Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]([CH2:21][C:22]([OH:24])=[O:23])[O:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.O1CCOC[CH2:26]1>CO>[CH3:26][O:23][C:22](=[O:24])[CH2:21][CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12](=[C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[NH:8][C:7]2=[O:11])[O:13]1
Reactant: C1COCCO1
Reactant: O=C(O)CC1OC(=C2C(=O)Nc3cc(F)ccc32)c2ccccc21
Solvent: CO
Product: COC(=O)CC1OC(=C2C(=O)Nc3cc(F)ccc32)c2ccccc21
Yield: 93 %

Procedure:
To a slurry of [3-(6-fluoro-2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-yl]-acetic acid (300 mg, 0.922 mmol) in a mixture of dioxane (15 ml) and MeOH (7 ml) was added 2.0M (trimethylsilyl)diazomethane/Hexanes (507 μl) and the resultant solution was stirred for 15 minutes at room temperature. The solvent was rotary evaporated and the residue was partitioned between EtOAc and saturated NaHCO3. The organic layer (combined a EtOAc solution from a previous 100 mg (0.307 mmol) scale test reaction) was then washed with dilute HCl aqueous solution, water, brine, dried with anhydrous Na2SO4, and rotary evaporated to a yellow solid. The solid was triturated with 30% EtOAc in hexane to yield [3-(6-fluoro-2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-yl]-acetic acid methyl ester as a bright yellow solid (388 mg, 93%).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[N:10]=[C:9]1[CH:18]([NH:24][C:25](=[O:40])[C:26]1[CH:31]=[CH:30][C:29]([C:32]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:33])=[C:28]([CH3:39])[CH:27]=1)[CH2:19][CH2:20][C:21](O)=[O:22])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:72]1[CH2:76][CH2:75][C@@H:74]([OH:77])[CH2:73]1.FC(F)(F)C(O)=O.ClCl>C(#N)C.C(OCC)(=O)C.C(O)C>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]2[NH:8][C:9]([C@@H:18]([NH:24][C:25](=[O:40])[C:26]3[CH:31]=[CH:30][C:29]([C:32]([N:34]4[CH2:35][CH2:36][CH2:37][CH2:38]4)=[O:33])=[C:28]([CH3:39])[CH:27]=3)[CH2:19][C:20](=[C:21]=[O:22])[N:72]3[CH2:76][CH2:75][C@@H:74]([OH:77])[CH2:73]3)=[N:10][C:11]=2[CH:16]=1
Reactant: Cc1cc(C(=O)NC(CCC(=O)O)c2nc3cc(Cl)ccc3n2C(=O)OC(C)(C)C)ccc1C(=O)N1CCCC1
Reactant: O[C@@H]1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N[C@@H](CC(=C=O)N2CC[C@@H](O)C2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 90 %

Procedure:
Prepared analogously to Example 1g from N-[1-(1-tert-butoxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonylpropyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide, TBTU, diisopropylethylamine, (R)pyrrolidine-3-ol in acetonitrile, and subsequent reaction with trifluoroacetic acid analogously to Example 17. Yield: 90%; Rf value: 0.18 (silica gel; ethyl acetate/ethanol=85:15); C28H32ClN5O4 (538.05); mass spectrum: (M+H)+=538/540 (chlorine isotope).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([F:11])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1B(O)O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:11][C:5]1[C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]([C:14]2[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=2[F:12])=[CH:3][CH:4]=1
Reactant: O=C(O)c1nc(Br)ccc1F
Reactant: COc1ccc(F)c(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(F)c(C(=O)O)n2)c1
Yield: 89 %

Procedure:
Method 1 was followed using 6-bromo-3-fluoropicolinic acid (1.0 equiv.) and 2-fluoro-5-methoxyphenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.15 equiv.) to give 3-fluoro-6-(2-fluoro-5-methoxyphenyl)picolinic acid in 89% yield. LC/MS=266.1 (M+H), Rt=0.79 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([O:16][C:17]2[C:22](Br)=[CH:21][C:20]([S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])=[CH:19][N:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:29])[CH:11]=2)[CH:6]=1.[CH2:31](B(O)O)[CH3:32].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>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.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([O:16][C:17]2[C:22]([CH2:31][CH3:32])=[CH:21][C:20]([S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])=[CH:19][N:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:29])[CH:11]=2)[CH:6]=1
Reactant: CCB(O)O
Reactant: CCS(=O)(=O)c1cnc(Oc2c(C)c(CC(=O)OC)cc3ccc(F)cc23)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCc1cc(S(=O)(=O)CC)cnc1Oc1c(C)c(CC(=O)OC)cc2ccc(F)cc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
A mixture of [4-(3-bromo-5-ethanesulfonyl-pyridin-2-yloxy)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (42 mg, 0.085 mmol), ethylboronic acid (15 mg, 0.20 mmol), bis(triphenylphosphine)dichloropalladium(II) (7.0 mg, 0.01 mmol), potassium phosphate (64 mg, 0.30 mmol), triphenylphosphine (15.2 mg, 0.05 mmol) and toluene (1 mL) was stirred at 100° C. overnight under an argon atmosphere. The resulting mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by preparative TLC (20% ethyl acetate in petroleum ether) to afford [4-(5-ethanesulfonyl-3-ethyl-pyridin-2-yloxy)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (18 mg, 47.6%) as a white solid.
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]([O:16]C)=[O:15])[C:8]([C:18]([O:20]C)=[O:19])=[CH:7]2.[OH-].[Na+]>C(O)C.O>[F:22][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]([OH:16])=[O:15])[C:8]([C:18]([OH:20])=[O:19])=[CH:7]2
Reactant: COC(=O)c1cc2cc(OC(F)F)ccc2nc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc2cc(OC(F)F)ccc2nc1C(=O)O
Temperature: 5 °C

Procedure:
To a solution containing dimethyl 6-difluoromethoxyquinoline-2,3-dicarboxylate (0.162 mol) in 150 mL ethanol is added a solution of sodium hydroxide (0.5 mol) in 400 mL water and the mixture heated at reflux for five hours. The ethanol is removed in vacuo. The residue cooled to 5° C. and acidified with concentrated HCl. The product is removed by filtration, washed with water and dried to give 6-difluoromethoxyquinoline-2,3-dicarboxylic acid mp 226° C.
Reaction SMILES: [CH3:1][Si](C#C)(C)C.C([Li])CCC.[C:12]([O:16][C:17](=[O:39])[NH:18][C@:19]([CH:37]=O)(C)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:24][CH:23]=1)([CH3:15])(C)C>C1COCC1>[C:15]([CH:12]1[O:16][C:17](=[O:39])[NH:18][C@@:19]1([CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:26][CH:27]=1)[CH3:37])#[CH:1]
Reactant: C#C[Si](C)(C)C
Reactant: CCCCCCCOc1ccc(CC[C@](C)(C=O)NC(=O)OC(C)(C)C)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#CC1OC(=O)N[C@]1(C)CCc1ccc(OCCCCCCC)cc1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of trimethylsilylacetylene (0.18 ml, 1.27 mMol) in THF (18 ml) at −78° C. is added n-Butyllithium (0.49 ml, 2.5 M in cyclohexane). After 5 minutes, [(R)-1-Formyl-3-(4-heptyloxy-phenyl)-1-methyl-propyl]-carbamic acid tert-butyl ester (200 mg, 0.51 mMol) in THF (2 ml) is added and the reaction is stirred at −78° C. for 5 hours. After that time, the cooling is removed and the reaction is stirred for 16 hours at RT. The reaction mixture is then poured onto a biphasic mixture of AcOEt and NaHCO3 (saturated aqueous solution). The aqueous phase is extracted with AcOEt (3 times). The combined organic layers are dried (Na2SO4) and concentrated under reduced pressure. Column chromatography eluting with 8%-45% AcOEt in heptane gives (R)-5-Ethynyl-4-[2-(4-heptyloxy-phenyl)-ethyl]-4-methyl-oxazolidin-2-one and its C5 epimer.
Reaction SMILES: O.[NH2:2][C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[C:5]([Cl:10])[N:4]=1.[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[NH2:2][C:3]1[NH:8][C:7](=[O:9])[C:6]([N+:11]([O-:13])=[O:12])=[C:5]([Cl:10])[N:4]=1
Reactant: Nc1nc(O)cc(Cl)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1nc(Cl)c([N+](=O)[O-])c(=O)[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Following the method of O'Brien and Cheng (J. Med. Chem. 1966, 9, 573), to a stirred solution of 10.0 g (61.1 mmol) 2-amino-6-chloro-4-pyrimidinol monohydrate in 46 ml 98% sulfuric acid was added dropwise 9 ml 65% nitric acid at a rate such that the reaction temperature remainded around 40° C. After the addition was complete, stirring was continued for 1 hour at room temperature. The reaction mixture was then poured onto 150 ml ice-water and the resulting crystals were collected by filtration and washed sequentially with water, ethanol and ether to afford 12.6 g (99%) 2-amino-6-chloro-5-nitro-3H-pyrimidin-4-one as a light yellow crystalline solid. ES-MS m/e (%): 191 (M+H+, 100).
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][NH:11][CH2:12][C:13]1[C:16](=[O:17])[C:15](=[O:18])[C:14]=1[NH2:19])(=[O:8])[O:5]CC)C.Br[Si](C)(C)C>ClCCCl>[NH2:19][C:14]1[C:15](=[O:18])[C:16](=[O:17])[C:13]=1[CH2:12][NH:11][CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5]
Reactant: CCOP(=O)(CCNCc1c(N)c(=O)c1=O)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCCl
Product: Nc1c(CNCCP(=O)(O)O)c(=O)c1=O
Yield: 57.6 %

Procedure:
A suspension of [2-[(2-amino-3,4-dioxo-1-cyclobuten-1-yl)methylamino]ethyl]phosphonic acid diethyl ester (660 mg, 2.3 mmol) in anhydrous 1,2-dichloroethane (20 mL) under nitrogen was treated with bromotrimethylsilane (2.0 mL, 15 mmol) and heated to reflux for 10 minutes. The yellow solution was concentrated and the resulting solid was dissolved in water (75 mL), washed with diethyl ether (2×50 mL) and evaporated. The solid was dissolved in boiling methanol, filtered, and concentrated with the addition of ethyl acetate to a final volume of 75 mL to afford the title compound as a yellow solid (310 mg, 58%, mp 230°-260° C. dec); IR (KBr, cm-1): 3340, 1800; MS (-FAB): 233 (M-H, 32), 148 (100); 1H NMR (DMSO, 400 MHz): δ 7.62 (br s, NH2), 3.68 (br s, 2H), 3.16 (br s, 3 H), 1.90 (d of t, J=18 and 7.5 Hz, 2H).
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(N(CC)CC)C.Cl.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1>O1CCCC1.C(Cl)Cl>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([NH2:10])=[O:9])=[O:26])[CH:21]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: NC(=O)c1ccccc1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: NC(=O)c1ccccc1NC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.1 %

Procedure:
To a solution of anthranilamide (8.2 g, being on sale) and triethylamine (18.0 g)in 100 mL of tetrahydrofuran/methylene chloride (1:1), was added nicotinoyl chloride hydrochloride (10.8 g). The mixture was allowed to stir at room temperature, under nitrogen atmosphere, for six hours. The solution was then concentrated under reduced pressure. The concentrate was taken up in ethyl acetate and water and the mixture filtered. The solid material was triturated in ether and filtered to give the title compound (11.5 g) as a yellow powder having the following physical data.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[S:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+].O>CC(C)=O.CCOCC>[CH:2]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[S:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:1]
Reactant: COC(=O)CSc1sccc1C1OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CC(C)=O
Product: COC(=O)CSc1sccc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.9 %

Procedure:
To a solution of methyl [3-(2-dioxolanyl)-thiophene-2-ylthio]acetate (23.36 g) in acetone (100 mL) was added p-toluenesulfonic acid (0.25 g) and the reaction mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate (4 mL) was added with stirring followed by the addition of water (50 mL). After stirring for 10 minutes, the acetone was evaporated in vacuo to leave a gum and water. The gum was dissolved in ether (500 mL) and extracted with water (4×50 mL), dried (MgSO4), filtered and the solvent was evaporated in vacuo to leave 19.77 g of oily methyl (3-formylthiophene-2-ylthi-o)acetate which was used in the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[Br:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C>[C].[Rh].C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[Br:23])[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(Br)c(C=C2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [Rh]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(Br)c(CC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 40 °C
Reaction time: 16 h
Yield: 89.5 %

Procedure:
A mixture of N-tert-butoxycarbonyl-4-(2-bromo-5-methoxybenzal)piperidine (87.7 g, 0.229 mol), 5% rhodium-carbon (25.6 g), ethyl acetate (150 mL) and ethyl alcohol (150 mL) was stirred at 40° C. for 16 hours under a hydrogen atmosphere. The precipitate was filtered and then washed with ethyl acetate, and the filtrate was concentrated to dryness. The residue was diluted with ethyl acetate (800 mL) and washed with a saturated aqueous sodium chloride solution (100 mL). The dilution was dried over anhydrous magnesium sulfate and then concentrated to dryness to obtain 78.7 g (0.205 mol, 89%) of N-tert-butoxycarbonyl-4-(2-bromo-5-methoxybenzyl)piperidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].[Br:18]Br>C(O)(=O)C>[Br:18][CH:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: BrBr
Reactant: O=C(Cc1ccc(F)cc1F)c1ccccc1
Solvent: CC(=O)O
Product: O=C(c1ccccc1)C(Br)c1ccc(F)cc1F
Yield: 47 %

Procedure:
While cooling acetic acid solution prepared by dissolving 25 g (160.1 mmol) of 2,4-difluorophenyl acetophenone in an amount of 50 milliliter down to 10° C. or cooler, 25.5 g (160.1 mmol) of bromine was dripped and the resultant solution reacted for 7 hours. Throwing the resultant solution into 300 milliliter of water, the solution was extracted with the use of methylene chloride. After drying an organic layer with the use of magnesium sulfide, the solvent was removed. Refining the resultant residues by means of silica column (hexane), 23.4 g of α-bromo-2,4-difluorophenyl acetophenone Intermediate 1-2c as brown oil was obtained (yield: 62%). The brown oil was confirmed as the aimed compound from 1H-NMR spectrum. The measurement result is shown as follows:
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:15]([CH3:21])[C:16]([O:18]CC)=O)[CH:8]=[CH:9][C:10]=1[O:11]C(=O)C)(=O)C.[CH2:22]([NH2:27])[CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:22]([NH:27][C:16](=[O:18])[CH:15]([C:7]1[CH:8]=[CH:9][C:10]([OH:11])=[C:5]([OH:4])[CH:6]=1)[CH3:21])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCN
Reactant: CCOC(=O)C(C)c1ccc(OC(C)=O)c(OC(C)=O)c1
Product: CCCCCNC(=O)C(C)c1ccc(O)c(O)c1

Procedure:
Ethyl 3,4-diacetoxyphenylpropionate and n-pentylamine were used in the procedure described in Example 1, to obtain N-n-pentyl-3,4-dihydroxyphenylpropionamide as an oily product.
Reaction SMILES: [CH3:1][C:2]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1)([CH3:7])[C:3]([CH2:5][OH:6])=[O:4].[CH3:19]I>[Ag]=O>[CH3:7][C:2]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1)([CH3:1])[C:3]([CH2:5][O:6][CH3:19])=[O:4]
Reactant: CI
Reactant: CC(C)(NC(=O)c1cc(Cl)cc(Cl)c1)C(=O)CO
Agent: O=[Ag]
Product: COCC(=O)C(C)(C)NC(=O)c1cc(Cl)cc(Cl)c1

Procedure:
Methyl iodide (30 ml) and freshly prepared silver oxide (0.77 gm, 0.003 m) were added to N-(1',1'-dimethyl-3'-hydroxyacetonyl)-3,5-dichlorobenzamide (0.08 gm, 0.003 m) (Example 45) and the reaction mixture was refluxed for about 10 hours. Then fresh silver oxide (0.7 gm) was added and the mixture was refluxed for another 2 hours. The inorganic salts were removed by filtration, the filter cake was washed with ether and the solvents were stripped off to obtain 0.5 gm of product after recrystallization from ethylacetate and hexane.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[N:40])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[N:40])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(C(=O)N2CC[C@H](N(Cc3ccnc4ccccc34)C(=O)C(F)(F)F)C[C@H]2Cc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Product: N#Cc1cccc(C(=O)N2CC[C@H](NCc3ccnc4ccccc34)C[C@H]2Cc2ccccc2)c1

Procedure:
0.248 g (0.446 mmol) of (2R*,4S*)-2-benzyl-1-(3-cyanobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine is reacted with 0.068 g (1.78 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR74## is obtained (0.157 g, 62%) as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.51, FD-MS: M+ =460.
Reaction SMILES: O[CH:2]1[CH2:15][N:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]2=[O:16])=[CH:11][CH:10]=[C:9]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:8]=3)[CH2:4][CH2:3]1.CCN(S(F)(F)[F:31])CC>C(Cl)Cl>[F:31][CH:2]1[CH2:15][N:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]2=[O:16])=[CH:11][CH:10]=[C:9]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:8]=3)[CH2:4][CH2:3]1
Reactant: O=c1c2ccc(C#Cc3ccccn3)cc2nc2n1CC(O)CC2
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=c1c2ccc(C#Cc3ccccn3)cc2nc2n1CC(F)CC2
Reaction time: 3 h

Procedure:
To a stirred solution of 8-hydroxy-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one (100 mg, 0.315 mmol, 1 eq) in DCM was added excess DAST under N2 at −78° C. After stirring at the same temperature for 3 hours, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the desired product, which was purified by silica gel chromatography. MS (ESI): 320 (MH+); 1H NMR (300 MHz, DMSO-d6) δ 8.65-8.65 (d, J=3.30 Hz, 1H), 8.17-8.14 (d, J=8.16 Hz, 1H), 7.92-7.87 (t, J=7.5 Hz, 1H), 7.79 (s, 1H), 7.74-7.72 (d, J=7.71 Hz, 1H), 7.67-7.64 (d, J=8.04 Hz, 1H), 7.48-7.47 (m, 1H), 5.50-5.34 (d, J=48.6 Hz, 1H), 4.62-4.52 (t, J=15.9 Hz, 1H), 3.93-3.79 (dd, J=38.1, 15.3 Hz, 1H), 2.96-2.94 (m, 2H), 2.45-2.10 (m, 2H).
Reaction SMILES: [Sb:1](=O)([O-])([O-])[O-].[Na+].[Na+].[Na+].[Sb].[CH2:10]([SH:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl>O>[CH2:10]([SH:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[Sb+5:1]
Reactant: O=[Sb]([O-])([O-])[O-]
Agent: CCCCCCCCCCS
Agent: Cl
Agent: [Na+]
Solvent: O
Product: [Sb+5]
Temperature: 4 °C

Procedure:
Sodium antimonate obtained from U.S. Antimony Corporation (9.49 g, 0.02347 mole) was placed in a reaction vessel and 1-decanethiol from Eastman Kodak (50 ml, 0.2347 mole) added and stirred. Concentrated hydrochloric acid (3.9 ml, 0.0468 mole) was added dropwise and an immediate temperature increase of 4° C. was observed. The mixture was heated and the byproduct of the reaction, water, was distilled over at 28° C. and a vacuum of 50 mm Hg. After 2.5 hours 45.57 g of antimony (V) decanethiol was obtained. The product was filtered to remove unreacted sodium antimonate and the additional byproduct of the reaction, sodium chloride.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][C:6]([C:10]([O:12][CH3:13])=[O:11])([CH2:7][CH2:8]1)[CH2:5][CH2:4][CH2:3]2.[CH3:14][C:15]1[N:20]=[C:19]([C:21](O)=[O:22])[CH:18]=[N:17][CH:16]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.O>C(Cl)Cl>[CH3:14][C:15]1[N:20]=[C:19]([C:21]([NH:1][C:2]23[CH2:9][C:6]([C:10]([O:12][CH3:13])=[O:11])([CH2:7][CH2:8]2)[CH2:5][CH2:4][CH2:3]3)=[O:22])[CH:18]=[N:17][CH:16]=1
Reactant: COC(=O)C12CCCC(N)(CC1)C2
Reactant: Cc1cncc(C(=O)O)n1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: ClCCl
Product: COC(=O)C12CCCC(NC(=O)c3cncc(C)n3)(CC1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To a solution of methyl 5-aminobicyclo[3.2.1]octane-1-carboxylate (0.98 g, 5.36 mmol) and 6-methylpyrazine-2-carboxylic acid (0.89 g, 6.45 mmol) in DCM (30 mL) and TEA (2 mL) was added PyBOP (3.35 g, 6.44 mmol). After stirring at room temperature overnight, water (30 mL) was added and the mixture was extracted with DCM (3×50 mL). The combined organic layer was washed with Sat. NaHCO3 (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate: 1/1) to afford 1.28 g (79%) of methyl 5-(6-methylpyrazine-2-carboxamido)bicyclo[3.2.1]octane-1-carboxylate as an off-white solid. ESI-MS m/z: 304 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[C:22]4[C:17](=[CH:18][C:19]([CH:23]=[C:24]5[C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[NH:26][C:25]5=[O:33])=[CH:20][CH:21]=4)[NH:16][N:15]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:34][O:35]C1C=C2C(=CC=1)NC(=O)C2>>[CH3:34][O:35][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:33])[C:24]2=[CH:23][C:19]1[CH:18]=[C:17]2[C:22]([C:14]([C:11]3[CH:12]=[N:13][C:8]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:9][CH:10]=3)=[N:15][NH:16]2)=[CH:21][CH:20]=1
Reactant: CN1CCN(c2ccc(-c3n[nH]c4cc(C=C5C(=O)Nc6ccccc65)ccc34)cn2)CC1
Reactant: COc1ccc2c(c1)CC(=O)N2
Product: COc1ccc2c(c1)C(=Cc1ccc3c(-c4ccc(N5CCN(C)CC5)nc4)n[nH]c3c1)C(=O)N2

Procedure:
According to the procedure for the synthesis of 3-((3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indazol-6-yl)methylene)indolin-2-one, except substituting 5-methoxyoxindole (28 mg, 0.087 mol), the title compound was prepared as a yellow solid (14.4 mg, 35%). A mixture of (E)- and (Z)-isomers (83:17 by NMR) was obtained. 1H NMR (400 MHz, CD3OD) 8.74 (d, J=2.3 Hz, 1H), 8.14 (dd, J=8.8, 2.3 Hz, 1H), 8.07 (d, J=8.5 Hz, 1H), 7.87 (d, J=10.0 Hz, 2H), 7.49 (d, J=8.3 Hz, 1H), 7.26 (s, 1H), 7.01 (d, J=8.8, 1H), 6.83 (s, 2H), 3.75-3.69 (br. m, 4H), 3.62 (s, 3H), 2.82-2.76 (br. m, 4H), 2.51 (s, 3H); MS ESI 467.2 [M+H]+, calcd for [C27H26N6O2+H]+ 467.21.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([Li])[N:3]=[CH:2]1.[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][CH:23]=1)[CH:13]=[N:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[CH3:8]>>[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][CH:23]=1)[CH:13]([NH:14][C:15]1[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=1)[C:4]1[N:3]=[CH:2][O:1][CH:5]=1)[CH3:8]
Reactant: CCOc1cccc(C=Nc2ccncc2)c1
Reactant: [Li]c1cocn1
Product: CCOc1cccc(C(Nc2ccncc2)c2cocn2)c1

Procedure:
The title compund is prepared in a similar manner to Examples 5,6 and 7 from 4-oxazolyl lithium (obtained from 4-bromooxazole and butyl lithium) and 4-(m-ethoxybenzylideneamino)pyridine.