Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH:10]([C:19]1[CH:24]=[CH:23][C:22]2[O:25][CH2:26][O:27][C:21]=2[CH:20]=1)[CH2:11][C:12]([C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)=O.CC(O)=O.C[N:34](C)C=O>>[O:25]1[C:22]2[CH:23]=[CH:24][C:19]([C:10]3[CH:11]=[C:12]([C:14]4[CH:18]=[CH:17][S:16][CH:15]=4)[N:34]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[OH:1])[CH:9]=3)=[CH:20][C:21]=2[O:27][CH2:26]1
Reactant: CN(C)C=O
Reactant: O=C(CC(CC(=O)c1ccccc1O)c1ccc2c(c1)OCO2)c1ccsc1
Solvent: CC(=O)O
Product: Oc1ccccc1-c1cc(-c2ccc3c(c2)OCO3)cc(-c2ccsc2)n1

Procedure:
A mixture of 1-(2-hydroxyphenyl)-3-(3,4-methylenedioxyphenyl)-5-(thiophen-3-yl)-1,5-pentanedione on Wang resin. (2.0 g, 1.76 mmol), NH4OAc (1.0 g), and AcOH (1.5 mL) in dimethylformamide (40 mL) was heated at 100° C. for 18 h. The resin was filtered, and washed with dimethylformamide (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight. The dried resin was treated with 50% TFA/CH2Cl2 (15 mL) for 1 h. After filtration of the reaction mixture, the filtrate was concentrated to dryness. The residue was repeatedly dissolved in CH2Cl2 (10 mL) and concentrated to remove traces of TFA. Purification by flash chromatography gave 2-(4-benzo[1,3]dioxol-5-yl-6-thiophen-3-yl-pyridin-2-yl)-phenol; mp 120-121° C.; 1H NMR (DMSO-d6) d 6.15 (s, 2H), 6.97 (m, 2H) 7.13 (d, J=8.2 Hz, 1H), 7.35 (m, 1H), 7.66 (dd, J=8.2, 1.9 Hz, 1H), 7.80 (m, 3H), 8.16 (d, J=1.4 Hz, 1H), 8.31 (m, 2H), 8.37 (dd, J=2.9, 1.4 Hz, 1H), 14.58 (s, 1H); IR (KBr) 1602 cm−1; MS [M+H]+ m/z=374. Anal. calcd for C22H15NO3S: C, 70.76; H, 4.05; N, 3.75; Found: C, 70.66; H, 4.02; N, 3.59.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([Si:15]([CH3:22])([CH3:21])[O:16][CH2:17][CH2:18][CH2:19]O)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.[CH2:30]([O:32][C:33]([CH:35]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:34])[CH3:31]>ClCCl>[Si:15]([O:16][CH2:17][CH2:18][CH:19]=[CH:35][C:33]([O:32][CH2:30][CH3:31])=[O:34])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C=CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Methyl sulphoxide (1.9 ml, 26.8 mmol) was added to a cooled (−78° C.) solution of oxalyl chloride (2.16 ml, 24.7 mmol) in dichloromethane (100 ml), and after 10 minutes, a solution of 3-(tert-butyl-dimethyl-silanyloxy)-propan-1-ol (3 g, 15.8 mmol) in dichloromethane (25 ml) was added dropwise. Once addition was complete, the solution was stirred for a further 15 minutes. Triethylamine (8 ml, 57.5 mmol) was added, followed by dropwise addition of a solution of (ethoxycarbonylmethylene)triphenylphosphorane (10 g, 29.9 mmol) in dichloromethane (50 ml), and the reaction mixture allowed to warm to room temperature. The mixture was washed with water (4×), dried (MgSO4) and concentrated under reduced pressure. The residue was pre-adsorbed onto silica gel and purified by column chromatography using diethyl ether:pentane (2.5:97.5) as eluant to afford the title compound, 1.3 g; 1H NMR (CDCl3, 400 MHz) δ: 0.02 (s, 6H), 0.87 (s, 9H), 1.26 (t, 3H), 2.40 (m, 2H), 3.74 (t, 2H), 4.18 (q, 2H), 5.84 (d, 1H), 6.95 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[NH:13][C:5]2[C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH:10](O)[C:4]=2[C:3]=1[Cl:14].S(O)(O)(=O)=O.[NH2:20][C:21]1[NH:22][CH:23]=[CH:24][N:25]=1.CCOCC>CS(O)(=O)=O>[NH2:20][C:21]1[NH:25][C:24]([CH:10]2[CH2:9][CH2:8][NH:7][C:6](=[O:12])[C:5]3[NH:13][C:2]([Cl:1])=[C:3]([Cl:14])[C:4]2=3)=[CH:23][N:22]=1
Reactant: Nc1ncc[nH]1
Reactant: O=C1NCCC(O)c2c1[nH]c(Cl)c2Cl
Agent: CS(=O)(=O)O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: Nc1ncc(C2CCNC(=O)c3[nH]c(Cl)c(Cl)c32)[nH]1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of 2,3-dichloro-4-hydroxy-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one (60 mg, 0.256 mmol), prepared as in reference 2, in methanesulfonic acid (0.5 mL) is added 2-aminoimidazole sulfate (40.5 mg, 0.153 mmol). The mixture is stirred at 45° C. overnight, cooled to room temperature and Et2O (5 mL) is added resulting in brown oil. After discarding the supernatant, the oil is purified by silica gel column chromatography and eluted with MeOH—CH2Cl2 to give 4-(2-amino-3H-imidazol-4-yl)-2,3-dichloro-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one; 1H NMR (Methanol-d4) δ 2.09-2.17 (m, 1H), 2.23-2.31 (m, 1H), 3.20-3.29 (m, 2H), 4.23 (t, 1H, J=3.6 Hz), 6.18 (s, 1H); m/z [M++1] 300.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.[NH2:14][NH2:15]>C1COCC1>[NH:14]([C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1)[NH2:15]
Reactant: NN
Reactant: CCOC(=O)c1cnc(Cl)nc1C
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(NN)nc1C
Yield: 93 %

Procedure:
The title compound was prepared as described in Example 18, but employing a solution of ethyl 2-chloro-4-methylpyrimidine-5-carboxylate (0.08 g, 0.39 mmol) and hydrazine (0.06 g, 2.0 mmol) in THF (7.8 mL) resulting in a 93% yield (0.07 g); 1H NMR (CDCl3) δ 8.86 (s, 1H), 6.64 (bs, 1H), 4.33 (q, 2H), 2.70 (s, 3H), 1.38 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([O:13][CH2:22][CH:21]=[CH2:20])[CH:7]=[CH:6]2
Reactant: C=CCBr
Reactant: COc1ccc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.5 %

Procedure:
6-Methoxy-2-naphthol (22.1 g, 127.0 mmol) was dissolved in acetone (200 ml). Potassium carbonate (70.2 g, 508.0 mmol) and allyl bromide (16.5 ml, 191.0 mmol) were added to the resulting solution followed by stirring for 2 days at room temperature. After the reaction mixture was filtered, the organic solvent was distilled off under reduced pressure. Water was added to the residue, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The organic solvent was distilled off again to give 6-methoxy-2-(2-propenyloxy)naphthalene (24.9 g, Yield 91%) as a crude product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]([CH3:14])[C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[OH:10])([O-])=O.Cl.[OH-].[Na+]>C(O)C.O.C(Cl)(Cl)Cl>[NH2:1][C:4]1[CH:5]=[C:6]([CH:11]([CH3:14])[C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: CC(C#N)c1ccc(O)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C#N)c1ccc(O)c(N)c1
Temperature: 0 °C
Reaction time: 19 h

Procedure:
2-(3-Nitro-4-hydroxyphenyl) propionitrile (123.8 g., 0.64 mole.) was suspended in absolute ethanol (950 ml.) and added during 20 minutes, with cooling, to a solution of stannous chloride dihydrate (437.8 g., 1.94 mole.) in concentrated hydrochloride acid (591 ml., 7 mole.). The addition was made at such a rate that the temperature of the reaction mixture did not exceed 20°C. Stirring of the mixture was continued for a further 19 hours at room temperature. The resulting solution, together with ice (1.75 kg.) was added during one hour to a cooled solution of sodium hydroxide (650 g.) in water (600 ml.). The temperature of the reaction mixture was maintained at 15° - 20°C during the addition. The mixture was stirred for a further 1 hour, and the pH then adjusted to 6 by the addition of concentrated hydrochloric acid. The resulting suspension was filtered and the filtrate saturated with sodium chloride, then extracted with ether (×6). The combined ether extracts were dried (Na2SO4) and evaporated to leave a solid (69.15 g.) which was suspended in chloroform and extracted with 2N-hydrochloric acid (×6). The combined acid extracts were neutralised to pH 7-8 by the addition of sodiium bicarbonate. The resulting suspension was extracted with ether (×4). The combined ether extracts were washed twice with water, dried (Na2SO4), and evaporated to yield 2-(3-amino-4-hydroxyphenyl) propionitrile was a light brown solid (62.85 g.), m.p. 110° - 112°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:28])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17](I)=[C:16]([O:21][CH:22]([F:24])[F:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C[Si](C)(C)N[Si](C)(C)C.C(N(C(C)C)CC)(C)C.Cl.C[N:49](C)[CH:50]=[O:51]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:28])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:50]([NH2:49])=[O:51])=[C:16]([O:21][CH:22]([F:24])[F:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: FC(F)Oc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1I
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1OC(F)F
Temperature: 90 °C
Reaction time: 12 h

Procedure:
In a solution of 0.30 g of 5-(3,5-dichlorophenyl)-3-(3-difluoromethoxy-4-iodophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole, 0.80 mL of 1,1,1,3,3,3-hexamethyldisilazane and 0.20 mL of diisopropylethylamine in 10 ml of N,N-dimethylformamide, 0.062 g of 1,1′-bis(diphenylphosphino) ferrocene and 0.013 g of palladium (II) acetate were added, and stirred under carbon monoxide atmosphere at 90° C. for 12 hours and then at room temperature for 3 days. After the completion of the reaction, 10 mL of 1N hydrochloric acid was added, and stirred for 10 minutes, extracted with ethyl acetate (10 mL×2). The combined organic phases were washed with water, and then dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that were eluated with ethyl acetate-hexane (2:3) to obtain 0.30 g of the aimed product as yellow resinous substance.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([Br:12])[CH:6]=1)[OH:4].Cl[O-].[Na+].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Br:12][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[C:2]([F:13])([F:14])[F:1])[CH:10]=[CH:9][C:8]=1[F:11]
Reactant: OC(c1ccc(F)c(Br)c1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc(F)c(Br)c1)C(F)(F)F

Procedure:
6.4 g (0.023 mol) of 2,2,2-trifluoro-1-(3-bromo-4-fluorophenyl)ethanol and 0.4 g (0.0012 mol) of tetrabutylammonium hydrogen sulfate are dissolved in 100 ml of methylene chloride at room temperature. 14.4 ml (0.028 mol) of an approximately 12% strength sodium hypochlorite solution are metered in within 15 minutes with vigorous stirring and the mixture is stirred for a further 4 hours during which the reaction temperature rises to 27° C. The reaction mixture is added to 100 ml of water, the phases are separated, the aqueous phase is extracted several times with methylene chloride and the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying the organic phase with sodium sulfate, the volatiles are distilled off. Following distillation of the crude product in a kugelrohr (0.5 mbar, 80°-100° C. bath temperature), 3.9 g (61.5% of theory) of 2-bromo-4-trifluoroacetylfluorobenzene are obtained. nD20 : 1.4905.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][N:13]([CH3:27])[C:14]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH2:28]([CH:18]1[CH2:19][C:14]([N:13]([CH3:27])[CH3:12])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:15][CH2:16][C:17]1=[O:20])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: BrCc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(=O)C(Cc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
Diisopropylamine (2.1 ml, 15 mmol) was provided in dry THF (30 ml) in argon and mixed with a solution of butyl lithium in hexane (2.5M, 6 ml, 15 mmol) at −30° C. (bath temperature. The reaction mixture was cooled to −78° C. After this temperature was reached, 4-(dimethylamino)-4-phenylcyclohexanone (2.17 g, 10 mmol), dissolved in dry THF (10 ml), was added in drops within 15 min. The batch was left for 30 min at −78° C. Benzyl bromide (3.6 ml, 30 mmol), dissolved in dry THF (20 ml), was then added within 10 min. The reaction mixture was stirred for a further 15 min at 78° C. (?), then the cooling removed. After room temperature was reached, the batch was stirred for a further 18 h. For work up the batch was carefully mixed with water (1 ml), then saturated NH4Cl solution (40 ml) was added. The organic phase was separated and the aqueous solution extracted with ethyl acetate (3×20 ml). The combined organic phases were washed with saturated NH4Cl solution (2×40 ml). The organic phases were then mixed with 1N HCl (50 ml) and thoroughly shaken out. The acid aqueous phase was separated, the organic phase washed with water (2×20 ml). The combined aqueous phases were washed with ethyl acetate (1×30 ml). The aqueous solution was then placed on 70 ml of 2N NaOH. An oil separated out of the alkaline solution. The formed mixture was extracted with ethyl acetate (3×30 ml). The combined organic phases were dried over MgSO4 and then concentrated to low volume. One of the possible diastereoisomers was isolated from the residue (2.27 g) by chromatographic purification [silica gel 60 (50 g); ethyl acetate (1000 ml)].
Reaction SMILES: I[C:2]1[C:3](=[O:21])[N:4]([CH3:20])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[CH2:22]([O:24][CH:25]([O:28][CH2:29][CH3:30])[C:26]#[CH:27])[CH3:23].C(N(CC)CC)C.O>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I>[CH2:22]([O:24][CH:25]([O:28][CH2:29][CH3:30])[C:26]#[C:27][C:2]1[C:3](=[O:21])[N:4]([CH3:20])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8])[CH3:23]
Reactant: C#CC(OCC)OCC
Reactant: Cc1c(I)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(C#Cc1c(C)n(-c2cccc(C(F)(F)F)c2)c(=O)n(C)c1=O)OCC
Yield: 1079.3 %

Procedure:
A solution of 5-iodo-3,6-dimethyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 60) (20.0 mg), propargylaldehyde diethyl acetal (62.5 mg), tetrakis(triphenylphosphine)palladium (5.6 mg), copper iodide (1.0 mg) and triethylamine (68 μL) in tetrahydrofuran (1.0 ml) was stirred at room temperature under nitrogen atmosphere for twelve hours. To the reaction mixture was added water (10 ml) and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 5-(3,3-diethoxyprop-1-ynyl)-3,6-dimethyl-1-(3-trifluoromethylphenyl)-pyrimidin-2,4(1H,3H)-dione (216.0 mg).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:22][NH2:23])=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:26]([O:30][C:31]([NH:33][C@@H:34]([CH:38]([CH3:40])[CH3:39])[C:35](O)=[O:36])=[O:32])([CH3:29])([CH3:28])[CH3:27].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C1COCC1>[C:26]([O:30][C:31](=[O:32])[NH:33][C@@H:34]([CH:38]([CH3:39])[CH3:40])[C:35]([NH:23][NH:22][C:20](=[O:21])/[CH:19]=[CH:18]\[N:15]1[CH:16]=[N:17][C:13]([C:5]2[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:24])([F:1])[F:25])[CH:4]=2)=[N:14]1)=[O:36])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NNC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: -60 °C
Reaction time: 1 h
Yield: 18.1 %

Procedure:
In a 10 mL round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide (0.25 g, 1.0 eq.) was dissolved in THF (5 mL) and cooled to −60° C. where (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (0.19 g, 1.3 eq.) was introduced dropwise. T3P (50% in EtOAc) (0.81 mL, 2 eq.) was added dropwise followed by DIPEA (0.48 mL, 4 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (S,Z)-tert-butyl(1-(2-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)hydrazinyl)-3-methyl-1-oxobutan-2-yl)carbamate (0.07 g, yield: 18%). In a 10 mL round-bottom flask, (S,Z)-tert-butyl(1-(2-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)hydrazinyl)-3-methyl-1-oxobutan-2-yl)carbamate was then dissolved in dichloromethane (2 mL). TFA (0.05 mL) was added and the reaction mixture was stirred at RT for 5 h. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product (0.01 g), which was triturated with petroleum ether and dried under reduced pressure to yield (S,Z)-2-amino-N′-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-3-methylbutanehydrazide 2,2,2-trifluoroacetate (0.006 g, yield: 2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1.[CH2:13]=[O:14]>CO.CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([CH2:9][CH2:13][OH:14])[CH:8]=1
Reactant: COc1ccc([N+](=O)[O-])c(C)c1
Reactant: C=O
Solvent: CO
Solvent: CS(C)=O
Product: COc1ccc([N+](=O)[O-])c(CCO)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 47.7 %

Procedure:
Triton B (2 ml, 35% in MeOH) was added at 80° C. to a mixture of 5-methoxy-2-nitrotoluene (25 g, 150 mmol) and paraformaldehyde (2.3 g, 73 mmol) in DMSO (20 ml, synthesis quality, additionally dried for 2 d over molecular sieve 4 Å). After being stirred 2.5 h at this temperature, it was cooled to room temperature and neutralized with a few drops of conc. HCl. The mixture was diluted with H2O (50 ml) and extracted with EtOAc (5×100 ml). The organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to a distillation in a high vacuum (p=0.1 torr), whereby a fraction containing starting material (12.1 g) was obtained at 70° C. The residual crude product was purified by column chromatography (240 g SiO2, solvent: toluene/EtOAc 8:1 1400 ml, 7:1 1600 ml, 6:1 400 ml, 5:1 400 ml, 3:1 400 ml, 2:1 600 ml and 1:1 600 ml). 2-(5-methoxy-2-nitrophenyl)ethanol (6.87 g, 48%) was obtained as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:3]([N:8]2[CH2:11][CH:10]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:23]1([CH3:22])[CH:24]=[CH:25][CH:26]=[C:27]([C:2]2[C:3]([N:8]3[CH2:11][CH:10]([C:12]4[CH:21]=[CH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[N:13]=4)[CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH:28]=1
Reactant: Clc1nccnc1N1CC(c2ccc3ccccc3n2)C1
Reactant: Cc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(-c2nccnc2N2CC(c3ccc4ccccc4n3)C2)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
To a solution of 2-[1-(3-chloro-pyrazin-2-yl)-azetidin-3-yl]-quinoline, as prepared in the above Step 3 of Example 57, (150 mg, 0.51 mmol), 3-methyl-phenylboronic acid (75 mg, 0.51 mmol) and K3PO4 (211 mg, 1 mmol) in 1,4-dioxane (12 mL) and H2O (3 mL) was added Pd(dppf)Cl2 (35 mg, 0.05 mmol) then the reaction mixture was stirred at 110° C. under N2 overnight. The reaction mixture was filtered through CELITE™ and washed with CH2Cl2 (50 mL). The organic layer was concentrated and the crude product was purified by silica gel column to give 2-[1-(3-m-tolyl-pyrazin-2-yl)-azetidin-3-yl]-quinoline (50 mg, 0.14 mmol, yield 28%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[I:10]I>O.OO>[Cl:1][C:2]1[C:3]([I:10])=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: II
Agent: OO
Solvent: O
Product: Oc1cc(Cl)cc(Cl)c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.9 %

Procedure:
To a suspension of 3,5-dichlorophenol (0.6 g; 3.68 mmol) in H2O (15 ml), 30% H2O2 was added followed by I2 (0.47 g; 1.85 mmol). The resulting mixture was vigorously stirred for 8 h at room temperature, then extracted with CH2Cl2 (15 ml) and the organic phase was dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2; CH2Cl2) to give the title compound (0.55 g; 52%) as colourless solid. 1H-NMR (CDCl3) 5.58 (s, 1H); 6.89 (s, 1H); 7.06 (s, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]3[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccccc3)c2c1Cl
Product: Cc1sc2nc(-n3cccn3)nc(NCc3ccccc3)c2c1Cl

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2,5-dichloro-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5-chloro-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Li+].[B-](CC)(CC)CC.O1CCCC1.[C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](OC)=[O:25])=[CH:18][CH:17]=1)#[N:15].C(C1C=CC(C=O)=CC=1)#N.C1(P(=CC(OC)=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>O1CCCC1.O>[C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:18][CH:17]=1)#[N:15]
Reactant: COC(=O)CCc1ccc(C#N)cc1
Agent: CC[B-](CC)CC
Agent: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(CCCO)cc1
Yield: 67.1 %

Procedure:
A solution of 1M superhydride/tetrahydrofuran (3.3 ml) in anhydrous tetrahydrofuran (5 ml) was cooled to -50° to -60° C. under an argon gas stream. Thereto was added dropwise a solution of 210 mg of methyl 3-(4-cyanophenyl)propionate synthesized from 4-cyanobenzaldehyde and methyl (triphenylphosphoranylidene)acetate by the procedure of Reference Examples 69 and 76) in 2 ml of tetrahydrofuran. The resultant mixture was stirred at that temperature for 10 minutes, then made acidic by addition of water and 1N hydrochloric acid in that order at the same temperature, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 120 mg of 3-(4-cyanophenyl)propanol.