Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Li])([CH2:3][CH3:4])[CH3:2].CO[N:8](C)[C:9](=O)[CH2:10][CH3:11].FC(F)(F)C(O)=O.[CH2:21]1[CH2:25][O:24][CH2:23][CH2:22]1>ClCCl>[CH2:3]([C:1]1[NH:8][C:9]2[C:22]([CH:2]=1)=[CH:21][C:25]([O:24][CH3:23])=[CH:11][CH:10]=2)[CH3:4]
Reactant: CCC(=O)N(C)OC
Reactant: [Li]C(C)CC
Reactant: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc2cc(OC)ccc2[nH]1
Temperature: -40 °C
Yield: 35 %

Procedure:
N-(t-Boc)-4-Methoxy-2-methylaniline (1.00 g, 4.2 mmol) was dissolved in anhydrous THF (15 mL) under an atmosphere of Ar (g). The solution was cooled to −40° C. and sec-butyllithium (1.4 M in cyclohexane, 6.65 mL, 0.60 g) was added slowly to maintain an internal temperature of <−25° C. After reaching 1 equivalent of sec-butyllithium (˜3.3 mL) the reaction mixture turned bright yellow signifying the deprotonation of the amide nitrogen. The reaction mixture was then cooled to −50° C. over 10 minutes and a solution of N-methoxy-N-methylpropanamide (520 mg, 4.4 mmol) in THF (3 mL) was added in a dropwise fashion. The reaction mixture was allowed to warm to −10° C. over 30 minutes while stirring. Upon completion, the mixture was partitioned between Et2O (50 mL) and 0.5 N HCl (50 mL). The aqueous layer was extracted once more with Et2O (25 mL). The combined ether layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated in vacuo providing a yellowish-brown oil. The crude reaction mixture was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (3 mL) was added to the reaction mixture and stirred at room temperature for 48 hours. When the reaction reached completion, DCM (50 mL) was added and the reaction mixture was transferred to a separatory funnel and washed with saturated NaHCO3 (50 mL) followed by brine (50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo giving a deep yellow oil which was purified by column chromatography (0-20% ethyl acetate/hexanes) to yield a yellow/brown oil (0.261 g, 35%): TLC Rf 0.43 in 20% EtOAc/hexanes. 1H NMR (600 MHz, CDCl3) δ 7.78 (s, 1H), 7.20-7.18 (d, 1H, J=8.64 Hz), 7.04 (d, 1H, J=2.4 Hz), 6.80-6.78 (dd, 1H J1=8.64 Hz, J2=2.4 Hz), 6.20 (s, 1H), 3.86 (s, 3H), 2.82-2.76 (q, 2H, J=7.62 Hz), 1.36-1.34 (t, 3H, J=7.62 Hz); 13C NMR (150 MHz, CDCl3) δ 154.3, 142.4, 131.2, 129.5, 111.09, 110.96, 102.3, 98.8, 56.1, 21.7, 13.5. Elemental analysis calculated for C11H13NO: C, 76.16; H, 7.99; N, 7.40. Found: C, 76.28; H, 7.97; N, 7.39.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[CH:17][N:18]([CH2:19][C:20](=[O:27])[N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:12]2=[N:11][C:10]=1[C:28]1[S:29][C:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[CH:31][N:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:50](Cl)(=[O:55])[C:51]([CH3:54])([CH3:53])[CH3:52].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[CH:17][N:18]([CH2:19][C:20](=[O:27])[N:21]3[CH2:26][CH2:25][N:24]([C:50](=[O:55])[C:51]([CH3:54])([CH3:53])[CH3:52])[CH2:23][CH2:22]3)[C:12]2=[N:11][C:10]=1[C:28]1[S:29][C:30]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)=[CH:31][N:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cn1ccn2c(=O)c(OCc3ccccc3)c(-c3ncc(Cc4ccc(F)cc4)s3)nc12)N1CCNCC1
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)N1CCN(C(=O)Cn2ccn3c(=O)c(OCc4ccccc4)c(-c4ncc(Cc5ccc(F)cc5)s4)nc23)CC1
Temperature: 0 °C
Yield: 89.5 %

Procedure:
A mixture of the product of example 112 (200 mg, 0.36 mmol) and DIPEA (50.94 mg, 0.39 mmol) in CH2Cl2 (10 ml) was stirred at 0° C. Then pivaloyl chloride (47.48 mg, 0.39 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours, after which saturated sodium bicarbonate was added and then extracted with ethyl acetate. The extracts were combined, washed with brine, and then dried over sodium sulfate. The product was purified by column chromatography (CH2Cl2/MeOH=10/1) to give the desired product (207 mg, 90% yield).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28](OCC)=[O:29])[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:43]1([CH2:46][NH2:47])[CH2:45][CH2:44]1>>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([NH:47][CH2:46][CH:43]3[CH2:45][CH2:44]3)=[O:29])[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Reactant: NCC1CC1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc3c(C(=O)NCC4CC4)noc3c2F)C[C@H](C)O1

Procedure:
Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and cyclopropylmethanamine
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[Cl:14][C:15]1[C:16]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[N:17][CH:18]=[N:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:14][C:15]1[C:16]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=4)[N:7]=3)=[CH:25][CH:24]=2)=[N:17][CH:18]=[N:19][CH:20]=1
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)nn12
Reactant: Oc1ccc(CNc2ncncc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cnc2ccc(Oc3ccc(CNc4ncncc4Cl)cc3)nn12
Temperature: 80 °C
Reaction time: 3 h
Yield: 76.8 %

Procedure:
0.18 g (3.6 mmol) of 6-chloro-3-nitro-imidazo[1,2-b]pyridazine are added to a solution of 0.85 g (3.6 mmol) of 4-[(5-chloro-pyrimidin-4-ylamino)-methyl]-phenol (from example A14) and 2.5 g (18 mmol) of potassium carbonate in 10 ml of dry N,N-dimethylformamide and the reaction mixture is stirred at 80° C. for 3 h. The temperature is allowed to raise to room temperature and the mixture is poured into water (100 ml). The precipitate is filtered off and purified by silica gel chromatography (toluene/dioxane=2:1) to yield 1.1 g (78%) of the title compound as a beige powder of m.p. 185° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[S:6][CH2:5][CH2:4]1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>CO.C([BH3-])#N.[Na+]>[CH2:16]([NH:1][CH2:2][CH:3]1[C:15]2[C:7](=[N:8][C:9]3[C:14]=2[CH2:13][CH:12]=[CH:11][CH:10]=3)[S:6][CH2:5][CH2:4]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccccc1
Reactant: NCC1CCSc2[nH]c3ccccc3c21
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: C1=CCC2=C3C(=NC2=C1)SCCC3CNCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a solution of 4-aminomethyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole (150 mg) in methanol (5 ml) are added a solution of benzaldehyde (76 mg) in methanol (1.5 ml) and sodium cyanoborohydride (132 mg). The mixture is adjusted to pH 7 with a solution of hydrochloride in methanol, stirred at room temperature for 1 hour and evaporated to remove the solvent. The residue is dissolved in ether, washed with a 10% aqueous solution of sodium hydroxide and a saline solution, dried and evaporated to give the title compound (210 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([C@@:8]2([OH:32])[C@@H:12]([CH2:13][O:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20]C(Cl)=[CH:18][CH:17]=3)[O:11][C@@H:10]([N:24]3[CH:31]=[CH:30][C:28](=O)[NH:27][C:25]3=[O:26])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH:35]([Cl:38])(Cl)Cl.[N:39]12CCN(CC1)CC2.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C@@:8]2([OH:32])[C@@H:12]([CH2:13][O:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:35]([Cl:38])=[CH:18][CH:17]=3)[O:11][C@@H:10]([N:24]3[CH:31]=[CH:30][C:28]([NH2:39])=[N:27][C:25]3=[O:26])[CH2:9]2)=[O:7])=[CH:33][CH:34]=1
Reactant: C1CN2CCN1CC2
Reactant: O=C(OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@]1(O)C(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: ClC(Cl)Cl
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: Nc1ccn([C@H]2C[C@@](O)(C(=O)c3ccc(Cl)cc3)[C@@H](COC(=O)c3ccc(Cl)cc3)O2)c(=O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
To 3.0 g of 3′,5′-O-bis(4-chlorobenzoyl)-2′-deoxyuridine was added 30 mL of chloroform, 0.72 g of triethylamine, 0.80 g (1.2 times moles of uridine derivative) of 1,4-diazabicyclo[2.2.2]octane and 1.36g of p-toluenesulfonyl chloride, and the resulting mixture was stirred at room temperature for 30 minutes. Ammonia gas was bubbled into the reaction mixture at room temperature for 1 hour, and the mixture was stirred in an ice bath for 1 hour. After sludging by the addition of 100 mL of water and 100 mL of methanol, the crystals were filtered and washed with the mixed solution of water and methanol (1:1) to give 2.42 g of 3′,5′-O-bis(4-chlorobenzoyl)-2′-deoxycytidine. Yield 80.9%.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].O.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C(=O)([O-])O.[Na+]>CC(C)=O>[CH2:16]([O:15][C:13]([O:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C(C#N)=NO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(C#N)=NOC(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 80.1 %

Procedure:
A mixture of ethyl 2-hydroxyimino-2-cyanoacetate (8.5 g). water (30 ml) and acetone (4 ml) is stirred at 0°C, and benzyl chloroformate (9.4 g) is added thereto. The resulting mixture is, after adjusted to pH 7 to 8 with the addition of an aqueous solution of sodium hydrogencarbonate, stirred for 3 hours and then filtered. The residue is washed with water and dried to give ethyl 2-benzyloxycarbonyloxyimino-2-cyanoacetate (12.2 g) as crystals. M.P. 101° to 102.5°C.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[C:7]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:8][C:9]([CH3:11])=[O:10]>C(O)(=O)C>[C:7]([C:8]1[CH2:11][CH:9]([CH:8]=[CH2:7])[O:10][C:9]=1[CH3:11])([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: C=CC1CC(C(=O)OCC)=C(C)O1
Temperature: 60 °C
Yield: 99 %

Procedure:
4-Carbethoxy-5-methyl-2-vinyl-2,3-dihydrofuran was prepared in accordance with the oxidative addition procedure described by Vinogradov et. al. in Izv. Akad Nauk SSR, Ser. Khimm, 1981, (9), 2088-84. For the reaction, 98 grams manganous acetate tetrahydrate was combined with 300 mls acetic acid in a glass reaction vessel. The mixture was heated to 60° C. with stirring and 15.8 grams potassium permanganate slowly added. The temperature was maintained below 70° C. during the addition and, when the addition was complete, the mixture was stirred for thirty minutes and then cooled to approximately 20° C. Two grams cupric acetate and 180 grams ethyl acetoacetate were then charged to the reactor and, after the mixture was stirred for five minutes, butadiene was slowly bubbled into the mixture which was maintained at 25° C. After thirty grams butadiene was added, the mixture was stirred for five minutes at 30° C. and then heated at 60° C. for fifteen minutes. At this point, the color of the reaction mixture changed from pink to brown (indicating reduction of Mn (III) to Mn (II) and essentially all of the starting ethyl acetoacetate was determined by gas chromatographic analysis to be reacted. The mixture was cooled and filtered to remove insoluble salts. The salts were washed twice with acetic acid (50 mls) and the combined filtrates stripped on a rotary evaporator at 90° C. and reduced pressure to remove the acetic acid. The resulting residue was poured into 250 mls water and extracted three times with n-hexane (75 mls). The combined organic extracts were then washed with aqueous sodium bicarbonate, dried over sodium sulfate, and stripped on a rotary evaporator under reduced pressure to remove the organic solvent. The crude product was vaccum distilled to obtain a 65% yield of essentially pure (99%) 4-carbethoxy-5-methyl-2-vinyl-2,3-dihydrofuran (B.P. 108-110 5/8 10 mm Hg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C=O.Cl[CH:33](Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][N:19]([CH3:33])[C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(NCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Reactant: CC(Cl)Cl
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CN(CC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(2-{(1S,2S)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl)-4-(methylsulfonyl)aniline (6 mg, 0.014 mmol) from Example 7 and paraformaldehyde were added to dichloroethane (0.2 mL), then sodium triacetoxyborohydride (10.1 mg, 0.041 mmol) was added and stirred overnight at room temperature. The reaction was quenched with sodium bicarbonate saturated solution (10 mL), extracted with EtOAc (10 mL), second wash with Brine (10 mL). The organic phase was dried by magnesium sulfate, filtered, concentrated and purified by purified by preparative-TLC (Analtech Silica Gel GF 1500 μM, 20×20 cm) using 50% ethyl acetate/hexane to give the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[NH:4][N:3]=1.[C:12]1([C:21]2[CH:26]=[CH:25][C:24]([C:27]([O-:29])=O)=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:15]([C:18]([O-:20])=O)=[CH:14][CH:13]=1>>[O:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5]1[NH:4][N:3]=[C:2]([NH:1][C:27]([C:24]2[CH:23]=[CH:22][C:21]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([NH:1][C:2]4[CH:6]=[C:5]([C:7]5[O:8][CH:9]=[CH:10][CH:11]=5)[NH:4][N:3]=4)=[O:20])=[CH:16][CH:17]=3)=[CH:26][CH:25]=2)=[O:29])[CH:6]=1
Reactant: O=C([O-])c1ccc(-c2ccc(C(=O)[O-])cc2)cc1
Reactant: Nc1cc(-c2ccco2)[nH]n1
Product: O=C(Nc1cc(-c2ccco2)[nH]n1)c1ccc(-c2ccc(C(=O)Nc3cc(-c4ccco4)[nH]n3)cc2)cc1

Procedure:
Compound 468 was prepared from 3-amino-5-(2-furanyl)pyrazole and 4,4′-biphenyldicarboxylate. [M+H]+ calcd for C28H21N6O4: 505.16; found: 504.93.
Reaction SMILES: [ClH:1].[CH:2]1([C:5](=[O:33])[CH:6]([N:14]2[CH2:19][CH2:18][CH:17]([SH:20])/[C:16](=[CH:21]\[C:22]3[N:23]([CH2:27][C:28]([O:30]CC)=[O:29])[CH:24]=[CH:25][N:26]=3)/[CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[CH2:4][CH2:3]1.Cl>C(#N)C>[ClH:1].[C:28]([CH2:27][N:23]1[CH:24]=[CH:25][N:26]=[C:22]1/[CH:21]=[C:16]1/[CH2:15][N:14]([CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:5]([CH:2]2[CH2:3][CH2:4]2)=[O:33])[CH2:19][CH2:18][CH:17]/1[SH:20])([OH:30])=[O:29]
Reactant: CCOC(=O)Cn1ccnc1/C=C1/CN(C(C(=O)C2CC2)c2ccccc2F)CCC1S
Agent: Cl
Solvent: CC#N
Product: O=C(O)Cn1ccnc1/C=C1/CN(C(C(=O)C2CC2)c2ccccc2F)CCC1S
Yield: 75.4 %

Procedure:
Following a procedure similar to that described in Example 134, (Z-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-{[1-(ethoxycarbonylmethyl)-1H-imidazol-2-yl]methylidene}-4-sulfanylpiperidine hydrochloride (73.5 mg) was treated with 3N hydrochloric acid (3 ml) at 50° C. for 2 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024 N hydrochloric acid, 10/90, v/v) to afford the title compound (52.3 mg, yield: 95%) as a colourless amorphous solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:9]=[CH:8][NH:7][N:6]=1.[S:10]([O-:14])([O-:13])(=[O:12])=[O:11].CS[C:17]([NH2:19])=[NH2+:18].CS[C:22]([NH2:24])=[NH2+:23].CO>C(O)C>[S:10]([OH:14])([OH:13])(=[O:12])=[O:11].[NH:7]1[CH:8]=[CH:9][C:5]([CH2:4][CH2:3][CH2:2][NH:1][C:17]([NH2:19])=[NH:18])=[N:6]1.[NH:7]1[CH:8]=[CH:9][C:5]([CH2:4][CH2:3][CH2:2][NH:1][C:22]([NH2:24])=[NH:23])=[N:6]1
Reactant: O=S(=O)([O-])[O-]
Reactant: NCCCc1cc[nH]n1
Reactant: CSC(N)=[NH2+]
Solvent: CCO
Solvent: CO
Product: N=C(N)NCCCc1cc[nH]n1
Product: O=S(=O)(O)O
Reaction time: 1 h

Procedure:
An intimate mixture of 3-(3-aminopropyl)pyrazole (4.7 g) and S-methylthiouronium sulphate (4.9 g) is fused at 140° C for one hour. After cooling, methanol is added and the filtered methanol solution is subsequently diluted with ethanol. The solid obtained is recrystallised from methanol-ethanol affording 3-(3-pyrazolyl) propylguanidine hemisulphate, m.p. 210° C.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9]/[N:10]=[C:11](\[CH3:20])/[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O>Cl.O1CCOCC1>[CH3:20][C:11]1[N+:10]([O-:9])=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:8][C:12]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: C/C(=N\O)C(=O)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2)oc(-c2ccccc2)[n+]1[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.6 %

Procedure:
To a solution of benzaldehyde (325 mg, 311 μL, 3.06 mmol) in HCl (4M in dioxane, 10 mL was added (E)-2-(hydroxyimino)-1-phenylpropan-1-one (500 mg, 3.06 mmol) at 0-5° C. The ice bath was removed and the mixture was stirred at RT for 24 h. All volatiles were removed and the residue was dissolved in HCl (4M in dioxane, 10 mL). The reaction mixture was stirred at RT for 6 h and concentrated. The obtained suspension was filtered, washed with diethyl ether and dried in vacuo to give the product as colorless solid (398 mg, 1.58 mmol, 51.7%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([NH:12][CH2:13][C:14]#[CH:15])=[CH:5][C:3]=1[NH2:4].[C:16]1(=O)[O:21][C:19](=[O:20])[C:18]2[CH2:22][CH2:23][CH2:24][CH2:25][C:17]1=2.O>C(O)(=O)C>[F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([NH:12][CH2:13][C:14]#[CH:15])=[CH:5][C:3]=1[N:4]1[C:19](=[O:20])[C:18]2[CH2:22][CH2:23][CH2:24][CH2:25][C:17]=2[C:16]1=[O:21]
Reactant: C#CCNc1cc(N)c(F)cc1[N+](=O)[O-]
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Solvent: O
Product: C#CCNc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1[N+](=O)[O-]
Yield: 36.7 %

Procedure:
A mixture of 2-fluoro-4-nitro-5-(2-propynylamino)-aniline (1.41 g) and 3,4,5,6-tetrahydrophthalic anhydride (1.33 g) was suspended in acetic acid (7 ml), followed by heating under reflux for 4 hours. The reaction mixture was cooled, water was added thereto, and the resultant mixture was extracted with ethyl acetate. The extract was washed with water and an aqueous sodium bicarbonate solution, dried and concentrated to give 2-[2-fluoro-4-nitro-5-(2-propynylamino)phenyl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.85 g). m.p., 183.5° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.Cl.[CH3:19][S:20]([C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26])(=[O:22])=[O:21]>>[CH3:19][S:20]([C:23]1[CH:24]=[C:25]([NH:26][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[N:5]=[CH:4][N:3]=2)[CH:27]=[CH:28][CH:29]=1)(=[O:21])=[O:22]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Agent: Cl
Product: CS(=O)(=O)c1cccc(Nc2cc(-c3ccc(C(F)(F)F)cc3)ncn2)c1

Procedure:
Analogous to the procedure used to prepare Example 5(b), 4-chloro-6-(4-trifluoromethylphenyl)pyrimidine, Example 5(a), (200 mg, 0.77 mmol) and 3-methylsulphonylaniline hydrochloride (80 mg, 0.39 mmol, Acros) afforded a crude reaction product mixture, which was partitioned between EtOAc (100 mL) and 1 N NaOH (50 mL). The organic layer was washed with 1 N NaOH (50 mL), water (50 mL), satd NaCl (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (9:1 CH2Cl2/EtOAc) provided the title product as a white solid. MS (ESI, pos. ion) m/z: 394 (M+1). MP: 204–205° C.
Reaction SMILES: [CH3:1][C:2]1[CH:34]=[CH:33][C:5]2[CH:6]([C:16]3[C:17](=[S:32])[NH:18][C:19](=[O:31])[N:20]([CH2:22][C:23]4[O:24][CH:25]=[C:26]([C:28](O)=[O:29])[N:27]=4)[CH:21]=3)[C:7]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[CH3:59][S:60]([NH2:63])(=[O:62])=[O:61].C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:15][C:12]1[CH:13]=[CH:14][C:7]2[CH:6]([C:16]3[C:17](=[S:32])[NH:18][C:19](=[O:31])[N:20]([CH2:22][C:23]4[O:24][CH:25]=[C:26]([C:28]([NH:63][S:60]([CH3:59])(=[O:62])=[O:61])=[O:29])[N:27]=4)[CH:21]=3)[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:34][C:33]=3[CH:10]=[CH:9][C:8]=2[CH:11]=1
Reactant: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(Cc2nc(C(=O)O)co2)c(=O)[nH]c1=S
Reactant: CS(N)(=O)=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(Cc2nc(C(=O)NS(C)(=O)=O)co2)c(=O)[nH]c1=S

Procedure:
The product of example 37(0.2 g), bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (0.38 g), 4-dimethylaminopyridine (0.07 g), methanesulphonamide (0.095 g) and N,N-diisopropylethylamine (0.43 ml) in N,N-dimethylformamide (2 ml) was stirred at room temperature for 16 h. The mixture was partitioned between aqueous tartaric acid and ethyl acetate. The organic solution was dried (MgSO4) and evaporated. Purification was by reverse phase silica gel chromatography (C18-sep-pak) eluting with 50% methanol in 0.1% aqueous ammonium acetate. Yield 0.032 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][O:20][CH3:21])=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[C:22]([O:29][CH3:30])(=[O:28])[CH2:23][C:24]([O:26][CH3:27])=[O:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:23]([C:22]([O:29][CH3:30])=[O:28])[C:24]([O:26][CH3:27])=[O:25])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][O:20][CH3:21])=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)CC(=O)OC
Reactant: COCOc1ccc(C(=O)C=Cc2ccc(Cl)cc2)cc1
Product: COCOc1ccc(C(=O)CC(c2ccc(Cl)cc2)C(C(=O)OC)C(=O)OC)cc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 3-(4-chlorophenyl)-1-(4-methoxymethoxy-phenyl)prop-2-en-1-one and dimethyl malonate, dimethyl 2-(1-(4-chlorophenyl)-3-(4-(methoxymethoxy)phenyl)-3-oxopropyl)malonate was obtained as colourless solid.
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=[O:13])[NH:5][C:6]2[C:11]\1=[C:10]([CH3:12])[CH:9]=[CH:8][CH:7]=2.O/C=C1\C(=O)NC2C\1=CC=CC=2.[Br:26][C:27]1[C:28]([NH2:38])=[N:29][NH:30][C:31]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.NC1C=CNN=1>O1CCCC1>[Br:26][C:27]1[C:28]([NH:38][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[CH3:12])[NH:5][C:4]2=[O:13])=[N:29][NH:30][C:31]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1cccc2c1/C(=C/O)C(=O)N2
Reactant: Nc1n[nH]c(-c2ccccc2)c1Br
Agent: Nc1cc[nH]n1
Agent: O=C1Nc2ccccc2/C1=C/O
Solvent: C1CCOC1
Product: Cc1cccc2c1C(=CNc1n[nH]c(-c3ccccc3)c1Br)C(=O)N2

Procedure:
The named compound is prepared by substituting E & Z-3-[(hydroxy)-methylene]-4-methyl-1,3-dihydro-indol-2-one for E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one and 4-bromo-5-phenyl-1H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-4-methyl-1,3-dihydro-indol-2-one (0.1622 gms.) is reacted with 0.4530 gms. of 4-bromo-5-phenyl-1H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (3.0 mL).