, 50%); δH (CDCl3): 7.92 (d, J=8.11 Hz, 1H), 7.4-7.19 (m, 8H), 7.15-7.08 (m, 5H), 5.5 (s, 2H), 2.76 (t, J=7.16 Hz, 2H), 2.4 (t, J=7.15 Hz, 2H), 1.91 (p, J=7.21 Hz, 2H); LCMS m/z: 350.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:15]([O:19][C:20](=[O:35])[NH:21][C@H:22]([C:26]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[C:28]([F:34])[CH:27]=1)[C@@H:23]([OH:25])[CH3:24])([CH3:18])([CH3:17])[CH3:16].[N+:36]([C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1)([O-:38])=[O:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:15]([O:19][C:20]([NH:21][C@H:22]([C:26]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[C:28]([F:34])[CH:27]=1)[C@H:23]([O:25][C:43](=[O:44])[C:42]1[CH:41]=[CH:40][C:39]([N+:36]([O-:38])=[O:37])=[CH:47][CH:46]=1)[CH3:24])=[O:35])([CH3:16])([CH3:17])[CH3:18]
Reactant: C[C@H](O)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
In nitrogen atmosphere, diisopropylazodicarboxylate (6 mL) was dropwise added under ice-cooling to a THF solution (100 mL) of [(1R,2S)-2-hydroxy-1-(3,4,5-trifluorophenyl)propyl]carbamic acid tert-butyl ester (5.88 g), 4-nitrobenzoic acid (4.84 g), and triphenylphosphine (7.59 g). The resulting reaction solution was stirred at room temperature for 2 hr and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:ethyl acetate=97:3), and then the obtained powder was triturated with toluene-hexane to give 6.69 g of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:10][CH2:11][CH2:12][Cl:13]
Reactant: Fc1ccccc1S
Reactant: ClCCCBr
Product: Fc1ccccc1SCCCCl

Procedure:
Prepared by Procedure R and Scheme Z using 2-fluorobenzenethiol and 1-bromo-3-chloropropane.
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:26]([OH:27])=[CH:25][C:20]4[O:21][CH2:22][CH2:23][O:24][C:19]=4[C:18]=3[F:28])[C:9]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:30]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[C:26](=[CH:25][C:20]5[O:21][CH2:22][CH2:23][O:24][C:19]=5[C:18]=4[F:28])[O:27][CH2:36]3)[C:9]2=[O:29])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1C(c2c(O)cc3c(c2F)OCCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc3c(c(F)c12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-3-(5-fluoro-7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-9-fluoro-2,3-dihydro-spiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (95%) as an off-white solid: MS (ES+) m/z 479.8 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[C:4]([CH3:9])=[C:3]1[CH3:10].[Li].[Cl-].[CH3:13][Al+:14][CH3:15]>C1(C)C=CC=CC=1>[CH3:13][Al:14]([CH3:15])[C:4]1([CH3:9])[C:3]([CH3:10])=[C:2]([CH3:1])[C:6]([CH3:7])=[C:5]1[CH3:8]
Reactant: C[Al+]C
Reactant: CC1=C(C)C(C)C(C)=C1C
Agent: [Cl-]
Agent: [Li]
Solvent: Cc1ccccc1
Product: CC1=C(C)C(C)([Al](C)C)C(C)=C1C
Temperature: 80 °C
Yield: 78 %

Procedure:
1.14 g of lithium pentamethylcyclopentadiene (C5Me5Li) and 50 ml of toluene were added into a 100-ml Schlenk flask bottle at room temperature. Then 8 ml of dimethylaluminum chloride (1M in hexane) was added to the mixture. The mixture solution was heated at 80° C. for four hours. After the removal of LiCl, the filtrate was vacuum dried to obtain a yellowish dimethyl(pentamethylcyclopentadienyl)aluminum. The yield was 78%.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([OH:17])[CH:12]=3)[S:7][C:6]=2[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH2:25]>>[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH:25][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([OH:17])[CH:12]=3)[S:7][C:6]=2[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1
Reactant: CN(C)CCN
Reactant: O=c1c2cc(O)ccc2sc2c([N+](=O)[O-])ccc(Cl)c12
Product: CN(C)CCNc1ccc([N+](=O)[O-])c2sc3ccc(O)cc3c(=O)c12

Procedure:
1-[[2-(Dimethylamino)ethyl]amino]-7-hydroxy-4-nitro-9H-thioxanthen-9-one was prepared similarly from 10 g of 1-chloro-7-hydroxy-4-nitrothioxanthone and 5.7 g of N,N-dimethylethylenediamine to provide 7.2 g, mp>300°.
Reaction SMILES: [CH2:1]([N:6]1[C:11](=[O:12])[CH:10]2[C:8]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)([CH2:9]2)[C:7]1=[O:22])CCCC>C(O)C.[Pd]>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([C:8]23[CH2:9][CH:10]2[C:11](=[O:12])[N:6]([CH2:1][C:8]([CH3:10])([CH3:9])[CH3:7])[C:7]3=[O:22])=[CH:18][CH:17]=1
Reactant: CCCCCN1C(=O)C2CC2(c2ccc([N+](=O)[O-])cc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)CN1C(=O)C2CC2(c2ccc(N)cc2)C1=O

Procedure:
Following the procedure of Example 3, a solution of 0.85 g of 3-n-pentyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione in 30 ml of ethanol is hydrogenated in the presence of 0.1 g of 5% palladium on carbon and worked up, affording the title compound which melts at 140°-143° C. after recrystallisation from ether/petroleum ether.
Reaction SMILES: [F:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]([OH:14])=O)=[CH:7][CH:6]=2.N1(C(N2C=CN=C2)=O)C=CN=C1.[NH2:27][NH:28][C:29]([NH2:31])=[S:30]>CN(C=O)C>[F:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]([NH:27][NH:28][C:29]([NH2:31])=[S:30])=[O:14])=[CH:7][CH:6]=2
Reactant: NNC(N)=S
Reactant: O=C(O)c1ccc2cnc(F)cc2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: NC(=S)NNC(=O)c1ccc2cnc(F)cc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.5 %

Procedure:
A mixture of 3-fluoroisoquinoline-6-carboxylic acid (0.71 g, 3.72 mmol) and di(1H-imidazol-1-yl)methanone (1.21 g, 7.44 mmol) in DMF (9.0 mL) was stirred at room temperature for 1 hour and 20 minutes until no gas was evolved. The reaction mixture was heated at 70° C. for 40 minutes. Thiosemicarbazide (1.02 g, 11.2 mmol) was added, and the reaction mixture was stirred at 70° C. for another 30 minutes. The solvents were removed under reduced pressure. HCl (1.0 N, 50 mL) was added, and the solids were recovered by filtration, and washed with water to provide the product as an off-white solid (0.86 g, 89%). LCMS (API-ES) m/z: 265 (M+H+).
Reaction SMILES: [Br:1][CH2:2]/[C:3](=[CH:7]/[C:8]([OH:10])=[O:9])/[C:4]([OH:6])=O.[OH-].[Na+].C(O)CCC>O>[Br:1][CH2:2][C:3]1[C:4]([O:10][C:8](=[O:9])[CH:7]=1)=[O:6]
Reactant: O=C(O)/C=C(/CBr)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCO
Product: O=C1C=C(CBr)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2[2-(4-aminophenyl)-2-thiaethyl]-maleic acid(4). 2-(Bromomethyl)-maleic anhydride (2) is prepared from compound 1 according to the method of Laursen et al. (1971) J. Med. Chem. 14:619-621 with the modification by Greenlee and Woodward (1980) Tetrahedron 36:3367-3375. This material (2 g) is hydrolyzed in water (20 mL) for about 1 hour at room temperature to 2-(bromomethyl)-maleic acid (3) and the solution is neutralized with 1 N NaOH (21.2 mL), degassed and kept under N2. The solution is added to a previously prepared solution of 4-aminothiophenol (1.51 g) that has been dissolved in degassed 1 N NaOH (11.6 mL) with gentle heating under N2 and filtered to remove the insoluble dimer. The filtrate is diluted with degassed water (12 mL) before being added to the above solution of compound 3. The final reaction solution is brought to about pH 11.0 with 1 N NaOH and stirred under N2 at room temperature overnight. The solution is then filtered to remove small amounts of bis-(4-aminophenyl)-disulfide, cooled on ice, and acidified with 1N HCl, which gives a yellow precipitate. n-Butanol is added (40 mL) and the mixture is vigorously stirred on ice for 5 minutes. This removes the fumaric acid analog of compound 4. The solid is then collected by filtration, washed successively with 0.1 N HCl and water, and finally dried in a vacuum desiccator over P2O5, to yield the neutral compound 4.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([OH:7])=[O:6].[CH3:12][CH:13]([CH3:15])[O-:14].[Na+]>C(O)(C)C>[Cl:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([O:14][CH:13]([CH3:15])[CH3:12])[N:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Reactant: CC(C)[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)Oc1cc(C(=O)O)cc(Cl)n1
Temperature: 150 °C
Yield: 54 %

Procedure:
To a solution of 2,6-dichloroisonicotinic acid (1.26 g, 6.56 mmol) in isopropanol (20 mL) was added 27 mL (16.40 mmol) of freshly made sodium isopropoxide (0.61 M in isopropanol). This mixture was split evenly into four 20 mL microwave vials and each vial was heated under microwave irradiation at 150° C. for 10 min. The combined reaction solutions were eluted through a column of Dianion HP-20 PS resin eluting first with water followed by 100% acetonitrile to provide 770 mg (54%) of 2-chloro-6-isopropoxyisonicotinic acid. 1H NMR (300 MHz, DMSO-d6) δ 1.27 (d, 6H, J=6 Hz), 5.08-5.14 (m, 1H), 6.95 (s, 1H), 7.23 (s, 1H)
Reaction SMILES: N(C(C)C)C(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[N:22]2)[N:15]=1.N1([CH2:35][OH:36])C2C=CC=CC=2N=N1>C1COCC1>[Br:13][C:14]1[N:15]=[C:16]([CH:20]([N:21]2[CH:25]=[CH:24][N:23]=[N:22]2)[CH2:35][OH:36])[CH:17]=[CH:18][CH:19]=1
Reactant: Brc1cccc(Cn2ccnn2)n1
Reactant: OCn1nnc2ccccc21
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OCC(c1cccc(Br)n1)n1ccnn1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
A solution of i-Pr2NH (370 μL, 2.59 mmol) in THF (3.0 mL) was cooled to −20° C., and n-butyllithium (970 μL, 2.43 mmol) was added dropwise. After stirring for 15 minutes at −20° C., the colorless solution was cooled to −78° C. before adding 2-bromo-6-(1H-1,2,3-triazol-1-ylmethyl)pyridine (200 mg, 0.84 mmol) in THF (2.0 mL) dropwise over 30 minutes. After stirring for an additional 30 minutes at −78° C., 1H-benzotriazole-1-methanol (250 mg, 1.67 mmol) in THF (5.0 mL) was added dropwise over 25 minutes. The solution was stirred at −78° C. for 2 h. The reaction was quenched (while cold) with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Flash chromatography (50-100% EtOAc/hexanes) afforded the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:8][N:7]([C:9]([O:11]C(C)(C)C)=O)[C@H:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:5]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=2)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:9]([N:7]3[CH2:8][C:4](=[N:3][O:2][CH3:1])[CH2:5][C@H:6]3[C:16]([O:18][CH3:19])=[O:17])=[O:11])=[CH:29][CH:28]=2)=[CH:25][CH:26]=1
Reactant: CON=C1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)cc1
Product: CON=C1C[C@@H](C(=O)OC)N(C(=O)c2ccc(-c3ccc(F)cc3)cc2)C1
Yield: 39 %

Procedure:
Following the general methods as outlined in Example 4, starting 1-tert-butyl 2-methyl (2S,4EZ)-4-(methoxyimino)-1,2-pyrrolidinedicarboxylate and 4′-fluoro[1,1′-biphenyl]-4-carboxylic acid, the title compound was isolated, after flash-chromatography, as a mixture of two isomers as an oil in 39% yield (97.6% purity by HPLC).