Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:30](OC(C)(C)C)=[O:31])=[N:11][C:12]([CH2:16][CH:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1[C:46]([C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])=[N:47]C(CC2CCN(C3C=CC(C4C=CC(CO)=CC=4)=CC=3)CC2)=NC=1C)C1C=CC=CC=1.[ClH:80].C(OC(=O)CN)(C)(C)C>>[ClH:80].[C:76]([O:75][C:73](=[O:74])[CH2:46][NH:47][C:30]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([CH3:15])[N:13]=[C:12]([CH2:16][CH:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)[N:11]=1)=[O:31])([CH3:79])([CH3:78])[CH3:77]
Reactant: Cc1nc(CC2CCN(C(=O)OC(C)(C)C)CC2)nc(C(=O)OC(C)(C)C)c1OCc1ccccc1
Reactant: Cc1nc(CC2CCN(c3ccc(-c4ccc(CO)cc4)cc3)CC2)nc(C(=O)OC(C)(C)C)c1OCc1ccccc1
Agent: CC(C)(C)OC(=O)CN
Agent: Cl
Product: Cc1nc(CC2CCNCC2)nc(C(=O)NCC(=O)OC(C)(C)C)c1OCc1ccccc1
Yield: 72 %

Procedure:
In accordance with Examples 1-(11) and 1-(7), but using tert-butyl 5-(benzyloxy)-2-{[1-(tert-butoxycarbonyl)piperidin-4-yl]methyl}-6-methylpyrimidine-4-carboxylate obtained in Example 1-(6) instead of tert-butyl 5-(benzyloxy)-2-{(1-[4′-(hydroxymethyl)biphenyl-4-yl]piperidin-4-yl}methyl)-6-methylpyrimidine-4-carboxylate, and glycine tert-butyl ester hydrochloride instead of glycine ethyl ester hydrochloride, the title compound (yield 72%) was afforded as a white solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:7][O:8][C:9]2[C:10]([F:20])=[C:11]([C:16]([F:19])=[CH:17][CH:18]=2)[C:12](=[N:14][OH:15])[NH2:13])[S:5][CH:6]=1.[CH3:21][O:22][C:23]1[S:24][C:25]([Sn](CCCC)(CCCC)CCCC)=[CH:26][N:27]=1.O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:20][C:10]1[C:9]([O:8][CH2:7][C:4]2[S:5][CH:6]=[C:2]([C:25]3[S:24][C:23]([O:22][CH3:21])=[N:27][CH:26]=3)[N:3]=2)=[CH:18][CH:17]=[C:16]([F:19])[C:11]=1[C:12](=[N:14][OH:15])[NH2:13]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(OC)s1
Reactant: NC(=NO)c1c(F)ccc(OCc2nc(Br)cs2)c1F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncc(-c2csc(COc3ccc(F)c(C(N)=NO)c3F)n2)s1
Temperature: 100 °C
Yield: 27.4 %

Procedure:
To a solution of 3-((4-bronnothiazol-2-yl)methoxy)-2,6-difluoro-N′-hydroxy benzimidamide (0.20 g, 0.55 mmol) in DMF (4.0 ml) was added 2-methoxy-5-(tributylstannyl)thiazole (0.23 g, 0.55 mmol) and the resulting reaction mixture was purged with nitrogen for 15 min. Tetrakis(triphenylphosphine) palladium (0) (0.06 g, 0.05 mmol) was then added and the reaction mixture was heated at 100° C. for 3 h under the nitrogen atmosphere. The reaction mixture was then cooled to room temperature, added water (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (60-120 M, 35% EtOAc-Hexane) yielding the title compound as white solid (0.06 g, 27%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5](N)=[C:4]([F:9])[CH:3]=1.[C:10](O)(=O)[CH3:11].N([O-])=O.[Na+].Cl>C1C=CC=CC=1.[Fe].CO.O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([C:11]2[CH:10]=[CH:4][CH:3]=[CH:2][CH:8]=2)=[C:4]([F:9])[CH:3]=1
Reactant: CC(=O)O
Reactant: Nc1ccc(Br)cc1F
Agent: [Fe]
Agent: Cl
Agent: O=N[O-]
Solvent: c1ccccc1
Solvent: O
Solvent: CO
Product: Fc1cc(Br)ccc1-c1ccccc1
Temperature: 65 °C
Reaction time: 12 h
Yield: 102.9 %

Procedure:
A solution of 96 grams (0.50 mole) of crude 4-bromo-2-fluoroaniline and 60.0 grams (1.0 mole) of glacial acetic acid in 100 ml of benzene is added dropwise over 7 hours to a mixture of 69.0 grams (1.0 mole) of sodium nitrite, 69 ml water, and 700 ml of benzene kept at 65° C. The mixture is then allowed to stir at 65° C. overnight (12 hours) under a nitrogen atmosphere. The cooled mixture is washed twice with 400 ml of 1 N hydrochloric acid, then heated under reflux overnight (13 hours) with 20 grams (0.36 mole) of iron powder, 250 ml of methanol, and 150 ml (1.8 moles) of concentrated hydrochloric acid. The resultant solution is cooled and the benzene layer is washed with 490 ml of water, and evaporated at 40° C./40 mm Hg. The resultant dark oil is distilled at 10 mm Hg pressure to obtain 64.6 grams (51.5%) of 4-bromo-2-fluorobiphenyl as the entire distillate of boiling point mostly ~132~141° C./8 mm. The product crystalizes on seeding.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][N:13]([CH3:18])[S:14](Cl)(=[O:16])=[O:15]>C(OCC)(=O)C.CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:12][N:13]([CH3:18])[S:14]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2)(=[O:16])=[O:15]
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: CN(C)S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)Nc1ccc2c(c1)CC(=O)N2
Yield: 32.3 %

Procedure:
To 5-aminoindolin-2-one (100 mg, 0.68 mmol) in ethyl acetate/DMF 1:1 (2 mL) was added dimethylsulfamoyl chloride (290 mg, 2.04 mmol) and DMAP (1 mg). After 72 h the product was precipitated with ether, filtered and dried to give 56 mg, 32% of a white solid. 1H NMR (400 MHz, CD3OD) δ 7.21 (s, 1H), 7.16 (d, J=7.0 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 3.53 (s, 2H), 2.77 (s, 6H).
Reaction SMILES: [C:1]1([C@@H:7]([C@H:9]([C:11]([OH:13])=[O:12])[OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(=O)(O)[O-].[Na+].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O.ClCCl>[C:20]([NH:8][C@@H:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C@H:9]([C:11]([OH:13])=[O:12])[OH:10])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N[C@@H](c1ccccc1)[C@@H](O)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(N[C@@H](c1ccccc1)[C@@H](O)C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
To a solution of compound 5.HCl (219 mg, 1.00 mmol) in water (10 mL) containing sodium bicarbonate (500 mg, 5.95 mmol) was added a solution of benzoyl chloride (0.14 mL, 1.20 mmol) in dichloromethane (5.0 mL). The mixture was vigorously stirred for 16 h at room temperature. The reaction mixture was acidified with 0.1N HCl and the crude product was extracted with ethyl acetate (40 mL×3). The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to dryness. The residue was purified on a short silica gel column using chloroform/methanol (2/1) as the eluant to give N-benzoyl-(2R,3S)-3-phenylisoserine (6) (205 mg, 72%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([O:24][CH2:25][CH:26]3[CH2:30][O:29][C:28]([CH3:32])([CH3:31])[O:27]3)[N:21]=[C:20]([C:33](O)=[O:34])[CH:19]=2)[CH2:14][CH2:13]1)=[O:10].Cl.[O:37]([NH2:39])[CH3:38]>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([O:24][CH2:25][CH:26]3[CH2:30][O:29][C:28]([CH3:32])([CH3:31])[O:27]3)[N:21]=[C:20]([C:33]([NH:39][O:37][CH3:38])=[O:34])[CH:19]=2)[CH2:14][CH2:13]1)=[O:10]
Reactant: CON
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)nc(OCC4COC(C)(C)O4)n3)CC2)c(Cl)c1Cl
Agent: Cl
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(OCC2COC(C)(C)O2)n1

Procedure:
The title compound was synthesized by an analogous method to Example 8 starting from 6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]pyrimidine-4-carboxylic acid (Example 314) and methoxylamine hydrochloride.
Reaction SMILES: [Cl-].[Br:2][C:3]1[C:4]([O:31][C:32]([CH:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:36][CH2:35]2)=O)=[C:5]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].O.Cl>C(#N)C>[Br:2][C:3]1[C:4]2[O:31][C:32]([CH:34]3[CH2:35][CH2:36][N:37]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:38][CH2:39]3)=[CH:11][C:5]=2[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CCOC(=O)N1CCC(C(=O)Oc2c(Br)cc(OC)cc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)N1CCC(c2cc3cc(OC)cc(Br)c3o2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
In the course of 30 minutes, at 25° to 30°, with the exclusion of air, 50 g of [(3-bromo-2-[(1-ethoxycarbonylpiperid-4-yl)carbonyloxy]-5-methoxy-phenyl)methyl]-triphenyl-phosphonium chloride are introduced into a suspension of 20 g of ground potassium carbonate (anhydrous) in 100 ml of acetonitrile. The mixture is stirred for 2 hours at room temperature, then 80 ml of water are added thereto, and the mixture is acidified to pH 1.0 with concentrated hydrochloric acid. The organic phase is separated off and concentrated by evaporation. The oily residue is taken up in 50 ml of toluene and at 20°, in the course of 1 hour, 100 ml of hexane are added; the major portion (approx. 90%; content according to HPLC: 90%) of the triphenylphosphane oxide that forms crystallises out. The crystal suspension is filtered with suction and the filter cake is washed twice with 40 ml of hexane/toluene (3:2) each time. Concentration of the combined filtrates by evaporation and chromatography of the residue on silica gel with toluene/ethyl acetate (2:1) as eluant yield 4-(7-bromo-5-methoxy-benzofuran-2-yl)-1-ethoxycarbonyl-piperidine [m.p.: 85°; 1H-NMR (360 MHz, CDCl3): 1.28 (t, 3H, CO2CH2CH3), 1.69 (m, 2H), 2.09 (m, 2H), 2.95 (m, 3H), 3.80 (s, 3H, OCH3), 4.16 (q, 2H, CO2CH2CH3), 4.14 to 4.35 (br. m, 2H), 6.36 (s, 1H), 6.90 (d, 1H), 7.00 (d, 1H) ppm]; yield 90% of the theoretical yield.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][C:5]([NH2:8])=[N:4]1.Br[CH2:10][CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[CH2:14]([O:13][CH2:12][CH2:11][CH2:10][N:3]1[CH:7]=[CH:6][C:5]([NH2:8])=[N:4]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1cc[nH]n1
Reactant: BrCCCOCc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccn(CCCOCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
To a solution of 60% sodium hydride (496 mg) in DMF (10 mL) was added a solution of 1H-pyrazol-3-amine (1.03 g) in DMF (5 mL) under ice-cooling, followed by stirring at room temperature for 30 minutes. A solution of [(3-bromopropoxy)methyl]benzene (2.93 g) in DMF (10 mL) was added thereto under ice-cooling, followed by stirring at room temperature overnight. Saturated brine and saturated aqueous sodium bicarbonate were added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate=1:1-1:3) to obtain 1-[3-(benzyloxy)propyl]-1H-pyrazol-3-amine (835 mg) as a pale yellow oily substance.
Reaction SMILES: C(OC(OCC)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)C.CN(CCN(C)C)C.C([Li])CCC.[CH3:26][C:27]1[C:32]([CH3:33])=[C:31]([C:34]([CH3:36])=[O:35])[CH:30]=[CH:29][CH:28]=1>CC1CCCO1>[CH3:33][C:32]1[C:27]([CH3:26])=[CH:28][CH:29]=[CH:30][C:31]=1[C:34]([C:6]1[NH:5][CH:9]=[CH:8][N:7]=1)([OH:35])[CH3:36]
Reactant: CCOC(OCC)n1ccnc1
Reactant: CC(=O)c1cccc(C)c1C
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CC1CCCO1
Product: Cc1cccc(C(C)(O)c2ncc[nH]2)c1C
Temperature: -40 °C
Yield: 76.1 %

Procedure:
1-(Diethoxymethyl)imidazole (76.0 g, 446 mmol) and N,N,N,N-tetramethylethylene diamine (67.6 mL, 446 mmol) were dissolved in 2-methyltetrahydrofuran (400 ml) and cooled to −40° C., under nitrogen. n-Butyl lithium (2.5M in hexane, 180 ml, 446 mmol) was added slowly maintaining the reaction temperature at <−25° C. throughout. The reaction mixture was stirred for an hour and allowed to warm to 0° C., after which 2,3-dimethylacetophenone (44.00 g, 297.00 mmol) was added whilst maintaining the reaction temperature at <15° C. throughout. The reaction was stirred at room temperature overnight and then quenched with aqueous hydrochloric acid (2N, 1 l). The mixture was extracted with ethyl acetate (500 ml) and to the aqueous layer was added sodium carbonate. The aqueous layer was further extracted with ethyl acetate (800 ml) and the combined extracts were washed with water (500 ml), dried (MgSO4) and concentrated in vacuo to give the title compound (48.9 g).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.CN(C)C=O.[H-].[Na+].Cl[CH:14]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:15]1[CH:16]=[CH:17][C:18]2[N:22]=[N:21][N:20]([CH3:23])[C:19]=2[CH:24]=1>O>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:14]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[C:15]2[CH:16]=[CH:17][C:18]3[N:22]=[N:21][N:20]([CH3:23])[C:19]=3[CH:24]=2)=[CH:26][CH:27]=1
Reactant: Cn1nnc2ccc(C(Cl)c3ccc(Cl)cc3)cc21
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nnc2ccc(C(c3ccc(Cl)cc3)n3cncn3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.2 %

Procedure:
To a stirred solution of 28.4 parts of 1H-1,2,4-triazole in 135 parts of N,N-dimethylformamide were added 11.4 parts of a sodium hydride dispersion 80% under nitrogen atmosphere. After stirring for 1 hour at room temperature, a solution of 40 parts of 6-[chloro(4-chlorophenyl)methyl]-1-methyl-1H-benzotriazole in 90 parts of N,N-dimethylformamide was added to the mixture. The whole was stirred for 1 hour at 60° C. The reaction mixture was diluted with 50 parts of water and the whole was evaporated. The residue was extracted with ethyl acetate. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 1,1'-oxybisethane. The product was filtered off and dried, yielding 13 parts (29.2%) of 6-[(4-chlorophenyl)-(1H-1,2,4-triazol-1-yl)methyl]-1-methyl-1H-benzotriazole; mp. 178.9° C. (compound 64).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9]([NH:11][C:12]2[S:13][C:14]3[CH:20]=[C:19]([SH:21])[CH:18]=[CH:17][C:15]=3[N:16]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.P([O-])(O)(O)=O.[K+].SCC(C(CS)O)O.Cl[C:37]1[N:41]2[N:42]=[C:43]([O:46][CH3:47])[CH:44]=[CH:45][C:40]2=[N:39][N:38]=1>O.C(O)C>[CH3:47][O:46][C:43]1[CH:44]=[CH:45][C:40]2[N:41]([C:37]([S:21][C:19]3[CH:18]=[CH:17][C:15]4[N:16]=[C:12]([NH:11][C:9]([NH:8][CH2:7][CH2:6][N:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)=[O:10])[S:13][C:14]=4[CH:20]=3)=[N:38][N:39]=2)[N:42]=1
Reactant: COc1ccc2nnc(Cl)n2n1
Reactant: O=C(NCCN1CCCC1)Nc1nc2ccc(S)cc2s1
Agent: O=P([O-])(O)O
Agent: OC(CS)C(O)CS
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc2nnc(Sc3ccc4nc(NC(=O)NCCN5CCCC5)sc4c3)n2n1
Yield: 23.7 %

Procedure:
The 1-{6-[(6-methoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulphanyl]-1,3-benzothiazol-2-yl}-3-[2-(pyrrolidin-1-yl)ethyl]urea was prepared according to the method described in Example 17a, but using 547 mg of 1-[2-(pyrrolidin-1-yl)ethyl]-3-(6-sulphanyl-1,3-benzothiazol-2-yl)urea, 25 cm3 of degassed ethanol, 8 mg of potassium dihydrogen phosphate in 0.2 cm3 of water, 787 mg of DL-dithiothreitol and 313 mg of 3-chloro-6-methoxy[1,2,4]-triazolo[4,3-b]pyridazine. 189 mg of 1-{6-[(6-methoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulphanyl]-1,3-benzothiazol-2-yl}-3-[2-(pyrrolidin-1-yl)ethyl]urea are thus obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([OH:9])=O)[CH2:5][N:4]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:3]1=[O:17].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N1CCOCC1)C.[Cl:49][C:50]1[C:55]([F:56])=[C:54]([F:57])[CH:53]=[CH:52][C:51]=1[CH2:58][NH2:59]>ClCCl.CN(C)C=O>[ClH:49].[Cl:49][C:50]1[C:55]([F:56])=[C:54]([F:57])[CH:53]=[CH:52][C:51]=1[CH2:58][NH:59][C:7]([CH:6]1[CH2:5][N:4]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:3](=[O:17])[N:2]1[CH3:1])=[O:9]
Reactant: NCc1ccc(F)c(F)c1Cl
Reactant: CN1C(=O)N(Cc2ccccn2)CC1C(=O)O
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CN1C(=O)N(Cc2ccccn2)CC1C(=O)NCc1ccc(F)c(F)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.1 %

Procedure:
A mixture of crude 3-methyl-2-oxo-1-(2-pyridinylmethyl)-4-imidazolidinecarboxylic acid (˜0.7 mmol), 1-hydroxybenzotriazole hydrate (113 mg, 0.84 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (161 mg, 0.84 mmol), and N-ethyl morpholine (0.27 ml, 2.1 mmol) in dichloromethane (20 ml)/N,N-dimethylformamide (2 ml) was stirred at room temperature for 10 minutes. A solution of [(2-chloro-3,4-difluorophenyl)methyl]amine (150 mg, 0.84 mmol) in dichloromethane (5 ml) was added and the reaction stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane and the solution was washed with saturated sodium hydrogen carbonate solution, water and brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane. The residue was triturated with ether/hexanes and the solid was dried. The residue was dissolved in dichloromethane (2 ml), hydrogen chloride (1M in ether, 0.1 ml) was added and the solvent was evaporated. The solid was co-evaporated with ethyl acetate and ether and then triturated with ether. The solid was collected and dried to give N-[(2-chloro-3,4-difluorophenyl)methyl]-3-methyl-2-oxo-1-(2-pyridinylmethyl)-4-imidazolidinecarboxamide hydrochloride (40 mg). LC/MS [M+H]+=395, retention time=1.85 minutes.
Reaction SMILES: S(=O)(=O)(O)O.[NH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[CH2:12][CH2:13][OH:14].[OH-].[Ba+2].[OH-].C(=O)=[O:19]>O.[O-2].[O-2].[O-2].[Cr+6]>[NH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[CH2:12][C:13]([OH:19])=[O:14]
Reactant: O=C=O
Reactant: OCCC1CCCCN1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [Ba+2]
Solvent: O
Product: O=C(O)CC1CCCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of chromium trioxide (20 g, 200 mmol) in water (300 ml) and concentrated sulfuric acid (40 g, 73.6 ml) was added dropwise in the course of 1.5 h, while cooling with ice, to a solution of 2-piperidineethanol (10.0 g, 10.1 ml, 77.4 mmol) in water (10 ml). The reaction mixture was stirred for 3 h at room temperature. The solution was then rendered alkaline with saturated aqueous barium hydroxide solution. Carbon dioxide was then passed into the solution, and the resulting suspension was filtered through Celite. The filtrate was concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]([CH2:17][CH3:18])[CH2:15][C:14](=[O:19])[CH2:13][CH:12]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[Si](Cl)(C)C.[CH2:30](O)[CH2:31][OH:32]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]([CH2:17][CH3:18])[CH2:15][C:14]3([O:32][CH2:31][CH2:30][O:19]3)[CH2:13][CH:12]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CC(=O)CC(CC)N1S(=O)(=O)c1ccc(Cl)cc1
Reactant: OCCO
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Product: CCOC(=O)C1CC2(CC(CC)N1S(=O)(=O)c1ccc(Cl)cc1)OCCO2
Yield: 95.5 %

Procedure:
Ethyl 1-(4-chlorophenylsulfonyl)-6-ethyl-4-oxopiperidine-2-carboxylate (109; 5.31 g, 14.2 mmol), TMSCl (5.41 ml, 42.6 mmol), and ethylene glycol (3.96 ml, 71.0 mmol) were added to CH2Cl2 (50 ml) and refluxed under nitrogen for 3 hours. The reaction mixture was concentrated tinder reduced pressure, and taken up in equal portions of EtOAc and water. The aqueous layer was washed with several more portions of EtOAc, dried over Na2SO4, and concentrated to give 5.67 g (96%) of a mixture of cis/trans (4:96) isomers as a clear oil which solidified upon standing. The material was used without further purification.
Reaction SMILES: [CH2:1]([S:8][CH:9]1[N:12]([CH2:13][C:14]([OH:16])=O)[C:11](=[O:17])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH2:43]>CN(C)C=O>[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:14](=[O:16])[CH2:13][N:12]1[CH:9]([S:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:10][C:11]1=[O:17]
Reactant: NCCCCCCc1ccc(F)cc1F
Reactant: O=C(O)CN1C(=O)CC1SCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)CC1SCc1ccccc1)NCCCCCCc1ccc(F)cc1F
Yield: 73 %

Procedure:
Sequential treatment of (4-benzylthio-2-oxoazetidin-1-yl)acetic acid with 1-cyclohexyl-3-(2-morpholinethyl)carbodiimide metho-p-toluenesulfonate and 6-(2,4-difluorophenyl)hexylamine in dimethyl formamide by the method described for Example 29 gave the title compound as a colourless solid, m.p. 65-66° C., in 73% yield 1H NMR δ (CDCl3) 1.3-1.36 (4H, m, 4×CH2), 1.50-1.60 (4H, m, 4×CH2), 2.58 (2H, t, J=7.6 Hz, PhCH2), 2.93, 2.97 (1H, dd, J=2.4, 15.6 Hz, H3), 3.23 (2H, m, NHCH2), 3.35, 3.39 (1H, dd, J=5.2, 15.2 Hz, H3), 3.57, 3.71 (each 1H, d, J=16.4 Hz, NCH2), 3.81 (2H, s, SOCH2), 4.80 (1H, m, H4), 6.02 (1H, m, HH), 6.76-7.33 (8H, m, 2Ph--H); νc=o 1774 cm-1Found: C, 64.5; H, 6.3; N, 6.5%, C24H28F2N2O2S requires: C, 64.6; H, 6.3; N, 6.3%
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](O)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:17][CH3:18].P(Cl)(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[Cl:21][C:10]1[C:9]2[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])=[C:7]([O:17][CH3:18])[CH:8]=2)[N:13]=[CH:12][N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2c(O)ncnc2cc1OCCCCl
Solvent: Cc1ccccc1
Product: COc1cc2c(Cl)ncnc2cc1OCCCCl
Temperature: 125 °C
Yield: 78 %

Procedure:
To a solution of the intermediate from Step 4 (3.00 g, 11.16 mmol) in toluene (30 mL) in a pressure vessel was added phosphorous oxychloride (8 mL). The mixture was heated to 125° C. for 5 hours. Completion of the reaction was monitored by LCMS. The mixture was concentrated to dryness and excess ethyl acetate was added. The solution was washed with water and brine and was dried (Na2SO4) and concentrated to afford the pure compound 4-chloro-7-(3-chloro-propoxy)-6-methoxy-quinazoline (2.51 g, 78%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.85 (s, 1H), 7.48 (s, 1H), 7.35 (s, 1H), 4.35 (t, 2H), 4.00 (s, 3H), 3.75 (t, 2H), 2.25 (q, 2H). LC-MS (ESI)m/z 287 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH:12]1[CH2:20][CH2:19][C:15]2[S:16][CH:17]=[CH:18][C:14]=2[CH2:13]1)(=[O:10])=[O:9].[C:21]1(=[O:27])[O:26][C:24](=[O:25])[CH2:23][CH2:22]1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[C:24]([CH2:23][CH2:22][C:21]([C:17]1[S:16][C:15]2[CH2:19][CH2:20][CH:12]([NH:11][S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])(=[O:9])=[O:10])[CH2:13][C:14]=2[CH:18]=1)=[O:27])([OH:26])=[O:25]
Reactant: O=C1CCC(=O)O1
Reactant: Cc1ccccc1S(=O)(=O)NC1CCc2sccc2C1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cc1ccccc1S(=O)(=O)NC1CCc2sc(C(=O)CCC(=O)O)cc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 116.3 %

Procedure:
To 2.25 g of 5-[(2-methylphenyl)sulfonylamino]-4,5,6,7-tetrahydrobenzo[b]thiophene and 1.61 g of succinic anhydride suspended in 25 ml of dichloroethane was added 4.39 g of anhydrous aluminum chloride under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. After the resulting organic layer was washed and dried, the solvent was removed to obtain 3.47 g of 2-(3-carboxypropionyl)-5-[(2-methylphenyl)sulfonylamino]-4,5,6,7-tetrahydrobenzo[b]thiophene.