Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]([C@H:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([OH:13])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>O1CCOCC1>[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47]([O:12][C:11](=[O:13])[CH:10]([N:3]([CH3:2])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:46]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CN(c1ccccc1)[C@@H](C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Product: CN(c1ccccc1)C(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 37.5 %

Procedure:
(R)-(Methyl-phenyl-amino)-phenyl-acetic acid hydrochloride (I74) (97 mg, 0.35 mmol), HOBT (107 mg, 0.70 mmol), DCC (144 mg, 0.70 mmol) and (R)-quinuclidin-3-ol (89 mg, 0.70 mmol) are dissolved in dioxane (5 mL) and the mixture is stirred at RT for 15 hours. The white precipitate is filtered and discarded whereas the clear solution is evaporated to dryness. The residue is dissolved in EtOAc and washed with sat. Na2CO3 and then brine. The organic phase is dried over sodium sulphate, filtered and evaporated to dryness. The resulting crude is purified by flash chromatography on silica gel (DCM/MeOH=97/3 to 95/5) to obtain the title compound as a pale yellow oil (46 mg, 38% yield, mixture of diastereoisomers).
Reaction SMILES: C(OC(=O)[N:7]([C:16]1[CH:21]=[CH:20][C:19](Br)=[C:18]([F:23])[N:17]=1)[CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([F:15])[CH:14]=1)(C)(C)C.C(OC(=O)[N:31]([C:40]1[CH:45]=[CH:44][C:43](Br)=[C:42](F)[N:41]=1)[CH2:32][C:33]1[CH:38]=CC(Cl)=CC=1)(C)(C)C>>[F:15][C:13]1[CH:14]=[C:9]([CH2:8][NH:7][C:16]2[CH:21]=[CH:20][C:19]([CH2:38][C:33]3[C:45]4[C:40](=[N:41][CH:42]=[CH:43][CH:44]=4)[NH:31][CH:32]=3)=[C:18]([F:23])[N:17]=2)[CH:10]=[N:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cncc(F)c1)c1ccc(Br)c(F)n1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)cc1)c1ccc(Br)c(F)n1
Product: Fc1cncc(CNc2ccc(Cc3c[nH]c4ncccc34)c(F)n2)c1

Procedure:
was prepared following the protocol of Scheme 201, replacing 5-bromo-6-fluoro-pyridin-2-yl)-(5-fluoro-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester 631 with (5-Bromo-6-fluoro-pyridin-2-yl)-(4-chloro-benzyl)-carbamic acid tert-butyl ester 637 (prepared as described in Example 60) in Step 4. MS (ESI) [M+H+]+=391.9.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>CN(C)C=O.C(N(CC)CC)C>[CH3:14][N:15]([CH3:17])[CH:16]=[CH:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C=Cc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A solution of 5 gm (29 mMol) 6-chloro-3-nitro-2-picoline in 40 mL dimethylformamide was treated with 5.83 mL (44 mMol) dimethylformamide dimethylacetal and the resulting mixture heated at 100° C. for 1.5 hours. At this point, 2 drops of triethylamine followed by 1.9 mL dimethylformamide dimethylacetal were added and heating continued for 2 more hours. The reaction mixture was concentrated under reduced pressure to provide the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])=[O:5].[OH:29]O>CO>[NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)=[O:29])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])=[O:5]
Reactant: COc1ccccc1NC(=O)c1c(N)cccc1Sc1ccc([N+](=O)[O-])cc1
Reactant: OO
Solvent: CO
Product: COc1ccccc1NC(=O)c1c(N)cccc1S(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 66 °C
Yield: 44.3 %

Procedure:
Compound 25 (1.0 equiv.) was dissolved in CH3OH (30 mL) with a magnetic stirrer at RT, and 35% H2O2 (3.0 equiv.) was added slowly to this solution. This reaction mixture was heated in an oil bath at 66° C. and monitored using TLC. The reaction was quenched with MnO2 at RT. The mixture was filtered and the residue was washed with ethyl acetate (3×5 mL). The liquid layer was concentrated under reduced pressure and the oily residue was purified by silica gel column chromatography (1:4 v/v ethyl acetate/petroleum ether) to provide a yellow solid; 44.3% yield;
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[CH3:10]OS(OC)(=O)=O.CI>>[OH:9][C:8]1[CH:7]=[C:5]([OH:6])[N:4]=[C:2]([S:3][CH3:10])[N:1]=1
Reactant: O=C1CC(=O)NC(=S)N1
Reactant: COS(=O)(=O)OC
Solvent: CI
Product: CSc1nc(O)cc(O)n1

Procedure:
Another method described by Wheeler and Jamieson, Am. Chem. J. 32, p. 345 (1904) initiates the synthesis with 2-thiobarbituric acid which is methylated. Either dimethylsulfate or methyl iodide is used to obtain 4,6-dihydroxy-2-methylthiopyrimidine. Dichlorination at 4- and 6- positions is accomplished with phosphorus oxychloride in the presence of dimethylaniline, and the 4,6-dichloro-2-(methylthio)pyrimidine thus obtained is reacted with aqueous alcoholic ammonia to produce the desired 4-amino-6-chloro-2-(methylthio)pyrimidine.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:24][O:25][CH3:26])[C:7]([NH:9][C@@H:10]1[C:22](=[O:23])[N:12]2[C:13]([C:19]([OH:21])=[O:20])=[C:14]([CH2:17][OH:18])[CH2:15][S:16][C@H:11]12)=[O:8].C(N(CC)CC)C.[Cl:34][CH2:35][CH2:36][N:37]=[C:38]=[O:39]>CN(C)C=O>[Cl:34][CH2:35][CH2:36][NH:37][C:38]([O:18][CH2:17][C:14]1[CH2:15][S:16][C@@H:11]2[C@H:10]([NH:9][C:7](=[O:8])[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[N:24][O:25][CH3:26])[C:22](=[O:23])[N:12]2[C:13]=1[C:19]([OH:21])=[O:20])=[O:39]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1ccco1
Reactant: O=C=NCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)NCCCl)CS[C@H]12)c1ccco1
Reaction time: 1 h

Procedure:
A solution of (6R,7R)-7-[2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid (syn isomer) (1.50 g) in N,N-dimethylformamide (30 ml, purified by filtration through basic alumina) was cooled to 5° and was treated with triethylamine (1.1 ml) and 2 -chloroethyl isocyanate (1.66 g). The reaction was stirredfor 1 hour at 5° when the ice-bath was removed and stirring continued for 1.5 hours at ca. 20°. The solution was partitioned between aqueous sodium bicarbonate solution (3%, 100 ml) and ethyl acetate (100 ml). The layers were separated and the aqueous solution was washed with ethyl acetate (3 × 100 ml), then covered with ethyl acetate (100 ml) and acidified to pH 1.8 with concentrated hydrochloric acid. The layers were separated and the aqueous layer extracted with further ethyl acetate (4 × 100 ml). The combined organic extracts were washed with water (5 × 150 ml) and saturated sodium chloride solution (100 ml) and dried (MgSO4), and the solvent was removed in vacuo to give a yellow froth which was triturated with ether (50 ml) to give the title compound as a yellow powder (0.59 g [α]D + 40° (c 1, DMSO); λmaxpH6 275 nm (ε 17,400).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[S:6][CH:7]=1)=[O:2].[BH4-].[Na+]>>[OH:2][CH2:1][C:3]1[CH:4]=[C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[S:6][CH:7]=1
Reactant: COC(=O)/C=C/c1cc(C=O)cs1
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)/C=C/c1cc(CO)cs1
Yield: 92.6 %

Procedure:
By a method similar to Production Example 120, step 1, methyl (2E)-3-(4-formylthiophen-2-yl)prop-2-enoate (1.700 g, 8.664 mmol) was reduced with sodium borohydride to give methyl (2E)-3-[4-(hydroxymethyl)thiophen-2-yl]prop-2-enoate (1.591 g, yield 92.6%) as a white solid.
Reaction SMILES: N(OCCC(C)C)=O.[F:9][C:10]([F:23])([F:22])[O:11][C:12]1[CH:21]=[CH:20][C:15]2[N:16]=[C:17](N)[S:18][C:14]=2[CH:13]=1.[ClH:24]>C(#N)C.[Cu](Cl)Cl>[Cl:24][C:17]1[S:18][C:14]2[CH:13]=[C:12]([O:11][C:10]([F:23])([F:22])[F:9])[CH:21]=[CH:20][C:15]=2[N:16]=1
Reactant: Cl
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: FC(F)(F)Oc1ccc2nc(Cl)sc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution containing dry copper (II) chloride (3.44 g, 25.62 mmol) and tri(ethylene glycol) dimethyl ether (10 g) in acetonitrile (150 mL) was added isoamyl nitrite (4.5 mL, 32.02 mmol). The reaction mixture was stirred at rt under argon for 30 minutes. To this suspension was added dropwise, a solution containing 6-trifluoromethoxy-1,3-benzothiazol-2-ylamine (5 g, 21.35 mmol) and tri(ethylene glycol) dimethyl ether (10 g). The reaction mixture was stirred at rt for 10 minutes, and then heated at 50° C. for 3 h. The mixture was cooled to rt, poured cautiously into aqueous 6 N HCl, and extracted with ethyl acetate. The organic layer was washed with 1N aqueous HCl and brine, and concentrated under reduced pressure to give the desired compound in near-quantitative yield, which was used without further purification in the next step.
Reaction SMILES: [C:1]([O:4][C@@H:5]([CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C@H:27]3[CH2:31][O:30]C(C)(C)[O:28]3)=[CH:21][CH:20]=2)([CH3:18])[CH3:17])=[CH:12][CH:11]=1)[CH2:6][Cl:7])(=[O:3])[CH3:2].[O-]S(C(F)(F)F)(=O)=O.[Bi+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(#N)C>[C:1]([O:4][C@@H:5]([CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C@H:27]([OH:28])[CH2:31][OH:30])=[CH:21][CH:20]=2)([CH3:18])[CH3:17])=[CH:12][CH:11]=1)[CH2:6][Cl:7])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](CCl)COc1ccc(C(C)(C)c2ccc(OC[C@H]3COC(C)(C)O3)cc2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Bi+3]
Solvent: CC#N
Product: CC(=O)O[C@H](CCl)COc1ccc(C(C)(C)c2ccc(OC[C@H](O)CO)cc2)cc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of crude (S)-1-chloro-3-(4-(2-(4-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propan-2-yl acetate in anhydrous acetonitrile (8.0 mL) was added bismuth triflate (300 mg, 0.46 mmol) in one portion. After 0.5 h, the reaction mixture was partitioned twice with sodium bicarbonate and ethyl acetate. The organic phased were combined, dried over anhydrous magnesium sulfate, and filtered. Solvents were evaporated, and the resulting crude material was purified by silica gel flash chromatography (eluent: 2% to 5% methanol in dichloromethane) to provide the title compound (734 mg, 86%) as a sticky solid.
Reaction SMILES: C(O[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])C.Cl.[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:20])=[C:16]([NH:18][NH2:19])[CH:17]=1.C(N(CC)C(C)C)(C)C>CO>[NH2:9][C:8]1[N:18]([C:16]2[CH:17]=[C:12]([F:11])[CH:13]=[CH:14][C:15]=2[CH3:20])[N:19]=[CH:4][C:5]=1[C:6]#[N:7]
Reactant: CCOC=C(C#N)C#N
Reactant: Cc1ccc(F)cc1NN
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1-n1ncc(C#N)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.11 %

Procedure:
(Ethoxymethylene)malononitrile (CAS no. 123-06-8) (3.18 g, 26.04 mmol) was added portionwise to the stirred solution of (5-fluoro-2-methylphenyl)hydrazine hydrochloride (CAS no. 325-50-8) (4.6 g, 26.04 mmol) and N,N-diisopropylethylamine (5.90 mL, 33.86 mmol) in MeOH (50 mL), under nitrogen at 5° C. The resulting solution was allowed to stir for a further 30 minutes at this temperature. The reaction mixture was then heated to reflux and was stirred for 3 hours. The reaction mixture was allowed to cool to ambient temperature. The reaction mixture was evaporated to dryness, redissolved in EtOAc (200 mL), washed with water (50 mL), and saturated brine (50 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. This was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane to afford the product (1.076 g, 19.11%). 1H NMR (400 MHz, DMSO) δ 2.00 (3H, s), 6.56 (2H, s), 7.20 (1H, dd), 7.29 (1H, td), 7.43 (1H, t), 7.75 (1H, s); m/z (ES+) (M+H)+=217; HPLC tR=1.61 min.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[C:14]([C:17](=[O:22])[C:18](=[CH2:21])[CH2:19][CH3:20])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]([CH3:11])[C:6]([O:8]CC)=[O:7].C(=O)(O)[O-].[Na+]>C(O)C.O>[Cl:1][C:2]1[C:15]([Cl:16])=[C:14]([C:17](=[O:22])[C:18](=[CH2:21])[CH2:19][CH3:20])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]([CH3:11])[C:6]([OH:8])=[O:7]
Reactant: C=C(CC)C(=O)c1ccc(OC(C)C(=O)OCC)c(Cl)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=C(CC)C(=O)c1ccc(OC(C)C(=O)O)c(Cl)c1Cl
Reaction time: 5 h

Procedure:
To a solution of 2,3-dichloro-4-(2-methylenebutyryl)-phenol (4.90 g., 0.02 mole) in dimethylformamide (20 ml.) is added potassium carbonate (6.08 g., 0.044 mole) and ethyl 2-bromopropionate (7.97 g., 0.044 mole). The reaction mixture is heated at 55°-60° C. for one hour with stirring. The reaction mixture is cooled. Water (50 ml.) is added and the resulting oil is extracted with ether (3 × 100 ml.). The combined ether extracts are dried over anhydrous magnesium sulfate, filtered and the ether is evaporated under reduced pressure to afford ethyl 2-[2,3-dichloro-4-(2-methylenebutyryl)phenoxy]propionate. The ester is dissolved in ethanol (75 ml.) and treated with a solution of sodium bicarbonate (5.04 g., 0.06 mole) in water (150 ml.). The mixture is heated on a steam bath with stirring for 5 hours and then concentrated under reduced pressure to a volume of 50 ml. Water (50 ml.) is added and the solution is acidified to a pH of 4 with hydrochloric acid (6N). The resulting oil is extracted with ether (3 × 100 ml.) and the combined extracts are dried over anhydrous magnesium sulfate. The ether is evaporated under reduced pressure to afford 6.34 g. (100%) of a white, waxy solid. Recrystallization from cyclohexane affords 5 g. (79%) of crude product, m.p. 115°-119° C. Further purification by recrystallization from butyl chloride affords substantially pure 2-[2,3-dichloro-4-(2-methylenebutyryl)phenoxy]propionic acid, m.p., 122.5°-123.5° C.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[O:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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>[O:20]1[CH:24]=[CH:23][C:22]([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[CH:21]1
Reactant: OB(O)c1ccoc1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccoc2)C1
Yield: 99.6 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 3-furan boronic acid (102 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (190 mg, 99.5%) as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH3:38][Zn]C>C1(C)C=CC=CC=1>[F:36][C:30]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=1[S:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:9]2[N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:38])[N:7]=2)[C:20]=1[F:37])(=[O:28])=[O:27]
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F
Reactant: C[Zn]C
Solvent: Cc1ccccc1
Product: Cc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 25 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (150 mg, 0.265 mmol) and 2N dimethylzinc in toluene ((0.265 mL, 0.529 mmol), the title compound was obtained as a solid (116 mg, 73% yield). MS (ESI): 547 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:11]=1)=[N:7][CH:8]=[CH:9][N:10]=2.[CH:12]([Sn](CCCC)(CCCC)CCCC)=[CH2:13]>C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:12]([C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:11]=1)=[N:7][CH:8]=[CH:9][N:10]=2)=[CH2:13]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1ccc2nccnc2n1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=Cc1ccc2nccnc2n1
Temperature: 65 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
6-chloropyrido[2,3-b]pyrazine (Intermediate 4.2) (3 g, 18.12 mmol, 1.00 eq.) was dissolved in THF (150 mL) and degassed with nitrogen at rt for 10 minutes. Tetrakis (triphenylphosphine) palladium(0) (1.46 g, 1.27 mmol, 0.07 eq.) and vinyltributylstannane (7.47 mL, 23.5 mmol, 1.3 eq.) were added and reaction mixture was stirred at 65° C. for 3 hours. THF was evaporated and crude purified directly by flash chromatography using cyclohexane/ethyl acetate (8/2) to give 2.3 g of the expected compound (Intermediate 4.3) as an orange oil. Amount: 2.3 g; Yield: 81%; Formula: C9H7N3; HPLC Purity: 98%; HPLC H2O TFA 0.1%-ACN TFA 0.05%): Rt (min); Area %=1.32 min; 98%; 1H NMR (DMSO-d6) δ 9.10 (s, 1H), 8.98 (s, 1H), 8.46 (d, 1H, J=8 Hz), 7.95 (d, 1H, J=8 Hz), 6.90 (dd, 1H, Jtrans=17 Hz, Jcis=10 Hz), 6.50 (dd, 1H, Jtrans=17 Hz, Jgem=1.5 Hz), 5.80 (dd, 1H, Jcis=10 Hz, Jgem=1.5 Hz). LC-MS: M/Z ESI: Rt (min) 0.78 min, 158.13 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.[CH3:13][NH:14][CH2:15][CH2:16][NH:17][CH3:18].COCC(O)C>>[CH3:13][N:14]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1)[CH2:15][CH2:16][NH:17][CH3:18]
Reactant: Cc1cc(Cl)c2ccccc2n1
Reactant: CNCCNC
Solvent: COCC(C)O
Product: CNCCN(C)c1cc(C)nc2ccccc12
Temperature: 110 °C
Reaction time: 8 h

Procedure:
4-Chloroquinaldine (1.5 g, 5 mmol) was mixed with N,N′-dimethylethylenediamine (2.45 ml, 25 mmol) and 1-methoxy-2-propanol (8 ml) and stirred at 110° C. overnight. The mixture was purified by column chromatography (pre-packed silica column, gradient of heptane/ethyl acetate each containing 1% triethylamine). 0.4 g were obtained (1.75 mmol; 35%). MS (APCI) m/z=230.0 [M+H]+.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([C:12]2[S:16][C:15]([CH3:17])=[N:14][C:13]=2[CH3:18])[C:9](=[O:19])[NH:8][C:7]1=[O:20].Cl.C(N(CC)CC)C>O1CCCC1>[CH3:17][C:15]1[S:16][C:12]([C:10]2[C:9](=[O:19])[NH:8][C:7](=[O:20])[N:6]([CH2:5][CH2:4][CH:3]=[O:2])[CH:11]=2)=[C:13]([CH3:18])[N:14]=1
Reactant: COC(CCn1cc(-c2sc(C)nc2C)c(=O)[nH]c1=O)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(C)c(-c2cn(CCC=O)c(=O)[nH]c2=O)s1
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
1-[3,3-bis(methyloxy)propyl]-5-(2,4-dimethyl-1,3-thiazol-5-yl)-2,4(1H,3H)-pyrimidinedione (Prep35, 321 mg, 0.987 mmol) was dissolved in Tetrahydrofuran (THF) (20 mL), 1N Hydrochloric acid aqueous solution (5.92 mL, 5.92 mmol) was added and the mixture was stirred at 45° C. for 1.5 hours. Volatiles were evaporated under vacuum (cold bath) then triethylamine (0.825 mL, 5.92 mmol) and THF (6 mL) were added. Solvents were eliminated until dryness and the white foam thus obtained was used in the next step without further purification.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[C:15]1[C:16]2[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[O:26])[C:17]=2[N:18]=[CH:19][N:20]=1)[CH3:3].[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:13])([F:12])[F:14])=[CH:7][C:6]=1[C:15]1[C:16]2[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]3[CH2:29][CH2:30][N:31]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:32][CH2:33]3)=[O:26])[C:17]=2[N:18]=[CH:19][N:20]=1)[CH3:3]
Reactant: CCC(=O)Cl
Reactant: CCOc1ccc(C(F)(F)F)cc1-c1ncnc2c(C(=O)NC3CCNCC3)c(C)[nH]c12
Agent: Cl
Product: CCOc1ccc(C(F)(F)F)cc1-c1ncnc2c(C(=O)NC3CCN(C(=O)CC)CC3)c(C)[nH]c12

Procedure:
Starting from 4-[2-ethoxy-5-(trifluoromethyl)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f34) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [OH-].[Na+].[CH2:3]([SH:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl.Cl[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]Cl>C(O)C>[CH2:3]([S:13][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][S:13][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: ClCCNCCCl
Reactant: CCCCCCCCCCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCSCCNCCSCCCCCCCCCC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of NaOH (3 g, 75 mmol) and decanethiol (15.5 ml, 75 mmol) in ethanol (75 ml) was added to a solution of bis(2-chloroethyl)amine hydrochloride (4.4 g, 25 mmol) in ethanol (50 ml) at 0° C. The solution was stirred for 2 hours at 0° C. and then for another 16 h at room temperature. After filtering, the filtrate was evaporated to dryness. The residue was taken up with dry ether and filtered again. After evaporation of the solvent under vacuum, the product remained as a colourless semi-solid. Yield: 9.4 g (90%). 1H-NMR (CDCl3) δ 0.87 (6H, t, CH3), 1.25-1.4 (28H, m, SC2H4C7H14CH3), 1.56 (4H, qn, SCH2CH2C8H17), 1.88 (1H, s, NH), 2.52 (4H, qt, SHCH2C9H19), 2.69 (4H, t, SCH2CH2NH), 2.82 (4H, t, NCH2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:16]1([S:21]([C:24]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)(=O)C.Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH:15][CH2:28][C:27]3[CH:30]=[CH:31][C:24]([S:21]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)(=[O:23])=[O:22])=[CH:25][CH:26]=3)[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Reactant: O=Cc1ccc(S(=O)(=O)N2CCCC2)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: O=S(=O)(c1ccc(CNc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
To a solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (100 mg, 410 μmol) in MeOH (3.5 ml) was added 4-(pyrrolidin-1-ylsulfonyl)benzaldehyde (118 mg, 492 μmol) followed by acetic acid (36.7 mg, 35 μl, 611 μmol). The reaction was stirred at room temperature for 15 minutes, 2-picoline borane complex (65.7 mg, 615 μmol) was added and the stirring was continued for 6 days. The reaction mixture was poured into 0.1N HCl solution (25 ml) to give a suspension, which was filtered to give a white solid as desired product (151 mg, 79% yield). MS +m/z: 467 (M+H)+