Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([Cl:27])[CH:18]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[OH:38][CH2:39][CH2:40][C:41]#[CH:42]>C1(C)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.[Cu]I>[Cl:27][C:19]1[CH:18]=[C:17]([C@@H:10]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([C:42]#[C:41][CH2:40][CH2:39][OH:38])=[CH:7][N:6]=2)=[O:28])[CH:22]=[CH:21][C:20]=1[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: C#CCCO
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C#CCCO)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
A suspension of N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (prepared as in Example 6, 729 mg, 1.5 mmol) in toluene (8 mL) was treated with N,N-diisopropylethylamine (2 mL), 4-hydroxybutyne (210 mg, 3.0 mmol), dichlorobis(triphenylphosphine)palladium(II) (60 mg), and copper(I) iodide (30 mg). The mixture was stirred at 25° C. overnight, and an oily black precipitate was obtained. The top clear solution was decanted, and the oily precipitate was rinsed first with toluene (5 mL) and then with hexanes (5 mL). The residue was dissolved in methylene chloride and extracted with methylene chloride and a 0.2N aqueous hydrochloric acid solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, elution with 1/1 ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(4-hydroxy-but-1-ynyl)-pyrazin-2-yl]-propionamide (650 mg, 88.4%) as a fluffy solid: (ES)+-HRMS m/e calcd for C23H26ClN3O4S (M+H)+ 476.1406, found 476.1395.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:4](=[O:18])[N:3]=1.[C:19](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[C:12]1([S:9]([N:5]2[CH:6]=[C:7]([F:8])[C:2](=[NH:1])[N:3]([CH3:19])[C:4]2=[O:18])(=[O:10])=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1nc(=O)n(S(=O)(=O)c2ccccc2)cc1F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(=N)c(F)cn(S(=O)(=O)c2ccccc2)c1=O
Temperature: 60 °C
Yield: 50.6 %

Procedure:
4-Amino-1-benzenesulfonyl-5-fluoro-1H-pyrimidine-2-one (200 mg, 0.74 mmol) was stirred at room temperature in dimethyl formamide (3 mL) together with anhydrous potassium carbonate (210 mg, 1.5 mmol). Iodomethane (210 mg, 1.5 mmol) was added and the mixture was heated at 60° C. for 3 hours. After cooling to room temperature, the mixture was partitioned between ethyl acetate (EtOAc) and water. The organic phase was dried over magnesium sulfate, filtered, and evaporated. The crude product was purified by chromatography on silica gel (gradient, 20 to 80% EtOAc in petroleum ether) to isolate 1-benzenesulfonyl-5-fluoro-4-imino-3-methyl-3,4-dihydro-1H-pyrimidin-2-one (106 mg, 50%) as a white solid: mp 144° C.; 1H NMR (600 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.03-8.00 (m, 2H), 7.97 (d, J=5.9 Hz, 1H), 7.80-7.76 (m, 1H), 7.67-7.63 (m, 2H), 3.09 (s, 3H); ESIMS m/z 284 ([M+H]+).
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][O:9][N:10]=[C:6]2[CH2:5][CH:4]([O:11][CH2:12][O:13][CH3:14])[CH:3]1[O:15][C:16]([O:18][CH3:19])=[O:17].N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>C(Cl)Cl.C(OCC)C>[Si:25]([O:1][CH:2]1[CH:7]2[CH2:8][O:9][N:10]=[C:6]2[CH2:5][CH:4]([O:11][CH2:12][O:13][CH3:14])[CH:3]1[O:15][C:16]([O:18][CH3:19])=[O:17])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COCOC1CC2=NOCC2C(O)C1OC(=O)OC
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: ClCCl
Product: COCOC1CC2=NOCC2C(O[Si](C)(C)C(C)(C)C)C1OC(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
4-Hydroxy-5-methoxycarbonyloxy-6-(methoxymethoxy)-3,3a,4,5,6,7-hexahydro-2,1-benzoisooxazole (275 mg) was dissolved in 10 ml of methylene chloride, and 200 mg of imidazole and 226 mg of tert-butyldimethylsilyl chloride were added, followed by stirring the mixture overnight at room temperature. The reaction mixture was diluted with diethyl ether, and washed with dilute hydrochloric acid, a sodium hydrogen carbonate aqueous solution and a sodium chloride aqueous solution in sequence. The organic layer was dried over anhydrous sodium sulfate, and concentration was effected under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 285 mg of 4-(tert-butyldimethylsilyloxy)-5- methoxycarbonyloxy-6-(methoxymethoxy)-3,3a,4,5,6,7-hexahydro-2,1-benzoisooxazole having the following property (yield 73%).
Reaction SMILES: [CH3:1]C1C=C(O)C=CC=1O.CC1C(C)=C(C=CC=1O)O.[CH3:20][C:21]1[C:22]([OH:30])=[C:23]([CH3:29])[C:24]([CH3:28])=[C:25]([CH:27]=1)[OH:26]>[Zn].CO>[CH3:20][C:21]1[C:22]([OH:30])=[C:23]([CH3:29])[C:24]([CH3:28])=[C:25]([OH:26])[C:27]=1[CH3:1]
Reactant: Cc1cc(O)ccc1O
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: Cc1c(O)ccc(O)c1C
Agent: [Zn]
Solvent: CO
Product: Cc1c(C)c(O)c(C)c(C)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into an autoclave (inner volume: 9 ml, made of SUS 316, equipped with a manometer) were charged 0.092 g of methylhydroquinone, 3.895 g of methanol and 7.2 mg of zinc powders (manufactured by High Purity Chemicals Co.). The reaction was started by elevating the temperature up to 350° C. with sand bath. The pressure during the reaction was 17 MPa. After 2 hours, the autoclave was quickly cooled and the reaction solution was taken out from the autoclave when the temperature was cooled back to the room temperature. The measurement according to the process described above revealed that the conversion of methylhydroquinone was 23% by mole, the selectivity of dimethylhydroquinone was 92% by mole, the selectivity of trimethylhydroquinone was 8% by mole and no tetramethylhydroquinone was produced.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[CH3:36][N:37]([CH3:48])[CH2:38][CH2:39][NH:40][C@H:41]1[CH2:46][CH2:45][C@H:44]([CH3:47])[CH2:43][CH2:42]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:36][N:37]([CH3:48])[CH2:38][CH2:39][N:40]([C@H:41]1[CH2:42][CH2:43][C@H:44]([CH3:47])[CH2:45][CH2:46]1)[C:6](=[O:8])[CH:5]=[CH:4][C:3]1[CH:9]=[CH:10][C:11]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[CH:12][C:2]=1[Cl:1]
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Reactant: O=C(O)C=Cc1ccc(OC2CCCCO2)cc1Cl
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCN(C(=O)C=Cc1ccc(OC2CCCCO2)cc1Cl)[C@H]1CC[C@H](C)CC1

Procedure:
Using 1.7 g of 2-chloro-4-(2-tetrahydropyranyloxy)cinnamic acid, 1.4 ml of diethyl chlorophosphate, 1.4 ml of triethylamine, 60 ml of methylene chloride, 1.4 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine (Example 78), and 0.25 g of 4-dimethylaminopyridine, a reaction similar to that performed in Example 81 was carried out. As a result, 3.01 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-2-chloro-4-(2-tetrahydropyranyloxy)cinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH3:1][C:2](=[O:5])[CH2:3][CH3:4].[CH3:6][C:7]12[CH2:12][CH:11]1[CH2:10][CH:9]([CH2:13][CH:14]=O)[C:8]2([CH3:17])[CH3:16].[OH-].[K+].CO>O>[CH3:4][C:3](=[CH:14][CH2:13][CH:9]1[CH2:10][CH:11]2[C:7]([CH3:6])([CH2:12]2)[C:8]1([CH3:16])[CH3:17])[C:2](=[O:5])[CH3:1]
Reactant: CC1(C)C(CC=O)CC2CC21C
Reactant: CCC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)C(C)=CCC1CC2CC2(C)C1(C)C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
560 g (8.5 mol) of butan-2-one and 234 g (1.4 mol) of (1,2,2-trimethylbicyclo[3.1.0]hex-3-yl)ethanal were added to 48 g (0.75 mol) of potassium hydroxide dissolved in 500 ml of water and 1.41 of methanol. The reaction mixture was stirred overnight with ice-bath cooling, poured into 3 1, of water and extracted with diethyl ether. The extract was washed with water, dried (MgSO4) and evaporated in vacuo. The residue was distilled at 108° C./0.1 Torr to give 140 g (45% yield) of 3-methyl-5-(1,2,2-trimethylbicyclo[3.1.0]hex-3-yl)pent-3-en-2-one.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O.C(O)(=O)C>C(O)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[C:12]([CH3:14])[C:11]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(C)=O
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C)=NNc1ccc(Br)cc1
Temperature: 25 °C
Yield: 71 %

Procedure:
4-Bromophenylhydrazine hydrochloride (15 g), ethyl pyruvate (11 ml) and acetic acid (1 ml) were dissolved in ethanol and heated to reflux for 2 hours, then cooled to room temperature, resulting in precipitation of a yellow solid, which was filtered off and dried in vacuo to give the ethyl pyruvate 4-bromophenylhydrazone (16.3 g, 71%), mp 153-154°; NMR δ(CD3SOCD3) 1.23 (t, 3H), 2.03 (s, 3H), 4.18 (q, 2H), 7.19 (d, 2H), 7.40 (d, 2H), 9.88 (brs, 1H); M/z (−) 285 (M+), 283, 171, 169, 113.
Reaction SMILES: [O:1]1[C@H:3]2[CH:4]=[C:5]3[C@@H:21]([C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:2]124)[CH2:20][CH2:19][C@@:18]1([CH3:29])[C@H:6]3[CH2:7][CH2:8][C@@H:9]1[C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][CH2:38][NH2:39].C(O)CCC>COC(C)(C)C>[CH3:17][C@@H:10]([C@@H:9]1[C@@:18]2([CH3:29])[CH2:19][CH2:20][C@@H:21]3[C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C@:2]4([OH:1])[C@H:3]([NH:39][CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33][CH2:32][CH2:31][NH2:30])[CH:4]=[C:5]3[C@@H:6]2[CH2:7][CH2:8]1)[CH2:11][CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C[C@@H]4OC45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@]12C
Reactant: NCCCCNCCCN
Solvent: COC(C)(C)C
Solvent: CCCCO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C[C@@H](NCCCNCCCCN)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 58 %

Procedure:
5,6α-epoxicholest-7-en-3β-ol (8.9 g, 22.1 mmol, 1 eq) and spermidine (6.4 g, 44.1 mmol, 2 eq) were charged in a round-bottomed flask equipped with a magnetic stirrer bar. 1-Butanol (70 ml, 5 vol) was added and the mixture heated to reflux for 40 h. The reaction mixture was cooled at r.t., diluted with methyl-tertbutyl-ether (5 vol) and washed with water (5 vol) and with brine (5 vol). The organic layer was passed through a silica pad (40 g) eluted with methyl-tertbutyl-ether (3 vol) then 10% Methanol/ethyl acetate (60 vol). Fractions of interest were pooled and the solvent was removed under reduced pressure to give Dendrogenin B (5α-Hydroxy-6β-[4-(3-aminopropylamino)-butylamino]-cholest-7-en-3β-ol) as a white solid (7.0 g, 58%). In same conditions, use of ethanol as solvent (40 vol) and Ca(OTf)2 as catalyst gave a 14% yield.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]([CH3:10])=[N:3]1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][C:33]=1[Cl:34])[O:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([N:22]=[C:23]([NH:25][C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[N:24]=2)[CH:21]=1>CN(C)C(=O)C>[Cl:34][C:33]1[CH:32]=[CH:31][C:14]([O:15][C:16]2[CH:17]=[CH:18][C:19]3[N:20]([N:22]=[C:23]([NH:25][C:26]([CH:28]4[CH2:30][CH2:29]4)=[O:27])[N:24]=3)[CH:21]=2)=[CH:13][C:12]=1[NH:11][C:7]([C:6]1[N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH:5]=1)=[O:8]
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1Cl
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)ccc2Cl)n(C)n1
Yield: 40 %

Procedure:
In the same manner as in Example 24 and using 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (89.2 mg, 0.562 mmol), N,N-dimethylacetamide (5 mL) and N-[6-(3-amino-4-chlorophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (170 mg, 0.495 mmol) as starting materials, the title compound (92.2 mg, 40%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:17][CH2:18][OH:19])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](Cl)=[O:23]>N1C=CC=CC=1>[F:1][C:2]1[C:3]([NH:17][CH2:18][O:19][C:22](=[O:23])[C:21]([CH3:26])([CH3:25])[CH3:20])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: OCNc1nc(OCc2ccc(F)cc2)ncc1F
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCNc1nc(OCc2ccc(F)cc2)ncc1F
Temperature: 60 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To a mixture of [5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamino]methanol (0.10 g, 0.37 mmol) in pyridine (2 mL) was added trimethylacetyl chloride (0.048 g, 0.40 mmol), and the mixture was agitated on an orbital shaker at 60° C. for 4 h. The reaction mixture was cooled, evaporated to dryness, and partitioned between EtOAc and water. The organic layer was dried over Na2SO4, filtered, and evaporated to yield the title compound (0.078 g, 60% yield) as a white solid: mp 134-135° C.; 1H NMR (300 MHz, CDCl3) δ 7.97 (d, J=2.5 Hz, 1H), 7.49-7.44 (m, 2H), 7.11-7.03 (m, 2H), 6.17 (bt, J≈7 Hz, 1H), 6.17 (d, J=7.4 Hz, 2H), 5.33 (s, 2H), 1.20 (s, 9H); HPLC-MS m/z 352 (M+H)+.
Reaction SMILES: C(O[C:6](=[O:9])[NH:7][NH2:8])(C)(C)C.[C:10](O)(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]C>FC(F)(F)C(O)=O>[C:6]([NH:7][NH2:8])(=[O:9])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CC(C)(C)OC(=O)NN
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCCCC(=O)NN
Reaction time: 0.25 h
Yield: 76.3 %

Procedure:
1.8 g (4.52 mmol) stearic acid tert-butylcarbazate is dissolved in 3 ml trifluoracetic acid, stirred for 15 min and the solvent is removed under vacuum. The mixture is treated with 30 ml dry ether and the precipitate formed is filtered out and washed twice with 50 ml dry diethyl ether. After drying under high vacuum, 1.03 g stearic acid hydrazide is obtained; Rf=0.66 (ethyl acetate/methanol 1/1)
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([I:18])[C:11]=1[C:12]#[N:13].[CH:19](OC)=[O:20].O>C1COCC1>[F:9][C:10]1[C:17]([CH:19]=[O:20])=[CH:16][CH:15]=[C:14]([I:18])[C:11]=1[C:12]#[N:13]
Reactant: N#Cc1c(F)cccc1I
Reactant: COC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(I)ccc(C=O)c1F
Reaction time: 1 h
Yield: 71.9 %

Procedure:
LDA (24.3 mL, 2.0 M solution in THF) was added dropwise to a stirred solution of 2-fluoro-6-iodobenzonitrile (10.0 g, 40.5 mmol) in THF (200 mL) at −78° C., and the mixture was stirred for 1 h. Methyl formate (5.0 mL, 81.0 mmol) was added via syringe and the resulting mixture was stirred at −78° C. for 30 min then at rt for 1 h. H2O was added and the mixture was extracted with EtOAc. The extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica gel eluting with 20-25% EtOAc/hexanes to give the desired product (8.01 g). MS (ESI(+)) m/e 274.9 (M+H)+.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].S(=O)(=O)(O)O.[F:14][C:15](I)([F:17])[F:16].OO>[Fe].CS(C)=O>[F:14][C:15]([F:17])([F:16])[C:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][CH:8]=1
Reactant: FC(F)(F)I
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: [Fe]
Agent: O=S(=O)(O)O
Agent: OO
Solvent: CS(C)=O
Product: O=c1[nH]cc(C(F)(F)F)c(=O)[nH]1
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 32 %

Procedure:
0.11 g (1.0 mmol) of uracil and 0.028 g (0.5 mmol) of iron powder were weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 2.0 ml of dimethyl sulfoxide, 2.0 ml of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 ml of a 3.0 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide and 0.2 ml of a 30% hydrogen peroxide aqueous solution. The mixture was stirred at 40 to 50° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 5-trifluoromethyluracil (19F-NMR yield: 32%) was confirmed in the same manner as in Example 1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[C:16]3[C:17]4([CH2:20][O:21][C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH2:19][CH2:18]4)=[N:8][CH:9]=1)([O-])=O.O.[Cl-].[NH4+]>O1CCCC1>[C:17]12([C:16]3[C:11]([O:10][C:7]4[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=4)=[CH:12][CH:13]=[CH:14][C:15]=3[O:21][CH2:20]1)[CH2:19][CH2:18]2
Reactant: O=[N+]([O-])c1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
To a solution of 5-nitro-2-(spiro[1-benzofuran-3,1′-cyclopropan]-4-yloxy)pyridine (Intermediate 86, 99 mg) in tetrahydrofuran (5 ml)/water (2.5 ml) iron (97 mg, 1.741 mmol) and then ammonium chloride (93 mg, 1.741 mmol) were added and the reaction mixture was stirred for 4 hours at room temperature. The catalyst was filtered off and the residue was diluted with an aqueous saturated solution of NaHCO3 (5 ml) and extracted with ethyl acetate (3×10 ml). The organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 8:2 to cyclohexane/ethyl acetate 1:1 as eluents affording the title compound as a light yellow solid (85 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[C:10]=1[N:11]1[CH2:15][CH2:14][C@H:13]([NH:16][C:17](=[O:19])[CH3:18])[CH2:12]1.O1C2C=CC=C(N3CC[C@H](N)C3)C=2CC1.[Cl:35]N1C(=O)CCC1=O>>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:35])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[C:10]=1[N:11]1[CH2:15][CH2:14][C@H:13]([NH:16][C:17](=[O:19])[CH3:18])[CH2:12]1
Reactant: CC(=O)N[C@H]1CCN(c2c(Cl)ccc3c2CCO3)C1
Reactant: O=C1CCC(=O)N1Cl
Agent: N[C@H]1CCN(c2cccc3c2CCO3)C1
Product: CC(=O)N[C@H]1CCN(c2c(Cl)cc(Cl)c3c2CCO3)C1

Procedure:
The crude product isolated in Example 34 from the reaction of (S)-N-(2,3-dihydrobenzofuran-4-yl)-3-(amino)pyrrolidine (0.1 mmol) and N-chlorosuccinimide (0.11 mmol) was purified by preparative HPLC and the minor product of the reaction was isolated to yield the title compound.
Reaction SMILES: C([Sn](Cl)(Cl)CCCC)CCC.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]([CH:24]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:25]OCC3CCCCC3)[C:22]3[CH:40]=[C:41]([F:45])[C:42]([F:44])=[CH:43][C:21]=3[N:20]=2)=[CH:15][CH:14]=1.[NH2:46][C:47]1[CH:54]=[CH:53][C:50]([C:51]#[N:52])=[CH:49][CH:48]=1.C1([SiH3])C=CC=CC=1>O1CCCC1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]([CH:24]([CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]3)[CH2:25][NH:46][C:47]3[CH:54]=[CH:53][C:50]([C:51]#[N:52])=[CH:49][CH:48]=3)[C:22]3[CH:40]=[C:41]([F:45])[C:42]([F:44])=[CH:43][C:21]=3[N:20]=2)=[CH:15][CH:14]=1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COCC3CCCCC3)C3CCCCC3)c2cc1F
Reactant: N#Cc1ccc(N)cc1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: N#Cc1ccc(NCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Temperature: 100 °C
Yield: 67 %

Procedure:
To a solution of 7 mg (0.023 mmol) dibutyltin dichloride in 1 ml tetrahydrofuran were added 0.10 g (0.23 mmol) [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetaldehyde (Example 143, intermediate c), 0.038 g (0.23 mMol) 4-aminobenzonitrile (commercially available) and 0.06 ml (0.46 mmol) phenylsilane (commercially available). The pale yellow solution was heated to 100° C. under microwave irradiation for 21 min. The light yellow solution was treated with silica gel and the suspension evaporated to dryness. The remaining solid was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane:ethyl acetate (100:0 to 70:30). The fractions containing the product were pooled and chromatographed a second time under the same conditions to give the title compound as a white solid (67%). MS (Turbo Spray): m/z=491.2 [M+H].
Reaction SMILES: C(OC(NC1C=C(F)C(F)=CC=1C(NCC(NC[CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=O)=O)=O)(C)(C)C.[Br:31][C:32]1[CH:33]=[CH:34][C:35]([O:40][CH2:41][CH3:42])=[C:36]([CH:39]=1)[CH:37]=O.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[Br:31][C:32]1[CH:33]=[CH:34][C:35]([O:40][CH2:41][CH3:42])=[C:36]([CH:39]=1)[CH2:37][N:22]1[CH2:23][CH2:24][CH2:19][CH2:20][CH2:21]1
Reactant: CCOc1ccc(Br)cc1C=O
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOc1ccc(Br)cc1CN1CCCCC1
Temperature: 50 °C
Reaction time: 13 h

Procedure:
To a mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (0.050 mmol), 5-bromo-2-ethoxybenzaldehyde (0.15 mmol), methanol (1.2 mL), and acetic acid (0.030 mL) was added NaBH3CN (0.25 mmol) in methanol (0.50 mL). The reaction mixture was stirred at 50° C. for 13 h. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×3). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated. To the resulting material were added dichloromethane (1 mL) and trifluoroacetic acid (TFA) (0.50 mL) and the solution was stirred at room temperature for 10 min. The reaction mixture was concentrated, and the residue was dissolved in methanol, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated. Preparative TLC (SiO2, ethyl acetate/methanol=10/1) gave 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl)amino}methyl]-1-(5-bromo-2-ethoxybenzyl)piperidine (Compound No. 2052) (10.2 mg, 38%): The purity was determined by RPLC/MS (96%); ESI/MS m/e 539.2 (M++H, C24H29BrF2N4O3).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22](=[O:25])[NH:23][N:24]=3)[CH:16]=2)[CH2:11]1.Br.[CH2:27]([N:30]=[C:31]=[O:32])[CH:28]=[CH2:29]>COCCO>[CH2:27]([NH:30][C:31]([NH:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22](=[O:25])[NH:23][N:24]=3)[CH:16]=2)[CH2:11]1)=[O:32])[CH:28]=[CH2:29]
Reactant: NCC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Reactant: C=CCN=C=O
Agent: Br
Solvent: COCCO
Solvent: CCN(CC)CC
Product: C=CCNC(=O)NCC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.5 %

Procedure:
Triethylamine (1.05 g) was added to 40 ml of a suspension containing 2.70 g of 2-aminomethyl-5-[pyridazin-3(2H)-on-6-yl]indane·hydrobromide suspended in 2-methoxyethanol, and the mixture was stirred at room temperature for 10 minutes. To the mixture was added 1.10 g of allyl isocyanate, and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into ice water, and crystals precipitated were collected by filtration. The crystals obtained were washed with water, dried and then recrystallized from methanol to obtain 2.35 g of 2-[(ALLYLCARBAMOYL) amino]methyl-5-[pyridazin-3(2H)-on-6-yl]indane.