Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][C@@H:12]1[CH2:16][O:15][CH2:14][C@H:13]1[NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>ClCCl>[O:11]=[C:12]1[CH2:16][O:15][CH2:14][CH:13]1[NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(N[C@@H]1COC[C@H]1O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1COCC1=O)OCc1ccccc1
Reaction time: 0.25 h
Yield: 91.6 %

Procedure:
Dimethyl sulfoxide (3.54 mL, 49.8 mmol) was added dropwise over 10 min to a vigorously stirred mixture of a 2 M dichloromethane solution of oxalyl chloride (12.46 mL, 24.91 mmol) and dichloromethane (40 mL) at −78° C. After another 15 min at −78° C., a solution of benzyl trans-4-hydroxytetrahydrofuran-3-ylcarbamate (3.94 g, 16.61 mmol, from Step 2) in dichloromethane (20 mL) was added dropwise over 15 min. After 30 min at −78° C., the mixture was diluted with dichloromethane (20 mL). Triethylamine (9.26 mL, 66.4 mmol) was added. The mixture became a thick slurry (a large stir bar was necessary for efficient stirring). The mixture was stirred at −78° C. for 30 min, at ambient temperature for 40 min, quenched with water (150 mL) and extracted with dichloromethane (3×100 mL). The combined extracts were dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 20-50% ethyl acetate in hexanes, gave benzyl 4-oxotetrahydrofuran-3-ylcarbamate as tan solid (3.579 g, 92% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 7.28-7.47 (5 H, m), 5.21 (1H, br. s.), 5.01-5.16 (2 H, m), 4.69 (1 H, t, J=8.58 Hz), 4.15-4.31 (2 H, m), 3.92 (1 H, d, J=17.61 Hz), 3.79 (1 H, t, J=9.57 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][N:11]=1.[CH2:17](C([Sn])=C(CCCC)CCCC)[CH2:18]CC>C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:17]=[CH2:18])=[CH:12][N:11]=1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Fc1cccc(F)c1Nc1ccc(I)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=Cc1ccc(Nc2c(F)cccc2F)nc1
Temperature: 80 °C
Yield: 66 %

Procedure:
To a mixture of (2,6-Difluoro-phenyl)-(5-iodo-pyridin-2-yl)-amine and Pd(PPh3)4 (approximately 10 mol %) in toluene (approximately. 80 mL/g) at room temperature was added tributylvinyltin (1.1 eq.). The reaction was placed under a N2 atmosphere and heated to 80° C. overnight. The solution was cooled, diluted with ethyl acetate (approximately 80 mL/g) and filtered through a pad of celite. The celite was washed with a further portion of ethyl acetate. The organic layer was dried over MgSO4 and concentrated in vacuo to give the crude reaction product as a yellow oil. Purification by column chromatography, using 10% ethyl acetate:hexane as eluant provided (2,6-Difluoro-phenyl)-(5-vinyl-pyridin-2-yl)-amine (Rf 0.14) in 66% yield.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:30])[CH3:29].CC(O)=O.O>CCO>[C:28]([NH:27][CH2:26][CH2:25][NH:24][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4])(=[O:30])[CH3:29]
Reactant: CC(=O)NCCN
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)NCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Yield: 52.6 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (20 mg, 0.065 mmol) and N-(2-amino-ethyl)-acetamide (20 mg, 0.19 mmol), in EtOH (2 mL) was refluxed for 16 h. After cooling to r.t., AcOH (0.1 mL) and water (20 mL) were added. The resulting cloudy solution was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-10% MeOH/CH2Cl2) to give 13 mg of the title compound as an off-white solid. MS: (+) m/z 381.34 (M+1).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].C[S-:12].[Na+]>CN1CCCC1=O>[SH:12][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5]
Reactant: Cc1cccc(Cl)c1C#N
Reactant: C[S-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cccc(S)c1C#N
Temperature: 140 °C
Yield: 33.8 %

Procedure:
A mixture of 2-chloro-6-methylbenzonitrile (3.00 g, 19.80 mmol), and sodium thiomethoxide (2.91 g, 41.58 mmol) in 1-methyl-2-pyrrolidinone (25 mL) was heated at 140° C. overnight. The reaction mixture was cooled to 0° C. and quenched with 50% aqueous HCl. A light yellow precipitate formed and the reaction was cooled for 1 h while stirring. The yellow solid was collected by vacuum filtration, washed with ice-cold water and dried under reduced pressure overnight to provide 2-mercapto-6-methylbenzonitrile (1.0 g). The crude product was carried forward without further purification. MW=149 confirmed by LC-MS, tr=2.98 min (Method E) MH+=150.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[CH:11][NH:12][CH:13]=1.C(N(CC)CC)C.[CH3:21][N:22]([CH3:27])[S:23](Cl)(=[O:25])=[O:24]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[CH:11][N:12]([S:23](=[O:25])(=[O:24])[N:22]([CH3:27])[CH3:21])[CH:13]=1
Reactant: Clc1ccc(-c2c[nH]cn2)c(Cl)c1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cnc(-c2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-(2,4-dichlorophenyl)-1H-imidazole (12.14 g), triethylamine (13 ml) and dimethylsulphamoyl chloride (7.5 ml) in tetrahydrofuran (50 ml) was stirred for 18 hours at room temperature and then heated under reflux until almost no starting material remained. The organic phase was diluted with ethyl acetate (300 ml), washed with dilute hydrochloric acid, water and aqueous sodium bicarbonate, dried and the solvent evaporated to give an oily solid which was treated to flash column chromatography and the product recrystallised to give 4-(2,4-dichlorophenyl)-1-(dimethylsulphamoyl)imidazole, m.p. 169°-171°.
Reaction SMILES: O[CH:2](O)[CH2:3][N:4]1[CH:9]=[CH:8][C:7]2[O:10][C:11]([CH3:13])=[CH:12][C:6]=2[C:5]1=[O:14].C(O)(=O)C.[CH2:20]([N:22]1[C:28](=[O:29])[C:27]([CH3:31])([CH3:30])[C:26](=[O:32])[N:25]([CH3:33])[C:24]2[CH:34]=[C:35]([CH2:38][NH:39][CH2:40][C:41]3[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=3)[CH:36]=[CH:37][C:23]1=2)[CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:20]([N:22]1[C:28](=[O:29])[C:27]([CH3:31])([CH3:30])[C:26](=[O:32])[N:25]([CH3:33])[C:24]2[CH:34]=[C:35]([CH2:38][N:39]([CH2:2][CH2:3][N:4]3[CH:9]=[CH:8][C:7]4[O:10][C:11]([CH3:13])=[CH:12][C:6]=4[C:5]3=[O:14])[CH2:40][C:41]3[CH:42]=[CH:43][N:44]=[CH:45][CH:46]=3)[CH:36]=[CH:37][C:23]1=2)[CH3:21]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNCc3ccncc3)ccc21
Reactant: Cc1cc2c(=O)n(CC(O)O)ccc2o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCn3ccc4oc(C)cc4c3=O)Cc3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
5-(2,2-Dihydroxyethyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one(0.21 g) and acetic acid(0.1 ml) were added to a 1,2-dichloroethane solution(15 ml) of 1-ethyl-3,3,5-trimethyl-7-{[(pyridin-4-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(0.38 g), and the mixture was stirred for 30 minutes at room temperature. Sodium triacetoxy borohydride(0.42 g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol=1:0→4:1). The purified product was condensed under reduced pressure, and the residue was recrystallized from ether to give the title compound(0.47 g) as a white powder.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2)(=[O:3])[CH3:2].[Br:16]Br.O>C(O)(=O)C>[Br:16][C:12]1[CH:13]=[CH:14][C:5]([O:4][C:1](=[O:3])[CH3:2])=[C:6]2[C:11]=1[NH:10][C:9](=[O:15])[CH2:8][CH2:7]2
Reactant: CC(=O)Oc1cccc2c1CCC(=O)N2
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Oc1ccc(Br)c2c1CCC(=O)N2
Reaction time: 0.5 h

Procedure:
20.5 Grams of 5-acetyloxy-3,4-dihydrocarbostyril was dissolved in 200 ml of acetic acid, into this solution, 16 g of bromine dissolved in 60 ml of acetic acid was added dropwise under water-cooled condition with stirring for 30 minutes and the reaction was continued for 2 hours at the same temperature. Then 300 ml of water added to this reaction mixture and allowed to stand for 3 hours, and crystals formed in the mixture were obtained by filtration and recrystallized from methanol. 21 Grams of 8-bromo-5-acetyloxy-3,4-dihydrocarbostyril was obtained as in the form of colorless needle-like crystals. Melting point: 237°-239° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[NH2:9].[CH:10]1([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=2)[CH2:12][CH2:11]1.C(OCC)(=O)C>N1C=CC=CC=1.C1COCC1>[CH:10]1([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([NH:9][C:3]3[CH:4]=[N:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[O:20])=[CH:22][CH:23]=2)[CH2:12][CH2:11]1
Reactant: Nc1cnc(Cl)cc1Cl
Reactant: O=C(Cl)c1ccc(OCC2CC2)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1cnc(Cl)cc1Cl)c1ccc(OCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36.3 %

Procedure:
To a solution of 4,6-dichloropyridin-3-amine (2.00 g) in pyridine (30 mL) was added a solution of 4-(cyclopropylmethoxy)benzoyl chloride (3.88 g) in THF (5 mL), and the mixture was stirred at room temperature for 10 min. The reaction mixture was subjected to silica gel column chromatography (NH, ethyl acetate), and the solvent was evaporated, and the obtained solid was washed with diethyl ether/hexane to give the title compound (1.50 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:19]=[O:20]>>[CH:19]([C:8]1[C:7]([O:9][CH3:10])=[CH:6][C:5]([OH:11])=[CH:4][C:3]=1[O:2][CH3:1])=[O:20]
Reactant: COc1cc(O)cc(OC)c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(O)cc(OC)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
To a solution of 3,5-dimethoxyphenol (50 g, 320 mmol) in phosphorous oxychloride (60 mL, 650 mmol) at 0° C. was added dimethylformamide (37 mL, 490 mmol) over a period of 30 min and the mixture was warmed to room temperature and stirred overnight. The mixture was added to icewater (600 mL) and the mixture was washed with ether (3×200 mL). Then an 32% aqueous solution of sodium hydroxide was added until pH was 5.5 and the compound precipitated. The precipitate was separated and washed with water (100 mL) and ether (100 mL) and dried in vacuo. The precipitate was recrystallized from ethanol (600 mL) to give 22.6 g of 4-formyl-3,5-dimethoxyphenol.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][NH:19]C(=O)OC(C)(C)C)[CH:15]=[CH:14][CH:13]=2)=[N:3]1.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[NH2:19][CH2:18][C:16]1[N:17]=[C:12]([C:4]2[S:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2](=[O:1])[N:3]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: O=C(O)C(F)(F)F
Product: NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
tert-Butyl [6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methylcarbamate (0.25 g, 0.67 mmol) was dissolved in trifluoroacetic acid (4 ml), and the mixture was stirred at room temperature for 2 hrs. The solvent was evaporated and the residue was recrystallized from methanol-diisopropyl ether to give the titled compound (0.22 g, 85%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH:20]=O.CO.[NH2:24][C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1.[OH-].[Na+]>[Pd].C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH2:20][NH:24][C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: Nc1ncccn1
Reactant: O=Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=CO
Product: O=c1c2cc(F)ccc2nc(CNc2ncccn2)n1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(2-chloro-phenyl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde (0.200 g, 0.66 mmol), methanol (20 mL), and 2-aminopyrimidine (0.059 g, 0.62 mmol) was refluxed 29 hours. The mixture was cooled to room temperature and 10% palladium on carbon (0.236 g) and formic acid (1.1 mL) were added. The mixture was allowed to stir at ambient temperature overnight. The reaction was treated with 6 N sodium hydroxide to adjust the pH to 10. The mixture was filtered through celite and the pad was washed with ethyl acetate. The filtrate was dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (20 g) with elution proceeding as follows: 10% ethyl acetate/hexane (500 mL), nil; 20% ethyl acetate/hexane (250 mL), unweighed impurity, 20% ethyl acetate/hexane (100 mL), mixed fraction, unweighed; 20% ethyl acetate/hexane (150 mL) and 30% ethyl acetate/hexane (150 mL), unweighed 3-(2-chloro-phenyl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-methanol (a side product). Elution was continued: 30% ethyl acetate/hexane 410 mL), nil; 40% ethyl acetate/hexane (450 mL), nil; 40% ethyl acetate/hexane (50 mL) and 50% ethyl acetate/hexane (450 mL), 0.028 g (8%) of 3-(2-Chloro-phenyl)-6-fluoro-2-(pyrimidin-2-ylaminomethyl)-3H-quinazolin-4-one as a white solid which had: mp 182-185° C.; 1H NMR δ 8.29 (d, J=5 Hz, 2 H), 7.92 (dd, J=3, 8 Hz, 1 H), 7.82 (dd, J=5, 9 Hz, 1 H), 7.66-7.64 (m, 1 H), 7.55-7.49 (m, 3 H), 7.40-7.38 (m, 1 H), 6.63 (t, J=5 Hz, 1 H), 4.28 (dd, J=4.5, 18 Hz, 1 H), 4.11 (dd, J=4, 18 Hz, 1 H). Analysis calculated for C19H11ClFN5O.0.75 H2O: C, 58.05; H, 3.20; N, 17.81. Found: C, 58.06; H, 3.25; N, 17.33. APCI MS m/z=382 (P+1).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:49][C:50]1[N:55]=[CH:54][C:53]([C:56]2[CH:57]=[C:58]([NH2:62])[CH:59]=[CH:60][CH:61]=2)=[CH:52][CH:51]=1>CN(C=O)C>[OH:49][C:50]1[N:55]=[CH:54][C:53]([C:56]2[CH:57]=[C:58]([NH:62][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:59]=[CH:60][CH:61]=2)=[CH:52][CH:51]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(-c2ccc(O)nc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccc(O)nc2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 18.6 %

Procedure:
DIEA (0.008 mL, 0.048 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.009 g, 0.043 mmol) and HATU (0.018 g, 0.048 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(6-hydroxy-pyridin-3-yl)-phenylamine (0.008 g, 0.043 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.003 g of product in 15% yield: LCMS (ESI) m/z 375 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]([NH2:18])[CH3:17])=[CH:12][CH:11]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[Cl:8][C:4]1[N:3]=[C:2]([NH:18][C@H:16]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)[CH3:17])[CH:7]=[CH:6][CH:5]=1
Reactant: Clc1cccc(Cl)n1
Reactant: C[C@H](N)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@H](Nc1cccc(Cl)n1)c1ccc(F)cc1
Temperature: 85 °C
Reaction time: 2 h
Yield: 41.3 %

Procedure:
300 mg of 2,6-dichloropyridine, 296 mg of (S)-(−)-1-(4-fluorophenyl)ethylamine, 119 mg of 2-(di-t-butylphosphino)biphenyl, 487 mg of sodium t-butoxide and 45 mg of palladium acetate were added in turn to 6 ml of degassed toluene, and the mixture was stirred at 85° C. for 2 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 210 mg of the objective compound as pale yellow oil.
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23]CC2C=CC([N+]([O-])=O)=CC=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[C@H:44]([C:60]([NH:62][C:63]2[CH2:66][N:65](C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH:64]=2)=[O:61])[CH2:43]1>>[NH:65]1[CH2:66][CH:63]([NH:62][C:60]([C@@H:44]2[CH2:43][C@H:42]([S:41][C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([OH:23])=[O:22])[CH2:46][NH:45]2)=[O:61])[CH2:64]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: O=C(NC1=CN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)NC4CNC4)C3)[C@H](C)[C@H]12
Yield: 14.7 %

Procedure:
Following a procedure similar to that described in Example 121(1), followed by a procedure similar to that described in Example 49, but using 0.80 g of 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 123) and 0.95 g of (2S,4S)-4-mercapto-2-[1-(4-nitrobenzyloxycarbonyl)azetin-3-ylaminocarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 33), 86 mg of the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]#[N:16].C[O-].[Na+].C(O)(C)C>O>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[C:15]([C:11]2[O:10][CH:14]=[CH:13][CH:12]=2)[N:16]=1
Reactant: N#Cc1ccccc1N
Reactant: N#Cc1ccco1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Nc1nc(-c2ccco2)nc2ccccc12

Procedure:
5.4 g. (0.05 mol) of o-aminobenzonitrile, 4.7 g. (0.05 mol) of 2-furonitrile and 5.4 g. (0.1 mol) of sodium methoxide in 150 ml. of isopropanol are refluxed for 48 hours under a nitrogen atmosphere. The reaction mixture is then decomposed with water and the isopropanol is distilled off. 80 ml. of diethyl ether and 80 ml. of water are added and the precipitate is filtered off. The ethereal layer is separated and the ether is distilled off. The residue is identical to the solid already filtered off. The product is crystallized from a mixture of ethanol and petroleum ether (boiling range 40°-60°C.) to give 4-amino2-(2-furyl)quinazoline, m.p. 219°-221°C. The base is converted into the monohydrochloride, and the salt after crystallization from ethanol melts above 300°C.
Reaction SMILES: CO[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1.[NH:31]1C2C(=CC(C=O)=CC=2)[CH:33]=[CH:32]1>>[NH:31]1[C:3]2[C:30](=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]3[S:15][CH:16]=[CH:17][C:18]=3[NH:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]4[NH:26][CH:27]=[CH:28][C:21]=34)=[O:13])=[CH:5][CH:4]=2)[CH:33]=[CH:32]1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Product: O=C(NCCNCc1ccc2[nH]ccc2c1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using indole-5-carboxaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 431 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.49 (1H, br. s.) 10.93 (1H, br. s.) 10.27 (1H, s) 7.96-8.06 (1H, m) 7.75 (1H, d, J=5.47 Hz) 7.41-7.51 (1H, m) 7.22-7.31 (1H, m) 7.02 (1H, dd, J=8.30, 1.46 Hz) 6.78 (1H, d, J=5.47 Hz) 6.41 (1H, dd, J=3.51, 1.76 Hz) 6.30 (1H, dd, J=2.54, 1.56 Hz) 3.73 (2H, s) 3.33 (2H, d, J=5.86 Hz) 2.64 (2H, t, J=6.25 Hz)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]1([Li])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[O:13]=[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
To a cooled (−78° C.) solution of 3-(tert-butoxycarbonylamino)propanoic acid (1.0 g, 5.3 mmol) in THF (53 mL) was added phenyllithium (9.9 mL, 16 mmol, 1.6 M solution in cyclohexane/ether). After warming slowly to 0° C. and then stirring for 1 hour, the reaction mixture was quenched with saturated NH4Cl (10 mL), diluted with water (70 mL) and extracted with ether. The combined organics were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was chromatographed (20% ethyl acetate in hexanes) to provide the product (0.69 g, 59%) as yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[CH3:12][NH:13][CH2:14][C:15]1[S:16][CH:17]=[CH:18][N:19]=1.C(N(CC)CC)C>C1COCC1.O>[Cl:9][C:6]1[N:5]=[C:4]([S:10][CH3:11])[N:3]=[C:2]([N:13]([CH3:12])[CH2:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[C:7]=1[F:8]
Reactant: CNCc1nccs1
Reactant: CSc1nc(Cl)c(F)c(Cl)n1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1nc(Cl)c(F)c(N(C)Cc2nccs2)n1
Reaction time: 8 h
Yield: 103.5 %

Procedure:
4,6-Dichloro-5-fluoro-2-(methylthio)pyrimidine (see Intermediate E) (0.3313 g, 1.563 mmol), N-methyl-1-(1,3-thiazol-2-yl)methanamine (0.200 g, 1.5625 mmol), and triethylamine (0.26 mL, 1.8654 mmol) were dissolved in THF (5 mL) and left to stir overnight. Then the reaction mixture was diluted with water and the aqueous layer was extracted with ethyl acetate. The organics were dried (Na2SO4) and concentrated to produce 6-chloro-5-fluoro-N-methyl-2-(methylthio)-N-(1,3-thiazol-2-ylmethyl)-4-pyrimidinamine as a yellow oil (0.4928 g). LCMS: (M+H)+=305.0.