Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.Cl[Si:14]([CH3:22])([CH3:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCOCC>[CH3:21][Si:14]([CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: C[Si](C)(Cl)c1ccccc1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: C[Si](C)(c1ccccc1)c1cccnc1
Reaction time: 1 h
Yield: 9.8 %

Procedure:
In a 1 liter, 4 neck round bottom flask stirring under N2 was charged 80.6 milliliters (ml) of n-BuLi (1.55 Molar (M) solution, 0.125 moles, 1.25 equivalents (eq.)) to 300 ml of ether with stirring at -78° C. To the reaction was added, dropwise, 15.8 grams (g) of 3-bromopyridine (0.10 moles, 1.0 eq.) in 100 ml of ether, over 20 minutes while maintaining the temperature between -50° C. and -70° C. After stirring for 20 minutes, 21.3 g of chlorodimethylphenylsilane (0.125 moles, 1.25 eq.) in 50 ml of ether was added dropwise maintaining the temperature below -50° C. after which the reaction was allowed to come to ambient temperature. After 1 hour, gas liquid chromatography (GLC) indicated complete consumption of the silyl chloride. The reaction mixture was stirred overnight at room temperature. The reaction was quenched by adding 200 ml of water, and extracted with ether/ethyl acetate (200 ml/450 ml) and washed with water (2×200 ml). Drying and concentrating afforded 26.0 g of crude product of which 6.7 g was purified by flash chromatography with 3:7 ethyl acetate/hexane and afforded 2.1 g of an oil (31.2% yield based on the 6.7 g chromatographed portion).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:22])[N:13]([CH2:19][CH2:20]Cl)[C:14](=[O:18])[NH:15]2)=[CH:10][CH:9]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>CN(C)C=O>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][N:34]([CH2:20][CH2:19][N:13]2[C:12](=[O:22])[C:11]3[C:16](=[CH:17][C:8]([NH2:7])=[CH:9][CH:10]=3)[NH:15][C:14]2=[O:18])[CH2:33][CH2:32]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: Nc1ccc2c(=O)n(CCCl)c(=O)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCn2c(=O)[nH]c3cc(N)ccc3c2=O)CC1
Yield: 38.4 %

Procedure:
Four hundred miligrams of sodium carbonate was added to 1.5 g of 7-amino-3-(2-chloroethyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione, 1.4 g of 1-(2-methoxyphenyl)piperazine and 1.4 ml of dimethylformamide to react at 80° C. for 50 hours. The reaction liquid was concentrated and the resultant residue was purified through the silica gel chromatography to obtain 0.95 g of the titled compound (yield: 38%).
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]([NH:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=2)=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[N:27]3[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]3=[N:25][N:24]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NNc2ccc(F)cn2)CC1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2nnc3ccc(F)cn23)CC1
Reaction time: 2 h
Yield: 80.7 %

Procedure:
Hexachloroethane (990 mg, 4.18 mmol) was added portionwise to a solution of Intermediate 4a (707 mg, 2.09 mmol), triphenylphosphine (1.103 g, 4.18 mmol) and triethylamine (1.2 mL, 8.36 mmol) in dry THF (30 mL) at RT. The mixture was stirred for 2 h. The resulting precipitate was filtered off and the filtrate evaporated. The residue was purified by SCX-2, eluting with MeOH followed by 2M NH3 in MeOH, to give a pale orange coloured solid. This was triturated (diethyl ether) to give the title compound as a buff-coloured solid (540 mg, 80%). LCMS (Method 1): Rt 2.79 min, m/z 321 and 221(-Boc) [MH+].
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:39])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11](CC1C=CC=CC=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].C[O-].[Na+].[C:43]([O-:46])(O)=[O:44].[Na+]>>[CH2:35]([N:14]1[C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:12]2[C:7](=[CH:8][CH:9]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:31][CH:30]=3)[C:10](=[O:28])[NH:11]2)[C:6]([OH:39])=[C:5]1[C:3]([NH:11][CH2:10][CH2:9][C:43]([OH:46])=[O:44])=[O:4])[C:32]1[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccc(C(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Reactant: O=C([O-])O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)C1=C(O)C2=CC(c3ccc(C(F)(F)F)cc3)C(=O)NC2=C(c2cccnc2)N1Cc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-8-pyridin-3-yl-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (32 mg, 0.060 mmol), (3-alanine (537 mg, 6.0 mmol) and NaOMe solution (9.6 mL, 4.8 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (10-100% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 18 mg of the title compound. MS: (+) m/z 589.36 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH2:2]1.[C:6]([OH:11])(=[O:10])[C:7]([CH3:9])=[CH2:8]>C=CC1C=CN=CC=1.Cl.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[C:6]([O:11][CH:5]1[CH2:4][CH2:3][CH2:2][O:1]1)(=[O:10])[C:7]([CH3:9])=[CH2:8]
Reactant: C1=COCC1
Reactant: C=C(C)C(=O)O
Agent: C=Cc1ccncc1
Agent: Cl
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=C(C)C(=O)OC1CCCO1
Yield: 71.4 %

Procedure:
A mixture of 4.97 g of crosslinked poly(4-vinylpyridine hydrochloride) (Fluka Chemical Corp., catalog number 82803, 6 meq/g), 192 g (207 mL, 2.74 mol) of 2,3-dihydrofuran, 118 g (116 mL, 1.36 mol) of methacrylic acid, and 1 g of phenothiazine was heated at 2° C. per minute. When the temperature reached 45° C., an exothermic reaction caused the temperature to rise to 82° C. The catalyst was removed by filtration. NMR analysis of the filtrate showed no residual methacrylic acid. After addition of sodium carbonate and calcium hydride, excess dihydrofuran was removed with a rotary evaporator, and distillation gave 151.7 g of tetrahydrofuranyl methacrylate, b.p. 43°-44° C. (0.75 mm).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]3[O:23][CH2:22][CH2:21][CH2:20][N:19]([CH2:24][C:25]([OH:27])=O)[C:18]=3[CH:28]=1)=[O:12])=[CH:5]2.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C1COCC1>[O:27]=[C:25]([N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:24][N:19]1[C:18]2[CH:28]=[C:14]([NH:13][C:11]([C:6]3[NH:7][C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=4)=[O:12])[CH:15]=[CH:16][C:17]=2[O:23][CH2:22][CH2:21][CH2:20]1
Reactant: C1CCNC1
Reactant: O=C(O)CN1CCCOc2ccc(NC(=O)c3cc4cc(Cl)ccc4[nH]3)cc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2c(c1)N(CC(=O)N1CCCC1)CCCO2)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
{2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl}-acetic acid (80 mg) and pyrrolidine (14.2 mg) were dissolved in anhydrous THF. To that solution was added BOP and the resulting mixture treated with triethylamine (40.5 mg). The reaction was stirred overnight at room temperature. The reaction was evaportated and the crude product purified by TLC using EtOAc as solvent to yield 68 mg of the product. LCMS: AP+ 453/455.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([N:8]2[C:12]3[N:13]=[CH:14][N:15]=[C:16](Cl)[C:11]=3[CH:10]=[CH:9]2)[CH2:7][CH2:6]1)=[O:4].[OH-].[NH4+]>C(O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1([N:8]2[C:12]3[N:13]=[CH:14][N:15]=[CH:16][C:11]=3[CH:10]=[CH:9]2)[CH2:6][CH2:7]1)=[O:4]
Reactant: COC(=O)C1(n2ccc3c(Cl)ncnc32)CC1
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C1(n2ccc3cncnc32)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 59 %

Procedure:
A solution of 1-(4-chloro-pyrrolo[2,3-d]pyrimidin-7-yl)-cyclopropanecarboxylic acid methyl ester (Preparation 245, 920 mg, 3.65 mmol) in ethanol (20 mL) was degassed with argon for 15 min. Ammonium hydroxide (4 mL) and 10% palladium on charcoal were added and the reaction mixture was stirred at room temperature under hydrogen (balloon pressure) for 5 hours. The reaction mixture was filtered on a celite bed, washed with ethanol (2×10 mL) and the filtrate was evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of DCM:methanol 100:0 to 98:2) to afford the title compound as a gum in 59% yield, 470 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([NH2:8])[CH:7]=1.[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[S:16](Cl)(=[O:18])=[O:17]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([NH:8][S:16]([C:12]2[O:11][CH:15]=[CH:14][CH:13]=2)(=[O:18])=[O:17])[CH:7]=1
Reactant: CSc1ccc(Cl)cc1N
Reactant: O=S(=O)(Cl)c1ccco1
Product: CSc1ccc(Cl)cc1NS(=O)(=O)c1ccco1
Yield: 47.2 %

Procedure:
Following General Procedure B, the title compound (215 mg, 47%) was prepared from 5-chloro-2-methylsulfanyl-phenylamine (260 mg, 1.50 mmol) and furan-2-sulfonyl chloride (250 mg, 1.50 mmol).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([OH:9])[C:6](=[O:8])[CH:7]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].Cl>O>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([OH:9])=[CH:4][C:3]=1[OH:10]
Reactant: O=C1C=C(O)C(=O)C=C1O
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Oc1cc(O)c(O)cc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,5-Dihydroxy-1,4-benzoquinone (4.00 g, 28.55 mmol) was suspended in water (50 ml, distilled) followed by Na2S2O4 (10.00 g, 57.47 mmol) and HCl (5.5 g, 55.75 mmol conc. soln.). The mixture was stirred 30 min. at room temperature and evaporated to dryness. The residue was washed with THF (40 ml) and filtered. The THF was evaporated yielding 2.00 g (14.07 mmol, 49.3%) of the title substance.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[N+:19]([C:22]1[CH:32]=[CH:31][C:25]([CH2:26][O:27][C:28](Cl)=[O:29])=[CH:24][CH:23]=1)([O-:21])=[O:20].C(N(CC)CC)C>CO.[Pd].C(Cl)Cl>[OH:18][CH:16]1[CH2:17][N:14]([C:28]([O:27][CH2:26][C:25]2[CH:31]=[CH:32][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=2)=[O:29])[CH2:15]1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CC(O)C1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 37.1 %

Procedure:
A solution of 1-benzhydryl-3-hydroxyazetidine (9.00 g, 37.6 mmol) in methanol (270 ml) was subjected to catalytic hydrogenation in the presence of 10% palladium on charcoal (9.00 g) in a water bath (50° C.) for 5.5 hours. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst and the filtrate concentrated under reduced pressure. The residue was partitioned between ethyl acetate and distilled water. The organic layer was concentrated under reduced pressure and dried in vacuo to give a crude product. To a solution of the crude product in a mixture of methylene chloride (82 ml) and methanol (55 ml) were added chloroformic acid p-nitrobenzyl ester (8.90 g, 41.3 mmol) and triethylamine (5.79 ml, 41.3 mmol) in an ice bath. The mixture was stirred at room temperature for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1)→ethyl acetate as the eluant to afford 3-hydroxy-1-(p-nitrobenzyloxycarbonyl)azetidine (3.52 g, yield 37%) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([CH:13]=[CH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19])[CH:6]=[CH:5]2.[CH:23]([Mg]Br)=[CH2:24]>C1(C)C=CC=CC=1.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([CH:13]=[CH:14][C:15]1[CH:16]=[C:17]([CH:18]([OH:19])[CH:23]=[CH2:24])[CH:20]=[CH:21][CH:22]=1)[CH:6]=[CH:5]2
Reactant: C=C[Mg]Br
Reactant: O=Cc1cccc(C=Cc2ccc3cc(F)c(F)cc3n2)c1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CC(O)c1cccc(C=Cc2ccc3cc(F)c(F)cc3n2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
The aldehyde of Step 2 (35.93 g, 122 mmol) was suspended in 360 mL of toluene and cooled to 0° C. 1.0 M Vinylmagnesium bromide in THF (135 mL) was added into the addition funnel and the whole system was degassed by applying vacuum and flushed with nitrogen 3 times. The Grignard reagent was then added slowly at 0° C. and the mixture was stirred at 0° C. for 15 min. Cold 25% aq. NH4OAc was then added and the product was extracted in hot toluene, washed with brine, and dried over Na2SO4. The cloudy solution was filtered through celite, concentrated, and filtered through silica with EtOAc: toluene 10:90 to afford 32.04 g (81%) of the title product.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][N:5]=[N+:6]=[N-:7].[C:12]([C:15]([OH:17])=[O:16])#[C:13]C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][N:5]1[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[N:7]=[N:6]1
Reactant: CC#CC(=O)O
Reactant: [N-]=[N+]=NCc1ccccc1F
Solvent: Cc1ccccc1
Product: O=C(O)c1cn(Cc2ccccc2F)nn1
Temperature: 25 °C

Procedure:
The starting material may be prepared as follows: A solution of 50 g (0.33 mole) of o-fluorobenzyl azide, 23.1 g (0.33 mole) of propinecarboxylic acid and 400 ml of toluene is stirred for 24 hours at 70° C. After the reaction mixture has cooled to room temperature, the precipitated product is filtered with suction and washed first with toluene and then with diethyl ether, affording 1-(o-fluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid with a melting point of 151° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:22][CH2:23][N:24]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:25][CH2:26]4)=[CH:19][CH:20]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(C)c(-c2ccnc(Nc3ccc(N4CCNCC4)cc3)n2)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(N4CCN(S(C)(=O)=O)CC4)cc3)n2)s1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 59.7 %

Procedure:
A mixture of [4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl]-(4-piperazin-1-yl-phenyl)-amine (86 mg, 0.23 mmol) in anhydrous CH2Cl2 (2 mL) was added Et3N (39 μL, 0.28 mmol). After cooling to 0° C., methanesulfonyl chloride (22 μL, 0.28 mmol) was added dropwise. After 15 min stirring, the reaction mixture was warmed to room temperature and stirring was continued for 18 h. After evaporation, the residue was purified by SiO2 chromatography (98:2 to 95:5 EtOAc/2 M NH3 in MeOH) to afford the title compound (61 mg) as a yellow solid. 1H-NMR (CDCl3) δ: 2.69 (s, 3H, CH3), 2.71 (s, 3H, CH3), 2.84 (s, 3H, CH3), 3.26 (t, 4H, J=5.1 Hz, CH2), 3.41 (t, 4H, J=5.1 Hz, CH2), 6.91 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 6.98 (d, 2H, J=8.8 Hz, Ph-H), 7.10 (br. s, 1H, NH), 7.56 (d, 2H, J=8.8 Hz, Ph-H), 8.30 (d, 1H, J=5.1 Hz, pyrimidinyl-H). MS (ESI+) m/z 446 (C20H24N6O2S2 requires 444.6).
Reaction SMILES: C([O:3][P:4]([CH:9]([NH:18][C:19]1[S:20][C:21]([CH3:24])=[CH:22][N:23]=1)[P:10]([O:15]CC)(=[O:14])[O:11]CC)(=[O:8])[O:5]CC)C.Cl>>[CH3:24][C:21]1[S:20][C:19]([NH:18][CH:9]([P:10]([OH:14])(=[O:11])[OH:15])[P:4]([OH:5])(=[O:3])[OH:8])=[N:23][CH:22]=1
Reactant: CCOP(=O)(OCC)C(Nc1ncc(C)s1)P(=O)(OCC)OCC
Agent: Cl
Product: Cc1cnc(NC(P(=O)(O)O)P(=O)(O)O)s1

Procedure:
1.97 g (4.9 mmol) of 1-(5-methylthiazol-2-ylamino)methane-1,1-diphosphonic acid tetraethyl ester are heated under reflux in 20 ml of N hydrochloric acid for 6 hours. Upon cooling and leaving the reaction mixture to stand at room temperature, the product crystallises. It is filtered and washed with acetone and petroleum ether. Yield: 0.64 g (45% of the theoretical yield) of 1-(5-methylthiazol-2-ylamino)-methane-1,1-diphosphonic acid of m.p. 208° (decomposition).
Reaction SMILES: Br.Br.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[N:16]([CH2:19][CH:20]([O:23][CH3:24])[O:21][CH3:22])=[C:17]=[S:18].[OH-].[Na+]>CO>[CH3:22][O:21][CH:20]([O:23][CH3:24])[CH2:19][NH:16][C:17]([N:6]1[CH2:5][CH2:4][N:3]([C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[S:18]
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: COC(CN=C=S)OC
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(CNC(=S)N1CCN(c2ccc(O)cc2)CC1)OC

Procedure:
A mixture of 10.8 parts of 4-(1-piperazinyl)phenol dihydrobromide, 2.6 parts of 2-isothiocyanato-1,1-dimethoxyethane and 54 parts of methanol is stirred and refluxed for 30 minutes. Then there are added 4.7 parts of sodium hydroxide and the whole is stirred overnight at room temperature. The precipitated product is filtered off and crystallized from 4-methyl-2-pentanone, yielding 4.9 parts of N-(2,2-dimethoxyethyl)-4-(4-hydroxyphenyl)-1-piperazinecarbothioamide; mp. 161.4° C.
Reaction SMILES: [CH2:1]([N:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]([N:11]([C:18](=O)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:5]1[CH2:26][O:27][CH3:28])[CH2:2][CH3:3].[BH4-].[Na+].B(F)(F)F.CCOCC.Cl>O1CCCC1>[CH2:1]([N:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]([N:11]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:5]1[CH2:26][O:27][CH3:28])[CH2:2][CH3:3]
Reactant: CCCN1C=CC=CC(N(C(=O)c2ccccc2)c2ccccc2)=C1COC
Agent: Cl
Agent: FB(F)F
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCN1C=CC=CC(N(Cc2ccccc2)c2ccccc2)=C1COC
Temperature: 0 °C

Procedure:
15 g of the compound prepared in Example 3, dissolved in 35 ml of tetrahydrofuran, were added under a nitrogen atmosphere to a reactor containing a suspension of 4.95 g of sodium borohydride in 100 ml of tetrahydrofuran, the temperature being maintained at 0° C. 29.6 ml of boron trifluoride etherate in 39 ml of tetrahydrofuran were then added dropwise. After the reaction medium had been allowed to return to room temperature, 69 ml of 10% strength hydrochloric acid were added. The solvent was then removed by distillation at atmospheric pressure, and the residue cooled and then alkalinized with caustic soda solution and then extracted with methylene chloride. After drying and evaporation of the solvent, the product was distilled, and then purified by preparative liquid chromatography on silica gel, using as solvent 2% strength and then 4% strength methanol in dichloromethane.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C=CC=CC=1.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[C:31]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17](=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)(=[O:33])[CH3:32]
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2ccc(Cl)cc21
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(C)=O)c2ccc(Cl)cc21
Reaction time: 4 h
Yield: 54 %

Procedure:
To a solution of 3-amino-2-benzoyl-6-chloro-1-(ethoxycarbonyl)indole (300 mg, 0.88 mmol; example 1, step 2) in a mixture of dichloromethane (10 ml) and pyridine (0.08 ml, 0.96 mmol) was added acetyl chloride (0.07 ml, 0.96 mmol). After stirring for 4 h, the mixture was partitioned between 10% aqueous citric acid (50 ml) and diethyl ether (100 ml). The organic extract was washed consecutively with water (50 ml), saturated sodium bicarbonate (50 ml), water (50 ml) and brine (50 ml). After drying (MgSO4) and removal of solvent, the crude product was purified by flash chromatography eluting with ethyl acetate/hexane (1:1) to afford 183 mg (54%) of the titled compound as a yellow oil.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:10]1[N:15]=[C:14]([O:16][CH3:17])[N:13]=[C:12]([O:18][CH3:19])[N:11]=1>C1COCC1>[C:1]1([C:10]2[N:15]=[C:14]([O:16][CH3:17])[N:13]=[C:12]([O:18][CH3:19])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1nc(Cl)nc(OC)n1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: COc1nc(OC)nc(-c2ccccc2)n1
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
A solution of phenylmagnesium bromide (1M in THF, 3.9 mL, 3.9 mmol) is added to a solution of 2-chloro-4,6-dimethoxy-1,3,5-triazine (300 mg, 1.70 mmol) and Fe(acac)3 (30 mg, 0.085 mmol) in THF (10 mL) at −30° C. After stirring for 30 min at that temperature, the reaction is quenched with brine, the aqueous layer is extracted with Et2O, the combined organic phases are dried over Na2SO4 and evaporated, and the residue is purified by flash chromatography (hexane/ethyl acetate, 10:1). After eluting a first fraction containing biphenyl (103 mg), one obtains 2-phenyl-4,6-dimethoxy-1,3,5-triazine as a colorless solid (231 mg, 63%). 1H NMR (300 MHz, CD2Cl2) δ 8.47 (d, 2H), 7.47–7.56 (m, 3H), 4.08 (s, 3H). 13C NMR (75 MHz, CD2Cl2) δ 175.0, 173.3, 135.6, 133.0, 129.2, 128.8, 55.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:21]([OH:23])=O)=[N:9]2)=[CH:4][CH:3]=1.[C:24](N1C=CN=C1)([N:26]1C=CN=[CH:27]1)=O.Cl.CNC.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:21]([N:26]([CH3:27])[CH3:24])=[O:23])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(-c2cc(C(=O)O)nn2-c2ccc(F)cc2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1ccc(-c2cc(C(=O)N(C)C)nn2-c2ccc(F)cc2)cc1
Yield: 80.1 %

Procedure:
A mixture of 1-(4-fluorophenyl)-5-[4-(methylthio)phenyl]pyrazole-3-carboxylic acid (3 g) and 1,1'-carbonyldiimidazole (1.6 g) in tetrahydrofuran (39 ml) was refluxed for 1 hour. Dimethylamine hydrochloride (1.04 g) and potassium carbonate (1.33 g) were added, and the resulting mixture was stirred and refluxed for 3 hours. The mixture was diluted with ethyl acetate, washed with water, an aqueous solution of sodium bicarbonate, dilute hydrochloric acid and water, successively, dried and concentrated to give a pale brown oil of 1-(4-fluorophenyl)-N,N-dimethyl-5-[4-(methylthio)phenyl]pyrazole-3-carboxamide (2.6 g).