Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:26][CH2:25][C@:4]2([N:8]=[C:7]([C:9]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)[CH:12]=[CH:11][N:10]=3)[CH2:6][CH2:5]2)[C:3]1=[O:27].[B-](F)(F)(F)[F:29].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.FC(F)(F)C(O)=O.[OH-].[Na+]>CC#N>[F:29][CH:6]1[CH2:5][C@@:4]2([CH2:25][CH2:26][N:2]([CH3:1])[C:3]2=[O:27])[N:8]=[C:7]1[C:9]1[CH:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CN1CC[C@@]2(CCC(c3cc(-c4ccc(C(F)(F)F)cc4)ccn3)=N2)C1=O
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CN1CC[C@@]2(CC(F)C(c3cc(-c4ccc(C(F)(F)F)cc4)ccn3)=N2)C1=O
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
Anhydrous MeCN (5 mL) was added to a dry vial charged with (5S)-7-methyl-2-[4-[4-(trifluoromethyl)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]non-1-en-6-one (which may be prepared as described in Description 118) (339.99 mg, 0.9100 mmol). Selectfluor (1500 mg, 4.23 mmol) was added to the solution followed by trifluoroacetic acid (0.04 mL, 0.5300 mmol). The vial was sealed under nitrogen and was heated to 90° C. for 24 h. The reaction mixture was allowed to cool to room temperature whence it was poured onto 0.5M sodium hydroxide. The mixture was left to stir for 10 min and extracted with ether. The combined organic layer was dried (sodium sulfate), filtered and the filtrate was evaporated to give an amber oil. The crude residue was purified by silica gel chromatography (10 g SiO2) eluting with ethyl acetate in iso-hexane (10-100%). Evaporation of desired fractions gave (5R)-3-fluoro-7-methyl-2-[4-[4-(trifluoromethyl)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]non-1-en-6-one, as an amber oil, a 2:1 mixture of epimers. The isomers were separated by chiral semi-prep hplc using a ChiralPak AD-H column eluting with ethanol/n-heptane (20%:80%) to obtain a faster running epimer (D119a) (28 mg);
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[N:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH2:13]([N:15]([CH2:18][CH2:19][N:20]=[C:21]=[S:22])[CH2:16][CH3:17])[CH3:14]>>[CH2:13]([N:15]([CH2:16][CH3:17])[CH2:18][CH2:19][NH:20][C:21]([NH:1][CH:2]1[C:11]2[N:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1)=[S:22])[CH3:14]
Reactant: Cc1cnc2c(c1)CCCC2N
Reactant: CCN(CC)CCN=C=S
Product: CCN(CC)CCNC(=S)NC1CCCc2cc(C)cnc21

Procedure:
8-amino-3-methyl-5,6,7,8-tetrahydroquinoline may be treated with diethylaminoethyl isothiocyanate according to the procedure of Example 4 to give the title compound.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([CH:10]=O)=[CH:8][S:9][C:4]2=[CH:3][CH:2]=1.[S:12]([NH2:16])([NH2:15])(=[O:14])=[O:13].[BH4-].[Na+]>C(O)C.O>[S:9]1[CH:8]=[C:7]([CH2:10][NH:15][S:12]([NH2:16])(=[O:14])=[O:13])[C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]1=2
Reactant: O=Cc1csc2ccccc12
Reactant: NS(N)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)NCc1csc2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Thianaphthene-3-carboxaldehyde (1.62 g, 10.0 mmol) was dissolved in anhydrous ethanol (50 mL). Sulfamide (4.0 g, 42 mmol) was added and the mixture was heated to reflux for 16 hours. The mixture was cooled to room temperature. Sodium borohydride (0.416 g, 11.0 mmol) was added and the mixture was stirred at room temperature for three hours. The reaction was diluted with water (50 mL) and extracted with chloroform (3×75 mL). The extracts were concentrated and chromatographed (5% methanol in DCM) to yield the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:10]2[C:9]3[CH2:11][NH:12][CH2:13][CH2:14][C:8]=3[NH:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[OH-].[K+]>C(O)(C)(C)C.CCOC(C)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:15]([NH:22][C:2]1[C:10]2[C:9]3[CH2:11][NH:12][CH2:13][CH2:14][C:8]=3[NH:7][C:6]=2[N:5]=[CH:4][CH:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1ccnc2[nH]c3c(c12)CNCC3
Reactant: NCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)(C)O
Product: c1ccc(CNc2ccnc3[nH]c4c(c23)CNCC4)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
4-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (100 mg, 0.48 mmol), benzylamine (0.16 mL, 1.44 mmol), Pd(OAc)2 (5 mg, 0.02 mmol), X-Phos (23 mg, 0.05 mmol), and KOH (162 mg, 2.89 mmol) were dissolved in tert-butanol (2.0 mL), and stirred overnight at 100° C. The reaction mixture diluted with EtOAc/H2O, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude material was triturated with EtOAc, filtered, washed with EtOAc, and dried under vacuum to provide 4 (12 mg, 9% yield) as a tan solid. LC-MS (M+H=279, obsd.=279).
Reaction SMILES: [NH:1]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:2][C:3]([NH:5][C@H:6]([C:8]([OH:10])=O)[CH3:7])=[O:4].[NH2:21][C@H:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25].Cl.C(N(CC)CC)C.C(OP(C#N)(=O)OCC)C>ClCCl>[NH:1]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:2][C:3]([NH:5][C@H:6]([C:8]([NH:21][C@H:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:10])[CH3:7])=[O:4]
Reactant: C[C@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)CNC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of Z-Gly-Ala-OH (3) (20.0 g, 0.071M) and Leu-OMe.HCl (12.9 g, 0.071M) in 250 ml dichloromethane was added 21.9 ml (0.157M) triethylamine (TEA) dropwise over a period of 10 min. This addition was followed by the addition of 11.9 ml (0.078M) of diethylcyanophosphonate (DECP). The mixture was stirred overnight and the solvent removed. The residue was dissolved in ethyl acetate and washed with 1N HCl, saturated NaHCO3, and brine. The solution was dried with MgSO4, filtered and the solvent removed. Recovered 29.0 g of product that is homogeneous by TLC. 13C NMR (CDCl3) 15.93, 18.60, 21.77, 22.69, 24.72, 40.80, 44.20, 48.70, 50.87, 52.13, 65.28, 66.84, 127.92, 128.00, 128.41, 136.36, 156.76, 169.31, 172.58, 173.24.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10](I)=[N:11][NH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:11][NH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1n[nH]c2cccc(Oc3ccccc3)c12
Reactant: OB(O)c1ccccc1
Product: c1ccc(Oc2cccc3[nH]nc(-c4ccccc4)c23)cc1

Procedure:
In Scheme I, fluoronitrotoluene a is reacted with phenol b in the presence of mild base such as potassium carbonate, to afford a phenoxy nitrotoluene c. Phenoxy nitrotoluene c is then reduced, using catalyzed hyrdogenation or othe reduction technique, to provide phenoxy aminotoluene d. Phenoxy aminotoluene d undergoes a cyclization reaction by treatment with isoamyl nitrate to form phenoxy indazole e. Phenoxy indazole e is subject to iodine under basic conditions to yield a phenoxy iodoindazine f, which is then protected via Boc, Fmoc or other suitable protection scheme, to afford a protected phenoxy iodoindazole g. The protected phenoxy iodoindazole g is treated with a phenyl boronic acid h in the presence of a suitable catalyst to form a phenoxy phenylindazole i, which is deprotected to provide an indazole derivative j in accordance with the invention.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2=O.[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2=[N:25][S:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24]
Reactant: O=c1c2cc(Br)ccc2oc2c(F)nc(Cl)cc12
Reactant: CC(C)(C)[S@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=c1c2cc(Br)ccc2oc2c(F)nc(Cl)cc12
Temperature: 70 °C
Yield: 57 %

Procedure:
A suspension of 7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-one (20 g, 60.9 mmol), (R)-2-methyl-2-propanesulfinamide (14.76 g, 122 mmol), and titanium (IV) ethoxide (25.2 mL, 122 mmol) in THF (250 mL) was heated to 70° C. for 24 h. Additional (R)-2-methyl-2-propanesulfinamide (1.0 equiv) and titanium (IV) ethoxide (1.0 equiv) were added and the reaction mixture was heated for additional 24 h. Additional (R)-2-methyl-2-propanesulfinamide (1.0 equiv) and titanium (IV) ethoxide (1.0 equiv) were added and the reaction mixture was heated for additional 8 h. The reaction mixture was quenched with brine (150 mL). The resulting suspension was filtered through celite, and the filter cake was washed with EtOAc. The filtrate was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography (100% hexanes) to afford racemic N-(7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-ylidene)-2-methylpropane-2-sulfinamide as an orange solid (15 g, 34.7 mmol, 57.1% yield).
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:6]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([F:28])([F:27])([F:26])([F:25])[F:24])[CH:18]=2)=[CH:7][C:8]([CH3:15])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3].[H-].[Na+].CI.[C:33]([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:1][S:2]([C:5]1[C:6]([N:16]([CH3:33])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([F:27])([F:26])([F:28])([F:24])[F:25])[CH:18]=2)=[CH:7][C:8]([CH3:15])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(Nc2cccc(S(F)(F)(F)(F)F)c2)cc1C
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(S(C)(=O)=O)c(N(C)c2cccc(S(F)(F)(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
150 mg of methyl 5-methanesulfonyl-2-methyl-4-(3-pentafluorosulfanyl-phenylamino)benzoate (example 5 c) were dissolved in 2 ml of DMF (anhydrous), 13.5 mg of NaH were added, and the mixture was stirred at RT for 15 minutes. Then 15 μl of CH3I were injected and the mixture was left to stand at RT for 18 h. The reaction mixture was then poured into 10 ml of a saturated aqueous NaHCO3 solution and extracted with 40 ml of EA. The organic phase was subsequently washed with 10 ml of water. Drying over MgSO4 and removal of the solvent in vacuo resulted in 120 mg of a pale yellow foam.
Reaction SMILES: [C:1]([N:5]([C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24][CH2:25]Cl>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:23][O:24][CH2:25][N:6]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COCCl
Reactant: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Product: COCN(C(=O)c1ccccc1)N(C(=O)c1ccccc1)C(C)(C)C
Reaction time: 3 h

Procedure:
N'-t-butyl-N,N'-dibenzoylhydrazine (2 g, 0.007M) was stirred at room temperature in a two phase system of toluene-50% sodium hydroxide with 100 mg of phase transfer catalyst (tetra-n-butylammonium hydrogen sulfate). Methoxymethyl chloride (1.2 g, 0.015M) was added dropwise and the mixture was stirred 3 hours. The layers were separated and the toluene layer was washed several times with water (until the water washes were neutral). The toluene solution was dried over anhydrous magnesium sulfate and the toluene removed under vacuum to afford N-methoxymethyl-N'-t-butyl-N,N'-dibenzoylhydrazine as a thick oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)CCC>>[CH2:1]([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(Br)cc2)CC1
Product: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(-c3ccccn3)cc2)CC1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 261. Starting from 1-(4-Bromo-benzyl)-4-(4-methoxy-benzensulfonyl)-piperidine-4-carboxylic acid ethyl ester (4.65 g, 9.38 mmol) and 2-(tributylstannyl)-pyridine (12.08 g, 32.8 mmol). Yield 2.79 g (60%); brown oil; MS: 495.1 (M+H)+
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:26]2[N:27]=[N:28][S:29][C:30]=2[C:31]2[C:32]([C:37]([F:40])([F:39])[F:38])=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:12]=[C:13]([N+:23]([O-:25])=[O:24])[C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1.B(Br)(Br)Br>ClCCl>[N+:23]([C:13]1[CH:12]=[C:11]([C:26]2[N:27]=[N:28][S:29][C:30]=2[C:31]2[C:32]([C:37]([F:40])([F:39])[F:38])=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:10]=[C:9]([OH:8])[C:14]=1[OH:15])([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cc(-c2nnsc2-c2cccnc2C(F)(F)F)cc(OCc2ccccc2)c1OCc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(-c2nnsc2-c2cccnc2C(F)(F)F)cc(O)c1O
Temperature: -40 °C

Procedure:
4-(3,4-bis(benzyloxy)-5-nitrophenyl)-5-(2-(trifluoromethyl)pyridin-3-yl)-1,2,3-thiadiazole (0.147 g, 0.26 mmol) in dichloromethane (10 mL) was cooled to −78° C. with stirring and treated under argon with boron tribromide (0.26 g, 1.03 mmol). The resulting deep purple suspension was then allowed to stir at room temperature for one hour before cooling again to −40° C. The mixture was quenched by the careful addition of methanol. After stirring at room temperature for thirty minutes, the volatiles were evaporated and the residue stirred with 2 N hydrochloric acid (5 mL) for thirty minutes. The resulting solid was filtered off, washed with water (25 mL) and then cold isopropanol (5 mL) to give 3-nitro-5-(5-(2-(trifluoromethyl)pyridin-3-yl)-1,2,3-thiadiazol-4-yl)benzene-1,2-diol as a yellow solid, 0.089 g (89%).
Reaction SMILES: FC1C=CC([C:8](C2C=CC(F)=CC=2)=[C:9](C2N(C(C)C)N=NN=2)[CH:10]=[O:11])=CC=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=2)=[C:35]([C:38]2[N:39]=[N:40][N:41]([CH:43]([CH3:45])[CH3:44])[N:42]=2)C=O)=[CH:30][CH:29]=1>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=2)=[C:35]([C:38]2[N:39]=[N:40][N:41]([CH:43]([CH3:44])[CH3:45])[N:42]=2)[CH:8]=[CH:9][CH:10]=[O:11])=[CH:30][CH:29]=1
Reactant: CC(C)n1nnc(C(C=O)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Reactant: CC(C)n1nnnc1C(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Product: CC(C)n1nnc(C(C=CC=O)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Yield: 82 %

Procedure:
The general procedure of Example 23, Step A was repeated, except that the 3,3-bis(4-fluorophenyl)-2-[1-(1-methylethyl)-1H-tetrazol-5-yl]-2-propenal utilized therein was replaced by 3,3-bis(4-fluorophenyl)-2-[2-(1-methylethyl)-2H-tetrazol-5-yl]-2-propenal and there was thereby produced mostly 5,5-bis(4-fluorophenyl)-4-[2-(1-methylethyl)-2H-tetrazol-5-yl]-2,4-pentadienal in 82% yield; MS (CI): m/e=381 for (M+H)+. This product was then subjected to the general procedure of Example 23, Step B and there was thereby produced ethyl 9,9-bis(4-fluorophenyl)-5-hydroxy-8-[2-(1-methylethyl)-2H-tetrazol-5-yl]-3-oxo-6,8-nonadienoate containing some inseparable ethyl 7,7-bis(4-fluorophenyl)-5-hydroxy-6-[2-(2-(1-methylethyl)-2H-tetrazol-5-yl]-3-oxo-6-heptenoate in 69.7% yield.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[CH:14]=1)[C:8]([O:10]C)=[O:9])(=[O:4])=[O:3].O.[OH-].[Li+]>O1CCOCC1.O>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[CH:14]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3]
Reactant: COC(=O)c1cc(N2CCCC2=O)cc(S(C)(=O)=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 3-methylsulfonyl-5-(2-oxopyrrolidin-1-yl)-benzoate (D18) (0.717 g) was suspended in dioxan (3.6 ml) and treated with a solution of lithium hydroxide monohydrate (0.153 g) in water (3.6 ml). The mixture was stirred for 2 h at room temperature and a clear solution was formed. The pH was adjusted to ˜4 by addition of Amberlyst-15 H+ resin. The resin was removed by filtration and washed well with dioxan. The combined filtrates were evaporated and the residue dried. Trituration with ether gave D19 (0.51 g) as a pale cream solid.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[CH:19]=[CH:18][S:17][CH:16]=3)[CH:12]=[CH:11][C:10]=2[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].[Na+].[I-].[Br-]>CC#N>[C:23]([O:22][C:21]([NH:20][C:10]1[CH:11]=[CH:12][C:13]([C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)=[CH:14][C:9]=1[NH:8][C:6]([C:5]1[CH:28]=[CH:29][C:2]([NH:1][CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[CH:3][CH:4]=1)=[O:7])=[O:27])([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccsc2)cc1NC(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [I-]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CNc1ccc(C(=O)Nc2cc(-c3ccsc3)ccc2NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl [2-[(4-aminobenzoyl)amino]-4-(3-thienyl)phenyl]carbamate (945 mg, 2.31 mmol) in CH3CN (5.0 mL) was added K2CO3 (639 mg, 4.62 mmol), tert-butyl bromoacetate (1.35 mL, 9.24 mmol), and NaI (139 mg, 0.92 mmol). The reaction mixture was heated at reflux for 12 hours and an additional portion of bromide and NaI were added to obtain mono and bis alkylated product. The reaction was cooled to room temperature, filtered and the organic layer was concentrated in vacuo. The crude residue was purified by reverse-phase chromatography (10-100% MeCN/H2O with 0.05% TFA) to separate mono and bis alkylated product (ratio of mono to bis is ˜1:2). The appropriate fractions were combined, diluted with EtOAc (20 mL) and washed with sat.'d aq. NaHCO3 (1×10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo and gave the desired tert-butyl {[4-({[2-[(tert-butoxycarbonyl)amino]-5-(3-thienyl)phenyl]amino}carbonyl)phenyl]amino}acetate which was confirmed MS: cal'd 524.2 (MH+), exp 524.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][C:3]=1[SH:19].[Br-].C(=O)([O-])[O-].[Na+].[Na+].CN1[CH2:32][CH2:31][CH2:30][C:29]1=O>>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][C:3]=1[S:19][CH2:29][C@H:30]1[CH2:14][CH2:15][C@H:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:32][CH2:31]1
Reactant: Nc1c(S)cc(O)c2c1C(=O)c1ccccc1C2=O
Reactant: CN1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Product: CCCCC[C@H]1CC[C@H](CSc2cc(O)c3c(c2N)C(=O)c2ccccc2C3=O)CC1
Temperature: 0 °C

Procedure:
To 30 ml of N-methylpyrrolidone, 1 g of 1-amino-2-mercapto-4-hydroxyanthraquinone, 1.2 g of trans-4-n-penthylcyclohexylmethyl bromide and 0.6 g of sodium carbonate were added. The resulting mixture was heated at 120° to 125° C. for 7 hours. After cooling to 60° to 70° C., the mixture was poured on 100 g of ice, followed by separation of the product and washing with water until neutral was obtained. The product thus obtained was dried and purified by column chromatography using silica gel as carrier and chloroform as separating solvent to give 0.7 g of 1-amino-2-(trans-4-n-pentylcyclohexylmethylmercapto)-4-hydroxyanthraquinone having a melting point of 129°-130° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][C:14]#[N:15])([O-:3])=[O:2].[OH-].[Na+].[CH3:18]I.O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[CH3:18][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:7]([CH2:13][C:14]#[N:15])=[CH:8]1
Reactant: CI
Reactant: N#CCc1c[nH]c2ccc([N+](=O)[O-])cc12
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cn1cc(CC#N)c2cc([N+](=O)[O-])ccc21
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To a suspension of 11.5 g (0.057 mole) of 5-nitroindole-3-acetonitrile and 1.46 g (0.006 mole) of benzyltriethyl ammonium chloride in 120 ml of 50% (aq.) NaOH, stirred at 0°, was added, dropwise over 1.5 hours, a solution of 8.26 g (0.058 mole) of CH3I in 80 ml of CH2Cl2. The temperature was raised to 25° and the stirring continued for 2 hours. The suspension was then poured into 800 ml of H2O and filtered. The CH2Cl2 layer of the filtrate was taken to dryness in vacuo and the resulting yellow solid combined with the solid from the filtration. The combined solids were washed with H2O, dried and recrystallized from n-BuOH to give 9.35 g (76%) of a yellow solid: m.p. 165°-166°; nmr (d6 -DMSO) δ(TMS) 8.54 (1, d, J=2.5 Hz), 8.16 (1, d of d, Jortho =9 Hz, Jmeta =2.5 Hz), 7.37 (1, d, J=9 Hz), 7.29 (1, S), and 3.86 ppm (5, S, N--CH3 and --CH2 --CN).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[N+:4]([O-])[C:3]=1[C:9]#[N:10].O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:5]1[N:4]=[C:3]([C:9]#[N:10])[C:2]([CH3:1])=[CH:7][CH:6]=1
Reactant: Cc1ccc[n+]([O-])c1C#N
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc(Cl)nc1C#N
Temperature: 25 °C

Procedure:
3-Methylpyridine-2-carbonitrile 1-oxide (8.42 g, 62.8 mmol) was stirred in refluxing POCl3 (60 mL, 646 mmol) for 6 hours. The mixture was cooled to room temperature and slowly poured into ice-water. The resulting beige precipitate was collected by filtration to give the title compound.