Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]#[N:12])=[CH:9][C:4]=2[O:3]C1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:3][C:4]1[CH:9]=[C:8]([CH2:10][C:11]#[N:12])[CH:7]=[CH:6][C:5]=1[OH:1]
Reactant: N#CCc1ccc2c(c1)OCO2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: N#CCc1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a solution of benzo[1,3]dioxol-5-yl-acetonitrile (0.50 g, 3.1 mmol) in CH2Cl2 (15 mL) was added dropwise BBr3 (0.78 g, 3.1 mmol) at −78° C. under N2. The mixture was slowly warmed to room temperature and stirred overnight. H2O (10 mL) was added to quench the reaction and the CH2Cl2 layer was separated. The aqueous phase was extracted with CH2Cl2 (2×7 mL). The combined organics were washed with brine, dried over Na2SO4 and purified by column chromatography on silica gel (Petroleum Ether/EtOAc 5:1) to give (3,4-dihydroxy-phenyl)-acetonitrile (0.25 g, 54%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 9.07 (s, 1H), 8.95 (s, 1H), 6.68-6.70 (m, 2H), 6.55 (dd, J=8.0, 2.0 Hz, 1H), 3.32 (s, 2H).
Reaction SMILES: [CH2:1]([C:4]1[CH2:5][CH:6]([OH:10])[CH2:7][C:8]=1[CH3:9])[CH:2]=[CH2:3].N1C=CC=CC=1.[CH3:17][C:18]1([CH3:28])[C@H:20]([CH:21]=[C:22]([CH3:24])[CH3:23])[C@H:19]1[C:25](Cl)=[O:26]>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C1(C)C=CC=CC=1>[CH3:17][C:18]1([CH3:28])[C@H:20]([CH:21]=[C:22]([CH3:23])[CH3:24])[C@H:19]1[C:25]([O:10][CH:6]1[CH2:7][C:8]([CH3:9])=[C:4]([CH2:1][CH:2]=[CH2:3])[CH2:5]1)=[O:26]
Reactant: C=CCC1=C(C)CC(O)C1
Reactant: CC(C)=C[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C=CCC1=C(C)CC(OC(=O)[C@@H]2[C@@H](C=C(C)C)C2(C)C)C1
Yield: 74 %

Procedure:
To a mixture of (RS)-3-(2-propenyl)-4-methyl-3-cyclopenten-1-ol (190 mg), 2,6-di-tert-butyl-4-methylphenol (5 mg), pyridine (140 mg) and toluene (10 ml), (1R)-trans-2,2-dimethyl-3-(2-methyl-1-propenyl)-cyclopropanecarbonyl chloride was added under ice-cooling. The resulting reaction mixture was further allowed to react for 8 hours at room temperature. Then the reaction mixture was subjected to the same post-treatment as in Example 1 to afford 295 mg of (RS)-3-(2-propenyl)-4-methyl-3-cyclopenten-1-yl (1R)-trans-2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate (Compound No. 40). Yield 74% nD25 1.4891
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:11]([NH:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:10][CH2:9][N:8]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:7]1)=[O:5])C.[OH-].[Li+]>O1CCCC1>[C:26]([O:25][C:23]([N:8]1[CH2:9][CH2:10][C@@H:11]([NH:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[C@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1NC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](C(=O)O)C1
Reaction time: 68 h
Yield: 112.1 %

Procedure:
In a flask (3R,4R)-4-benzyloxycarbonylamino-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-ethyl Ester (2.98 g, 7.33 mmol) was dissolved in tetrahydrofuran (120 mL) and lithium hydroxide (15 mL of a 1N aqueous solution, 15 mmol) was added. The mixture was stirred for 68 hours. The reaction was concentrated in vacuo to one-third the original volume. Water (50 mL) and diethyl ether (50 mL) were added and the layers separated. The aqueous layer was extracted with diethyl ether twice (30 mL). The aqueous layer was acidified with aqueous hydrochloric acid (6.5 mL of a 2M solution) and then extracted with ethyl acetate three times (30 mL). The combined organic layers were dried with magnesium sulfate, filtered, and concentrated in vacuo to give a crude white solid (3.11 g) which was used without further purification. 1H NMR (300 MHz, CDCl3), δ: 7.36 (m, 5H), 5.12 (m, 2H), 4.91 (bs, 1H), 4.24 (bs, 1H), 4.09 (bs, 1H), 3.92 (bs, 1H), 3.01 (bs, 1H), 2.87 (m, 1H), 2.44 (m, 1H), 2.05 (bs, 1H), 1.45 (s, 9H), 1.40 (m, 1H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]1)=[N+:2]=[N-:3].[CH:13](OCC)=[S:14]>CCOCC>[CH:13]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[CH2:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])=[S:14]
Reactant: CCOC=S
Reactant: [N-]=[N+]=NCCCC1CCCCN1
Solvent: CCOCC
Product: [N-]=[N+]=NCCCC1CCCCN1C=S
Reaction time: 8 h

Procedure:
To a solution of 2-(3'-azidopropyl)-piperidine (1.8 g) in ether (10 ml) was added ethyl thioformate (1.5 ml). The solution was kept at 4° C. overnight and evaporated to leave an oil which was purified by chromatography on silica gel. The IR-spectrum (CHCl3) showed strong bands at 2950, 2100, 1485, 1445 and 1250 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]#[C:12][CH2:13][NH:14][C:15](=[O:22])[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.[NH4+].[Cl-]>[Fe]>[NH2:27][C:25]1[CH:24]=[CH:23][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[C:11]#[C:12][CH2:13][NH:14][C:15](=[O:22])[CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:2]([F:1])[CH:26]=1
Reactant: O=C(CN1CCCC1)NCC#Cc1cnccc1Oc1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: Nc1ccc(Oc2ccncc2C#CCNC(=O)CN2CCCC2)c(F)c1

Procedure:
The title compound was prepared by the reduction of N-(3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-ynyl)-2-(pyrrolidin-1-yl)acetamide (35 mg, 0.088 mmol) in the manner similar to that of Step E of Example 35 using Fe powder (67 mg, 1.21 mmol) and NH4Cl (128 mg, 2.42 mmol). The product was used in subsequent reactions without any purification. Yellow oil (30 mg, 93%). MS (ESI+): m/z 319.24 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH:18]=[C:17]3[S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[OH-].[NH4+]>C(O)C.O>[C:26]1([S:23]([C:17]2[C:16]3[C:20](=[CH:21][CH:22]=[C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:15]=3)[NH:19][CH:18]=2)(=[O:24])=[O:25])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3[nH]cc(S(=O)(=O)c4ccccc4)c3c2)CC1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=S(=O)(c1ccccc1)c1c[nH]c2ccc(N3CCNCC3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
4-(3-Benzenesulfonyl-1H-indol-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.5 g, 1.13 mmol) was dissolved in 5 mL of ethanol and 3 mL of conc. hydrochloric acid were added. The mixture was heated to a gentle boil for 2-3 min, cooled to room temperature, basified with ammonium hydroxide, and diluted with 20 mL of water. After the mixture was allowed to stand overnight, the solid was filtered, washed with water and dried to give 0.37 g of 3-benzenesulfonyl-5-piperazin-1-yl-1H-indole (201) as a tan crystalline solid, m.p. 254-264° C. (dec).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[F:25][C:26]([F:37])([F:36])[CH2:27]OS(C(F)(F)F)(=O)=O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:27][C:26]([F:37])([F:36])[F:25])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1CC(F)(F)F
Temperature: 70 °C
Reaction time: 0.83 h
Yield: 65.8 %

Procedure:
A solution of 5-benzyloxyindole-2-carboxylic acid ethyl ester (purchased at Biosynth, ref B2000, 2.26 g, 1.0 eq.) in dimethylformamide (15 mL) was added to a suspension of sodium hydride (60% dispersion in oil, 367 mg, 1.2 eq.) in dimethylformamide. The reaction mixture was stirred 50 min at 70° C. 2,2,2-Trifluoroethyltrifluoromethanesulfonate (3.0 g, 1.7 eq.) was added and the reaction mixture was stirred overnight at 70° C. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic fractions were washed with water and brine, evaporated to dryness and purified on silica eluting with 9:1 cyclohexane/ethyl acetate to yield 1.9 g (66%) of the desired product as light yellow solid. MS (m/e): 378.5 (MH+, 100%).
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:18][C:19]1[O:20][CH2:21][CH2:22][CH:23]=1.P([O-])([O-])([O-])=O>ClCCl.O.C(OCC)(=O)C>[C:3]([CH2:2][S:1][C:19]1([CH3:18])[CH2:23][CH2:22][CH2:21][O:20]1)([OH:5])=[O:4]
Reactant: O=C(O)CS
Reactant: CC1=CCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(SCC(=O)O)CCCO1

Procedure:
A solution of mercaptoacetic acid (10 mmol) in 5 mL of dichloromethane containing p-toluenesulfonic acid mono-hydrate (100 mg) is cooled with stirring to -10° to -25° C. 2-Methyl-4,5-dihydrofuran (10 mmol) in 10 mL of dichloromethane is added dropwise to the cold solution while the temperature is maintained between -10° C. to -25° C. Then 5 mL of phosphate buffer is added and the solution is allowed to come to room temperature. The mixture is poured into a 30 mL of ethyl acetate and 10 mL of water. Organic layer is separated and the aqueous layer is extracted with ethyl acetate. The combined ethyl acetate layer is dried and evaporated to give 26 as a colorless oil.
Reaction SMILES: [N+:1]([C@@:4]([C:20]([OH:22])=[O:21])([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[N:5]([N+:12]([O-:14])=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=[O:28].C[N:44]([CH3:47])[CH:45]=[O:46]>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[C:45]1(=[O:46])[NH:44][C:47](=[O:28])[CH:15]=[CH:4]1.[N+:1]([C@@:4]([C:20]([OH:22])=[O:21])([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[N:5]([N+:12]([O-:14])=[O:13])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Reactant: CN(C)C=O
Agent: NCCCC[C@@](C(=O)O)(N(c1ccccc1)[N+](=O)[O-])[N+](=O)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: O=C1C=CC(=O)N1

Procedure:
An aliquot (1.5 ml) of 8.8 mM dinitrophenyl-L-lysine (Tokyo Kasei, Tokyo, Japan) in 0.1M sodium phosphate buffer, pH 7.0, containing 5 mM EDTA was incubated with 0.15 ml of 8.8 mM N-succinimidyl-6-maleimidohexanoate (Dojin Kagaku, Kumamoto, Japan) in N,N-dimethylformamide at 30° C. for 30 minutes.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[NH:29][N:28]=[N:27][N:26]=3)=[CH:15][CH:14]=2)[C:8]([CH2:30]Br)=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].Br.[CH3:33][O-:34].[Na+]>C(O)(=O)C.CO>[CH2:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[NH:29][N:28]=[N:27][N:26]=3)=[CH:15][CH:14]=2)[C:8]([CH2:30][O:34][CH3:33])=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(CBr)c(NCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)n1
Reactant: C[O-]
Agent: Br
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCc1ncc(COC)c(NCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)n1

Procedure:
2-n-Butyl-5-hydroxymethyl-4-{N-[(2-1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}pyrimidine hydrochloride, the product of Example 2B, is converted to 2-butyl-5-bromomethyl-4-{N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}pyrimidine by treatment with hydrogen bromide in acetic acid according to the method of A. Schellenberger and K. Winter in Z. Physiol. Chem., 322, 164 (1960). The bromomethyl intermediate is then converted to the title compound by treatment with sodium methoxide in methanol.
Reaction SMILES: CON(C)[C:4]([C:6]1[S:7][C:8]([CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH2:20][C@H:21]3[CH2:23][C@@H:22]3[C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][N:25]=3)[N:16]=[C:15]([CH3:31])[N:14]=2)=[N:9][N:10]=1)=[O:5].C[Mg+].[Br-].[C:36](=O)(O)[O-].[Na+]>C1COCC1.C1(C)C=CC=CC=1>[CH3:31][C:15]1[N:14]=[C:13]([NH:12][CH2:11][C:8]2[S:7][C:6]([C:4](=[O:5])[CH3:36])=[N:10][N:9]=2)[CH:18]=[C:17]([O:19][CH2:20][C@H:21]2[CH2:23][C@@H:22]2[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][N:25]=2)[N:16]=1
Reactant: CON(C)C(=O)c1nnc(CNc2cc(OC[C@H]3C[C@@H]3c3ccc(C)cn3)nc(C)n2)s1
Reactant: O=C([O-])O
Agent: C[Mg+]
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)c1nnc(CNc2cc(OC[C@H]3C[C@@H]3c3ccc(C)cn3)nc(C)n2)s1
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To the solution of N-methoxy-N-methyl-5-((2-methyl-6-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-4-ylamino)methyl)-1,3,4-thiadiazole-2-carboxamide (17-1) (355 mg, 0.78 mmol) in THF (2 mL) was added CH3MgBr (1.3 mL, 3.90 mmol) in toluene dropwise at 0° C. The mixture was stirred for 30 min. Then the solution was adjusted to pH=9-10 with saturated sodium bicarbonate and extracted with ethyl acetate (20 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate and purified by Prep TLC (PE/EA=1:1). The product was obtained as a white solid (248 mg, 77%). 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.37 (d, J=7.6 Hz, 1H), 7.03 (d, J=7.9 Hz, 1H), 5.59 (s, 1H), 5.42 (s, 1H), 4.99 (d, J=6.3 Hz, 2H), 4.28 (m, 2H), 2.79 (s, 3H), 2.44 (s, 3H), 2.28 (s, 3H), 2.07 (m, 1H), 1.89-1.81 (m, 1H), 1.32-1.27 (m, 1H), 1.04-1.02 (m, 1H); LRMS (ES) calculated M+H for C20H23N6O2S: 411.5. Found:411.1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.C(N(C(C)C)CC)(C)C.[CH3:35][C:36]1[S:37][C:38]([CH3:45])=[CH:39][C:40]=1[S:41](Cl)(=[O:43])=[O:42]>O1CCCC1.C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:21][CH2:22][N:23]([S:41]([C:40]3[CH:39]=[C:38]([CH3:45])[S:37][C:36]=3[CH3:35])(=[O:43])=[O:42])[CH2:24][CH2:25]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)c3cc(C)sc3C)CC2)nc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a solution of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (50 mg, 0.145 mmol, Example 59) and diisopropylethylamine (Aldrich, 330 μL, 1.894 mmol) in anhydrous tetrahydrofuran (15 mL) cooled to 5° C., was added a solution of 2,5-dimethyl-3-thiophenesulfonyl chloride (Maybridge, 45.3 mg, 0.218 mmol) in methylene chloride (3 mL). The reaction mixture was stirred at room temperature overnight and then diluted with 50 mL of methylene chloride. The resulting solution was washed with saturated aqueous sodium bicarbonate (2×10 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 25% ethyl acetate in hexane yielded [4-amino-2-[1-(2,5-dimethyl-thiophene-3-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (69 mg, 92%) as white solids. HR-MS (ES, m/z) calculated for C23H26FN5O4S2 [(M+H)+] 520.1483, observed 520.1494.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[Br:11]Br.O>C(O)(=O)C>[Br:11][C:8]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:6]=[O:7]
Reactant: BrBr
Reactant: COc1cccc(C=O)c1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Br)c(C=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
50 g of 3-methoxybenzaldehyde are dissolved in 245 ml of acetic acid. 22 ml of bromine are added dropwise at 0° C., the medium is stirred at room temperature for 4 hours, and then left overnight at room temperature. 300 ml of water are added to the solution and the expected product crystallizes. After filtration and washing with water and drying, 68 g of 2-bromo-5-methoxybenzaldehyde having the empirical formula C8H7Br.O2 are obtained (M=114 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17]([Cl:20])[N:18]=3)[C:13](=[O:22])[C:12]([C:23]([O:25]CC)=[O:24])=[CH:11]2)[C:5]([F:9])=[CH:6][C:7]=1[F:8].Cl.C(O)(=O)C>O>[NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17]([Cl:20])[N:18]=3)[C:13](=[O:22])[C:12]([C:23]([OH:25])=[O:24])=[CH:11]2)[C:5]([F:9])=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)c1cn(-c2cc(N)c(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(Cl)nc32)c(F)cc1F
Yield: 96.8 %

Procedure:
To 0.6 g of ethyl 1-(3-amino-4,6-difluorophenyl)-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate was added 4 ml of a 3N hydrochloric acid/acetic acid mixture. The solution was heated at reflux for 2 hours. Distilled water (3 ml) was added to the solution, which was refluxed for 5 minutes. The precipitate was collected by filtration and washed with ethanol to give 0.54 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O.[CH3:21][S:22]([CH2:25][C:26](=O)[CH3:27])(=[O:24])=[O:23]>CC(O)C.O.O.[Na+].Cl[Au-](Cl)(Cl)Cl>[CH3:21][S:22]([C:25]1[C:26]([CH3:27])=[N:1][C:2]2[C:3]([C:13]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:4][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][CH:7]=2)(=[O:24])=[O:23]
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)c1ccccc1
Reactant: CC(=O)CS(C)(=O)=O
Agent: Cl[Au-](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cc1nc2ccc(OC(F)(F)F)cc2c(-c2ccccc2)c1S(C)(=O)=O
Yield: 40.4 %

Procedure:
(2-Amino-5-trifluoromethoxy-phenyl)-phenyl-methanone (0.3 g, 1 mmol), methylsulfonylacetone (0.22 g, 2 mmol) and sodium tetrachloroaurate (III) dihydrate (13 mg, 0.036 mmol) were mixed in 2-propanol (3 mL) and heated at reflux under nitrogen for 5 days. 2-propanol was evaporated and the residue was purified by flash chromatography on silica gel in heptane/ethyl acetate 2:1. One obtained 154 mg (34%) of a white solid. MS: m/z=382 (M+H).
Reaction SMILES: [CH2:1](O)[CH2:2][CH3:3].CC1C=CC=C(C)N=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:28]([O:35][NH2:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:28]([O:35][NH:36][CH2:1][CH2:2][CH3:3])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NOCc1ccccc1
Reactant: CCCO
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCCNOCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
To a solution of propan-1-ol (6.25 mL, 83.2 mmol) and 2,6-dimethylpyridine (11.6 mL, 99.8 mmol) in CH2Cl2 (500 mL) under a nitrogen atmosphere at −78° C. was added dropwise trifluoromethanesulfonic anhydride (14.0 mL, 83.2 mmol). After stirring for 30 min at −78° C., a solution of O-benzylhydroxylamine (10.7 ml, 91.5 mmol) in CH2Cl2 (10 mL) was added dropwise. The resulting mixture was stirred at −78° C. for 1 h, then warmed to room temperature, and stirred for additional 2 h. The reaction mixture was diluted with ice water (250 mL) and the organic layer was separated, washed with saturated aq. NaHCO3 (100 mL) and brine (100 mL). The aqueous layers were extracted again with EtOAc (1×200 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography (CH2Cl2). To the fraction containing product and 2,6-dimethylpyridine was added 2 M aq KOH (100 mL), that was then washed with MTBE. The aqueous layer was then brought to a pH of ˜5 with 1 M aq HCl and then extracted with MTBE (3×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to afford 11.2 g (75%) of O-benzyl-N-propylhydroxylamine.
Reaction SMILES: [CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@H:23]1[C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([OH:30])=[O:29])=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Ca+2:39].[OH-]>ClCCCl>[Ca+2:39].[CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@H:23]1[C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([O-:30])=[O:29])=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@H:23]1[C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([O-:30])=[O:29])=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Solvent: ClCCCl
Product: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.5 %

Procedure:
Dibenzylphosphoryl-L-alanyl-L-prolyl-L-proline (0.5 g, 0.9 mmol) was dissolved in 1,2-dichloroethane (15 ml) which had been previously saturated with water, and calcium hydroxide (34 mg, 0.465 mmole) was added thereto. The mixture was stirred for 4 hours at room temperature. Insoluble matter was removed by filtration and from the thus obtained filtrate the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate and n-hexane was added thereto while stirring to obtain dibenzylphosphoryl-L-alanyl-L-prolyl-L-proline calcium salt (0.37 g).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:13][C:14]([F:23])([F:22])[C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].[CH3:24][C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=1>>[CH3:24][C:25]1[CH:29]=[C:28]([CH3:30])[N:27]([C:2]2[N:11]=[C:10]([NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[C:15]([C:14]([F:22])([F:23])[F:13])[CH:16]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[N:26]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cc1cc(C)[nH]n1
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: Cc1cc(C)n(-c2nc(Nc3cccc(C(F)(F)F)c3)c3ccccc3n2)n1

Procedure:
Was prepared according to Method B from 2,4-dichloroquinazoline, 3-trifluoromethylaniline and 3,5-dimethylpyrazole. Mp. 233.1-239.6° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([Br:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br-].[OH:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[N+:22]([CH3:27])[CH:21]=[CH:20]2>C(#N)C>[Br-:14].[CH2:7]([O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[N+:22]([CH3:27])[CH:21]=[CH:20]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[n+]1ccc2cc(O)ccc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CC#N
Product: C[n+]1ccc2cc(OCc3ccccc3)ccc2c1

Procedure:
Sodium carbonate (5 g.), benzyl bromide (2 ml), 6-hydroxy-2-methylisoquinolinium bromide (2.5 g.) in acetonitrile (100 ml) were heated under reflux for 2 hr. The suspension was filtered hot and the filtrate was diluted with ether. The solid that precipitated was crystallised from acetonitrile, and had m.p. 210°-213°.