Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]#[CH:16])[CH:5]=[CH:4][C:3]1=2.I[C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=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)I.C(N(CC)CC)C>[CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]#[C:16][C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#CCc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#CCc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.4 g (32.7 mmol) of 3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propyne, 8.2 g (29.7 mmol) of ethyl 4-iodobenzoate and 50 ml of triethylamine are introduced into a three-necked flask under a stream of nitrogen. The reaction medium is degassed by bubbling nitrogen through, 360 mg (0.5 mmol) of bis(triphenylphosphine)palladium(II) chloride and 130 mg of copper iodide are introduced and the mixture is stirred at room temperature for eight hours. The reaction medium is evaporated to dryness, the residue is taken up in ethyl acetate and hydrochloric acid (1 N) and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (70/30). After evaporation of the solvents, a solid is collected which is triturated from heptane, filtered and dried. 9.3 g (84%) of the expected ethyl ester are collected, with a melting point of 59-60° C.
Reaction SMILES: C(OC([N:6]1[CH:10]=[C:9]([C:11]2[N:16]=[N:15][C:14]([NH2:17])=[N:13][CH:12]=2)[CH:8]=[N:7]1)C)C.Cl[CH:19]([CH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][CH:27]=[CH:26]2)[CH:20]=O.Cl>C(O)(C)C>[NH:7]1[CH:8]=[C:9]([C:11]2[CH:12]=[N:13][C:14]3[N:15]([C:19]([CH2:22][C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[N:29]=[CH:28][CH:27]=[CH:26]5)=[CH:20][N:17]=3)[N:16]=2)[CH:10]=[N:6]1
Reactant: CCOC(C)n1cc(-c2cnc(N)nn2)cn1
Reactant: O=CC(Cl)Cc1ccc2ncccc2c1
Agent: Cl
Solvent: CC(C)O
Product: c1cnc2ccc(Cc3cnc4ncc(-c5cn[nH]c5)nn34)cc2c1
Temperature: 110 °C
Yield: 64.2 %

Procedure:
A mixture of 6-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-1,2,4-triazin-3-amine (390.0 mg, 1.665 mmol) and 2-chloro-3-quinolin-6-ylpropanal (480 mg, 2.2 mmol) in isopropyl alcohol (20 mL) was heated at 110° C. for 2 days. After cooling to RT, 0.2 mL of concentrated HCl was added and stirred until completely deprotected. The solid formed was collected by filtration to give the desired product (0.35 g, 64%). LCMS: (M+H)=328.3.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[N:10][CH:9]=[CH:8]2>[Pt](=O)=O.CO>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][NH:10][CH2:9][CH2:8]2
Reactant: Clc1cccc2ccncc12
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: Clc1cccc2c1CNCC2

Procedure:
A solution of 11.0 g. of 8-chloroisoquinoline hydrochloride in 100 ml. of methanol was hydrogenated at atmospheric pressure over 0.5 g. of platinum dioxide as in Example 9. The mixture was filtered and concentrated to small volume. Ether was added, the mixture was filtered, and the solid recrystallized from ethanol to give 8-chloro-1,2,3,4-tetrahydroisoquinoline hydrochloride, m.p. 236°-238.5° C.
Reaction SMILES: [F:1][C:2]1[N:3]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:6]=1[CH:7]=O.CO.[CH3:26][NH2:27].[BH4-].[Na+].[ClH:30].C(=O)([O-])O.[Na+]>CO>[ClH:30].[F:1][C:2]1[N:3]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:6]=1[CH2:7][NH:27][CH3:26]
Reactant: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccccc2)c1F
Reactant: CN
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2ccccc2)c1F
Reaction time: 0.5 h
Yield: 25 %

Procedure:
2-Fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (110 mg) was dissolved in methanol (20 mL), 40% methylamine methanol solution (130 mg) was added at room temperature, and the mixture was stirred for 30 min. Sodium borohydride (38 mg) was added at room temperature, and the mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (20 mL) was added, and the mixture was stirred for 5 min. The reaction mixture was alkalized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=3:7→0:1), and dissolved in ethyl acetate (5 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound as pale-yellow crystals (yield 32 mg, 25%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Br:11])=[CH:8][C:9]=1[NH2:10])=[O:4].[CH3:12][C:13]1([CH3:20])[O:18][CH2:17][C:16](=O)[CH2:15][O:14]1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Br:11])=[CH:8][C:9]=1[NH:10][CH:16]1[CH2:17][O:18][C:13]([CH3:20])([CH3:12])[O:14][CH2:15]1)=[O:4]
Reactant: COC(=O)c1sc(Br)cc1N
Reactant: CC1(C)OCC(=O)CO1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(Br)cc1NC1COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 29.6 %

Procedure:
A suspension of 3-amino-5-bromo-thiophene-2-carboxylic acid methyl ester (0.5 g, 2.12 mmol) in dry THF (0.6 mL) was treated with 2,2-dimethyl-[1,3]dioxan-5-one (253 μl, 2.12 mmol), followed by dibutyltin dichloride (32 mg, 0.11 mmol). After 5 min phenyl silane (280 μl, 2.27 mmol) was added and the reaction was stirred at room temperature for 3 days. It was dissolved in ethyl acetate (100 mL), washed with NaHCO3 solution and brine. The organic layer was separated, dried over MgSO4, evaporated and left on vacuum pump overnight. The residue was triturated with hexane-ether (4:1) mixture (2×100 mL). The soluble portion was evaporated and purified by chromatography over silica gel (hexane:ethyl acetate—95:5) yielding pure 5-bromo-3-(2,2-dimethyl-[1,3]dioxan-5-ylamino)-thiophene-2-carboxylic acid methyl ester (220 mg, 29%).
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5].C(OCC)(=O)C>CS(C)=O>[CH3:15][C:14]([CH3:16])=[CH:13][CH2:12][CH2:11]/[C:9](/[CH3:10])=[CH:8]/[CH2:7][CH2:6]/[C:4](/[CH3:5])=[CH:3]/[CH:2]=[O:1]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/C=O
Reaction time: 2 h
Yield: 85 %

Procedure:
5 g of the composition prepared in Example 7 are introduced in small fractions over a period of 15 minutes into a solution of 1.6 g of farnesol in 40 ml of dimethyl sulfoxide while maintaining the temperature at from 20° C. to 25° C. After 2 hours under agitation, the solution is poured into 100 ml of hexanes (petrol G) and the precipitate is separated off and washed with water and then with petrol G. The organic phases are concentrated under vacuum and the residue obtained is purified by chromatography over 25 g of R60 Merck® silica in order to separate the remaining stabilizing agent from the farnesal obtained; the eluent is petrol G and then its mixture with ethyl acetate (9/1-v/v). The pure farnesal is isolated with a yield of 85%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[S:13](Cl)(=[O:15])=[O:14].[NH2:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([O:25][CH3:26])=[O:24].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[S:13]([NH:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([O:25][CH3:26])=[O:24])(=[O:15])=[O:14]
Reactant: O=S(=O)(Cl)c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: COC(=O)c1sccc1N
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1sccc1NS(=O)(=O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 69.9 %

Procedure:
Synthesized as described for 3 using 2,6-dichloro-4-(trifluoromethyl)benzene-1-sulfonyl chloride (2.5 g; 7.97 mmol), methyl 3-aminothiophene-2-carboxylate (1.14 g; 7.25 mmol), 4-dimethylaminopyridine (221.4 mg; 1.81 mmol), pyridine (11.81 mL; 145.0 mmol) and anhydrous dichloromethane (50 mL). Purification by automated silica gel chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 30% v/v over 400 mL gradient elution) afforded the title compound as a white solid (2.20 g).
Reaction SMILES: [O:1]=[C:2]([C:20]1[S:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)[CH2:3][CH2:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])=[CH:7][CH:6]=1.FC(F)(F)C(O)=O>>[O:1]=[C:2]([C:20]1[S:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=2)=[CH:23][CH:24]=1)[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1

Procedure:
2-(4-(3-Oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)acetic acid is prepared from tert-butyl 2-(4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)acetate according to general procedure E using 10 equivalents of trifluoroacetic acid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:10]2[C:14](=[O:15])[N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:12]=[CH:11]2)[S:5][C:6]=1[C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.[NH2:58][CH2:59][C:60]1[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[N:3]=[C:4]([N:10]2[C:14](=[O:15])[N:13]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=3)[N:12]=[CH:11]2)[S:5][C:6]=1[C:7]([NH:58][CH2:59][C:60]1[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=1)=[O:9]
Reactant: NCc1cccnc1
Reactant: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59 %

Procedure:
To a solution of 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid (0.15 g, 0.39 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.97 g, 0.51 mmol) and N,N-diisopropylethylamine (0.09 mL, 0.51 mmol) in N,N-dimethylformamide (3 mL) was added 1-hydroxybenzotriazole (0.07 g, 0.51 mmol). The resulting mixture was stirred at ambient temperature for 15 minutes and followed by the addition of 3-(aminomethyl)pyridine (0.05 mL, 0.05 mmol). The reaction mixture was stirred for 17 hours at ambient temperature, diluted with ethyl acetate (30 mL) and washed with water and brine. The organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography to afford the title compound as a white powder in 59% yield (0.11 g): mp 156-158° C.; 1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.51 (s, 1H), 8.27 (s, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.59 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 7.31-7.19 (m, 1H), 6.46 (t, J=5.8 Hz, 1H), 5.04 (s, 2H), 4.59 (d, J=5.8 Hz, 2H), 2.63 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.4, 153.4, 150.9, 149.9, 149.3, 149.2, 138.9, 135.7, 131.2, 128.7, 125.8, 123.7, 121.8, 49.1, 41.6, 17.2; MS (ES+) m/z 475.3 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=O)([O-:3])=[O:2].Cl.[O:15]([NH2:17])[CH3:16].C(N(CC)CC)C.CCOCC>CO>[CH3:16][O:15][N:17]=[C:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: O=C1CCc2c1cccc2[N+](=O)[O-]
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCOCC
Product: CON=C1CCc2c1cccc2[N+](=O)[O-]
Temperature: 25 °C
Yield: 96.1 %

Procedure:
To a solution of 4-nitroindane-1-one (4.75 g, 26.81 mmol) in MeOH was added methoxyl amine hydrochloride (4.50 g, 53.88 mmol) and triethyl amine (7.50 mL, 53.81 mmol). After refluxing overnight, the reaction mixture was cooled to room temperature and extracted with EtOAc (3×200 mL). The combined organic extracts were washed with H2O (3×200 mL), brine (1×200 mL), dried over MgSO4 and concentrated. Purification by column chromatography using hex: Et2O (4:1) as eluant afforded 5.31 g (97% yield) of the title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ (1st isomer) 2.92-2.98 (m, 2H), 3.50-3.56 (m, 2H), 4.01 (s, 3H), 7.45 (t, J=7.62 Hz, 1H), 8.00 (d, J=7.33 Hz, 1H), 8.20 (d, J=7.92 Hz, 1H). 2nd isomer: 2.90-2.98 (m, 2H), 3.49-3.58 (m, 2H), 4.02 (s, 3H), 7.45 (t, J=8.21 Hz, 1H), 8.19 (d, J=8.21 Hz, 1H), 8.66 (d, J=7.92 Hz, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([C:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[O:41])[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: O=C(Cl)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)c3ccccc3)CC2)cc1

Procedure:
{4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-phenylmethanone was prepared according to General Procedure I by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate F1) with benzoyl chloride (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.98-2.10 (m, 4H), 3.30 (methyl sulfonyl and water peak), 3.70-3.75 (m, 1H), 4.58-4.63 (m, 1H), 5.14-5.17 (m, 1H), 7.42-7.52 (m, 5H), 7.63-7.65 (m, 2H), 8.05-8.07 (m, 2H), 8.41 (s, 1H), 8.58 (s, 1H). Mass spectrum MH+=478.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([NH:11]C(=O)OC(C)(C)C)[CH2:6]1.[ClH:23]>O1CCOCC1>[ClH:23].[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([NH2:11])[CH2:6]1
Reactant: CC(C)(C)OC(=O)NC1CCCC(Oc2ccccc2F)C1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCCC(Oc2ccccc2F)C1

Procedure:
tert-Butyl 3-(2-fluorophenoxy)cyclohexylcarbamate was stirred in a solution of HCl in dioxane (4 M) at room temperature for overnight. The product, HCl salt of 3-(2-fluorophenoxy)cyclohexanamine, was obtained after removal of solvent.
Reaction SMILES: [CH:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[O:6][C:7]1C(C(C)C)=C(S([O-])(=O)=O)C=[CH:9][C:8]=1C)([CH3:3])[CH3:2].[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C)C=O>[CH:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[O:6][CH2:7][CH:8]([N:25]=[N+:26]=[N-:27])[CH3:9])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)[O-])c(C(C)C)c1Oc1ccccc1C(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(COc1ccccc1C(C)C)N=[N+]=[N-]
Yield: 164.2 %

Procedure:
A mixture consisting of 21.0 g of 2-(2-isopropylphenoxy)-1-methylethyl-p-toluenesulfonate, 3.9 g of sodium azide and N,N-dimethylformamide was heated at 70° to 75° C. for 5 hr. with stirring. Upon completion of the reaction, the mixture was extracted with ethyl acetate; the extract was washed consecutively with water and saturated saline; and subsequently dried with anhydrous sodium sulfate. The solvent was thereafter distilled off under reduced pressure and yielded 21.6 g of 2-(2-isopropylphenoxy)-1-methylethylazide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:24](=[O:27])(=[O:26])[NH2:25])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[C:7]([OH:9])=[O:8])([O-])=O.[N+](C1C=C(C=C(S(=O)(=O)N)C=1OC1C=CC=CC=1)C(O)=O)([O-])=O>>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:24](=[O:26])(=[O:27])[NH2:25])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:21])[F:23])[CH:15]=1)[C:7]([OH:9])=[O:8]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1cccc(C(F)(F)F)c1
Agent: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1ccccc1
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1cccc(C(F)(F)F)c1

Procedure:
By substituting 3-nitro-5-sulphamyl-4-(m-trifluoromethylphenoxy)-benzoic acid for the 3-nitro-4-phenoxy-5-sulphamyl-benzoic acid of Example 1 B, the above compound was obtained with a melting point of 270° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([C@@H:9]1[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][NH:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:32][C:33]1([C:36]([N:38]2[CH2:43][CH2:42][CH:41]([C:44](O)=[O:45])[CH2:40][CH2:39]2)=[O:37])[CH2:35][CH2:34]1.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>[C:1]([O:5][C:6](=[O:22])[N:7]([C@@H:9]1[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11]([C:44]([CH:41]2[CH2:40][CH2:39][N:38]([C:36]([C:33]3([CH3:32])[CH2:35][CH2:34]3)=[O:37])[CH2:43][CH2:42]2)=[O:45])[CH2:10]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C(=O)N2CCC(C(=O)O)CC2)CC1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)OC(C)(C)C)[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 75.2 %

Procedure:
To a solution of rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (2.78 g, 7.56 mmol) in DMF (28 mL) were added at 0° C. N,N-diisopropyl ethyl amine (8.26 mL, 48.2 mmol), 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid (2.78 g, 8.04 mmol), 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.67 g, 9.65 mmol). The resulting solution was stirred for 6 h at ambient temperature. After diluting with EtOAc (50 mL) the solution was washed twice with water (50 mL) and brine (50 mL). The aqueous layers were extracted with EtOAc (50 mL) and dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate:methanol=80:20:0 to 0:90:10) afforded the title compound (3.06 g, 75%) as a light brown foam. MS m/e: 538.3 [M+H]+.
Reaction SMILES: [BrH:1].[Br:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:11])=[C:7]([CH:10]=1)[CH2:8]O>>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:11])=[C:7]([CH:10]=1)[CH2:8][Br:1]
Reactant: Br
Reactant: OCc1cc(Br)ccc1Cl
Product: Clc1ccc(Br)cc1CBr
Temperature: 70 °C

Procedure:
An aqueous hydrobromide acid solution (2 M, 2 ml) was added to 5-bromo-2-chlorobenzyl alcohol (Aldrich Co., 1 g), and the mixture was stirred with heating at 70° C. for 1 hr. After completion of the reaction, the mixture was extracted three times with diethyl ether. The organic layer was dried and the solvent was evaporated under reduced pressure to give 5-bromo-2-chlorobenzylbromide (1.3 g).
Reaction SMILES: [Cl-].COC1C=C(OC)NN([N+]2(C)CCOCC2)N=1.[Cl:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[CH:36]=[N:37][N:38]([CH2:40][C:41](O)=[O:42])[CH:39]=3)=[N:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1.[F:44][C:45]1[CH:51]=[CH:50][CH:49]=[C:48]([F:52])[C:46]=1[NH2:47].O>CN(C)C=O>[Cl:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[CH:36]=[N:37][N:38]([CH2:40][C:41]([NH:47][C:46]4[C:45]([F:44])=[CH:51][CH:50]=[CH:49][C:48]=4[F:52])=[O:42])[CH:39]=3)=[N:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1
Reactant: Nc1c(F)cccc1F
Reactant: O=C(O)Cn1cc(Nc2ncnc3cc(OCCCCl)ccc23)cn1
Agent: COC1=CC(OC)=NN([N+]2(C)CCOCC2)N1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cn1cc(Nc2ncnc3cc(OCCCCl)ccc23)cn1)Nc1c(F)cccc1F
Reaction time: 2 h
Yield: 76.8 %

Procedure:
4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholinium chloride (0.391 g, 1.32 mmol) was added in one go, at room temperature, to a stirred suspension of (4-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-1-yl)acetic acid (0.400 g, 1.11 mmol) and 2,6-difluoroaniline (0.171 g, 1.32 mmol) in dimethylformamide (7 ml). The mixture was stirred for 2 hours and then poured into water (30 ml) the resultant solid was filtered to give 2-(4-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-1-yl)-N-(2,6-difluorophenyl)acetamide (0.403 g, 77% yield) as a pale brown solid:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:24]1([CH2:30][CH2:31][C:32](O)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:32](=[O:33])[CH2:31][CH2:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)CCc1ccccc1
Reaction time: 2 h
Yield: 93.5 %

Procedure:
To a solution of L-proline benzyl ester hydrochloride (20.0 g) in methylene chloride (250 ml) were added triethylamine (11.5 ml), 3-phenylpropionic acid (13.7 g) and DCC (18.8 g) under ice-cooling, and the mixture was stirred for 2 hours. After stirring at room temperature for 14 hours, the insoluble material was filtered off, and the filtrate was concentrated. The residue was dissolved in ethyl acetate, and the solution was washed with 1N hydrochloric acid, saturated aqueous solution of sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluate: hexane-ethyl acetate). To thus-obtained N-(3-phenylpropionyl)-L-proline benzyl ester (26.1 g) in 1% water-containing methanol (200 ml) was added 10% Pd--C (3.0 g), and the mixture was stirred at room temperature under hydrogen atmosphere for 2.5 hours. The catalyst was filtered off, and the filtrate was concentrated to give 17.4 g of the title compound.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=3)[NH:12][C:11]=2[C:20]([NH2:22])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][S:24]([CH3:23])(=[O:26])=[O:25])[CH:17]=3)[NH:12][C:11]=2[C:20]([NH2:22])=[O:21])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)c1[nH]c2ccc(N)cc2c1S(=O)(=O)c1ccccc1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)c3ccccc3)c2c1

Procedure:
Reaction of 3-phenylsulfonyl-5-aminoindole-2-carboxamide with methanesulfonyl chloride under the conditions of Example 47 provides the title compound.