Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH2:4]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Br)=[CH:8][CH:7]=1)[CH3:5]>CS(C)=O.O>[CH2:4]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10][C:1]#[N:2])=[CH:8][CH:7]=1)[CH3:5]
Reactant: CCc1ccc(CBr)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
A mixture of 2.72 g (20.0 mmol) of 4-ethylbenzyl alcohol (purchased from Aldrich) and 50 ml of 47% hydrobromic acid (purchased from Wako Junyaku Kogyo) was stirred at room temperature for 30 minutes vigorously and extracted with hexane to give 3.98 g of 4-ethylbenzyl bromide as a colorless oil. Subsequently, to a solution of 1.96 g (40.0 mmol) of sodium cyanide (purchased from Kokusan Kagaku) in 20 ml of dimethyl sulfoxide (purchased from Aldrich) heated at 50 ° C. was added 3.98 g of the above 4-ethylbenzylbromide, the solution was stirred at ambient temperature for 3 hours, the resultant reaction mass was dissolved in water and extracted with hexane, and hexane was removed to give 2.70 g (yield: 93.1%) of 4-ethylphenylacetonitrile as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[CH3:21][CH:22]1[CH2:27][NH:26][CH2:25][CH:24]([CH3:28])[NH:23]1>CN(C)C=O.C(OCC)C>[CH3:21][CH:22]1[NH:23][CH:24]([CH3:28])[CH2:25][N:26]([CH2:12][C:10]([OH:11])([CH2:9][C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:19][CH3:20])([CH3:18])[CH3:17])[C:13]([F:16])([F:15])[F:14])[CH2:27]1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: CC1CNCC(C)N1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CC(C)NC(C)C1)C(F)(F)F
Yield: 70.9 %

Procedure:
A solution of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (98.7 mg) and 2,6-dimethylpiperazine (77.2 mg) in dimethylformamide (1 mL) was heated at 100° C. for 5 hours. The resulting mixture was diluted with diethyl ether, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 1:98.5:0.5 methanol-methylene chloride-triethylamine) to give the title compound as a white solid (97.3 mg), m.p. 61° C.-62° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24]3[N:25]=[CH:26][C:27]4[C:32]5[CH:33]=[CH:34][N:35]=[C:36]([Cl:37])[C:31]=5[N:30]([CH:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)[C:28]=4[N:29]=3)=[N:21][CH:22]=2)[CH2:13][CH2:12]1)(C(C)(C)C)(C)C.Cl>CO>[Cl:37][C:36]1[C:31]2[N:30]([CH:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[C:28]3[N:29]=[C:24]([NH:23][C:20]4[N:21]=[CH:22][C:17]([N:14]5[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][OH:8])[CH2:12][CH2:13]5)=[CH:18][CH:19]=4)[N:25]=[CH:26][C:27]=3[C:32]=2[CH:33]=[CH:34][N:35]=1
Reactant: CC(C)(C)[Si](C)(C)OCCN1CCN(c2ccc(Nc3ncc4c5ccnc(Cl)c5n(C5CCCC5)c4n3)nc2)CC1
Agent: Cl
Solvent: CO
Product: OCCN1CCN(c2ccc(Nc3ncc4c5ccnc(Cl)c5n(C5CCCC5)c4n3)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
Compound 217 (0.094 g, 0.15 mmol) was combined with 10 mL of methanol and 4 mL of 1N HCl. The solution was stirred at room temperature overnight. The solution was concentrated under vacuum and the residue obtained was purified on CombiFlash column (dry loaded), eluting with a gradient of 2% methanol/0.1% NH4OH (˜28% in water)/DCM to 10% methanol/0.5% NH4OH (˜28% in water)/DCM. The fractions containing the product were combined and concentrated under vacuum to give a yellow solid. The solid was partially dissolved in methanol and then collected on filter paper. Washed the solid off of the filter paper with DCM/methanol through a fitted funnel and then concentrated under vacuum to give compound 213 (0.065 g, 85% yield) as a yellow solid. 1H-NMR (500 MHz, DMSO-d6) δ 9.92 (1 H, s), 9.33 (1 H, s), 8.22 (1 H, d, J=5.1 Hz), 8.10 (1 H, d, J=4.9 Hz), 8.04 (1 H, d, J=2.9 Hz), 8.02 (1 H, d, J=9.0 Hz), 7.46 (1 H, dd, J=9.0, 2.9 Hz), 5.95-6.05 (1 H, m), 4.43 (1 H, t, J=5.4 Hz), 3.54 (2 H, q, J=6.1 Hz), 3.12-3.19 (4 H, m), 2.55-2.65 (6 H, m), 2.45 (2 H, t, J=6.4 Hz), 1.98-2.08 (4 H, m), 1.65-1.75 (2 H, m) ppm; LCMS-ESI (POS), M/Z, M+1: Found 493.1.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(CC)CC)C.C(OCC)C>C(O)C>[N:11]1([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: CCOC(=O)CCCCBr
Reactant: C1COCCN1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CCCCN1CCOCC1
Yield: 86.1 %

Procedure:
A mixture of ethyl 5-bromovalerate (8 g, 38.3 mmole), morpholine (3.67 g, 42 mmole) and triethylamine (4.2 g, 42 mmole) in ethanol (100 mL) was heated to reflux overnight. The solution was concentrated to afford a gummy white solid which was mixed with diethyl ether and filtered to remove the solid. The filtrate was washed with saline (3×50 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford 7.1 g (87%) of ethyl 5-morpholin-4-ylpentanoate as a pale brown liquid. MS (m/z, ES+): 217 (M+2, 100%), 216 (M+1, 57%).
Reaction SMILES: [Na+].[I-:2].CC(=O)CC.Cl[CH2:9][CH2:10][N:11]1[C:15]2=[N:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:14]2[CH2:13][CH2:12]1>CCOC(C)=O>[I:2][CH2:9][CH2:10][N:11]1[C:15]2=[N:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:14]2[CH2:13][CH2:12]1
Reactant: ClCCN1CCn2c1nc1ccccc12
Reactant: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: ICCN1CCn2c1nc1ccccc12
Reaction time: 5 h
Yield: 91.1 %

Procedure:
A mixture of NaI (1.73 g, 11.57 mmol) and 2-butanone (20 mL) was heated under reflux for 30 minutes 1-N-(2-Chloroethyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole (1.70 g, 7.71 mmol) and additional 2-butanone (5 mL) were added and heating was continued for 5 hours. EtOAc (50 mL) was added and the mixture was filtered. The filtrate was washed with H2O, 10% sodium bisulfite (25 mL), saturated aqueous NaHCO3, dried (MgSO4) and concentrated to give 2.2 g (92%) of a light brown solid m.p. 101°-103° C.
Reaction SMILES: CN([CH:4]=[O:5])C.[Cl:6][C:7]1[CH:8]=[C:9]([C:13]2[C:22]3[C:17](=[N:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]([CH2:24][CH3:25])[C:15](=[O:26])[C:14]=2[CH2:27][CH2:28][CH2:29][OH:30])[CH:10]=[CH:11][CH:12]=1.[C:31](=O)([O-])[O-:32].[K+].[K+].CI>O>[Cl:6][C:7]1[CH:8]=[C:9]([C:13]2[C:22]3[C:17](=[N:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]([CH2:24][CH3:25])[C:15](=[O:26])[C:14]=2[CH2:27][CH2:28][CH2:29][O:30][C:31]([O:5][CH3:4])=[O:32])[CH:10]=[CH:11][CH:12]=1
Reactant: CCn1c(=O)c(CCCO)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: CCn1c(=O)c(CCCOC(=O)OC)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Temperature: 80 °C

Procedure:
To a 10 ml DMF solution containing 500 mg of 4-(3-chlorophenyl)-1-ethyl-3-(3-hydroxypropyl)-7-methyl-1,8-naphthyridin-2(1H)-one were added 500 mg of potassium carbonate and 0.5 ml of methyl iodide, followed by stirring under heating at an oil bath temperature of 80° C. for 2 hours. Thereafter, 1.0 g of potassium carbonate and 1.0 ml of methyl iodide were further added thereto, followed by stirring under heating at an oil bath temperature of 80° C. for a whole day and night. After the reaction mixture was cooled to room temperature, water was added thereto, and the whole was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by a silica gel column chromatography (hexane-ethyl acetate) and then recrystallized from hexane-diisopropyl ether to obtain 160 mg of 4-(3-chlorophenyl)-1-ethyl-3-[3-(methoxycarbonyloxy)propyl]-7-methyl-1,8-naphthyridin-2(1H)-one as colorless crystals.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1.[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[N:15]1([CH2:2][C:3]2[N:4]=[N:5][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:7][CH:8]=2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: BrCc1ccc(-c2ccccc2)nn1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc(-c2ccc(Cn3ccnc3)nn2)cc1

Procedure:
Synthesized using compound 65a (40 mg, 0.16 mmol), imidazole (44 mg, 0.64 mmol) and K2CO3 (111 mg, 0.80 mmol) in acetonitrile according to Method B. Crude product was purified by flash chromatography on silica-gel using ethyl acetate as eluent. After flash chromatography the solid was washed with ethyl acetate. Light orange solid. Yield: 22 mg, 58%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=5.58 (s, 2H), 7.08 (s, 1H), 7.17-7.26 (m, 2H), 7.55-7.61 (m, 3H), 7.72 (s, 1H), 7.88 (d, J=8.8 Hz, 1H), 8.09-8.14 (m, 2H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=50.9, 119.6, 125.1, 125.5, 127.4, 129.4, 130.7, 130.8, 135.8, 137.8, 157.2, 159.3; (ESI): m/z=236.91 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]3[CH:19]=[CH:20][CH:21]=[C:11]3[CH2:10][CH2:9]2)=[O:7])=[C:4]([Cl:24])[CH:3]=1.C(N(CC)CC)C.[F:32][C:33]1[C:34]([CH3:42])=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](Cl)=[O:37].[OH-].[Na+]>ClCCl>[CH:18]1[C:13]2[N:12]3[CH:19]=[CH:20][CH:21]=[C:11]3[CH2:10][CH2:9][N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:36](=[O:37])[C:35]4[CH:39]=[CH:40][CH:41]=[C:33]([F:32])[C:34]=4[CH3:42])=[CH:3][C:4]=3[Cl:24])=[O:7])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)c(Cl)c1
Reactant: Cc1c(F)cccc1C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(F)cccc1C(=O)Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.9 %

Procedure:
To a mixture of 0.10 g of 6,7-dihydro-5-(4-amino-2-chlorobenzoyl)-5H-pyrrolo-[1,2-a][1,5]benzodiazepine and 0.06 g of triethylamine in 6 ml of dichloromethane is added 0.08 g of 3-fluoro-2-methylbenzoyl chloride in 0.5 ml of dichloromethane. The mixture is stirred for 2 hours at room temperature and then 2 ml of 1N NaOH added. The volatiles are evaporated under vacuum and the residue dissolved in 2 ml of tetrahydrofuran and 1 ml of methanol. The mixture is stirred for 2 hours and evaporated and the residue diluted with 2 ml of 1N NaOH and 5 ml of water. The mixture is extracted with ethyl acetate (15 ml) and the extract washed with brine and dried (Na2SO4). The solvent is removed and the residue triturated with diethyl ether-hexane to give 0.15 g of white solid: Mass Spectrum (CI)474(M+H, Cl35); 476(M+H, Cl37).
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][C:5](=O)[CH3:6].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[C:27]([F:29])[CH:28]=1)[NH2:25].O1CCCC1>C1(C)C=CC=CC=1>[Cl:21][C:22]1[CH:23]=[C:24]([N:25]2[C:5]([CH3:6])=[CH:4][CH:3]=[C:2]2[CH3:1])[CH:26]=[C:27]([F:29])[CH:28]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1cc(F)cc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C)n1-c1cc(F)cc(Cl)c1

Procedure:
2,5-Hexanedione (4.51 mL) and p-toluenesulfonic acid monohydrate (73 mg) were added to a solution of 3-chloro-5-fluoroaniline (5.12 g) in toluene (40 mL)-tetrahydrofuran (40 mL), and the mixture was heated under reflux for 3.5 hours. After being cooled down, the reaction solution was concentrated in vacuo, and the resultant residue was dissolved in chloroform. The solution was washed successively with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulted residue was purified by column chromatography on silica gel (Solvent: n-hexane/ethyl acetate=97/3) to give the titled compound (7.63 g) as a yellow oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][C:17]([C:19](O)=[O:20])=[C:16]([C:22]3[CH:27]=[CH:26][C:25]([S:28](=[O:31])(=[O:30])[NH2:29])=[CH:24][CH:23]=3)[C:15]=2[N:32]([CH3:34])[CH3:33])=[CH:10][CH:9]=1.[CH3:35][N:36]([CH:38]=O)[CH3:37].C(N(CC)CC)C.Cl.[CH3:48][NH:49][O:50][CH3:51]>ClCCl>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[S:18][C:17]([C:19]([N:49]([O:50][CH3:51])[CH3:48])=[O:20])=[C:16]([C:22]3[CH:27]=[CH:26][C:25]([S:28](=[O:31])(=[O:30])[N:29]=[CH:38][N:36]([CH3:35])[CH3:37])=[CH:24][CH:23]=3)[C:15]=2[N:32]([CH3:33])[CH3:34])=[CH:12][CH:13]=1
Reactant: CN(C)C=O
Reactant: CNOC
Reactant: CN(C)c1c(-c2ccc(Cl)cc2)sc(C(=O)O)c1-c1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1sc(-c2ccc(Cl)cc2)c(N(C)C)c1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.6 %

Procedure:
Oxalyl chloride (0.58 g, 0.39 ml, 4.57 mmol) was added drop wise to a solution of 5-(4-chlorophenyl)-4-(dimethylamino)-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid (compound 34f, 1.00 g, 2.28 mmol) in a mixture of dichloromethane (30 ml) and DMF (0.33 g, 0.35 ml, 4.57 mmol) at 0° C. The reaction mixture was then allowed to warm to room temperature and stirred for 1.5 hr under a nitrogen atmosphere. The progress of the reaction was monitored by TLC. The mixture was then concentrated under reduced pressure. The residue so obtained was dissolved in dry dichloromethane (30 ml) and cooled to 0° C. To the cooled reaction mixture was then added triethylamine (1.38 g, 1.90 ml, 13.68 mmol) followed by the addition of N,O-dimethylhydroxylamine hydrochloride (0.40 g, 4.57 mmol) under stirring. The reaction mixture was then stirred at room temperature for 2 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then diluted with DCM (25 ml) and washed with water (2×25 ml). The combined organic layer was then dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 1.6% methanol in DCM as an eluent to obtain the title compound (0.8 g, 65.35%).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[C:18](Cl)=[N:17][C:16]([N:20]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH3:21])=[CH:15][N:14]=1)[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O>CN(C=O)C>[CH2:1]([N:8]1[CH2:12][C:13]2[N:14]=[CH:15][C:16]([N:20]([CH2:22][CH:23]3[CH2:25][CH2:24]3)[CH3:21])=[N:17][C:18]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CC1CC1)c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CC1CC1)c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Reaction time: 2.5 h
Yield: 80.1 %

Procedure:
To a solution of 2-[benzyl({3-chloro-5-[(cyclopropylmethyl)(methyl)amino]pyrazin-2-yl}methyl)amino]ethanol (0.50 g) in DMF (3 mL) was added potassium tert-butoxide (0.19 g) at 0° C., and the mixture was stirred for 2.5 hr. Water (10 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 10→40% ethyl acetate/hexane) to give the title compound (0.36 g, 79%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][N:2]([C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([NH2:14])=O)=[N:10][N:11]=2)[N:8]=1.C([O-])(O)=O.[Na+].C(Cl)Cl>CN(C=O)C.O=S(Cl)Cl>[CH3:1][N:2]([C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]#[N:14])=[N:10][N:11]=2)[N:8]=1
Reactant: C[C@@H](c1ccccc1)N(C)c1ccc2nnc(C(N)=O)n2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](c1ccccc1)N(C)c1ccc2nnc(C#N)n2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of compound (S)-6-(methyl(1-phenylethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxamide (0.1 g, 0.34 mmol) in 2 mL of DMF, 1 mL of SOCl2 was added dropwise at 0-5° C., the reaction mixture was stirred for 5 h at room temperature. The mixture was poured onto ice (20 mL) and the mixture was neutralized with NaHCO3. DCM (50 mL) was added; the separated organic layer was dried over anhydrous Na2SO4, and concentrated in vacuum. The residue was purified by flash chromatography eluting with PE/EA=5:1 to give product (S)-6-(methyl(1-phenylethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-3-carbonitrile as a yellow solid (Compound 9) (60 mg, 64%). LRMS (M+H+) m/z: calcd 279.43; found 279. 1H NMR (300 MHz, CDCl3): δ 7.98-7.94 (d, J=12 Hz, 1H), 7.35-7.30 (m, 5H), 7.11-7.08 (d, J=9 Hz, 1H), 5.77-5.75 (q, 1H), 2.94 (s, 3H), 1.69-1.66 (d, 3H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[N:11]=[C:10]([C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)[N:9]=1.[CH2:26]([N:28]=[C:29]=[O:30])[CH3:27]>O1CCOCC1>[CH2:26]([NH:28][C:29](=[O:30])[NH:23][C:22]1[CH:24]=[CH:25][C:19]([C:10]2[N:9]=[C:8]([N:3]3[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]3[CH3:1])[CH:13]=[C:12]([CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[N:11]=2)=[CH:20][CH:21]=1)[CH3:27]
Reactant: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(-c2ccc(N)cc2)n1
Reactant: CCN=C=O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1ccc(-c2nc(CS(C)(=O)=O)cc(N3CCOC[C@@H]3C)n2)cc1
Temperature: 70 °C
Yield: 93.1 %

Procedure:
4-[4-[(3S)-3-Methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]aniline (100 mg, 0.28 mmol) was dissolved in dioxane (4 mL). Ethylisocyanate (0.109 mL, 1.38 mmol) was added and the reaction heated at 70° C. for 4 hours. Reaction was complete and was evaporated to dryness. The resultant oil was purified by chromatography, eluting with 10-50% ethyl acetate in isohexane, to give 3-ethyl-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]urea as a pale yellow oil (113 mg, 94%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17](Cl)=[O:18])[CH:12]=2)[N:10]=1)=[O:5])[CH3:2].Br[CH2:21][C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([OH:29])=[O:28])=O.C(OCC)(=S)C(N)=O>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:18])[CH2:26][C:27]([OH:29])=[O:28])[CH:12]=2)[N:10]=1)=[O:5])[CH3:2].[CH2:1]([O:3][C:4]([C:6]1[S:7][CH:21]=[C:22]([C:24]2[CH:32]=[CH:31][CH:30]=[C:26]([C:27]([OH:29])=[O:28])[CH:25]=2)[N:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(-c2cccc(C(=O)Cl)c2)cs1
Reactant: O=C(O)c1cccc(C(=O)CBr)c1
Agent: CCOC(=S)C(N)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(-c2cccc(C(=O)CC(=O)O)c2)cs1
Product: CCOC(=O)c1nc(-c2cccc(C(=O)O)c2)cs1
Temperature: 60 °C

Procedure:
The 4-(3-carboxyacetyl-phenyl)-thiazole-2-carboxylic acid ethyl ester was prepared from 4-(3-chlorocarbonyl-phenyl)-thiazole-2-carboxylic acid ethyl ester [prepared by the following sequence: i.) A mixture of 3-(2-bromo-acetyl)-benzoic acid [CAS-no. 62423-73-8] (2.43 g) and ethyl thiooxamate [CAS-no. 16982-21-1] (1.6 g) in THF (40 mL) was heated to 60° C. for 4 h and then partitioned between EtOAc and brine. The organic layer was dried and evaporated and the residue was crystallized from EtOAc/hexane to give 4-(3-carboxy-phenyl)-thiazole-2-carboxylic acid ethyl ester (2.2 g) as off-white crystals, mp 225-228° C. ii.) This carboxylic acid (2.1 g) was heated with thionyl chloride in toluene and the resulting carboxylic acid chloride was used directly in the next step.] (2.24 g) and bis(trimethylsilyl)malonate with n-BuLi in ether at −60° C. to 0° C. according to general procedure K (method c2). The crude material was transformed into the title compound by stirring in isopropenyl acetate and conc. H2SO4 according to general procedure L (method a). Obtained as yellow oil (2.7 g).
Reaction SMILES: [CH3:1][S:2][CH3:3].ClCl.[NH2:6][C:7]1[N:11]([CH3:12])[N:10]=[CH:9][C:8]=1[Br:13].N1C=CC=CC=1>ClCCl>[Br:13][C:8]1[CH:9]=[N:10][N:11]([CH3:12])[C:7]=1[N:6]=[S:2]([CH3:3])[CH3:1]
Reactant: CSC
Reactant: Cn1ncc(Br)c1N
Agent: ClCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1ncc(Br)c1N=S(C)C

Procedure:
A solution of 0.60 mL (8.2 mmol) of dimethyl sulfide in 30 mL of dichloromethane was cooled to -20° C. and 0.50 g (7.0 mmol) of chlorine was added through a sparge tube with cooling and stirring. Subsequently, 1.0 g (5.7 mmol) of 5-amino-4-bromo-l-methylpyrazole and then 1.0 g (12.7 mmol) of pyridine were added with cooling and stirring. A 2 mL aliquot of this mixture was removed and the light yellow solids present were collected by filtration and washed with deuteroacetonitrile.
Reaction SMILES: CO[C:3]([C@H:5]1[CH2:9][C@H:8]([OH:10])[C@@H:7]([NH:11][C:12]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:13])[CH2:6]1)=[O:4].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]2=[O:33])=[CH:23][CH:22]=1>>[OH:10][C@H:8]1[CH2:9][C@H:5]([C:3](=[O:4])[NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]3=[O:33])=[CH:23][CH:22]=2)[CH2:6][C@@H:7]1[NH:11][C:12]([C:14]1[S:15][C:16]([Cl:19])=[CH:17][CH:18]=1)=[O:13]
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](O)C1
Reactant: Nc1ccc(-n2ccccc2=O)cc1
Product: O=C(N[C@H]1C[C@@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2)C[C@@H]1O)c1ccc(Cl)s1

Procedure:
In analogy to example 1C, (1R,3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-hydroxy-cyclopentanecarboxylic acid methyl ester (example 1B) was reacted with 1-(4-amino-phenyl)-1H-pyridin-2-one (CAS 13143-47-0) to give 5-chloro-thiophene-2-carboxylic acid {(1S,2S,4R)-2-hydroxy-4-[4-(2-oxo-2H-pyridin-1-yl)-phenyl-carbamoyl]-cyclopentyl}-amide. Orange solid. MS: 458.3 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:25]([O:27][CH3:28])=[O:26])=[C:9]([CH3:24])[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)=[N:11]2)=[CH:6][C:5]=1[S:29]([CH3:32])(=[O:31])=[O:30])[CH3:2].C1C(=O)N([Br:40])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:40][CH2:24][C:9]1[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)=[N:11][C:12]2[C:7]([C:8]=1[C:25]([O:27][CH3:28])=[O:26])=[CH:6][C:5]([S:29]([CH3:32])(=[O:31])=[O:30])=[C:4]([O:3][CH2:1][CH3:2])[CH:13]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)OC)c2cc1S(C)(=O)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CBr)c(C(=O)OC)c2cc1S(C)(=O)=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A suspension of methyl 7-(ethyloxy)-3-methyl-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2.92 g, 6.25 mmol), NBS (1.445 g, 8.12 mmol) and diphenylperoxyanhydride (0.151 g, 0.625 mmol) in carbon tetrachloride (30 mL) was heated to 100° C. and stirred overnight. The mixture was cooled to room temperature and the solvent was removed under reduced pressure to give methyl 3-(bromomethyl)-7-(ethyloxy)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate. This material was used without further purification. MS (m/z) 548.0 (M+H+).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[CH:10][C:11](=O)[NH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:17])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:17][C:11]1[CH:10]=[CH:9][C:8]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:13][N:12]=1
Reactant: O=c1ccc(Sc2ccccc2)c[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: Clc1ccc(Sc2ccccc2)cn1

Procedure:
A suspension of 5-(phenylthio)-2-pyridone (4.06 g., .02 mole) in 50 ml. of phosphorous oxychloride containing 10 g. of phosphorous pentachloride is heated at reflux for 6 hours. Excess phosphorous oxychloride is removed in vacuo and the residue is poured onto icewater mixture. The mixture is cooled and the pH adjusted to neutral with dilute aqueous sodium hydroxide. The resultant suspension is extracted with methylene chloride. The combined extracts are washed with water, dried and evaporated in vacuo to yield 2-chloro-5-(phenylthio)pyridine.