Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C@@H:14]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[NH2:15])[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11].[C:23]([O:27][C:28](=[O:40])[CH2:29][N:30]1[C:35](=[O:36])[CH:34]=[CH:33][C:32]([C:37](O)=[O:38])=[CH:31]1)([CH3:26])([CH3:25])[CH3:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[F:2][C:3]1[CH:4]=[C:5]([C@H:14]([NH:15][C:37]([C:32]2[CH:33]=[CH:34][C:35](=[O:36])[N:30]([CH2:29][C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:40])[CH:31]=2)=[O:38])[C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11]
Reactant: N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F
Reactant: CC(C)(C)OC(=O)Cn1cc(C(=O)O)ccc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cn1cc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)ccc1=O
Temperature: 23 °C
Reaction time: 17 h

Procedure:
A solution of (S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanamine hydrochloride (400 mg, 1.174 mmol, Intermediate 6), 1-(2-(tert-butoxy)-2-oxoethyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (327 mg, 1.292 mmol) and HATU (491 mg, 1.292 mmol) in DMF (10 mL) was treated with TEA (0.490 mL, 3.52 mmol). The reaction was then stirred at 23° C. under nitrogen. After 17 h, the solution was diluted with EtOAc (100 mL) and washed with brine (100 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 5-30% EtOAc/DCM), affording the title compound as a colorless oil. The compound was taken forward to the next step. MS (ESI, positive ion) m/z: 540.2 (M+H).
Reaction SMILES: [C:1]([CH2:6][N:7]1[C:11]([SH:12])=[N:10][N:9]=[N:8]1)([C:3]([OH:5])=[O:4])=O.Cl.[NH2:14][OH:15].[OH-].[Na+].Cl>O>[C:3]([C:1](=[N:14][OH:15])[CH2:6][N:7]1[C:11]([SH:12])=[N:10][N:9]=[N:8]1)([OH:5])=[O:4]
Reactant: NO
Reactant: O=C(O)C(=O)Cn1nnnc1S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(Cn1nnnc1S)=NO
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 52 %

Procedure:
A solution of 1-oxalomethyl-1H-tetrazole-5-thiol (10.0 g) and hydroxylamine hydrochloride (4.8 g) in water (100 ml) was adjusted to pH 6.0 with 2N aqueous solution of sodium hydroxide and stirred at room temperature for 3.5 hours. The solution was acidified with 10% hydrochloric acid to pH 2.0, extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1). The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated to give 1-(2-carboxy-2-hydroxyiminoethyl)-1H-tetrazole-5-thiol (5.61 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=2)=[CH:4][C:3]=1[NH2:18].[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=2)=[CH:4][C:3]=1[NH:18][C:19](=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cncc(C#Cc2ccc(F)c(N)c2)c1
Solvent: c1ccncc1
Product: COc1cncc(C#Cc2ccc(F)c(NC(C)=O)c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.3 %

Procedure:
Dissolve 2-fluoro-5-(5-methoxypyridin-3-ylethynyl)-phenylamine, (prepared as described in EXAMPLE 111), (200 mg, 0.83 mmol) in pyridine (3 mL) and add acetic anhydride (84 mg, 0.83 mmol). Stir under nitrogen at room temperature for 48 h and concentrate. Purify by silica gel chromatography, eluting with 100% ethyl acetate to give the title compound as a light yellow solid (180 mg, 76%).
Reaction SMILES: [CH3:1][NH:2][NH2:3].C(N(CC)CC)C.[CH2:11]([O:18][C:19](Cl)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1>[C:12]1([CH2:11][O:18][C:19]([N:2]([CH3:1])[NH2:3])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNN
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(N)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cold, stirred solution of 36.8 (0.8 mol; 42.49 ml) methylhydrazine and 161.6 g (1.6 mol, 224 ml) triethylamine in 700 ml tetrahydrofuran were added dropwise 136.5 g (0.8 mol, 113.6 ml) benzylchloroformate. After stirring at room temperature overnight, the tetrahydrofuran was evaporated and the residue was worked up with ethylacetate/water (pH=9.0. Insoluble material was removed by filtration and the organic phase was washed (H2O), dried (MgSO4) and evaporated. The oily residue was stirred with 1 1. of ether, the etherial solution was decanted from insoluble material and evaporated to give 61 g of an oil which was dissolved in 200 ml MeOH containing 25 ml conc. HCl. After evaporation to dryness, the residue was recrystallized from EtOH/ ethylacetate to give 22.0 g of the hydrochloride of 2 as colorless crystals. This material was dissolved in water and the pH was adjusted to 9.0. Extraction with ethylacetate, drying of the organic phase (MgSO4) and evaporation yielded 19.0 g of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:14]([I:15])=[CH:13][C:5]2[C:6](=[O:12])[CH2:7][CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.[CH3:16][N:17]([CH:19](OC)OC)[CH3:18].CCOCC>C1COCC1>[Cl:1][C:2]1[C:14]([I:15])=[CH:13][C:5]2[C:6](=[O:12])/[C:7](=[CH:16]\[N:17]([CH3:19])[CH3:18])/[CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)c2cc(I)c(Cl)cc2N1
Reactant: COC(OC)N(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)/C=C1/CC(=O)Nc2cc(Cl)c(I)cc2C1=O
Temperature: 60 °C
Reaction time: 17 h
Yield: 81.5 %

Procedure:
To a suspension of 8-chloro-7-iodo-3,4-dihydro-1H-1-benzazepine-2,5-dione (10.0 g, 29.8 mmol) in THF (44mL) was added DMF-DMA (21.1 mL, 149 mmol). The flask reaction mixture was allowed to stir 60° C. under an atmosphere of argon. A light orange solution containing a suspended solid resulted. After 17 h, the reaction mixture was allowed to cool to it. Ether (100 mL) was added and the solid was collected via suction filtration, washed with ether, and dried in a vacuum oven to yield (4Z)-8-chloro-4-[(dimethylamino)methylene]-7-iodo-3,4-dihydro-1H-1-benzazepine-2,5-dione (9.50g, 24.3 mmol, 82%) as a yellow solid. LCMS (FA): m/z=391 (M+H).
Reaction SMILES: C([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@@H:13]([C:15](=[O:21])[NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:12][CH2:11][C@@H:10]1[NH:22][C:23]([C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([Cl:34])=[CH:29][CH:28]=2)=[O:24])=O)(C)(C)C.Cl.[CH3:36][N:37]1[CH2:42][CH2:41][C:40]2[N:43]=[C:44](C([O-])=O)[S:45][C:39]=2[CH2:38]1.[Li+]>O1CCOCC1>[ClH:34].[C:17]([NH:16][C:15]([C@H:13]1[CH2:12][CH2:11][C@H:10]([NH:22][C:23]([C:25]2[NH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([Cl:34])=[CH:29][CH:28]=3)=[O:24])[C@H:9]([NH:8][C:6]([C:44]2[S:45][C:39]3[CH2:38][N:37]([CH3:36])[CH2:42][CH2:41][C:40]=3[N:43]=2)=[O:5])[CH2:14]1)=[O:21])([CH3:18])([CH3:20])[CH3:19]
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Reactant: CC(C)(C)NC(=O)[C@H]1CC[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Li+]
Solvent: C1COCCO1
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)NC(C)(C)C)CC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1

Procedure:
(1S,2R,4S)—N2-(tert-Butoxycarbonyl)-4-[N-(tert-butyl)carbamoyl]-N1-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine was treated with a 4N dioxane solution of hydrochloric acid and then condensed with lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in a similar manner to Example 118 to obtain the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)=[O:20].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:9]([C:8]1[CH:7]=[C:6]([CH:13]=[CH:12][CH:11]=1)[O:5][CH2:4][CH2:3][NH:2][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([C:19](=[O:20])[C:18]2[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:16]([O:15][CH3:14])[CH:17]=2)=[CH:22][CH:23]=1)#[N:10]
Reactant: N#Cc1cccc(OCCN)c1
Reactant: COc1ccc(C(=O)c2ccc(C(=O)O)cc2)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2ccc(C(=O)NCCOc3cccc(C#N)c3)cc2)cc1OC
Reaction time: 8 h

Procedure:
0.68 g (3.45 mmol) of 3-(2-aminoethoxy)benzonitrile monohydrochloride was dissolved in 20 ml of N,N-dimethylformamide (dehydrated). 0.9 g (3.14 mmol) of 4-(3,4-dimethoxybenzoyl)benzoic acid, 0.47 g (3.45 mmol) of 1-hydroxybenzotriazole, 0.48 ml (3.45 mmol) of triethylamine and 0.66 g (3.45 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added to the obtained solution, and they were stirred overnight. The solvent was evaporated, and the residue was treated with ethyl acetate as the extraction solvent in an ordinary manner to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[C:9]([CH3:21])=[CH:10][C:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[C:12]=2[C:19]=1[CH3:20])([CH3:4])([CH3:3])[CH3:2].[Br:23]N1C(=O)CCC1=O.O>C(#N)C>[Br:23][C:10]1[C:11]2[O:15][C:14]([CH3:16])([CH3:17])[C:13](=[O:18])[C:12]=2[C:19]([CH3:20])=[C:8]([NH:7][C:6](=[O:22])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:9]=1[CH3:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2c(c(C)c1NC(=O)OC(C)(C)C)C(=O)C(C)(C)O2
Solvent: CC#N
Solvent: O
Product: Cc1c(Br)c2c(c(C)c1NC(=O)OC(C)(C)C)C(=O)C(C)(C)O2
Temperature: 25 °C
Yield: 72 %

Procedure:
To a solution of tert-butyl(2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Reference Example 60 (4.86 g, 15.9 mmol) in acetonitrile (70 mL) was added N-bromosuccinimide (5.67 g, 31.8 mmol) was heated under reflux for 1.5 hours. The reaction solution was cooled to room temperature, followed by addition of water, which was extracted with ethyl acetate, and the organic layer was washed with water and a saturation brine, dried over anhydrous sodium sulfate, and then was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:7), and then was recrystallized with ethyl acetate-hexane to obtain 4.40 g (yield 72%) of the title compound. Melting point: 131-132° C.
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[N:5][C:4](Cl)=[CH:3][C:2]=1[C:9]([F:12])([F:11])[F:10].[OH-].[NH4+:14]>>[Cl:7][C:6]1[N:5]=[C:4]([NH2:14])[CH:3]=[C:2]([C:9]([F:12])([F:11])[F:10])[CH:1]=1
Reactant: FC(F)(F)c1cc(Cl)nc(Cl)c1
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1cc(C(F)(F)F)cc(Cl)n1
Temperature: 25 °C

Procedure:
A solution of 2,6-dichloro-4-(trifluoromethylpyridine) (Fluorochem, 10.0 g; 46.30 mmol; 1.0 eq.) in ammonium hydroxide (˜25% in water) (40.0 mL; 4.0 V) was heated to 180° C. for 3 h in a Parr apparatus and cooled down to rt. After this time, reaction mixture was filtered over a bed of celite, evaporated to dryness under reduced pressure, triturated with DCM and filtered. The mother liquors were concentrated under reduced pressure to give the title compound as a yellow oil that crystallized upon standing (4.83 g; 53%). HPLC, Rt: 3.58 min. (purity 96.9%). LC/MS, M+(ESI): 196.8, M−(ESI): 194.8.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:27])[CH2:23][C:22]([CH3:25])([CH3:24])[CH2:21][C:20](=O)[CH2:19]1>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[CH2:23][C:18]([CH3:27])([CH3:17])[CH2:19]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(F)cc1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(F)cc2)CC(C)(C)C1
Yield: 80.5 %

Procedure:
The general McMurry coupling procedure described for 14 was followed. To a stirred suspension of zinc powder (13.0 g, 0.2 mol) in THF (400 mL) was slowly added TiCl4 (11 mL, 0.10 mol) via a syringe at room temperature under a nitrogen atmosphere. The reaction mixture was heated at reflux for 1 h. A solution of (4-fluorophenyl)(4-hydroxyphenyl)methanone (4.32 g, 0.02 mol) and 3,3,5,5-tetramethylcyclohexanone (9.26 g, 0.06 mol) in THF (100 mL) was added to the reaction mixture. The reaction mixture was heated at reflux for an additional 2 h. Standar work-up followed by purification gave 5.450 g (80%) of compound 231 as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.14 (d, J=5.7 Hz, 1H), 7.12 (d, J=5.7 Hz, 1H), 7.04 (d, J=8.7 Hz, 2H), 6.97 (dd, J=8.7 Hz, 2H), 6.76 (d, J=8.7 Hz, 2H), 4.68 (s, 1H), 1.99 (s, 2H), 1.96 (s, 2H), 1.31 (s, 2H), 0.95 (s, 6H), 0.94 (s, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:7]([OH:8])[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[CH2:16]([O:23][C:24](ON1C(=O)CCC1=O)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[OH:8][CH:7]1[CH:3]([CH2:2][NH:1][C:24]([O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:25])[CH2:4][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C(CN)C1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(O)C(CNC(=O)OCc2ccccc2)C1
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a solution of 1,1-dimethylethyl 3-(aminomethyl)-4-hydroxy-1-pyrrolidinecarboxylate (3 g, 13.9 mmol) [Prepared according to Hong, C.-Y. J. Med. Chem. 1997, 40, 3584.] in DCM (100 mL) at 0° C. was added N-(benzyloxycarbonyloxy)succinimide (3.8 g, 15.3 mmol) portion-wise. After 1 h, the reaction was partitioned between H O-DCM. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried (Na SO), concentrated and purified by column chromatography (silica, 3% MeOH in DCM (1% NH OH)) yielding the title compound (4.8 g, quant.) as a clear oil: LCMS (ES) m/e 351 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:25][CH3:26])[C:15]([NH:17][C:18]([CH2:22][O:23][CH3:24])([CH3:21])[CH2:19][OH:20])=[O:16])=[CH:8][C:7]=2[CH3:27])#[CH:2].[CH2:28](Br)[C:29]#[CH:30].[H-].[Na+]>C1COCC1>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:25][CH3:26])[C:15]([NH:17][C:18]([CH3:21])([CH2:19][O:20][CH2:30][C:29]#[CH:28])[CH2:22][O:23][CH3:24])=[O:16])=[CH:8][C:7]=2[CH3:27])#[CH:2]
Reactant: C#CCBr
Reactant: C#Cc1cnc2c(C)cc(OC(SC)C(=O)NC(C)(CO)COC)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCOCC(C)(COC)NC(=O)C(Oc1cc(C)c2ncc(C#C)cc2c1)SC
Temperature: 55 °C
Reaction time: 4 h
Yield: 50.1 %

Procedure:
To a solution of 2-(3-ethynyl-8-methyl-quinolin-6-yloxy)-N-(2-hydroxy-1-methoxymethyl-1-methyl-ethyl)-2-methylsulfanyl-acetamide (120 mg) in dry THF (10 ml) NaH (27 mg, 60% in oil) was added at room temperature under a nitrogen atmosphere. After 30 minute propargyl bromide (115 mg) was added to the reaction mixture. After stirring during 5 h one equivalent of NaH and one equivalent of propargyl bromide were added. The mixture was stirred during 4 h at 55° C., then quenched with water and diluted with ethyl acetate. The water phase was extracted twice with ethyl acetate and the combined organic phases dried over sodium sulfate, filtered and evaporated. The crude residue was purified by column chromatography (cyclohexane/ethyl acetate, 3:2) to give 2-(3-Ethynyl-8-methyl-quinolin-6-yloxy)-N-(2-methoxy-1-methyl-1-prop-2-ynyloxymethyl-ethyl)-2-methylsulfanyl-acetamide (66 mg) as a light brown oil as a mixture of diastereoisomers.
Reaction SMILES: [C:1]([S@:5]([NH2:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[Br:8][C:9]1[N:14]=[C:13]([C:15](=O)[CH3:16])[C:12]([F:18])=[C:11]([Si:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:10]=1>C1COCC1.[Cl-].[Na+].O>[Br:8][C:9]1[N:14]=[C:13](/[C:15](=[N:7]/[S@@:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[O:6])/[CH3:16])[C:12]([F:18])=[C:11]([Si:19]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:24][CH3:25])[CH:10]=1
Reactant: CC[Si](CC)(CC)c1cc(Br)nc(C(C)=O)c1F
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC[Si](CC)(CC)c1cc(Br)nc(/C(C)=N/[S@](=O)C(C)(C)C)c1F
Yield: 82 %

Procedure:
A mixture of titantetraethoxide (4.26 g, 18.69 mmol), (R)-tert.-butylsulfinamide (1.246 g, 10.28 mmol) and 1-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-ethanone (3.45 g, 9.34 mmol, 90% pure) in THF (25 ml) was refluxed under a nitrogen atmosphere for 6 hours. The cold reaction mixture was poured onto icecold brine (200 ml) with gentle stirring. The precipitate was filtered through a pad of hyflo and washed with ethyl acetate. The filtrate was diluted with ethyl acetate and washed with brine, dried over sodium sulfate, filtered and evaporated. The crude yellow oil (4.55 g) was chromatographed over silica gel (cyclohexane/ethyl acetate 94:6) to give the title compound as a yellow oil. 3.35 g (82% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=3[CH3:22])[NH2:18])[N:9]=2)[CH:5]=[N:6][CH:7]=1.Cl.Cl.[CH2:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][C:35]=2[C:43]([F:46])([F:45])[F:44])[CH2:29][CH2:28]1)[CH3:26]>>[CH2:25]([N:27]1[CH2:28][CH2:29][N:30]([CH2:33][C:34]2[CH:42]=[CH:41][C:37]([C:38]([NH:18][C:17]3[CH:19]=[CH:20][C:21]([CH3:22])=[C:15]([NH:14][C:10]4[N:9]=[C:8]([C:4]5[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=5)[CH:13]=[CH:12][N:11]=4)[CH:16]=3)=[O:39])=[CH:36][C:35]=2[C:43]([F:46])([F:44])[F:45])[CH2:31][CH2:32]1)[CH3:26]
Reactant: CCN1CCN(Cc2ccc(C(=O)Cl)cc2C(F)(F)F)CC1
Reactant: Cc1ccc(N)cc1Nc1nccc(-c2cncc(Br)c2)n1
Agent: Cl
Product: CCN1CCN(Cc2ccc(C(=O)Nc3ccc(C)c(Nc4nccc(-c5cncc(Br)c5)n4)c3)cc2C(F)(F)F)CC1
Reaction time: 24 h

Procedure:
This compound was prepared in the same manner as in Example 1, except that 3-[4-(5-bromopyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline (Reference Example 19) and 4-(4-ethylpiperazin-1-ylmethyl)-3-trifluoromethylbenzoyl chloride dihydrochloride (Reference Example 5) were used, and that the reaction was conducted at room temperature for 24 hours and the amorphous obtained by purification with silica gel column chromatography was crystallized by adding chloroform-diethyl ether (1:1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[N:9]1[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:15][C:12]2[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=2)[CH:8]=1)([O-:3])=[O:2]
Reactant: OCc1ccncc1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnn(Cc2ccncc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.7 %

Procedure:
To a stirred solution of 4-nitro-1H-pyrazole (211 mg, 1.87 mmol), pyridine-4-methanol (0.28 ml, 2.56 mmol), and triphenylphosphine (538 mg, 2.05 mmol) in THF (10 ml) under nitrogen is added di-t-butyl azodicarboxylate (472 mg, 2.05 mmol) over 3 min. The reaction mixture was stirred at room temperature for 16 h. The mixture is concentrated and purified via flash column chromatography using a gradient elution of 0-3% CH2Cl2/methanol to afford the desired compound as a yellow oil (247 mg, 65%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][S:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.Cl.[CH:18](=O)/[CH:19]=[CH:20]/[CH3:21].N>>[CH3:18][C:19]1[CH:20]=[CH:21][C:14]2[C:13](=[CH:12][CH:11]=[C:10]([S:9][S:8][C:5]3[CH:4]=[C:3]4[C:2](=[CH:7][CH:6]=3)[N:1]=[C:3]([CH3:4])[CH:2]=[CH:7]4)[CH:15]=2)[N:16]=1
Reactant: C/C=C/C=O
Reactant: Nc1ccc(SSc2ccc(N)cc2)cc1
Agent: Cl
Agent: N
Product: Cc1ccc2cc(SSc3ccc4nc(C)ccc4c3)ccc2n1

Procedure:
To a stirred slurry of 4-aminophenyl disulfide (5.0 g, 0.02 mol) in refluxing 6M HCl (65 ml) was added crotonaldehyde (4.2 g, 0.06 mol) dropwise over 90 minutes. The resulting mixture was refluxed for an additional 2 hours, then cooled to ambient. Conc aqueous ammonia was added to adjust the pH to neutral and the mixture extracted with ethyl acetate. The combined extracts were washed with water, then saturated aqueous brine, dried (MgSO4), filtered and concentrated. The crude was purified on silica gel, eluting with 50 to 100% ethyl acetate/petrol. The product was an oil (2.57 g, 37%); MS ES+349.17.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:9][CH2:8]3.[C:14](Cl)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>N1C=CC=CC=1>[CH2:17]([O:16][C:14]([NH:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:9][CH2:8]3)=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccc2c(c1)C(=O)C1(CC1)O2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1ccc2c(c1)C(=O)C1(CC1)O2)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of 5-aminospiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one (1.35 g.) in pyridine (13.5 ml.) was added carbobenzyloxy chloride (30% toluene solution, 7 g.) under ice-cooling, and the mixture stirred for one hour. The reaction mixture was poured into ice-hydrochloric acid (14 ml.) and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to remove the solvent. The residue was recrystallized from ethanol. By the above procedure there was obtained 5-benzyloxycarbonylaminospiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one as pale yellow needles, m.p. 118°-119° C. Yield 1.57 g.
Reaction SMILES: C(OC([NH:8][C@:9]([CH3:29])([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:17][CH:16]=1)[C:10]([OH:12])=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@:9]([CH3:29])([CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:19][CH:20]=1)[C:10]([OH:12])=[O:11]
Reactant: CCCCCCCOc1ccc(CC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCOc1ccc(CC[C@@](C)(N)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (R)-2-tert-butoxycarbonylamino-4-(4-heptyloxy-phenyl)-2-methyl-butyric acid (43 mg, 0.11 mMol) in CH2Cl2 (2 ml) is added trifluoroacetic acid (0.1 ml). The mixture is stirred at RT for 8 hours. After that time, the reaction mixture is concentrated under reduced pressure. Column chromatography eluting with 5%→25% MeOH in CH2Cl2 gives the title compound as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](CC#N)[CH:5]=[C:6]([O:8]C)[CH:7]=1.Br.[C:14]([OH:17])(=[O:16])[CH3:15]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:15][C:14]([OH:17])=[O:16])[CH:5]=[C:6]([OH:8])[CH:7]=1
Reactant: CC(=O)O
Reactant: COc1cc(Br)cc(CC#N)c1
Agent: Br
Product: O=C(O)Cc1cc(O)cc(Br)c1
Temperature: 100 °C

Procedure:
The product of step (iv) (4.5 g), in glacial acetic acid (30 ml) was treated with 48% aqueous HBr (30 ml) and heated at 100° C. for 24 h. The reaction mixture was partitioned between water and ethyl acetate, the organics were separated then dried (MgSO4) and evaporated under reduced pressure to give a tan solid which was triturated with ether/isohexane (4.24 g).