Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][NH:7][C:6]2=[O:15].Br[CH2:17][CH2:18][CH2:19][Cl:20].C(Cl)(Cl)Cl.CO>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]([CH2:17][CH2:18][CH2:19][Cl:20])[C:6]2=[O:15]
Reactant: ClCCCBr
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc2ncn(CCCCl)c(=O)c2cc1OC

Procedure:
1-(6,7-Dimethoxy-4-(3H)-quinazolinone-3-yl)-3-chloro-propane was prepared analogous to Example 1 (a) by reaction of 6,7-dimethoxy-4(3H)-quinazolinone with 1-bromo-3-chloro-propane in dimethyl-formamide. Rf -value (chloroform/methanol = 19/1) : 0.75.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[Br:6][C:7]1[CH:8]=[C:9]([C:15]2([OH:18])[CH2:17][CH2:16]2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].C(N(CC)CC)C>C1COCC1.O>[Br:6][C:7]1[CH:8]=[C:9]([C:15]2([O:18][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH2:17][CH2:16]2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: COc1ccc(C2(O)CC2)cc1Br
Reactant: C[Si](C)(C)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(O[Si](C)(C)C)CC2)cc1Br
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Trimethylsilyl chloride (6.54 ml) was added to a solution of 1-(3-bromo-4-methoxyphenyl)cyclopropanol (5.0 g) and triethylamine (8.61 ml) in THF (100 ml). The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (3.84 g).
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:12])([CH3:11])[C:3]1=[O:13].Cl.Cl[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.[CH:22](O)([CH3:24])[CH3:23]>>[CH3:12][C:4]1([CH3:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([N:1]([CH2:23][CH2:22][CH3:24])[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:3]1=[O:13]
Reactant: CC(C)O
Reactant: CC1(C)C(=O)N(N)c2ccccc21
Reactant: Clc1ccncc1
Agent: Cl
Product: CCCN(c1ccncc1)N1C(=O)C(C)(C)c2ccccc21
Temperature: 25 °C
Yield: 33 %

Procedure:
To a stirred solution of 1-amino-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (7.35 g) and isopropanol (167 ml) was added 4-chloropyridine hydrochloride (8.15 g). The flask was flushed with nitrogen and fitted with a condensor and nitrogen inlet. The reaction mixture was heated at reflux for 9 hours. Upon cooling to room temperature, the reaction mixture was poured into dilute aqueous sodium bicarbonate. The product was extracted thrice with ethyl acetate and once with dichloromethane. The combined organic layers were washed with brine and dried (K2CO3). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, 2% Et3N/0-2% MeOH/ether) afforded 3.5 g (33%) of the desired product.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Br.[OH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][CH2:27]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[OH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][N:26]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=1[F:16])[CH2:27]2
Reactant: Oc1cccc2c1CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Br
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3Cc4cccc(O)c4C3)c(F)cc2c1=O
Yield: 19.3 %

Procedure:
136 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 130 mg of 4-hydroxyisoindoline hydrobromide, 114 mg of 1,8-diazabicyclo[5,4,0]-7-undecene (DBU), and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 1 to produce 37 mg of the target compound.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].Cl[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1>C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: Clc1cnccn1
Reactant: CC(C)c1cccc(B(O)O)c1
Agent: [Pd]
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(-c2cnccn2)c1
Temperature: 80 °C

Procedure:
To a solution of commercial 3-isopropyl-benzene boronic acid (1.0 g) in a 2:2:1 mixture of toluene/1M Na2CO3/EtOH (122 ML), at r.t.,2-chloropyrazine (599 μL) and the bis[1,2-bis(diphenylphosphino)ethane]-palladium(0) catalyst (110 mg) were added. The reaction mixture was heated at 80° C. for 3 hr. It was then cooled down and partitioned between AcOEt/sat.aq. NaCl. The phases were separated and the organic layer was dried. The solids were filtered and the solvent evaporated. The crude oil was purified by flash chromatography (CH/AcOEt 7:3) obtaining the title compound as a clear oil (468 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[OH:11].[CH3:12][C:13]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C.O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[O:11][Si:16]([C:13]([CH3:15])([CH3:14])[CH3:12])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CCc2c(Br)cccc21
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CCc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-2,3-dihydro-1H-inden-1-ol INT-28 (2.56 g, 12.0 mm) in DMF (5 mL) were added TBDMSCl (2.17 g, 14.4 mmol) and imidazole (2 g, 30.0 mmol) and the reaction mixture stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with EA. The organic layers were washed with water and brine, and dried over MgSO4. The crude product was purified by chromatography (EA/hexane) to afford (4-bromo-2,3-dihydro-1H-inden-1-yloxy)(tert-butyl)dimethylsilane INT-29 (3.3 g, 84%) as a clear oil. LCMS-ESI (m/z) calculated for C15H23BrOSi: 327.3; found 195.0 [M−OTBS]+, tR=3.07 min. 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J=7.8 Hz, 1H), 7.06 (d, J=7.4 Hz, 1H), 6.92 (t, J=7.7 Hz, 1H), 5.13 (t, J=7.0 Hz, 1H), 2.85 (ddd, J=16.4, 9.1, 2.9 Hz, 1H), 2.57 (dt, J=16.5, 8.3 Hz, 1H), 2.36-2.17 (m, 1H), 1.76 (dtd, J=12.8, 8.8, 7.1 Hz, 1H), 0.83-0.72 (m, 9H), 0.05-−0.06 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[CH2:11]([N:18]1[C:22]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:21][N:20]=[CH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CS(O)(=O)=O.[OH-].[Na+]>O>[CH2:11]([N:18]1[C:22]([CH:23]2[C:5]3[C:6](=[C:7]([CH3:8])[C:2]([CH3:1])=[C:3]([O:9][CH3:10])[CH:4]=3)[C:25](=[O:26])[CH2:24]2)=[CH:21][N:20]=[CH:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1cccc(C)c1C
Reactant: O=C(O)C=Cc1cncn1Cc1ccccc1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c(c(C)c1C)C(=O)CC2c1cncn1Cc1ccccc1
Temperature: 92.5 °C

Procedure:
A mixture of 2,3-dimethylanisole (2.0 g), 3-(3-benzyl-3H-imidazol-4-yl)-acrylic acid (3.4 g) and methanesulfonic acid (60 ml) is heated at 90-95° C. for 45 minutes.The cooled reaction mixture is poured into water and is made alkaline with sodium hydroxide solution. The product is extracted into ethyl acetate which is washed with water, dried with sodium sulfate and evaporated in reduced pressure. The crude product is purified by flash chromatography by eluting with methylene chloride-methanol solution. The yield is 1.1 g.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]1([CH:16]=[CH:17][CH:18]([OH:21])[C:19]#[CH:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[O:21]=[C:18](/[CH:17]=[CH:16]/[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)/[CH:19]=[CH:20]/[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: C#CC(O)C=Cc1ccccc1
Reactant: N#Cc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(/C=C/C(=O)/C=C/c2ccccc2)cc1
Temperature: 120 °C

Procedure:
4-bromobenzonitrile (182 mg, 1 mmol), phenylpent-1-en-4-yn-3-ol (190 mg, 1.2 mmol), bis(triphenylphosphine)palladium(II)dichloride (14 mg, 0.02 mmol), copper iodide (3 mg, 0.03 mmol) and triphenylphosphine (52 mg, 0.2 mmol) were introduced in a 10 mL microwave vial flushed with argon. This was diluted with anhydrous triethylamine (700 μL, 4 mmol) in anhydrous degased 1,4-dioxane (1.3 mL). The solution was heated under microwave irradiation at 120° C. for 45 min. The reaction mixture was poured into a mix of 1M aqueous solution of hydrochloric acid (10 mL) and saturated aqueous ammonium chloride solution (10 mL), and this was extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over magnesium sulfate, filtered, and evaporated to dryness to give crude product which was purified by flash chromatography (SiO2, 30% ethyl acetate in dichloromethane). This gave pure final compound TG007A82 (160 mg, 62%) as a light yellow powder.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][Br:14].[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K].CN(C)C=O.O>ClCCl>[Br:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:19]1[C:15](=[O:25])[C:16]2[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:18]1=[O:20]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCCCCCCCCCCCCBr
Agent: [K]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCCCCCCCCCCBr
Temperature: 160 °C

Procedure:
1,12-dibromododecane (32.22 g, 98.2 mmol), potassium phthalimide (4.60 g, 24.5 mmol), and dimethylformamide (20 mL) were combined and refluxed at 160° C. for 2.5 hours. Upon cooling, water was added and the organic taken into dichloromethane (separated on a separatory funnel). The solvent was evaporated under reduced pressure and the crude product was columned in hexanes. The spots were not separated, and the fractions were combined, the solvent removed, and the crude material re-dissolved in 300 mL acetone. This was refluxed, and 10 g potassium phthalimide was added over 4 hours. The mixture was refluxed overnight. After cooling and removing the solvent, the crude product was columned using 1:1 ethyl acetate: hexanes. The top spot proved to be the desired product, which was collected as a white solid (9.30 g) that matched the reported literature: Helv. Chimica Acta. 2001, 84(3), 678-689.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>C1COCC1.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.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4]([C:17]2[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][C:18]=2[Cl:20])[N:3]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(Cl)nc1Cl
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: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(Cl)cc2Cl)nc1Cl

Procedure:
6 g (29.12 mmol) of methyl 2,6-dichloropyridine-3-carboxylate, 5.56 g (29.12 mmol) of 2,4-dichlorophenylboronic acid, 12.07 g (87.4 mmol) of potassium carbonate and then 1.68 g (1.46 mmol) of tetrakis(triphenylphosphine)palladium(0) were initially charged in 120 ml of degassed THF, and the mixture was heated under reflux conditions and under an argon atmosphere for 16 h. 300 ml of water and 500 ml of ethyl acetate were added. After separating the phases and removing the solvent, the residue was chromatographed on silica gel (cyclohexane/ethyl acetate 6:1). 2.5 g (27% of theory) of the product were isolated in solid form.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[N+:20]([CH3:23])([O-:22])=[O:21].Cl>CO>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[CH:23]/[N+:20]([O-:22])=[O:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: C[N+](=O)[O-]
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])/C=C/c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a mixture of 4-benzyloxybenzaldehyde (1.0 g, 4.7 mmol) and sodium methoxide (28% methanol solution, 150 μL, 0.74 mmol) and methanol (10 mL) were added nitromethane (330 μL, 6.1 mmol) and sodium methoxide (28% methanol solution, 1.0 mL, 4.9 mmol) at 0° C., which was stirred for 10 minutes at room temperature. The reaction mixture was cooled to 0° C., and 5 N aqueous hydrochloric acid solution (20 mL) was added thereto at the same temperature. The reaction mixture was then stirred for 15 minutes at room temperature. The precipitated solids were filtered to obtain the title compound (1.2 g, 100%).
Reaction SMILES: [CH:1]1[C:2]2[C:9](=O)[NH:8][CH:7]=[N:6][C:3]=2[NH:4][N:5]=1.P(Cl)(Cl)([Cl:13])=O.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[Cl:13][C:9]1[N:8]=[CH:7][N:6]=[C:3]2[NH:4][N:5]=[CH:1][C:2]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2[nH]ncc12
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Clc1ncnc2[nH]ncc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of allopurinol (20 g, 146.94 mmoles) in toluene (205.71 mL), add phosphoryl chloride (68.27 mL, 734.68 mmoles) and diisopropylethylamine (56.38 mL, 323.26 mmoles) and heat the mixture at 80° C. for 2 hours. Remove the solvent in vacuo to half and pour the mixture into 2 M potassium phosphate, dibasic (734.68 mL, 1.47 moles) in water at 4° C. Stir the mixture overnight at room temperature. Filter off the precipitate through a pad of celite and wash it subsequently with EtOAc. Separate the filtrate, wash the aqueous layer with more EtOAc, join the organic layers, dry it over MgSO4, filter and concentrate in vacuo to afford 4-Chloro-1H-pyrazolo[3,4-d]pyrimidine (16 g, 70.45% yield) as a yellow solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]1.[C:14]([O-])(=[O:16])[CH3:15].[Na+].C(C1C(=O)CC(C2C=CC(F)=CC=2)CC1=O)(=O)C>>[C:14]([CH:9]1[C:10](=[O:12])[CH2:11][CH:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH2:7][C:8]1=[O:13])(=[O:16])[CH3:15]
Reactant: O=C1CC(=O)CC(c2ccco2)C1
Reactant: CC(=O)[O-]
Agent: CC(=O)C1C(=O)CC(c2ccc(F)cc2)CC1=O
Agent: [Na+]
Product: CC(=O)C1C(=O)CC(c2ccco2)CC1=O

Procedure:
The title compound was prepared from 5-(2-furyl)-cyclohexane-1,3-dione (500 mg, 2.8 mmol) and sodium acetate (229 mg, 2.8 mmol), following the procedure describing the synthesis of 2-acetyl-5-(4-fluoro-phenyl)-cyclohexane-1,3-dione (example 3/a stage 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[NH:16][C:17]4[CH2:18][CH2:19][CH2:20][C:21](=[O:39])[C:22]=4[CH:23]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][C@@H:35]([OH:38])[CH2:36][OH:37])=[CH:29][CH:28]=4)[C:24]=3[C:25]#[N:26])[N:12]=2)=[CH:4][CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:24]([C:25]#[N:26])=[C:23]([C:27]4[CH:28]=[CH:29][C:30]([O:33][CH2:34][C@@H:35]([OH:38])[CH2:36][OH:37])=[CH:31][CH:32]=4)[C:22]4[C:21](=[O:39])[CH2:20][CH2:19][CH2:18][C:17]=4[N:16]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: N#CC1=C(SCc2csc(-c3ccc(Cl)cc3)n2)NC2=C(C(=O)CCC2)C1c1ccc(OC[C@@H](O)CO)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc2c(c1-c1ccc(OC[C@@H](O)CO)cc1)C(=O)CCC2

Procedure:
At RT, 100 mg (0.172 mmol) of the compound from Example 5A and 40 mg (0.174 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone were stirred overnight in 6 ml of dichloromethane. The reaction solution was diluted with dichloromethane and water, and the two phases were separated. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were concentrated and purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% TFA).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH:26]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH2:28][C@@H:29]([C:31]([O:33]C)=[O:32])[CH3:30].[BH-](OC(C)=O)(OC(C)=O)O[C:37](C)=O.[Na+].C=O>C(Cl)Cl.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][N:28]([CH3:37])[C@@H:29]([C:31]([OH:33])=[O:32])[CH3:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)c[nH]c34)no2)cc1Cl
Reactant: COC(=O)[C@@H](C)N
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CN(C)[C@H](C)C(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 40 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
To a stirred solution of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole-3-carbaldehyde (D61) (150 mg), methyl D-alaninate (81 mg) and acetic acid (24 mg) in DCM (10 mL) was added NaBH(OAc)3 (167 mg). The mixture was stirred at 40° C. for 2 h, followed by addition of formaldehyde (120 mg). This mixture was stirred at 40° C. overnight. After concentration, the residue was dissolved in THF (5 mL), followed by addition of aqueous NaOH (2 M, 2 mL). The mixture was stirred at 50° C. for 2 h, and then acidified with HCl (2 M) to pH 4-5, partitioned between ethyl acetate (25 mL) and water (25 mL). The organic phase was washed with water (25 mL) and brine (25 mL), dried over anhydrous sodium sulphate, and evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}-N-methyl-D-alanine (E53) (35 mg). δH (DMSO-d6, 400 MHz): 1.30 (3H, d), 1.36 (6H, d), 2.42 (3H, s), 3.40 (1H, q), 4.16 (2H, s), 4.90 (1H, m), 7.26 (1H, t), 7.45 (1H, d), 7.56 (1H, d), 7.97 (1H, d), 8.09 (1H, d), 8.21 (1H, dd), 8.38 (1H, d), 11.17 (1H, br s). MS (ES): C24H25ClN4O4 requires 468; found 366.1 (M—C4H8NO2+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[S:5].Cl[CH2:13][S:14][C:15]#[N:16]>>[S:14]([CH2:13][O:6][C:4](=[S:5])[C:3]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=1[Cl:1])[C:15]#[N:16]
Reactant: OC(=S)c1ccc(Cl)cc1Cl
Reactant: N#CSCCl
Product: N#CSCOC(=S)c1ccc(Cl)cc1Cl
Yield: 81 %

Procedure:
15.8 g (0.064 mol) of the K salt of 2,4-dichloro-thiobenzoic acid and 6.3 g (0.06 mol) of chloromethyl thiocyanate were reacted and processed as in Example 1 B. 13.5 g of a yellowish oil having a density of 1.45 (this corresponds to a yield of 81% of the theoretical conversion). Use Examples
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:29]=[CH:28][C:11]([C:12]([O:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=2)=O)=O)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([NH2:33])(=O)C.B(F)(F)F>>[CH2:1]([O:7][C:8]1[CH:29]=[CH:28][C:11]([C:12]2[O:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=3)[N:33]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(C(=O)OCC(=O)c2ccc(C(=O)OC)cc2)cc1
Reactant: CC(N)=O
Agent: FB(F)F
Product: CCCCCCOc1ccc(-c2nc(-c3ccc(C(=O)OC)cc3)co2)cc1
Temperature: 140 °C
Reaction time: 18 h
Yield: 18 %

Procedure:
140 mg (0.377 mmol) 2-[4-(methoxycarbonyl)phenyl]-2-oxoethyl 4-hexyloxybenzoate and 111 mg (5 eq) acetamide were dissolved in 5 mL xylenes. 10 uL (0.2 eq) boron trifluoride was added and the reaction was stirred at 140° C. for 18 h. Another 50 uL (1.0 eq) boron trifluoride was added and stirring continued for 24 h. The reaction was quenched with saturated sodium bicarbonate solution and extracted with DCM. The combined organic phases were dried and evaporated. Purification of the residue by flash chromatography (100% hexanes to 10% EA/hexanes) yielded 26 mg (0.068 mmol, 18%) of the product. MS: m/z=380.21 [M+1]+.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].C(N(CC)CC)C>C(Cl)(Cl)Cl.CCCCCC>[F:14][C:15]1[CH:16]=[C:17]([NH:18][C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:12])[CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Nc1cccc(F)c1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Nc1cccc(F)c1)C12CC3CC(CC(C3)C1)C2

Procedure:
Subject 3.6 g. (18 mmoles) of adamantane carboxylic acid chloride, 2.0 g. of m-fluoroaniline and 8.0 ml. of triethylamine to the process of Example 11. Crystallize the residue obtained thereby from a mixture of chloroform-hexane to obtain the title product, m.p. 174°-177° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].C(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[Cl:16])=[O:6]
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: Nc1ccccc1Cl
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Nc1cc(F)ccc1C(=O)Nc1ccccc1Cl
Yield: 52 %

Procedure:
Prepared according to Procedure A using 2-amino-4-fluorobenzoic acid (1.15 g, 7.41 mmol) and SOCl2 (1.4 mL, 18.5 mmol) in benzene (25 mL), followed by 2-chloroaniline (1.6 mL, 14.8 mmol) and CHCl3 (25 mL). The product was chromatographed in CH2Cl2, then triturated from hexanes to provide 1.02 g of an off-white solid (52%). 1H NMR (CDCl3) δ: 12.91 (br s, 1H); 8.72 (dd, J=2.7, 12 Hz, 1H); 8.34 (dd, J=6.4, 9.2 Hz, 1H); 8.29 (dd, J=5.9, 8.8 Hz, 1H); 7.81 (dd, J=6.2, 8.8 Hz, 1H); 7.28 (dt, J=2.4, 8.4 Hz, 1H); 7.21 (dd, J=2.4, 9.0 Hz, 1H); 6.92 (ddd, J=2.4, 7.3, 9.1 Hz, 1H); 6.54 (ddd, J=2.4, 7.8, 8.8 Hz, 1H); 6.45 (dd, J=2.4, 11 Hz, 1H); 5.93 (br s, 2H). MS (ES): m/z 265.0 (M+).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.[F:29][C:30]1([F:57])[C:38]2[C:33](=[CH:34][CH:35]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:37]=2)[N:32]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[C:31]1=[O:56]>>[F:29][C:30]1([F:57])[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:2]3[N:7]4[CH:8]=[C:9]([CH2:11][CH2:12][C:13]5[CH:22]=[CH:21][C:20]6[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=6)[N:14]=5)[N:10]=[C:6]4[C:5]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:4][CH:3]=3)[CH:37]=2)[N:32]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:53])[CH3:54])[C:31]1=[O:56]
Reactant: Brc1cnc(N2CCOCC2)c2nc(CCc3ccc4ccccc4n3)cn12
Reactant: CC1(C)OB(c2ccc3c(c2)C(F)(F)C(=O)N3COCC[Si](C)(C)C)OC1(C)C
Product: C[Si](C)(C)CCOCN1C(=O)C(F)(F)c2cc(-c3cnc(N4CCOCC4)c4nc(CCc5ccc6ccccc6n5)cn34)ccc21

Procedure:
Compound 3a was subjected to Suzuki coupling conditions with 3,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2(trimethylsilyl)ethoxy)methyl)indolin-2-one to obtain compound 37b using the method described in the Example 21, Step D. Mass Spectrum (LCMS, ESI pos.) Calcd. For C35H38F2N6O3Si: 657.2 (M+H). Found 657.5.