Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH3:8][O:9][C:10]1[CH:15]=CC(O)=[CH:12][CH:11]=1>>[C:5]([O:4][C:1]1[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:15][CH:2]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(O)cc1
Product: COc1ccc(OC(C)=O)cc1
Temperature: 0 °C

Procedure:
To 1500 ml. of acetic anhydride was added portionwise 248 g. (2.0 m) of p-methoxyphenol. Following the addition, the solution was heated on a steam bath for 3 hours, then poured into 5 liters of ice water. The solvents were removed by distillation to give an amber colored liquid weighing 273 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C@@H:12]2[CH2:16][N:15](C(OC(C)(C)C)=O)[C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[ClH:28].O1CCOCC1>CCOCC>[ClH:28].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][C@@H:12]2[CH2:16][NH:15][C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 0.22 M solution of 1-tert-butyl 2-methyl (2S,4S)-4-[((4-bromophenyl)sulfonyl)oxy]pyrrolidine-1,2-dicarboxylate (prepared as described in WO2006/119061) in Et2O at 0° C. was added dropwise a 4M solution of HCl in dioxane (25 eq.) and the resulting mixture was stirred at RT for 16 h, after which time a solid product was formed. The suspension was filtered and the filter cake was washed with cold Et2O. The solid product was dried in vacuo and the product used without further purification. MS (ES+) C12H14BrNO5S requires: 363. Found: 364, 365 (M+H+).
Reaction SMILES: [N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:29])[C:10]([C:26]([OH:28])=[O:27])=[CH:11][N:12]3CC3C=CC(OC)=CC=3OC)=[CH:7][C:6]=2[F:30])[CH2:4][CH2:3][CH2:2]1>FC(F)(F)C(O)=O>[N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:29])[C:10]([C:26]([OH:28])=[O:27])=[CH:11][NH:12]3)=[CH:7][C:6]=2[F:30])[CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(Cn2cc(C(=O)O)c(=O)c3cc(F)c(N4CCC4)nc32)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1c[nH]c2nc(N3CCC3)c(F)cc2c1=O

Procedure:
A solution of EXAMPLE 7H (1 g) in trifluoroacetic acid (10 mL) was heated at 50° C. for 3 hours and concentrated; and the concentrate was azeotroped with toluene and triturated with acetonitrile. NMR (300 MHz, DMSO-d6) δ 15.51 (s, 1H), 13.28 (br s, 1H), 8.42 (s, 1H), 7.92 (m, 1H), 4.40-4.20 (m, 4H), 2.43 (m, 2H).
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]=O.[Br:11][C:12]1[C:13]([NH:18][NH2:19])=[N:14][CH:15]=[CH:16][CH:17]=1>CN1C(=O)CCC1>[Br:11][C:12]1[C:13]([N:18]2[C:2]3=[N:9][CH:8]=[CH:7][C:6]([I:10])=[C:3]3[CH:4]=[N:19]2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1c(I)ccnc1F
Reactant: NNc1ncccc1Br
Solvent: CN1CCCC1=O
Product: Brc1cccnc1-n1ncc2c(I)ccnc21
Temperature: 185 °C
Yield: 74.8 %

Procedure:
To a dry 15 mL ChemGlass pressure bottle under N2 was added 2-fluoro-4-iodonicotinaldehyde (725 mg, 2.89 mmol), 3-bromo-2-hydrazinylpyridine (543 mg, 2.89 mmol) and anhydrous NMP (Volume: 4.0 mL). The reaction mixture was flushed with argon, securely capped, and heated to 185° C. for 45 min. The reaction mixture was worked up according to the procedure described in Intermediate 69A and the crude product was purified by Biotage Silica gel chromatography using a 12 g Thompson Single Step™ silica cartridge with a linear gradient from 100% CH2Cl2 to 100% ethyl acetate over 11 column volumes to give 867.4 mg (74.9%) of the title compound as a yellow solid. 1H NMR (500 MHz, CCl3D) δ ppm 8.64 (1 H, dd, J=4.58, 1.53 Hz), 8.09-8.25 (3 H, m), 7.65 (1 H, d, J=4.58 Hz), 7.37 (1 H, dd, J=7.93, 4.58 Hz). LC/MS (Condition B): ret. T=3.2 min, (M+H)+ 400.81, 402.81.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.N[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32].C([O-])([O-])=O.[K+].[K+]>O.CO.ClCCl>[N:1]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[N+:2]=[N-:3]
Reactant: NCCCCCCCCCCC(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: [N-]=[N+]=NCCCCCCCCCCC(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Sodium azide (2.38 gr, 44.3 mmol) was dissolved in 7.5 mL of water and added to a round bottom flask containing 15 mL of dichloromethane. The flask was cooled to 0° C. and trifluoromethanesulfonic anhydride (1.5 mL, 8.9 mmol) was added dropwise. The resulting solution was allowed to warm to room temperature and was stirred for two hours. The aqueous layer was extracted with dichloromethane (3×8 mL), and the combined organic phases were washed with a saturated solution of sodium carbonate. The resulting solution was then slowly added to a suspension of 11-aminoundecanoic acid (892 mg, 4.43 mmol), K2CO3 (915 mg, 6.62 mmol), and CuSO4.5H2O (11 mg, 0.0044 mmol) in 15 mL of water and 22.5 mL of methanol. The mixture was stirred overnight, and concentrated in vacuo. The solution was acidified with 1 M HCl solution and extracted with dichloromethane (4×50 mL). The organic phases where combined, dried with magnesium sulfate, filtered and concentrated in vacuo, yielding 5c at 92%. 1H-NMR (200 MHz, CDCl3): 1.25-1.4 (m; 12H), 1.5-1.7 (m; 4H), 2.35 (t; J=7.43 Hz; 2H), 3.25 (t; J=6.88 Hz; 2H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Br:26][C:27]1[C:28](=[O:40])[N:29]([CH2:37][CH:38]=O)[C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:38][CH2:37][N:29]4[C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH:36]=[C:27]([Br:26])[C:28]4=[O:40])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=CCn1c(=O)c(Br)cc2ccccc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)c(Br)cc3ccccc32)CC1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
To 3 mL of a chloroform solution containing 0.47 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.36 g of (3-bromo-2-oxoquinolin-1(2H)-yl)acetaldehyde, 30 μL of acetic acid and 0.43 g of sodium triacetoxyborohydride were added and stirred at room temperature for 2 nights. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; ethyl acetate], to give 0.54 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(3-bromo-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white foam.
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C:10]1([C:16]([NH:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH:20]2[OH:25])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:8].F[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[N+:34]([O-:36])=[O:35].C(N(CC)CC)C>C(O)C>[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C:10]1([C:16]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=3[N+:34]([O-:36])=[O:35])[CH2:21][CH:20]2[OH:25])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:8]
Reactant: O=C(NC1(C(=O)NC2CCNCC2O)CCCCC1)c1ccco1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NC1(C(=O)NC2CCN(c3ccc(F)cc3[N+](=O)[O-])CC2O)CCCCC1)c1ccco1

Procedure:
To the solution of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride (6.0 g) obtained in Step 4 of Example 76 in 50 ml of ethanol, were added 2,5-difluoronitrobenzene (3.7 ml) and triethylamine (4.8 ml). The reaction mixture was refluxed overnight and concentrated. The resulting yellow solid was filtered and dried to give 7.2 g of the titled compound.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[CH:10]=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]([F:14])=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1.Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)=[O:27]>>[CH2:2]([N:3]1[C:9]2[C:8](=[CH:13][C:12]([F:14])=[C:11]([N:15]3[CH2:20][CH2:19][N:18]([CH2:25][C:26]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)=[O:27])[CH2:17][CH2:16]3)[CH:10]=2)[C:6](=[O:7])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:1]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Reactant: COc1ccc(C(=O)CBr)cc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(=O)c4ccc(OC)cc4)CC3)cc21

Procedure:
1-Ethyl-6-fluoro-7-{4-[2-(4-methoxyphenyl)-2-oxoethyl]-1-piperazinyl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was prepared from norfloxacin (0.50 g, 1.56 mmole) [H. Koga et. al., J. Med. Chem. , 23, 1358 (1980).] and 2-bromo-4′-methoxyacetophenone (0.43 g, 1.86 mmole) by a method similar to that described for Example 4 (75% yield). Mp: 202° C. (dec). 1H NMR (DMSO-d6) δ 1.41 (t, 3H, J=7.0), 2.73 and 3.3 (two m, 8H), 3.85 (s, 3H), 3.88 (s, 2H), 4.58 (q, 2H, J=7.0), 7.02-7.2 (m, 3H), 7.87 (d, 1H, J=13.8), 8.01 (m, 2H), 8.94 (s, 1H), 15.33 (br s, 1H). Anal. Calcd. for C25H26FN3O5: C, 64.23; H, 5.61; N, 8.99. Found: C, 63.88; H, 5.61; N, 8.94.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:17][C@H:16]2[NH2:18])=[CH:11][CH:10]=1.Br[CH2:20][C:21]([NH2:23])=[O:22]>CN(C=O)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]2[CH2:17][C@H:16]2[NH:18][CH2:20][C:21]([NH2:23])=[O:22])=[CH:13][CH:14]=1
Reactant: N[C@@H]1C[C@H]1c1ccc(Br)cc1
Reactant: NC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)CN[C@@H]1C[C@H]1c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 30.7 %

Procedure:
To a suspension of K2CO3 (3.48 g, 25.4 mmol, 2.1 equiv) in dry DMF (30 mL) a solution of (trans)-2-(4-bromophenyl)cyclopropanamine hydrochloride (3 g, 12.09 mmol, 1 equiv) in dry DMF (6 mL) was added at 0° C. and stirred for 10 min, then 2-bromoacetamide (1.82 g, 13.3 mmol, 1.1 equiv) was added and stirred at RT for 2 h. After completion, the reaction mixture was poured into ice water (50 mL) and extracted with EtOAc (2×50 mL). The combined extracts were washed with water (2×50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and evaporated. The crude residue was purified by column chromatography (SiO2) using MeOH:CHCl3 (3:97) to get 2-((trans)-2-(4-bromophenyl)cyclopropylamino)acetamide (1 g, 31% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][CH:13]=[O:14])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[BH4-].[Na+].CC(C)=O>O1CCCC1.CC(O)C.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][CH2:13][OH:14])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Nc1cc(CCC=O)ccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1cc(CCCO)ccc1[N+](=O)[O-]
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
A solution of aldehyde 80 (253 mg, 1.3 mmol) in tetrahydrofurane (1 mL) and propan-2-ol (2 mL) was treated with solid sodium borohydride (175 mg, 4.6 mmol) and stirred at −5° C. for 15 min. Acetone (5 mL) was added, stirred at the same temperature for 10 min and then diluted with ethyl acetate (100 mL), washed with 5% KHSO4 in water, then saturated NaHCO3 and finally with water, dried (MgSO4), and used for the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([NH:22][C@H:23]([C:31]([C@:33]([C@H:38]([C@@H:40]([C@@H:42]([CH2:44][NH2:45])[OH:43])[OH:41])[OH:39])([OH:37])[C:34]([OH:36])=[O:35])=[O:32])[CH2:24][S:25][CH2:26][NH:27][C:28](=[O:30])[CH3:29])=[O:21])[CH2:10][CH:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:12](=[O:14])[OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH3:61][Si:62]([CH:65](O)[CH3:66])([CH3:64])[CH3:63]>CN(C)C=O>[CH3:61][Si:62]([CH2:65][CH2:66][O:35][C:34]([C@@:33]([C:31](=[O:32])[C@H:23]([CH2:24][S:25][CH2:26][NH:27][C:28](=[O:30])[CH3:29])[NH:22][C:20](=[O:21])[C@H:9]([CH2:10][CH:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:12](=[O:13])[OH:14])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([C@H:38]([C@@H:40]([C@@H:42]([CH2:44][NH2:45])[OH:43])[OH:41])[OH:39])[OH:37])=[O:36])([CH3:64])[CH3:63]
Reactant: CC(=O)NCSC[C@H](NC(=O)[C@H](CC(OC(C)(C)C)C(=O)O)NC(=O)OC(C)(C)C)C(=O)[C@](O)(C(=O)O)[C@@H](O)[C@H](O)[C@H](O)CN
Reactant: CC(O)[Si](C)(C)C
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(=O)NCSC[C@H](NC(=O)[C@H](CC(OC(C)(C)C)C(=O)O)NC(=O)OC(C)(C)C)C(=O)[C@](O)(C(=O)OCC[Si](C)(C)C)[C@@H](O)[C@H](O)[C@H](O)CN
Reaction time: 0.33 h

Procedure:
To 5 mL of a solution containing 1 mmol of the above acid 5, anhydrous dimethylformamide, and 1 mmol of N-methylmorpholine maintained at 0°-5° C., 1 mmol of isobutylchloroformate is added, and the mixture is kept at this temperature for 20 minutes. To this solution is added a solution of 1 mmol of trimethylsilylethanol in 2 mL of anhydrous dimethylformamide (previously cooled to 0°-5° C.), and the solution is stirred for 1 hour at this temperature and allowed to come to room temperature. The solvent is removed in vacuo and the residue is dissolved in 20 mL of ethyl acetate and washed with water. The organic layer is dried and evaporated to give 6.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:17]([OH:19])=O)=[N:10][C:11]=2[O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][C:21]([CH3:29])([C:23]1[N:27]=[C:26]([CH3:28])[O:25][N:24]=1)[NH2:22]>>[CH3:20][C:21]([NH:22][C:17]([C:9]1[CH:8]=[CH:7][C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[C:11]([O:12][CH2:13][CH:14]2[CH2:15][CH2:16]2)[N:10]=1)=[O:19])([C:23]1[N:27]=[C:26]([CH3:28])[O:25][N:24]=1)[CH3:29]
Reactant: O=C(O)c1ccc(C2CCCC2)c(OCC2CC2)n1
Reactant: Cc1nc(C(C)(C)N)no1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(C3CCCC3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 39 b) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0, Example 33 d) as starting materials, MS (LC/MS): 385.2 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:18])[N:10]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[C:28]2[NH:27][N:26]=[CH:25][C:24]=2[C:23]2[CH2:29][N:30]([CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:31](=[O:54])[C@H:32]([CH2:34][C:35](=[O:53])N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)[CH2:33][C:22]=2[CH:21]=1>>[Cl:19][C:20]1[C:28]2[NH:27][N:26]=[CH:25][C:24]=2[C:23]2[CH2:29][N:30]([CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:31](=[O:54])[C@H:32]([CH2:34][C:35](=[O:53])[N:15]3[CH2:14][CH2:13][CH:12]([N:10]4[CH:11]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[NH:8][C:9]4=[O:18])[CH2:17][CH2:16]3)[CH2:33][C:22]=2[CH:21]=1
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Reactant: O=c1[nH]c(-c2ccccc2)cn1C1CCNCC1
Product: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(n3cc(-c4ccccc4)[nH]c3=O)CC2)C1=O
Yield: 46 %

Procedure:
Title compound was prepared from 4-phenyl-1-(piperidin-4-yl)-1H-imidazol-2(3H)-one in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Material was obtained as white solid in 46% yield. MS m/e (M+H)+=589.2. 1H NMR (500 MHz, DMSO-D6): δ=13.55 (s, 1H), 10.68 (s, 1H), 8.37 (s, 1H), 7.50 (d, J=7.63, 2H), 7.32 (t, J=7.02, 2H), 7.24 (s, 1H), 7.16 (m, 2H), 5.37 (d, J=14.34, 1H), 4.63 (d, J=16.79, 1H), 4.51 (t, J=10.83, 1H), 4.13 (m, 2H), 3.89 (m, 1H), 3.57 (m, 1H), 3.18 (m, 1H), 3.03 (m, 3H), 2.89 (t, J-15.1 1, 1H), 2.66 (m, 1H), 2.34 (d, J=16.17 1H), 1.84 (m, 3H), 1.60 (m, 1H), 0.73 (d, J=13.73, 9H).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[N:5]([CH2:8][C@@H:9]([NH:14][C:15]1[C:20]([F:21])=[CH:19][N:18]=[C:17]([Cl:22])[N:16]=1)[C:10]([CH3:13])([CH3:12])[CH3:11])=[N+:6]=[N-:7]>C1COCC1.C1(C)C=CC=CC=1>[Cl:22][C:17]1[N:16]=[C:15]([NH:14][C@@H:9]([C:10]([CH3:12])([CH3:11])[CH3:13])[CH2:8][N:5]2[CH:3]=[C:2]([CH2:1][OH:4])[N:7]=[N:6]2)[C:20]([F:21])=[CH:19][N:18]=1
Reactant: CC(C)(C)[C@@H](CN=[N+]=[N-])Nc1nc(Cl)ncc1F
Reactant: C#CCO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)[C@@H](Cn1cc(CO)nn1)Nc1nc(Cl)ncc1F
Temperature: 120 °C

Procedure:
A mixture of prop-2-yn-1-ol (0.22 g, 3.85 mmol) and (S)—N-(1-azido-3,3-dimethylbutan-2-yl)-2-chloro-5-fluoropyrimidin-4-amine, 216a, (0.21 g, 0.77 mmol) in THF (4 mL) and toluene (4 mL) was heated in a pressure vial at 120° C. for 8 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product which contained two regioisomers was purified by silica gel chromatography (0-5% MeOH/CH2Cl2 gradient) to afford 100 mg of desired regioisomer, 217a, as well as 70 mg of the minor regioisomer (5-hydroxymethyl triazole).
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH2:21][N:22]3[CH:30]([OH:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])[CH2:17][CH:18]=2)=[CH:9][CH:8]=1.N.[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36]>CO.C(Cl)Cl.C(C(C)=O)C>[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].[CH3:34][O:32][CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30](=[O:31])[N:22]1[CH2:21][CH2:20][CH2:19][N:16]1[CH2:15][CH:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)[CH2:18][CH2:17]1
Reactant: O=C1c2ccccc2C(O)N1CCCN1CC=C(c2ccc(F)cc2)CC1
Agent: N
Agent: O=C(O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: ClCCl
Solvent: CCC(C)=O
Product: COC1c2ccccc2C(=O)N1CCCN1CC=C(c2ccc(F)cc2)CC1
Reaction time: 5 h
Yield: 153.1 %

Procedure:
28.5 cc of concentrated sulphuric acid is added to an agitated solution of 2-[3-(4-(4-fluorophenyl)-1,2,3,6-tetrahydro-1-pyridyl)propyl]-3-hydroxy-1-isoindolinone (5.7 g) in methanol (145 cc) at a temperature close to 20° C. in the course of 10 minutes. Agitation is continued for 5 hours at a temperature close to 65° C. After cooling the solution to a temperature close to 0° C., 70 cc of a 33% aqueous solution of ammonia is added in the course of 1 hour. The precipitate formed is filtered and washed with methanol (50 cc). The filtrate is diluted with distilled water (200 cc) and a 33% aqueous solution of ammonia (50 cc) and extracted with methylene chloride (3×200 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in methylene chloride (10 cc) and the solution poured onto silica (550 g) contained in a column of 8 cm diameter. Elution is carried out with a mixture of methylene chloride and methanol (90-10 by volume). The first 900 cc are eliminated and the following 200 cc are evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. The residue obtained is dissolved in methyl ethyl ketone (10 cc). A solution of oxalic acid (0.6 g) in methyl ethyl ketone (5 cc) is added and agitation continued for 1 hour at a temperature close to 20° C. The precipitate formed is separated by filtration. 2.4 g of 3-methoxy-2-[3-(4-(4-fluorophenyl)-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone oxalate are obtained, melting at 139° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5](Cl)=[O:6].C[O:13][P:14]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]2[CH:24]=[CH:25][CH:26]=[CH:27][C:16]=2[O:15]1>CC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([P:14]1(=[O:13])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]2[CH:24]=[CH:25][CH:26]=[CH:27][C:16]=2[O:15]1)=[O:6]
Reactant: COP1Oc2ccccc2-c2ccccc21
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Solvent: CC(C)=O
Product: Cc1cc(C)cc(C(=O)P2(=O)Oc3ccccc3-c3ccccc32)c1
Temperature: 115 °C

Procedure:
67.4 g (0.4 mol) of 3,5-dimethylbenzoyl chloride were warmed to 80° C. under a nitrogen atmosphere. 92 g (0.4 mol) of 6-methoxy-(6H)-dibenz[c,e][1,2]oxaphosphorin were added dropwise while stirring. The temperature during the addition was increased in steps to 115° C. When the reaction was complete, 50 ml of acetone were added at room temperature. After crystallization, 113 g (81% of theory) of the abovementioned compound of melting point 120° to 124° C. were obtained.
Reaction SMILES: [Na].[CH3:2][N:3]([CH3:14])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)=[O:5].C[O-].[Na+].C1([O-])C=CC=CC=1.[Cl:25][C:26]1[C:27]([CH2:33]Cl)=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=1>CS(C)=O.CO>[Cl:25][C:26]1[C:27]([CH2:33][O:13][C:10]2[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[N:3]([CH3:14])[CH3:2])=[CH:8][CH:9]=2)=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=1
Reactant: CN(C)C(=O)Nc1ccc(O)cc1
Reactant: ClCc1nc(Cl)ccc1Cl
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CS(C)=O
Solvent: CO
Product: CN(C)C(=O)Nc1ccc(OCc2nc(Cl)ccc2Cl)cc1

Procedure:
Sodium metal (0.67 grams; 0.03 mole) was dissolved in 35 ml. of methanol and N,N-dimethyl-4-hydroxyphenyl urea (5.23 grams; 0.03 mole) was added to the sodium methoxide solution and the resulting mixture stirred until it became clear. The resulting phenolate solution was added portionwise over a period of about 90 minutes to a solution of 3,6-dichloro-2-chloromethylpyridine in 20 ml. of dimethylsulfoxide while maintaining the reaction at a temperature between from about 25° to about 50° C. The reaction mixture was then distilled to remove the methanol and the residue quenched over ice. The solid isolated by filtration was recrystallized from benzene. As a result of these operations, the desired N'-(4-((3,6-dichloro-2-pyridinyl)methoxy)phenyl)-N,N-dimethyl urea compound was recovered as a crystalline solid having a melting point of 161.5° to 162.5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([NH:9][C:10]1[S:18][C:13]2[CH2:14][O:15][CH2:16][CH2:17][C:12]=2[C:11]=1[C:19]([O:21]CC)=O)=[O:8].[CH2:25]([NH2:27])[CH3:26]>>[CH2:25]([NH:27][C:19]([C:11]1[C:12]2[CH2:17][CH2:16][O:15][CH2:14][C:13]=2[S:18][C:10]=1[NH:9][C:7]([CH:3]1[C:4]([CH3:5])([CH3:6])[C:2]1([CH3:1])[CH3:24])=[O:8])=[O:21])[CH3:26]
Reactant: CCN
Reactant: CCOC(=O)c1c(NC(=O)C2C(C)(C)C2(C)C)sc2c1CCOC2
Product: CCNC(=O)c1c(NC(=O)C2C(C)(C)C2(C)C)sc2c1CCOC2

Procedure:
The product of Example 10B and ethylamine were processed as in Examples 29A and Example 29B to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.18 (s, 1H), 1.21 (s, 6H), 1.26 (t, J=7.3 Hz, 3H), 1.32 (s, 6H), 2.77-2.83 (m, 2H), 3.41-3.55 (m, 2H), 3.98 (t, J=5.3 Hz, 2H), 4.71 (t, J=1.7 Hz, 2H), 5.70-5.82 (m, 1H), 12.02 (s, 1H); MS (DCI/NH3) m/z 352 (M+H)+; anal. calculated for C18H26N2O3S: C, 61.69; H, 7.48; N, 7.99. Found: C, 61.58; H, 7.39; N, 7.94.