Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH2:11][CH2:10]1>CN(C1C=CN=CC=1)C.C(#N)C.N1C=CC=CC=1>[SH:1][CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9]([OH:14])(=[O:15])[CH2:10][CH2:11][C:12]([OH:5])=[O:13]
Reactant: O=C1CCC(=O)O1
Agent: CCOC(=O)CCS
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(O)CCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
As shown in FIG. 2, Ethyl 3-mercaptopropionate (2.95 g, 22 mmol) was added under argon to a stirring solution of succinic anhydride (2.0 g, 20 mmol) and DMAP (122 mg, 1 mmol) in 25 ml of acetonitrile-pyridine (9:1). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in 50 ml of EtOAc. The EtOAc solution was washed with 0.1 N HCl aqueous solution 30 ml×3, H2O×3, dried over anhydrous MgSO4. After filtration, the solution was concentrated to dry under reduced pressure and in vacuo. 1H NMR (CDCl3, 500 MHz) δ 10.23 (s, br), 4.14 (2H, q, J=7.0 Hz, —CH2—CH3), 3.13 (2H, t, J=7.0 Hz, —S—CH2—), 2.88 (2H, t, J=7.0 Hz, —S—CO—CH2—), 2.69 (2H, t, J=7.0 Hz, —S—CH2—CH2—), 2.62 (2H, t, J=7.0 Hz, —CH2—COOH), 1.25 (3H, t, J=7.0 Hz, —CH2—CH3).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[N:23]=[C:6]2[CH:7]=[C:8]([NH:11][C:12]([C:14]3[N:18]([CH3:19])[N:17]=[CH:16][C:15]=3[C:20]([OH:22])=O)=[O:13])[CH:9]=[CH:10][N:5]2[N:4]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:24][N:2]([CH3:1])[C:3]1[N:23]=[C:6]2[CH:7]=[C:8]([NH:11][C:12]([C:14]3[N:18]([CH3:19])[N:17]=[CH:16][C:15]=3[C:20]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:22])=[O:13])[CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: C1COCCN1
Reactant: CN(C)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1nc2cc(NC(=O)c3c(C(=O)N4CCOCC4)cnn3C)ccn2n1
Temperature: 70 °C
Reaction time: 18 h
Yield: 83.8 %

Procedure:
A mixture of 5-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (150 mg, 455 μmol), morpholine (317 μl, 3.64 mmol), propylphosphonic anhydride (50% in ethyl acetate, 671 μl, 1.14 mmol) and diisopropylethylamine (239 μl, 1.37 mmol) in tetrahydrofurane (8 ml) is stirred for 18 hours at 70° C. under nitrogen atmosphere. The solvent is evaporated and the residue triturated with sat. aqueous sodium hydrogencarbonate solution. The precipitated solid is collected by filtration, washed with water and dried affording N-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(morpholine-4-carbonyl)-1H-pyrazole-5-carboxamide (152 mg, 83.8%) as an off-white solid. Mp.: 196-8° C. MS: m/z=399.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:14]([NH:16][C:17]2[CH:18]=[N:19][N:20]([CH3:40])[C:21]=2[N:22]2[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29]C(=O)OCC3C=CC=CC=3)[CH2:24][CH2:23]2)=[O:15])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1CC=CCC=1>[Pd].C(O)C>[NH2:29][C@@H:25]1[CH2:26][CH2:27][CH2:28][N:22]([C:21]2[N:20]([CH3:40])[N:19]=[CH:18][C:17]=2[NH:16][C:14](=[O:15])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:6]=2)[CH2:23][CH2:24]1
Reactant: Cn1ncc(NC(=O)c2ccc(F)c(-c3ccccc3)n2)c1N1CCC[C@@H](NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3ccccc3)n2)c1N1CCC[C@@H](N)CC1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
In a 40 mL sealed vial was added (R)-benzyl 1-(4-(5-fluoro-6-phenylpicolinamido)-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate (62 mg, 0.11 mmol), 1,4-cyclohexadiene (0.11 mL, 1.14 mmol) and ethanol (7 mL). 10% Pd/C (18.2 mg, 0.017 mmol) was added and the reaction vial was vacuum purged with nitrogen three times. The reaction mixture was then stirred at 95° C. under nitrogen for 2 h. After cooling down to room temperature, the reaction mixture was filtered through Celite and rinsed thoroughly with methanol. The solvent was distilled off under reduced pressure to give the crude product which was purified via reverse phase HPLC to afford 229. 1H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 8.18-7.98 (m, 4H), 7.68-7.48 (m, 3H), 3.68 (s, 3H), 3.25-3.03 (m, 5H), 2.02-1.75 (m, 3H), 1.74-1.51 (m, 3H). MS (ESI) m/z: 409.2 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[CH3:11][O:12][C:13]([C:15]1[S:16][CH:17]=[CH:18][C:19]=1[NH2:20])=[O:14]>C(Cl)Cl>[CH3:11][O:12][C:13]([C:15]1[S:16][CH:17]=[CH:18][C:19]=1[NH:20][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:14]
Reactant: COC(=O)c1sccc1N
Reactant: COc1ccc(CCl)cc1
Solvent: ClCCl
Product: COC(=O)c1sccc1NCc1ccc(OC)cc1
Temperature: 85 °C
Yield: 91.6 %

Procedure:
4-Methoxybenzyl chloride (22.8 mL, 167.42 mmol) was added to a solution of methyl-3-amino-thiophene-2-carboxylate (17.55 g, 111 mmol) in dry CH2Cl2 (20 mL). The solution was mixed well. Excess CH2Cl2 was evaporated and the mixture was heated overnight at 85° C. under vacuum (3 torr). The mixture was cooled to room temperature. Hexane was added to the mixture, which was refluxed for 30 min, and cooled to 0° C. The solids formed were filtered, washed by hexane, and dried to yield 28.19 g (91%) of 3-(4-methoxybenzylamino)-thiophene-2-carboxylic acid methyl ester as red solids. 1H NMR (400 MHz, DMSO-d6) δ 3.71 (s, 6H), 4.42 (s, 2H), 6.77 (d, J=5.6 Hz, 1H), 6.88 (d, J=8.8 Hz, 2H), 7.25 (d, J=8.8 Hz, 2H), 7.63 (d, J=5.6 Hz, 1H), ppm; MS m/z=278 amu (M++1).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:10]([F:13])=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].Cl[CH:15]([Cl:19])[CH:16](Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>Cl>[Cl:19][C:15]1[CH:4]=[CH:3][C:2]([C:5]([C:4]2[C:10]([F:13])=[CH:11][CH:12]=[C:2]([F:1])[C:3]=2[C:8]([OH:7])=[O:9])=[O:6])=[CH:12][CH:16]=1
Reactant: ClC(Cl)C(Cl)Cl
Reactant: O=C1OC(=O)c2c(F)ccc(F)c21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)c1c(F)ccc(F)c1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 148.3 %

Procedure:
To a solution of 3,6-difluorophthalic anhydride (3.0 g, 16.00 mmol) in 1,1,2,2-tetrachloroethane (30 mL) chlorobenzene (2.0 mL, 18.00 mmol) was added followed by the addition of aluminum chloride (4.40 g, 33.00 mmol). The reaction mixture was stirred at room temperature for 120 minutes followed by the stirring at 60° C. for an additional 90 minutes. It was cooled to room temperature, poured into ice water (300 mL) and diluted with 1M aqueous hydrochloric acid. The aqueous slurry was extracted with ethyl acetate (300 mL) and the organic layer was washed with water (70 mL), brine (70 mL) and dried over anhydrous sodium sulfate. Filtration and concentration resulted in a crude product, which was crystallized from ethyl acetate by the addition of hexane. The product was collected by filtration and dried in vacuo to give 2-[(4-chlorophenyl)carbonyl]-3,6-difluorobenzoic acid (3.52 g, 73% yield). 1HMR (400 MHz, CD3OD): 7.77 (s, 1H), 7.75 (s, 1H), 7.53 (s, 1H), 7.51 (s, 1H), 7.53-7.34 (m, 2H). MS (EI) for C14H7ClF2O3: 281 (M−H2O).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[NH2:22][C:23]1[C:32](Br)=[N:31][C:30]([Br:34])=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]>>[NH2:22][C:23]1[C:32]([C:10]2[CH:11]=[CH:12][C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[CH:8][CH:9]=2)=[N:31][C:30]([Br:34])=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Reactant: COC(=O)c1cc(Br)nc(Br)c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1cc(Br)nc(-c2ccc(N3CCOCC3)cc2)c1N
Temperature: 110 °C
Yield: 466.5 %

Procedure:
A mixture of 4-morpholinophenylboronic acid (5.0 g, 24 mmol), sodium carbonate (6.91 g, 65.2 mmol), tetrakistriphenylphosphine palladium (0) (1.40 g, 1.21 mmol), and methyl 3-amino-2,6-dibromoisonicotinate (7.86 g, 25 4 mmol) in a pressure flask was flushed with nitrogen. Toluene (60 mL) and methanol (20 mL) were added and the flask was sealed heated at 110° C. for 44 h. After cooling to RT, the solid was collected by filtration and washed with sat. aq. NaHCO3 solution, water, and dried to give methyl 3-amino-6-bromo-2-(4-morpholinophenyl)-isonicotinate (7.32 gm, 77%). MS (ESI) m/z 392.15 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 7.78 (1H, s), 7.58 (2H, d, J=8.85 Hz), 7.01 (2H, d, J=8.85 Hz), 6.00 (2H, br. s.), 3.94 (3H, s), 3.88-3.92 (4H, m), 3.22-3.28 (4H, m).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[I:10]Cl.O>C(O)(=O)C>[F:1][C:2]1[CH:8]=[C:7]([I:10])[CH:6]=[C:5]([F:9])[C:3]=1[NH2:4]
Reactant: Nc1c(F)cccc1F
Reactant: ClI
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(F)cc(I)cc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
60 g of 2,6-difluoroaniline was dissolved in 180 ml of acetic acid. A solution containing 75 g of iodine chloride dissolved in 48 ml of acetic acid was added dropwise therein, and then agitated at 80° C. for 2 hours. The reaction solution was poured into water, and the resulting deposited crystals were filtrated and washed with water. The crystals were recrystallized with methanol, vacuum distilled (125° C./22 mmHg), and recrystallized again with methanol to obtain 57 g of 2,6-difluoro-4-iodoaniline.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][NH:14][C@H:13]([CH3:17])[CH2:12]3)=[N:10][C:6]=2[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1.Cl[C:23]1[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>O>[Cl:1][C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:23]4[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[CH:25][N:24]=4)[C@H:13]([CH3:17])[CH2:12]3)=[N:10][C:6]=2[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1
Reactant: C[C@@H]1CN(c2nc3cc(C(F)(F)F)cc(Cl)c3[nH]2)CCN1
Reactant: FC(F)(F)c1cccnc1Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(c2nc3cc(C(F)(F)F)cc(Cl)c3[nH]2)CCN1c1ncccc1C(F)(F)F
Temperature: 250 °C

Procedure:
A mixture of the piperazine from step (a) above (80 mg, 0.25 mmol), 2-chloro-3-trifluoromethyl-pyridine (54 mg, 0.3 mmol, Aldrich) and N,N-diisopropylethylamine (0.5 mL, 2.9 mmol, Aldrich) was heated in a microwave synthesizer for 120 min at 250° C. Water (10 mL) was added and the mixture was extracted with EtOAc (2×20 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 35% EtOAc/hexane to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 464 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[CH3:21][C:17]1[C:15]2[N:16]=[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[S:13][C:14]=2[CH:20]=[CH:19][CH:18]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2c(C)cccc2s1
Product: Cc1cccc2sc(CCC#Cc3ccccn3)nc12
Yield: 25.4 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (193 mg, 1.22 mmol) and 2-but-3-ynyl-4-methyl-benzo[d]thiazole (246 mg, 1.22 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 86 mg (0.31 mmol, 25%) of 4-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a brown oil.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:18][CH:17]=1>C1COCC1.CCO.[Pd]>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)c1ccc(/C=C/CCN2C(=O)c3ccccc3C2=O)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(CCCCN2C(=O)c3ccccc3C2=O)cc1
Reaction time: 6 h
Yield: 100.8 %

Procedure:
tert-Butyl 4-[(E)-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-butenyl]benzoate (15.1 g) was dissolved in 1:1 THF/EtOH (150 mL). 10% Pd on carbon (6.0 g) was added and the reaction placed on a Parr hydrogenator under 50 psi of H2. The reaction was shaken for 6 h. The reaction was filtered through a pad of celite and the celite washed with ethanol (3×100 mL). The organic extracts were concentrated to afford 15.3 g of tert-butyl 4-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butyl]benzoate: 1H NMR (CDCl3, 400 MHz) 7.88 (d, 2H, J=8.1 Hz), 7.82 (dd, 2H, J=3.0, 3.1 Hz), 7.77 (dd, 2H, J=3.0, 3.2 Hz), 7.2 (d, 2H, J=8.1 Hz), 3.7 (t, 2 h, J=6.9 Hz), 2.7 (t, 2H, J=6.9 Hz), 1.7 (m, 4H), 1.60 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](=[O:25])[CH2:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH:16]([OH:25])[CH2:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCc1ccc(-c2ccc(O)cc2)cc1)CCc1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Oc1ccc(-c2ccc(CCC(O)CCc3cccnc3)cc2)cc1

Procedure:
Prepared according to the method described in Example 7c) from 1-(4'-hydroxybiphenyl-4-yl)-5-(3-pyridyl)-3-pentanone (0.52 g) and sodium borohydride (0.062 g) in ethanol (10 ml) to give a yellow gum, which was purified by column chromatography over silica eluting with ethanol:ethyl acetate (1:9) to give the title compound as a yellow gum that solidified on standing (0.39 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][C@H:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][OH:12])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C>ClCCl>[CH3:22][S:23]([O:12][CH2:11][C@@H:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C

Procedure:
Preparation takes place in analogy to Example 84A from 250 mg (0.81 mmol) of tert-butyl{(3S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxybutyl}carbamate (Example 89A) in 20 ml of dichloromethane with 110 mg (0.97 mmol) of methanesulfonyl chloride and 0.23 ml (1.6 mmol) of triethylamine. The product is reacted without further purification.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][N:8]([C@@H:23]([C:25]1[N:26]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]([F:47])([F:46])[F:45])=[CH:38][CH:37]=2)[C:27](=[O:35])[C:28]2[CH:34]=[CH:33][CH:32]=[N:31][C:29]=2[N:30]=1)[CH3:24])[C:9](=[O:22])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=1)(=[O:5])=[O:4])C.C(S(CC)(=O)=O)=C>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C:9]([N:8]([CH2:7][CH2:6][S:3]([CH3:1])(=[O:4])=[O:5])[C@@H:23]([C:25]2[N:26]([C:36]3[CH:37]=[CH:38][C:39]([O:42][CH2:43][C:44]([F:47])([F:46])[F:45])=[CH:40][CH:41]=3)[C:27](=[O:35])[C:28]3[CH:34]=[CH:33][CH:32]=[N:31][C:29]=3[N:30]=2)[CH3:24])=[O:22])=[CH:12][C:13]=1[C:18]([F:21])([F:19])[F:20]
Reactant: CCS(=O)(=O)CCN(C(=O)Cc1ccc(F)c(C(F)(F)F)c1)[C@H](C)c1nc2ncccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: C=CS(=O)(=O)CC
Product: C[C@H](c1nc2ncccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1)N(CCS(C)(=O)=O)C(=O)Cc1ccc(F)c(C(F)(F)F)c1

Procedure:
Compound B2 was synthesized in two steps from A1 following the previously described synthetic sequence for A3, substituting methyl vinyl sulfone for ethyl vinyl sulfone in the first step. 1H NMR: a mixture of cis/trans amide rotamers in ca. 2.0:1 ratio (400 MHz; CDCl3; T=298 K) δmajor 8.98 (dd, J=4.46, 1.78 Hz, 1H), 8.62 (dd, 7.69, 1.78 Hz, 1H), 7.66 (dd, J=9.71, 3.33 Hz, 1H), 7.10-7.46 (m, 7H), 5.14 (q, J=7.26 Hz, 1H), 4.41 (q, J=7.94 Hz, 2H), 3.64-4.24 (m, 5H), 3.10 (s, 3H), 2.47 (m, 1H), 1.46 (d, J=7.2 Hz, 3H) and δminor 9.06 (m, 1H), 8.63 (obscured dd, J=7.28, 1.63 Hz, 1H), 5.01 (q, J=6.64 Hz, 1H), 2.83 (s, 3H), 1.58 (d, J=6.71 Hz, 3H) ppm. MS (ESI+) 675 [M+H]+.
Reaction SMILES: Br[C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.O>CS(C)=O>[C:13]1([C:2]([N:25]2[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][OH:19])[CH2:23][CH2:24]2)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(Br)(C(=O)OCC)c1ccccc1
Reactant: OCCN1CCNCC1
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)OCC)(c1ccccc1)N1CCN(CCO)CC1
Yield: 33.5 %

Procedure:
A solution of diethyl 2-bromo-2-phenylmalonate (16.8 g) in 150 ml of dimethylsulfoxide is heated to 90-100° C., then N-(2-hydroxyethyl)piperazine (27.9 g) is added and the reaction mixture is heated for additional 4 hours. The mixture is poured into water and extracted with ethyl acetate three times. The pooled organic extracts are washed with 1 N hydrochloric acid. The aqueous phase is basified with 1 N sodium hydroxide to pH=8-9 and it is extracted twice with ethyl acetate. The organic extracts are collected and are washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After removal of the solvent under reduced pressure, the residue is crystallized from diethylether petroleum ether 1:1 to give 6.5 g of the product, m.p. 63-64° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:11]([O:13][C:14]([C:16]1[C:17](=[O:36])[C:18]2[CH:23]=[N:22][C:21](S(C)(=O)=O)=[N:20][C:19]=2[N:28]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:29]=1)=[O:15])[CH3:12]>>[CH2:11]([O:13][C:14]([C:16]1[C:17](=[O:36])[C:18]2[CH:23]=[N:22][C:21]([NH:10][CH2:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[N:20][C:19]=2[N:28]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:29]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: NCCCN1CCOCC1
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(NCCCN3CCOCC3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 28 Step F, the title compound was prepared from 3-morpholin-4-yl-propylamine and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 35 Step E, 20 mg, 0.045 mmol). 8-Cyclohexyl-2-(3-morpholin-4-yl-propylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid (18 mg, 85%). Mass Spectrum (LCMS, ESI pos.) Calcd. For C23H33N5O4: 444.25 (M+H). Found: 4444.3.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[OH:5][C:6]1[C:23]2[C:22](=[O:24])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:25][CH3:26])[CH:20]=3)[C:15](=[O:27])[C:14]=2[CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][C:10](=[O:28])[CH2:11]2.Cl>C(Cl)Cl>[OH:28][C:10]1([C:1]#[CH:2])[CH2:9][CH2:8][C:7]2[C:12](=[CH:13][C:14]3[C:15](=[O:27])[C:16]4[C:21]([C:22](=[O:24])[C:23]=3[C:6]=2[OH:5])=[CH:20][C:19]([O:25][CH3:26])=[CH:18][CH:17]=4)[CH2:11]1
Reactant: CC[Mg]Br
Reactant: COc1ccc2c(c1)C(=O)c1c(cc3c(c1O)CCC(=O)C3)C2=O
Agent: Cl
Solvent: ClCCl
Product: C#CC1(O)CCc2c(cc3c(c2O)C(=O)c2cc(OC)ccc2C3=O)C1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Acetylene, purified by passing first through a trap cooled with ice and then through a trap containing concentrated sulfuric acid, is bubbled through 40 ml of anhydrous THF for 1 hour. Ethylmagnesium bromide (40 ml, 1M in THF, 40 mmol) is then added dropwise. After the addition, the solution is evaporated under reduced pressure and the residue is taken up with 80 ml of methylene chloride (CH2Cl2) distilled over P2O5. The ketone prepared in Example 1 (386 mg; 1.2 mmol), dissolved in CH2Cl2 (150 ml), is added dropwise to this solution, cooled to -40° C. The reaction mixture is stirred for 1 hour at between -40° C. and -20° C., then hydrolyzed with a 0.1N solution of hydrochloric acid and then extracted in the conventional manner with methylene chloride. Chromatography under pressure (CH2Cl2) makes it possible to separate the unreacted starting ketone (148 mg; 38%) from the ethynylcarbinol formed (165 mg; 43%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([PH:17](=[O:19])[OH:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N([Si](C)(C)C)[Si](C)(C)C.[C:29]([O:34][CH3:35])(=[O:33])[C:30]([CH3:32])=[CH2:31]>CCO>[CH3:35][O:34][C:29](=[O:33])[CH:30]([CH3:32])[CH2:31][P:17]([C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([OH:18])=[O:19]
Reactant: C=C(C)C(=O)OC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[PH](=O)O
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CCO
Product: COC(=O)C(C)CP(=O)(O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of 5.00 g of ((R)-1-tert-butoxycarbonylamino-2-phenyl-ethyl)-phosphinic acid and 18.3 ml of HN(TMS)2 was heated to 110° C. for 1 h. To the solution was added 2.5 ml of methyl methacrylate and heating was continued at 110° C. for 2 h. The solution was cooled to 70° slowly diluted with 10 ml of EtOH and evaporated. The residue was chromatographed on silica using a gradient of CH2Cl2/MeOH (9:1)→CH2Cl2/MeOH/AcOH (10:1:0.3) to give 4.10 g of the title compound. MS: 386.5 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=O)/[CH:6]=[C:7](/[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)\[O-])[CH3:2].[Li+].Cl.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:31][NH2:32])[CH:28]=[CH:29][CH:30]=1>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:31]2[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)=[CH:6][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:20])=[N:32]2)[CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)C(=O)/C=C(\[O-])c1cccc(C(F)(F)F)c1
Reactant: COc1cccc(NN)c1
Agent: Cl
Agent: [Li+]
Product: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)n(-c2cccc(OC)c2)n1
Yield: 85 %

Procedure:
Starting from 1.5 g (5.2 mmol) of lithium (1Z)-4-ethoxy-3,4-dioxo-1-[3-(trifluoro-methyl)phenyl]but-1-en-1-olate from example 1A and 1 g (5.73 mmol) of 3-methoxyphenylhydrazine hydrochloride, 1.73 g (4.4 mmol, 85% yield of theory) of product are obtained according to the method described in example 4A and after purification on silica gel (flash chromatography).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2[CH:22]=[CH:23][CH:24]=[CH:25][C:16]1=2.C(N(C(C)C)CC)(C)C.O>C(Cl)Cl>[N+:12]([C:3]1[CH:4]=[C:5]([S:8]([N:15]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]3[CH:22]=[CH:23][CH:24]=[CH:25][C:16]2=3)(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[Cl:1])([O-:14])=[O:13]
Reactant: c1ccc2c(c1)CCCCN2
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.9 %

Procedure:
To 4-chloro-3-nitrobenzenesulfonyl chloride (1.0 g, 3.9 mmol) in dry DCM (10 mL), was added 2,3,4,5-tetrahydro-1H-benzo[b]azepine (0.57 g, 3.9 mmol). Diisopropylethylamine (1.3 mL, 7.8 mmol) was added and the mixture was stirred at ambient temperature for 16 hrs. DCM (20 mL) and 30 mL of water were added. The DCM layer was separated, washed with brine (20 mL×2), dried over MgSO4 and evaporated to give 1-(3-nitro-4-chloro-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine 4-1 as a yellow solid (1.3 g, 85% yield). MS: 367 (M+H)+; tR=2.98 min (method 1).