Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([S:39]([CH2:41][C:42]5[N:46]([CH2:47][CH2:48][CH3:49])[CH:45]=[N:44][CH:43]=5)=[O:40])=[CH:35][CH:34]=4)=[O:31])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[C:51]([OH:56])(=[O:55])[C:52]([OH:54])=[O:53]>C(OCC)(=O)C.C(O)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:34]=[CH:35][C:36]([S:39]([CH2:41][C:42]5[N:46]([CH2:47][CH2:48][CH3:49])[CH:45]=[N:44][CH:43]=5)=[O:40])=[CH:37][CH:38]=4)=[O:31])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[C:51]([O-:56])(=[O:55])[C:52]([O-:54])=[O:53]
Reactant: O=C(O)C(=O)O
Agent: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)cc2)CCCN3CC(C)C)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C([O-])C(=O)[O-]
Reaction time: 8 h

Procedure:
To a solution of (−)-8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-propyl-1H-imidazol-5-yl]methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (100 mg) in ethyl acetate (4 ml) was added a solution of oxalic acid (6.46 mg) in ethanol (2 ml), after which the solvent was distilled off under reduced pressure. Ethyl acetate (5 ml) was added, and the solvent was again distilled off under reduced pressure, after which ethyl acetate (4 ml) was added, and the mixture was allowed to stand overnight under light shielding. The precipitated crystals were filtered, and further washed with ethyl acetate (5 ml), after which the resultant was dried under reduced pressure to give (−)-8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-propyl-1H-imidazol-5-yl]methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide/oxalate (50 mg) as yellow crystals (Compound 13).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Si:11]([O:18][C@@H:19]1[C@@H:24]([O:25][CH3:26])[C@@H:23]([CH3:27])[CH2:22][O:21][C@H:20]1[CH2:28][OH:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[Si:11]([O:18][C@@H:19]1[C@@H:24]([O:25][CH3:26])[C@@H:23]([CH3:27])[CH2:22][O:21][C@H:20]1[CH:28]=[O:29])([C:14]([CH3:16])([CH3:17])[CH3:15])([CH3:13])[CH3:12]
Reactant: CO[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO)OC[C@@H]1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CO[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](C=O)OC[C@@H]1C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 85.4 %

Procedure:
To a solution of oxalyl chloride (0.036 ml, 0.42 mmole) in dry CH2Cl2 (0.5 ml) there was added dropwise a solution of dry DMSO (0.049 ml, 0.69 mmole) in dry CH2Cl2 (0.1 ml) at -78° C. over 5 min. After stirring for 10 min at -78° C., a solution of (2S,3R,4S,5S)-[3-(tert-butyldimethylsilyloxy)-4-methoxy-5-methyltetrahydro-2H-pyran-2-yl]methanol (0.1 g, 0.345 mmole) in dry CH2Cl2 (0.1 ml) was added dropwise to the resulting milky suspension over 5 min at -78° C. After stirring for 15 min at -78° C., triethylamine (0.24 ml, 1.73 mmole) was added dropwise to the reaction mixture over 3 min, and stirring was continued for 30 min at -78° C. The reaction mixture was then warmed up to room temperature gradually and partitioned between CH2Cl2 (10 ml) and water (10 ml). The methylene chloride layer was washed with brine (5 ml×2), dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel using AcOEt/n-hexane (1:9) as an eluent to give (2R,3R,4S,5S)-3-(tert-butyldimethylsilyloxy)-4-methoxy-5-methyltetrahydro-2H-pyran-2-carbaldehyde (0.085 g, 86% yield) as a colorless oil; EI-MS: m/z 288 (M+); 1H-NMR (CDCl3)d: 0.85 (3H, d,J=7 Hz), 0.87 (9H,s), 2.28 (1H,m), 3.12 (1H,dd,J=4 & 5 Hz), 3.28 (3H,s), 3.59 (1H,dd,J=5 & 11.5 Hz), 3.81 (1H,d,J=4 Hz), 3.81 (1H,dd,J=9 & 11.5 Hz), 4.08 (1H,dd,J= 4 & 5 Hz), 9.80 (1H,s).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].O=S(Cl)Cl.[CH3:20]O>>[NH2:10][CH:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)[C:11]([O:13][CH3:20])=[O:12]
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(N)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-nitrophenylalanine 1 (25 g) in methanol (10 ml/g) at 0° C. is added SOCl2 (2 equ.). After 30 minutes, the reaction is stirred at room temperature for 1 night. Volatiles are then evaporated and the residue is diluted in water. The solution is alkalinized with NaOH 2N and extracted with CH2Cl2. The organic phase is dried over MgSO4 and evaporated. No further purification is needed.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(=O)OC(C)CO1>[Pd].C(OCC)C>[C:2]1([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccccc1
Reactant: Clc1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC1COC(=O)O1
Solvent: CCOCC
Product: C(=Cc1ccccc1)c1ccccc1
Temperature: 155 °C
Reaction time: 65 h

Procedure:
Under argon, a solution containing 122 mg of chlorobenzene, 229 mg of sodium carbonate, 141 mg of styrene and 1 ml of propylene carbonate stabilized colloid solution with a palladium content of 4.023 mg is heated at 155° C. with stirring in a sealed vessel for 65 h. At the end of the reaction, 2 ml of diethyl ether is added, and the mixture is filtered. The yield of desired product as determined by GC is 34%.
Reaction SMILES: [C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](Cl)=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1>>[F:17][C:18]1[CH:19]=[C:20]([F:24])[CH:21]=[CH:22][C:23]=1[C:8]([CH:7]1[CH2:11][CH2:12][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]1)=[O:9]
Reactant: Fc1cccc(F)c1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
N-Acetyl isonipecotoyl chloride (70.0 g, 0.369 mol) was added over a 20 minute period to a vigorously stirred suspension of AlCl3 (98 g, 0.735 mol) in 1,3-difluorobenzene (125 ml, 1.27 mol, Aldrich Chem. Co.) at 25° C. The mixture was then refluxed, under N2 for 4.5 hours, cooled to 25° C., and poured over 300 ml of ice/water. The layers were separated, the aqueous layer was extracted (2×100 ml CH2Cl2) and combined with the organic layer and dried with MgSO4. Concentration in vacuo gave 4-(2,4-difluorobenzoyl)-1-acetyl-piperidine (II) as a white solid (81 g, 82%), m.p. 94°-96° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]3)[C:7]=2[N:29]=1.[ClH:30].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:30].[NH2:21][CH:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][N:8]2[C:9](=[O:12])[CH:10]=[N:11][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:29][C:7]2=3)[CH2:20][CH2:19]1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2n1
Reaction time: 5 h

Procedure:
To a suspension of 0.23 g of tert-butyl (1-(2-(6-methoxy-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)carbamate in 3 mL of ethyl acetate, 4.0 mL of a 4.0 mol/L hydrogen chloride/ethyl acetate solution was added at room temperature. The mixture was stirred at the same temperature for 5 hours, and then left overnight. The solvent was distilled off under reduced pressure, diethyl ether was added to the resultant residue, and the solid was filtered off to obtain 0.23 g of 4-(2-(4-aminopiperidin-1-yl)ethyl)-6-methoxypyrido(2,3-b)pyrazin-3(4H)-one hydrochloride as a light brown solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:45][O:46][CH2:47][C:48]([OH:50])=[O:49])[C:8]([NH:10][CH:11]2[C:43](=[O:44])[N:13]3[C:14]([C:27]([O:29]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:28])=[C:15]([S:18]/[CH:19]=[CH:20]\[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C(Cl)Cl.C1(OC)C=CC=CC=1>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:45][O:46][CH2:47][C:48]([OH:50])=[O:49])[C:8]([NH:10][CH:11]2[C:43](=[O:44])[N:13]3[C:14]([C:27]([OH:29])=[O:28])=[C:15]([S:18]/[CH:19]=[CH:20]\[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: Nc1nc(C(=NOCC(=O)O)C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(S/C=C\c4cccnc4)CS[C@H]23)ns1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Nc1nc(C(=NOCC(=O)O)C(=O)NC2C(=O)N3C(C(=O)O)=C(S/C=C\c4cccnc4)CS[C@H]23)ns1
Reaction time: 0.75 h
Yield: 22.3 %

Procedure:
To a solution of benzhydryl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylate (syn isomer) (1.28 g) in a mixture of methylene chloride (3.8 ml) and anisole (1.28 ml) was added trifluoroacetic acid (2.6 ml) under ice-cooling. The mixture was stirred for 45 minutes at the same temperature The mixture was poured into diisopropyl ether (200 ml) to give a precipitate. The precipitate was collected, washed with diisopropyl ether and dissolved in a mixture of ethyl acetate and dilute aqueous solution of sodium bicarbonate at pH 5. The insoluble material was filtered off. The aqueous layer was separated and concentrated in vacuo in order to remove ethyl acetate. The aqueous solution was adjusted to pH 4.5 with dilute hydrochloric acid, subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20" (20 ml) and eluted with water. The fractions containing the object compound were combined and concentrated in vacuo to about 20 ml. The concentrated solution was adjusted to pH 2 with dilute hydrochloric acid under ice-cooling to give a precipitate. The precipitate was collected, washed with cold water and dried over phosphorus pentoxide to give 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylic acid (syn isomer) (220 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1>O>[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1
Reactant: O=Cc1ccc(F)cc1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN1CCN(c2ccc(C=O)cc2)CC1
Temperature: 101.5 °C
Yield: 94.9 %

Procedure:
Potassium carbonate (3.3 g, 24 mmol) and 1-methylpiperazine (2.8 g, 29 mmol) were dissolved in 16 mL of water and then 4-fluorobenzaldehyde (2.0 g, 16 mmol) was added. The mixture was heated at reflux (100-103° C.) under a nitrogen atmosphere for 21 hours when HPLC showed that the reaction was complete. The solution was cooled to 20-25° C. and then extracted with methylene chloride (2×30 mL). The methylene chloride extracts were combined, washed with water (2×30 mL), and then concentrated at reduced pressure to a yellow oil (3.1 g, 96% yield). The crude solid was triturated with hexanes to afford crystals. mp 60.5-62.0° C. 1H NMR (CDCl3) δ 9.77 (s, 1H), 7.74 (d, J=10 Hz, 2H), 6.91 (d, J=10 Hz, 2H), 3.40 (m, 4H), 2.53 (m, 4H), and 2.34 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](N(OC)C)=[O:10])[CH:5]=[CH:6][CH:7]=1.OS([O-])(=O)=O.[K+]>CCOCC.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)Cc1cccc(Cl)c1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: O=CCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of LiAIH4 (1.90 g, 51 mmol) in anhydrous ether (250 mL) was stirred at room temperature tinder nitrogen for about 1 hour. The suspension was cooled to about 45° C. To it was added drops of a solution of 2-(3-chlorophenyl)-N-methoxy-N-methyl-acetamide (8.19 9, 38.3 mmol, see Preparation 1) in 10 mL of anhydrous tetrahydrofuran (THF). The mixture was warmed to about 0° C. and stirred for about 3 hours. The solution was then cooled to about 45° C. To this solution was slowly added a solution of KHSO4 (13 g) in water (about 30 mL) the resulting mixture was filtered through CELITE®. The filtrate was concentrated in vacuo, the resulting solution was diluted with DCM and washed with 1N HCl aqueous solution (2 times), and brine (2 times) dried over anhydrous MgSO4, filtered and concentrated in vacuo. The title compound was obtained as a liquid (5.80 g), which was used immediately in the next step without further purification. Rf=0.71 (silica, EtOAc/hexane 1:3).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[N:12]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: Clc1ccnc2ccccc12
Reactant: C1CNCCN1
Solvent: Cc1ccccc1
Product: c1ccc2c(N3CCNCC3)ccnc2c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 4-chloroquinoline (2.0 g, 12.2 mmol) in toluene (100 mL) was added piperazine (7.98 g, 92.7 mmol). The reaction mixture was heated to reflux and stirred for 96 hours, after which it was cooled to room temperature and then further cooled to 0° C. The resulting mixture was filtered to remove the hydrochloride salts that had precipitated. After washing the salts with toluene, the combined filtrate was washed with 10% aqueous acetic acid (2×25 mL). The combined aqueous extracts were washed with diethyl ether (25 mL) and then basified to pH 8-10 by adding 1M NaOH. The resulting aqueous mixture was extracted with dichloromethane (3×25 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation. The crude residue, 4-Piperazinylquinoline, was obtained as a yellow solid (2.54 g, 97%) and used without further purification. 1H NMR was consistent with that reported in the literature (Abel, M. D., et al., Journal of Heterocyclic Chemistry (1996), 33(2), 415-420).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:24]([CH3:26])[CH3:25])[N:11]([CH:20]=[CH:21][CH:22]=[O:23])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.II.C>C(Cl)(Cl)(Cl)Cl.[W]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:24]([CH3:26])[CH3:25])[N:11](/[CH:20]=[CH:21]/[CH:22]=[O:23])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1C=CC=O
Agent: [W]
Agent: II
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/C=O
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a solution of 3-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-2-propenal (390 mg) as an E:Z (1:1) mixture in carbon tetrachloride (150 ml) was added iodine (0.1 g) and the reaction mixture was heated under reflux for 18 h using a 200 W-tungsten lamp. After this period, activated charcoal (6 g) was added and heating was continued for a further 1 h. The mixture was filtered and the resulting pale yellow solution was evaporated to yield the title compound (384 mg) as a dull-white solid whose spectroscopic properties were in accord with those described above for Intermediate 11 a.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].C(O)CCC>[OH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCCCCCCCl
Reactant: CNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: CN(CCCCCCO)c1ccccc1
Reaction time: 96 h
Yield: 71 %

Procedure:
A mixture of 153 g (1.43 mol) of freshly distilled N-methylaniline, 200 g (1.46 mol) 6-chlorohexanol, 200 g (1.45 mol) potassium carbonate, 6 g potassium iodide, and 750 mL n-butanol was heated at reflux under nitrogen with vigorous mechanical stirring for 4 days. The solution was cooled, filtered, and the solvent was removed at reduced pressure. The residue was distilled in vacuo to produce 210 g (71%) of a colorless oil, bp 153°-166° C. (0.10 mm).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH3:12])[CH:5]=[CH:4][N:3]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[Li+].C[Si]([N-:52][Si](C)(C)C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCCC1>[CH3:12][O:11][CH2:10][CH2:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:52])[CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COCCOc1ccnc(Cl)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: COCCOc1ccnc(N)c1
Temperature: 2.5 °C

Procedure:
2-Chloro-4-(2-methoxyethoxy)pyridine (30.0 g; 159.9 mmol), X-PHOS (3.03 g, 6.356 mmol), and tris(dibenzylideneacetone)dipalladium (2.26 g; 2.468 mmol) were combined in a reaction flask under an atmosphere of dry nitrogen. Anhydrous tetrahydrofuran (150 mL) was added. The mixture was degassed by alternately evacuating the flask followed by filling with dry nitrogen (three times). The mixture was cooled to 0-5° C. using an ice/water bath. LHMDS (325 mL, 325.0 mmol) was added by addition funnel while maintaining the temperature below 5° C. The ice/water bath was removed and the mixture was heated to reflux (60-65° C.) for 1.5 hours. After allowing the mixture to cool an ice/water bath was put in place. Hydrochloric acid (2N; 300 mL) was added with stirring, maintaining the temperature below 30° C. After stirring for 15 minutes the mixture was transferred to a reparatory funnel with the addition of methyl t-butyl ether (300 mL) and water (20 mL). The phases were separated. The aqueous phase was basified by the addition of sodium hydroxide (50%; 10 mL) and then extracted with dichloromethane. The combined dichloromethane extracts were dried over sodium sulfate and filtered. Heptane (300 mL) was added. The solution was concentrated under vacuum to about one third the initial volume. Heptane (200 mL) was added. Further concentration resulted in solids precipitating. The solids were collected by filtration and washed with heptane (100 mL). The solids were dried under vacuum at 55° C. to give 4-(2-methoxyethoxy)pyridin-2-amine as an off white solid (23.62 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[NH:13][N:12]=[N:11][N:10]=1.CI.[C:16](=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([CH3:16])[N:13]=1
Reactant: Fc1ccc(Br)c(-c2nnn[nH]2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1nnc(-c2cc(F)ccc2Br)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.4 %

Procedure:
A mixture of 5-(2-bromo-5-fluoro-phenyl)-1H-tetrazole (1.0 g, 4.12 mmol; Butt Park Ltd.), methyl iodide (1.12 g, 10 mmol) and potassium carbonate (1.5 g) in DMF (5 mL) was stirred at room temperature for 16 hrs, and the mixture concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, CH2Cl2) to provide 650 mg (2.53 mmol, yield 61%) of the title compound as a white powder (fast-moving 2-Me isomer): TLC, Rf 0.7 (CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 4.45 (3H, s) 7.03-7.11 (1H, m) 7.63 (1H, dd, J=8.9, 3.1 Hz) 7.69 (1H, dd, J=8.9, 5.5 Hz); 13C NMR (126 MHz, CDCl3) δ 39.86 (s) 116.28 (s) 118.66 (d, J=22 Hz) 118.76 (d, J=25 Hz) 130.13 (d, J=8.6 Hz) 135.73 (d, J=8.6 Hz) 161.74 (d, J=247.6 Hz) 163.53 (s); LC/MS m/z 257/259.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(OC(=O)C)(C)C.[ClH:28]>O>[ClH:28].[ClH:28].[C:2]1([CH2:1][N:8]2[CH2:13][CH2:12][CH:11]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C1CCCCN1Cc1ccccc1
Agent: Cl
Solvent: CC(=O)OC(C)C
Solvent: O
Product: c1ccc(CN2CCC(N3CCOCC3)CC2)cc1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
10.00 kg (52.84 mol) 1-benzylpiperidone (K) were taken and 9.21 kg (105.68 mol) morpholine (L) and 30.0 L isopropylacetate were added. Then the reaction mixture obtained was heated to reflux temperature (95° C.) using the water separator and stirred until no more water separated off. Then the mixture was hydrogenated at 4 bar and at an internal temperature of 60° C. in the presence of 0.50 kg Raney nickel catalyst. Then the solvent was completely distilled off in vacuo. Then 45.0 L ethanol were added and 10.87 kg (116.25 mol) ethanolic 10-mol hydrochloric acid were metered in. The resulting suspension was cooled to 20° C. and stirred for 30 minutes at 20° C. The product was centrifuged off and dried.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: Brc1ccc(CN2CCNCC2)cc1

Procedure:
Synthesized according to General Procedure A: 4-bromobenzyl bromide (4{9}, 7 g, 28.0 mmol, 1 equiv.), piperazine (14.5 g, 168.0 mmol, 6 equiv.), THF (61.2 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{9} (6.73 g, 94%) as a white solid. 1H-NMR (400 MHz, CDCl3): δ 7.42 (d, 2H, J=8.4 Hz) 7.19 (d, 2H, J=8.4 Hz), 3.42 (s, 2H) 2.87 (t, 4H, J=4.8 Hz), 2.38 (br s, 4H), 2.07 (br s, 1H). 13C-NMR (100 MHz, CDCl3): δ 137.1, 131.3, 130.9, 120.8, 62.8, 54.2, 45.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:30].O.C[N:33]1CCCC1=O>>[NH2:33][C:16]1[N:17]=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[C:13]2[CH:12]=[CH:11][C:10](=[O:30])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1
Reactant: CS(=O)(=O)c1nc(-c2ccccc2F)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN1CCCC1=O
Solvent: O
Product: Nc1nc(-c2ccccc2F)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 8-(2,6-difluoro-phenyl)-4-(2-fluoro-phenyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one (432 mg, 1 mmol) in 1-methyl-2-pyrrolidinone (5 mL) was added NaNH2 (195 mg, 5 mmol, 5 eq) and the mixture was heated to 50°. After 1 h, H2O (20 mL) was added then Et2O (20 mL) The layers were separated. The organic layer was washed with satd aq NaCl, dried (MgSO4), filtered and solvent was removed in vacuo. The yellow residue was then purified by Flash chromatography to afford 2-amino-8-(2,6-difluoro-phenyl)-4-(2-fluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (100 mg, 53% yield). 1H-NMR (CDCl3) δ 5.51 (br s, 2H), 6.42 (d, 1H, J=9.8 Hz), 7.08 (m, 2H), 7.30 (m, 2H), 7.50 (m, 4H), LC MS (m/e)=369 (MH+). Rt=1.77 min
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]#[N:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]#[N:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=CC#N)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CC#N)CC1

Procedure:
4-Cyanomethylene-piperidine-1-carboxylic acid tert-butyl ester (compound of Example 14; 6.9 g, 31.0 mmol) and Pd/C (0.7 g) in ethanol (150 mL) was maintained under hydrogen atmosphere for 8 h. The reaction mixture was filtered through Celite and the solvent was evaporated to afford the title compound.