Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27]([C:29](=[O:31])[CH3:30])=[CH:26][C:25]=2[CH:32]=1>CC#N>[C:29]([C:27]1[O:28][C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:8]3[C:9](=[O:10])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[S:6](=[O:19])(=[O:18])[C:7]=3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:32][C:25]=2[CH:26]=1)(=[O:31])[CH3:30]
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: CC(=O)c1cc2cc(N)ccc2o1
Solvent: CC#N
Product: CCCCN1C(=O)C(Nc2ccc3oc(C(C)=O)cc3c2)=C(c2ccccc2)S1(=O)=O
Temperature: 130 °C
Reaction time: 1 h
Yield: 29393388 %

Procedure:
A mixture of 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (300 mg, 0.90 nmol) and 1-(5-amino-1-benzofuran-2-yl)ethanone (387 mg, 2.21 mmol) in dry MeCN (4.5 mL) was heated in a microwave reactor at 130° C. for 1 h, then at 130° C. for 1 h, then at 140° C. for 1 h and finally at 140° C. for 1.5 h. The mixture was purified using preparative HPLC (Kromasil-column C8, 0.1M NH4OAc/MeCN, gradient) to give the title compound (116 mg, 28%); 1H NMR (400 MHz, CD3CN): δ 7.86 (bs, 1H), 7.34-7.32 (m, 1H), 7.26-7.22 (m, 1H), 7.03-7.15 (m, 7H), 3.76 (t, 2H), 1.78-1.87 (m, 2H) 1.43-1.54 (m, 2H), 1.05 (t, 3H); Mass Spectrum: M−H+ 437
Reaction SMILES: CS(NC1C=CC=CC=1N1CCN(C(OC(C)(C)C)=O)CC1)(=O)=O.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C@@H:33]([NH:58][C:59]([C@@H:61]2[CH2:70][C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[CH2:63][N:62]2C(OC(C)(C)C)=O)=[O:60])[C:34](=[O:57])[N:35]2[CH2:40][CH2:39][N:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[NH:47][S:48]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)(=[O:50])=[O:49])[CH2:37][CH2:36]2)=[CH:28][CH:27]=1.NC1C=CC=CC=1N1CCN(C(=O)[C@H](NC([C@@H]2CC3C(=CC=CC=3)CN2C(OC(C)(C)C)=O)=O)CC2C=CC(Cl)=CC=2)CC1.N1C=CC=CC=1.C1(S(Cl)(=O)=O)C=CC=CC=1>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:32][C@@H:33]([NH:58][C:59]([C@@H:61]2[CH2:70][C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[CH2:63][NH:62]2)=[O:60])[C:34](=[O:57])[N:35]2[CH2:36][CH2:37][N:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[NH:47][S:48]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)(=[O:49])=[O:50])[CH2:39][CH2:40]2)=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2NS(=O)(=O)c2ccccc2)CC1
Agent: CC(C)(C)OC(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1
Agent: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2N)CC1
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2NS(=O)(=O)c2ccccc2)CC1)[C@@H]1Cc2ccccc2CN1

Procedure:
Following the procedure for the synthesis of Preparation III, tert-butyl 3-{N-[(1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-(4-{2-[(phenylsulfonyl)-amino]phenyl}piperazinyl)ethyl]carbamoyl}(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate was prepared from tert-butyl 3-(N-{(1R)-2-[4-(2-aminophenyl)piperazinyl]-1-[(4-chlorophenyl)methyl]-2-oxoethyl}carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Preparation IX) (771 mg, 1.247 mmol), pyridine (110 μl, 1.4 mmol) and benzenesulfonyl chloride (160 μl, 1.3 mmol) (Aldrich). The crude was purified by flash chromatography (SiO2, 10% EtOAc in CH2Cl2) to afford 330 mg of the desired compound. MS (ESI, pos. ion) m/z: 758 (M+H), (ESI, neg. ion) m/z: 756 (M−H). Calc'd for C40H44ClN5O6S: 758.33. Anal. Calcd for C40H44ClN5O6S-0.5 C4H8O2: C, 62.87; H, 6.03; N, 8.73; Cl, 4.42. Found C, 62.49; H, 6.03; N, 8.52.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:9]([CH3:25])[O:10][CH2:11][C:12]([C:17]2[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=2[F:24])([CH:14]([F:16])[F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[C:27]([C:29]1[CH:30]=[CH:31][C:32]([C:35](O)=[O:36])=[N:33][CH:34]=1)#[N:28].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:9]([CH3:25])[O:10][CH2:11][C:12]([C:17]2[CH:22]=[C:21]([NH:23][C:35]([C:32]3[CH:31]=[CH:30][C:29]([C:27]#[N:28])=[CH:34][N:33]=3)=[O:36])[CH:20]=[CH:19][C:18]=2[F:24])([CH:14]([F:16])[F:15])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: CC1OCC(c2cc(N)ccc2F)(C(F)F)N=C1NC(=O)OC(C)(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1OCC(c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)(C(F)F)N=C1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.25 h

Procedure:
A solution of [5-(5-amino-2-fluoro-phenyl)-5-difluoromethyl-2-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (140 mg, 0.375 mmol), 5-cyano-2-pyridinecarboxylic acid (83 mg, 0.562 mmol) and HOAT (92 mg, 0.675 mmol) in 2 mL DMF was cooled to 0-5° C. EDC (108 mg, 0.562 mmol) followed by DIPEA (97 mg, 0.750 mmol) was added. The reaction mixture was allowed to warm up to room temperature. After 135 minutes, the mixture was partitioned between saturated aqueous NaHCO3 solution and EtOAc. The layers were separated, washed with saturated aqueous NaHCO3 solution, brine and EtOAc. The combined organic layers were dried over MgSO4.H2O and evaporated. The crude product was purified on a silica gel column by eluting with hexane/EtOAc 3/1→2/1 to give the title compound as a diasteromeric mixture (white foam).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1>C(O)(=O)C.C1COCC1.O>[OH:7][CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1
Reactant: c1cc(SCCOC2CCCCO2)ccn1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: OCCSc1ccncc1
Yield: 81.4 %

Procedure:
A solution of 4-(2-(tetrahydropyran-2-yloxy)ethylthio)pyridine (2.73 g, 11 mmol) in acetic acid (8 ml), THF (4 ml) and water (2 ml) was heated at 50° C. for 4 hours. The volatiles were removed by evaporation and the residue azeotroped with toluene to give 4-(2-hydroxyethylthio)pyridine (1.39 g, 79%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][NH:13][C:14](=[O:17])[CH2:15][CH3:16])[CH:5]=[C:6]([CH2:9][OH:10])[C:7]=1[Cl:8].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][NH:13][C:14](=[O:17])[CH2:15][CH3:16])[CH:5]=[C:6]([CH:9]=[O:10])[C:7]=1[Cl:8]
Reactant: CCC(=O)NCCc1cc(Cl)c(Cl)c(CO)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCC(=O)NCCc1cc(Cl)c(Cl)c(C=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of N-{2-[3,4-dichloro-5-(hydroxymethyl)phenyl]ethyl}propanamide (1 eq.) from the previous step and sodium bicarbonate (1.1 eq.) in dichloromethane (0.1 M) was added DMP (1.1 eq.) at 0° C. The resulting mixture was stirred at RT for 2 h before it was quenched with sat. aq. NaHSO3 and then extracted with Et2O. The combined organic extracts were washed further with 1 N aq. NaOH, water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 19:1 (v/v) Hex:EtOAc→3:7 (v/v) Hex:EtOAc) afforded the title compound as a white solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[H-].[Na+].[F:11][C:12]1[CH:30]=[CH:29][C:15]([CH:16]=[C:17](C2C=CC=CC=2)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=1.C(O)C>CN(C)C=O.O>[C:1]([CH:3]([CH:16]([C:15]1[CH:14]=[CH:13][C:12]([F:11])=[CH:30][CH:29]=1)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: CCOC(=O)C(=Cc1ccc(F)cc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(c1ccc(F)cc1)C(C#N)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.5 %

Procedure:
To 1 g of ethyl cyanoacetate dissolved in 5 mL of N,N-dimethylformamide, 0.5 g of sodium hydride was added under cooling with ice, and after stirring at room temperature for 30 minutes, 1.5 g of ethyl p-fluorophenylcinnamate was added. The reaction mixture was stirred at room temperature for 4 hours. After addition of ethanol under cooling with ice, the reaction mixture was poured into iced water and extracted with a solvent mixture of hexane and ethyl acetate. The extract was washed with water, and dried and concentrated. The resulting oily substance was separated by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain 1.8 g of diethyl 2-cyano-3-(p-fluorophenyl)glutarate as a diastereomer mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:16]1[CH:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=1)=[O:15].[Na+].[I-].[CH2:25]([NH2:27])[CH3:26]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:16]1[CH:20]=[C:19]([CH2:21][NH:27][CH2:25][CH3:26])[O:18][N:17]=1)=[O:15]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cc(CCl)on1
Reactant: CCN
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNCc1cc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)no1
Yield: 50 %

Procedure:
A mixture of the intermediate 7: N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(chloromethyl)isoxazole-3-carboxamide (0.088 g; 0.260 mmol) NaI (0.078 g; 0.520 mmol) and ethylamine (1.30 mL; 2M in THF) in THF (1 mL) was irradiated in a microwave oven at 130° C. for 10 min and concentrated under reduced pressure. The crude material was purified by flash chromatography (eluent 2 to 10% MeOH in dichloromethane) to afford N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-((ethylamino)methyl)isoxazole-3-carboxamide 0.044 g (50%).
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]([C:16]([NH:19][S:20]([CH2:23][C:24]([F:27])([F:26])[F:25])(=[O:22])=[O:21])([CH3:18])[CH3:17])[CH:13]=[CH:14][CH:15]=2)[N:7]([CH3:28])[N:6]=1)=[O:4].[NH4+].[Cl-]>CCO>[OH:4][CH2:3][C:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]([C:16]([NH:19][S:20]([CH2:23][C:24]([F:27])([F:26])[F:25])(=[O:22])=[O:21])([CH3:18])[CH3:17])[CH:13]=[CH:14][CH:15]=2)[N:7]([CH3:28])[N:6]=1
Reactant: Cn1nc(C=O)cc1-c1cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Cn1nc(CO)cc1-c1cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c1
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
NaBH4 (8.2 mg, 0.22 mmol) was added to a stirred solution of the aldehyde from Step 4 (85 mg, 0.22 mmol) in EtOH (5 mL) at RT and the mixture was stirred for a further 30 min. NH4Cl solution (5 ml) was added and the EtOH removed under reduced pressure. The aqueous residue was extracted with EtOAc (2×30 mL), and the organics dried and concentrated under reduced pressure to yield the crude alcohol (75 mg, 88%). 1H NMR (CDCl3, 360 MHz) δ 7.55-7.48 (2H, s), 7.42 (1H, t, J=7.5 Hz), 7.29 (1H, d, J=7.5 Hz), 6.25 (1H, s), 5.00 (1H, s), 4.64 (2H, s), 3.78 (3H, s), 3.41 (2H, q, J=8.9 Hz), 1.75 (6H, s). MS (ES+) C16H20F3N3O3S requires: 391, found: 392 (M+H+, 100%).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30]Br.[H-].[Na+]>>[CH:1]1([N:6]([CH2:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23]([OH:32])=[O:22])[C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=3)[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)c1ccc(-c2csc(NC3CCCC3)n2)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)c1ccc(-c2csc(N(Cc3ccccc3C(=O)O)C3CCCC3)n2)cc1
Yield: 16.1 %

Procedure:
2-({Cyclopentyl-[4-(4-isopropyl-phenyl)-thiazol-2-yl]-amino}-methyl)-benzoic acid (19 mg) was prepared following general method S2 using cyclopentyl-[4-(4-isopropyl-phenyl)-thiazol-2-yl]-amine (80 mg, 0.28 mmol), 2-bromomethyl-benzoic acid methyl ester (68 mg, 0.33 mmol) and NaH (34 mg, 60%, 0.84 mmol). Purification (Silica gel, ethyl acetate/hexane 5:95) provided the ester, which was hydrolyzed following general procedure T. Sodium 2-({cyclopentyl-[4-(4-isopropyl-phenyl)-thiazol-2-yl]-amino}-methyl)-benzoate was prepared following procedure J. LCMS m/z: 422 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:3]=1[NH:4][C:5]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:6]=1[C:7]([OH:9])=O.Cl.[CH2:23]([O:30][NH2:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>>[F:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:3]=1[NH:4][C:5]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:6]=1[C:7]([NH:31][O:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:9]
Reactant: NOCc1ccccc1
Reactant: O=C(O)c1cc(F)c(F)cc1Nc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1cc(F)c(F)cc1F
Yield: 103.6 %

Procedure:
Using General Method 2, the reaction of carbonyldiimidazole (2.85 g, 17.6 mmol) 2-(2,4,5-trifluoro-anilino)-4,5-difluorobenzoic acid (Example T, 4.54 g, 14.7 mmol), O-benzylhydroxylamine hydrochloride (2.34 g, 14.7 mmol), and triethylamine (2.45 mL, 17.6 mmol) provided 6.22 g of the crude title compound.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][N:8]=1)=[O:5])[CH3:2].I[C:23]1[CH:24]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[C:26](=[O:29])[NH:27][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[N:8]=[CH:9][C:10]([C:23]2[CH:24]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[C:26](=[O:29])[NH:27][CH:28]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: COC(=O)c1cc(I)c[nH]c1=O
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)Nc1ccc(-c2c[nH]c(=O)c(C(=O)OC)c2)cn1
Temperature: 25 °C

Procedure:
A solution of N-ethyl-N′-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)urea (Intermediate 1, 200 mg, 0.69 mmol), methyl 5-iodo-2-oxo-1,2-dihydro-3-pyridinecarboxylate (174 mg, 0.62 mmol), Tetrakispalladium (72.2 mg, 0.06 mmol), and cesium carbonate (224 mg, 0.69 mmol) in dioxane (4 mL) and water (1.000 mL) was heated to 100° C. in microwave for 1 h. The reaction mixture was filtered through Celite and washed with methanol. The resulting solution was concentrated under reduced pressure to give a yellow solid. The solid was triturated with acetone, then collected by filtration and added to hot acetone/water. The solution was cooled to room temperature, and the solid that formed was collected by filtration and placed under high vacuum to remove residual solvent (58 mg). MS (ESP): 317 (M+H+) for C15H16N4O4.
Reaction SMILES: [C:1]([CH:4]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:5]([NH:7][CH:8]([C:10]1[C:11](=[O:25])[NH:12][C:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[N:14][N:15]=1)[CH3:9])=O)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)=O>>[C:1]([CH:4]([C:5]1[N:15]2[C:10]([C:11](=[O:25])[NH:12][C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[N:14]2)=[C:8]([CH3:9])[N:7]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(=[O:3])[CH3:2]
Reactant: CCCCCCC(C(C)=O)C(=O)NC(C)c1nnc(Cc2ccc(OC)cc2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCC(C(C)=O)c1nc(C)c2c(=O)[nH]c(Cc3ccc(OC)cc3)nn12

Procedure:
Analogously to Example 1, 710 mg (1.65 mmol) of 2-acetyl-N-{1-[3-(4-methoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}octanamide (Example 27A) and 1.23 g (8.00 mmol) of phosphorus oxychloride are reacted to give 7-(1-acetylheptyl)-2-(4-methoxybenzyl)-5-methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C@H:7]2[C@H:12]3[C@H:10]([C:11]3([CH3:14])[CH3:13])[C:9](=[O:15])[O:8]2)[CH2:5][CH2:4][S:3]1.Cl>C(N(CC)CC)C>[O:1]=[C:2]1[C:6](=[CH:7][C@H:12]2[C@@H:10]([C:9]([OH:15])=[O:8])[C:11]2([CH3:14])[CH3:13])[CH2:5][CH2:4][S:3]1
Reactant: CC1(C)[C@@H]2[C@H]1C(=O)O[C@H]2C1CCSC1=O
Agent: Cl
Solvent: CCN(CC)CC
Product: CC1(C)[C@H](C(=O)O)[C@@H]1C=C1CCSC1=O
Temperature: 5 °C

Procedure:
A mixture of the solution of Step B and 6 ml of triethylamine was refluxed for 3 hours and was then cooled and poured into 2 N aqueous hydrochloric acid. The decanted organic phase was washed with water, dried and evaporated to dryness. The residue was taken up in 20 ml of hot methylene chloride and after the addition of 30 ml of n-heptane thereto, the mixture was cooled to 5° C. and vacuum filtered. The recovered product was washed with heptane and dried to obtain 3.025 g of (1R,3S) 3-[(dihydro-2-oxo-3(2H)-thienylidene)-methyl]-2,2-dimethyl-cyclopropane-1-carboxylic acid melting at 162° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Br[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[N:13][C:12]([Br:23])=[CH:11][N:10]=1.CCCCCCC>CS(C)=O.ClCCl>[Br:23][C:12]1[N:13]=[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[C:9]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:10][CH:11]=1
Reactant: COCCO
Reactant: Clc1ccc(-c2nc(Br)cnc2Br)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCCCCCC
Product: COCCOc1ncc(Br)nc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.9 %

Procedure:
To a solution of 0.077 g (0.001 mol) 2-methoxyethanol in 2 ml dimethylsulfoxide was added at room temperature 0.088 g (0.002 mol) sodium hydride (55% in oil) and the mixture was stirred at room temperature for 1 h. To the resulting solution was added 0.352 g 2,5-dibromo-3-(2,4-dichloro-phenyl)-pyrazine and the mixture was stirred at room temperature for 3 h. The resulting reaction mixture was partitioned between water and ethyl acetate, the phases were separated and the organic phase washed twice with water, dried with sodium sulfate and evaporated. The residue was purified by chromatography on silica gel using dichloromethane:heptane=3:1 to dichloromethane as eluent to yield 0.090 g (24% yield) of the title compound as the faster eluting compound as white crystals melting at 92-93° C. and 0.171 g (45% yield) of its isomer 2-bromo-3-(2,4-dichloro-phenyl)-5-(2-methoxy-ethoxy)-pyrazine as the slower eluting compound as yellowish oil.
Reaction SMILES: [C:1]([O:6][CH:7]([O:9][C:10]([NH:12][CH2:13][C:14]1([CH2:20][C:21]([O:23]CC2C=CC=CC=2)=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:6][CH:7]([O:9][C:10]([NH:12][CH2:13][C:14]1([CH2:20][C:21]([OH:23])=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: CC(OC(=O)NCC1(CC(=O)OCc2ccccc2)CCCCC1)OC(=O)C(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(OC(=O)NCC1(CC(=O)O)CCCCC1)OC(=O)C(C)C

Procedure:
Compound (10) (113 g) was dissolved in ethyl acetate (700 mL) and 10 g of 10% Pd—C was added. The reaction mixture was subjected to 50 psi of hydrogen gas in a Parr reactor for 40 min. Filtration through a sintered glass funnel and a hydrophobic membrane filtration cartridge (Millipore Opticap) removed the catalyst. The supernatant was concentrated to afford the product (11) as a white, crystalline solid (78 g, quantitative yield). Crystals formed in the freezer, then at room temperature over several days. 1H NMR (CDCl3, 400 MHz): 1.15 (d, 6H), 1.40-1.55 (m, 10H), 1.45 (d, 3H), 2.32 (s, 2H), 2.49-2.56 (m, 1H), 3.23 (d, 2H), 5.41 (t, 1H), 6.75 (q, 1H). MS(ESI) m/z 330.29 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCNCC1
Reactant: ClCCCOCc1ccccc1
Product: O=C1CCN(CCCOCc2ccccc2)CC1

Procedure:
1-(3-Benzyloxypropyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-3-benzyloxypropane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[CH3:14][N:12]1[CH:13]=[C:8]([C:6]2[CH:7]=[C:2]([NH:1][S:34]([CH3:33])(=[O:36])=[O:35])[CH:3]=[CH:4][C:5]=2[O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:9]2[CH:18]=[CH:17][NH:16][C:10]=2[C:11]1=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cc(-c2cc(N)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(-c2cc(NS(C)(=O)=O)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 129.6 %

Procedure:
To a solution of Example 3 (0.125 g, 0.377 mmol) and triethylamine (0.131 mL, 0.943 mmol) in dichloromethane (3.0 mL) was added dropwise methanesulfonyl chloride (0.064 mL, 0.830 mmol). The reaction mixture was stirred for 2 hours at ambient temperature and then concentrated. The residue was dissolved in a mixture of dioxane (5 mL) and 1M sodium hydroxide (2 mL) and heated for 1 hour at 90° C. The reaction mixture was cooled and diluted with ethyl acetate, brought to pH 7 with 1 M HCl and partitioned. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0-4% methanol in dichloromethane) to afford 0.20 g (77%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 3.02 (s, 3H) 3.48 (s, 3H) 6.23-6.30 (m, 1H) 6.85 (d, J=7.46 Hz, 2H) 6.99 (t, J=7.29 Hz, 1H) 7.04 (d, J=8.82 Hz, 1H) 7.20-7.29 (m, 5H) 7.39 (d, J=2.71 Hz, 1H) 9.72 (s, 1H) 12.01 (s, 1H). MS (ESI+) m/z 410 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]([NH:17][CH2:18][C:19]([O:21]CC)=[O:20])=[O:16].C(Cl)(Cl)Cl.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+].[NH:68]1[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]1>O1CCOCC1.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]>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:68]3[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]3)[CH:10]=2)[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16]
Reactant: C1CCNCC1
Reactant: CCOC(=O)CNC(=O)c1c(O)c2cc(I)ccc2n(C)c1=O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)c(C(=O)NCC(=O)O)c(O)c2cc(N3CCCCC3)ccc21
Temperature: 80 °C
Reaction time: 22 h
Yield: 8.1 %

Procedure:
A solution of ethyl 2-(4-hydroxy-6-iodo-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (250 mg, 581 μmol), Pd2dba3.CHCl3 (60 mg, 58 μmol), X-Phos (55 mg, 116 μmol) and sodium t-butoxide (279 mg, 2906 μmol) in 1,4-dioxane (5 ml) was treated with piperidine (287 μl, 2906 μmol). The reaction was stirred at 80° C. in a sealed tube. After 22 hours, the solution was cooled to 23° C., filtered through celite (washing with MeOH), concentrated, diluted with methanol/DMSO and purified by RP HPLC (0-100% MeCN/water+1% TFA, 10 min), affording 17 mg (8%) of 2-(4-hydroxy-1-methyl-2-oxo-6-(piperidin-1-yl)-1,2-dihydroquinoline-3-carboxamido)acetic acid as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12]([OH:15])(=O)=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.CN(C=O)C.S(Cl)([Cl:23])=O>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([S:12]([Cl:23])(=[O:15])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(O)c1cccc2c(Cl)nccc12
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1cccc2c(Cl)nccc12

Procedure:
A suspension of 1-chloro-5-isoquinolinesulphonic acid (1.14 g, 4.68 mmol) in thionyl chloride (13 mL) and DMF (0.3 mL, 3.9 mmol) was heated to reflux for 3 h. Concentration in vacuo and azeotroping with toluene gave 1-chloro-5-chlorosulphonylisoquinoline as an off-white solid which was used immediately.