Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:18]([NH:20][CH:21]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25]2[CH:34]=[CH:35][CH:36]=[CH:37][C:24]=2[N:23]([CH3:38])[C:22]1=[O:39])=[O:19])[CH:15]([CH3:17])[CH3:16]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:18]([NH:20][CH:21]2[N:27]=[C:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:25]3[CH:34]=[CH:35][CH:36]=[CH:37][C:24]=3[N:23]([CH3:38])[C:22]2=[O:39])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CC(C)[C@H](N)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Product: CC(C)[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-valinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-Y), the title compound was prepared as a solid (mp.=228-229° C.). The product was purified by slurrying in ether/hexanes. (80:20).
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[C:19](=[NH:32])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC(C)([O-])C.[K+]>O1CCOCC1.C(OCC)(=O)C.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].[Cl-].C(C1C=CC=C(C(C)C)C=1[N+]1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C=1)(C)C>[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([N:32]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cccc(C(C)C)c1-n1cc[n+](-c2c(C(C)C)cccc2C(C)C)c1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Clc1cccc(-c2cc(N=C(c3ccccc3)c3ccccc3)c3c(n2)CCC3)c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 34.5 %

Procedure:
A 20-mL vial, with stirrer bar, was charged with 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (1.00 g, 3.33 mmol), benzophenone imine (0.56 mL, 3.66 mmol), Pd(dba)2 (0.057 g, 0.10 mmol, 0.03 eq.), 1,3-bis(2,6-di-iso-propylphenyl)imidazolium chloride (0.042 g, 0.10 mmol) and potassium tert-butoxide (0.93 g, 8.32 mmol) in dioxane (12 mL) at rt. The reaction mixture was placed under argon and stirred at 100° C. for 24 h. The cooled reaction was diluted with ethyl acetate (150 mL) and washed with saturated sodium chloride (2×25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using hexanes/ethyl acetate (10:0 to 8:2) as the eluent to afford the title compound (0.47 g, 34%) as a yellow solid. MW=408.92. 1H NMR (CDCl3, 500 MHz) δ 7.85-7.70 (m, 3H), 7.69-7.63 (m, 1H), 7.56-7.39 (m, 3H), 7.36-7.26 (m, 5H), 7.22-7.10 (m, 2H), 6.81 (s, 1H), 2.97 (t, J=7.5 Hz, 2H), 2.62 (t, J=7.5 Hz, 2H), 2.07-1.98 (m, 2H); ESI MS m/z 409 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].BrBr.[C:10]1([O:16][CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(=O)C>[CH3:17][O:16][C:10]1[CH:15]=[CH:14][C:13]([CH:7]2[NH:1][C:2](=[O:3])[NH:4][C:5]2=[O:6])=[CH:12][CH:11]=1
Reactant: COc1ccccc1
Reactant: O=C1CNC(=O)N1
Agent: BrBr
Solvent: CC(=O)O
Product: COc1ccc(C2NC(=O)NC2=O)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
4.0 g (40 mmol) of hydantoin, 30 ml of acetic acid and 2.0 ml (40 mmol) of bromine were mixed at room temperature. The reaction mixture was then vigorously stirred at a temperature of 60° C. for 2 hours. After cooling the reaction mixture to room temperature, 8.64 g (80 mmol) of anisol was added to the reaction mixture and the reaction was further conducted at a temperature of 100° C. for 6 hours. The resulting precipitate was recovered by filtration, washed with water, and then dried to obtain 3.96 g (yield 48%) of 5-(p-methoxyphenyl)hydantoin.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH:9]=[C:10]([CH3:19])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2].C1(C=C(C)CC(C2C=CN=CC=2CC)C)C=CC=CC=1>>[CH2:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH2:9][CH:10]([CH3:19])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2]
Reactant: CCc1cnccc1C=C(C)CCc1ccccc1
Agent: CCc1cnccc1C(C)CC(C)=Cc1ccccc1
Product: CCc1cnccc1CC(C)CCc1ccccc1
Yield: 78.5 %

Procedure:
The procedure of Example 50 was repeated with the exception that 1.2 g of 1-(3-ethyl-4-pyridyl)-2-methyl-4-phenyl-1-butene (compound 55) obtained in Example 42 was used in place of 1-phenyl-2-methyl-4-(3-ethyl-4-pyridyl)-1-pentene in Example 50, to obtain 0.95 g (yield: 78.4%) of 1-(3-ethyl-4-pyridyl)-2-methyl-4-phenylbutane (hereinafter referred to as compound 100).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[C:9]([NH2:19])=[N:8][C:6]=2[N:7]=1.[H-].[Na+].[C:22]([N:26]=[C:27]=[O:28])([CH3:25])([CH3:24])[CH3:23]>CN(C)C=O>[C:22]([NH:26][C:27]([NH:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[C:9]([NH:19][C:27]([NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])=[N:8][C:6]=2[N:7]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)N=C=O
Reactant: Cc1ccccc1-c1cc2cnc(N)nc2nc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1cc2cnc(NC(=O)NC(C)(C)C)nc2nc1NC(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of 0.5 g of 2,7-diamino-6-o-tolyl-pyrido[2,3-d]pyrimidine, prepared as described above in Example 1, in 10 mL of dimethylformamide is reacted with 0.16 g of 60% sodium hydride and stirred at ambient temperature for 1.5 hours. To the suspension is added 0.49 mL of t-butylisocyanate and the mixture stirred overnight at ambient temperature. The reaction mixture is filtered to remove insoluble salts and the filtrate evaporated under reduced pressure. The residue is diluted with water, the insoluble crude product collected by filtration and dried in vacuo. Crystallization from a hexane:ethyl acetate: dichloromethane mixture (3:2:5 v/v/v) afforded the title compound, mp 209°-212° C. dec.
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]([N:15]=O)S(C1C=CC(C)=CC=1)(=O)=O.[Cl:17][C:18]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:19]=1[O:20][C:21]1[CH:22]=[CH:23][C:24]([N+:39]([O-:41])=[O:40])=[C:25]([CH:38]=1)[O:26][C:27]1[CH:37]=[CH:36][CH:35]=[CH:34][C:28]=1[O:29][CH2:30][C:31](Cl)=[O:32]>CO.CCOCC.O1CCCC1>[N+:4](=[CH:3][C:31](=[O:32])[CH2:30][O:29][C:28]1[CH:34]=[CH:35][CH:36]=[CH:37][C:27]=1[O:26][C:25]1[CH:38]=[C:21]([O:20][C:19]2[CH:42]=[CH:43][C:44]([Cl:46])=[CH:45][C:18]=2[Cl:17])[CH:22]=[CH:23][C:24]=1[N+:39]([O-:41])=[O:40])=[N-:15]
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: O=C(Cl)COc1ccccc1Oc1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: [N-]=[N+]=CC(=O)COc1ccccc1Oc1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 42 °C

Procedure:
A mixture of potassium hydroxide in methanol (20.0 mL of a 4M solution ) is heated to 42° C. and treated dropwise with a mixture of N-methyl-N-nitroso-p-toluenesulfonamide (4 g, 18.7 mmol) in ether (40 mL). The diazomethane is distilled over, condensed with a dry ice/acetone condenser and collected. The diazomethane/ether solution is stirred in an ice-bath, treated dropwise with a solution of {o-[5-(2,4-dichlorophenoxy)-2-nitrophenoxy]phenoxy}acetyl chloride (1.09 g, 2.32 mmol) in tetrahydrofuran, stirred for 30 minutes and concentrated in vacuo to give the title product as a yellow oil which is identified by NMR spectral analyses.
Reaction SMILES: [Cl-].[NH2:2][CH2:3][C:4]1([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2=[NH+:13][CH:14]=[CH:15][N:5]12.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH:42]1([C:48](O)=[O:49])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>CN(C=O)C.C(Cl)CCl>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([C:4]2([CH2:3][NH:2][C:48]([CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[O:49])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]3=[N:13][CH:14]=[CH:15][N:5]23)=[CH:17][CH:18]=1
Reactant: O=C(O)C1CCCCC1
Reactant: NCC1(c2ccc(Br)cc2)c2ccccc2-c2[nH+]ccn21
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(NCC1(c2ccc(Br)cc2)c2ccccc2-c2nccn21)C1CCCCC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(aminomethyl)-5-(4-bromophenyl)-5H-imidazo[2,1-a]isoindol-1-ium chloride (40 mg), EDC (28 mg) and HOAT (13 mg) in DMF (1 mL) was added Hunig's base (75 mg) followed by cyclohexanecarboxylic acid (19 mg). After stirring at 40° C. overnight the mixture was purified by reversed phase HPLC (21×100 mm Phenomenex Gemini, 15-75% MeCN/water containing 0.05% NH4OH over 20 min at 20 mL/min) to give title compound as a white solid. HRMS. Found, 450.1186; calcd for (M+H)+, 450.1176. 1H NMR (500 MHz, CDCl3): δ 7.85 (d, J=7.59 Hz, 1 H); 7.48 (d, J=8.42 Hz, 2 H); 7.46-7.40 (m, 1 H); 7.35-7.28 (m, 3 H); 7.07 (d, J=8.43 Hz, 2 H); 7.03 (d, J=1.34 Hz, 1 H); 4.84 (t, J=6.19 Hz, 1 H); 4.55 (dd, J=13.97, 6.66 Hz, 1 H); 4.24 (dd, J=13.99, 5.93 Hz, 1 H); 1.75-1.49 (m, 5 H); 1.39 (d, J=9.99 Hz, 1 H); 1.28 (d, J=12.70 Hz, 1 H); 1.05 (m, 4 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[N:36](S(C2C=CC(C)=CC=2)(=O)=O)[C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[CH2:26][CH2:25]3)=[C:17]2[CH:16]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[NH:36][C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][N:24]3[CH2:25][CH2:26][CH:27]([N:30]4[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]4)[CH2:28][CH2:29]3)=[C:17]2[CH:16]=1
Reactant: COc1cc2c(-c3cc4c(CN5CCC(N6CCCCC6)CC5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4c(CN5CCC(N6CCCCC6)CC5)ccnc4[nH]3)cn(C)c2cc1OC
Yield: 52.6 %

Procedure:
1-[2-(5,6-Dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl][1,4′]bipiperidyl is prepared as described in Example 179a starting with 0.025 g of 1′-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl][1,4′]bipiperidyl instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-trifluoromethylsulfanylbenzyl)amine used in Example 179a and 0.17 cm3 of 5N potassium hydroxide. 0.01 g of 1′-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl][1,4′]bipiperidyl is obtained, the characteristics of which are as follows:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([CH2:9][CH3:10])[CH3:8].Cl[CH2:20][C:21]1[O:25][N:24]=[C:23]([CH3:26])[CH:22]=1>CN(C)C=O>[CH:7]([O:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:20][C:21]2[O:25][N:24]=[C:23]([CH3:26])[CH:22]=2)=[CH:16][CH:17]=1)([CH2:9][CH3:10])[CH3:8]
Reactant: Cc1cc(CCl)on1
Reactant: CCC(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)Oc1ccc(OCc2cc(C)no2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
4.6 g of anhydrous potassium carbonate is added to 5.0 g of 4-sec-butyloxyphenol in 80 ml of absolute dimethylformamide, and the mixture is stirred for one hour at 80° C. At this temperature, 3.9 g of 5-chloromethyl-3-methylisoxazole is dripped in and the mixture is stirred for a further seven hours at 90° C. The batch is then stirred into 300 ml of ice water, extracted three times, each time with 100 ml of methyl tert-butyl ether and the organic phase is washed twice with 2N sodium hydroxide solution (50 ml in each instance) and then three times with water (50 ml in each instance). Drying over sodium sulfate and removal of the solvent under reduced pressure give 6.6 g of 5-[4-(sec-butyloxy)-phenoxymethyl]-3-methylisoxazole, which is obtained, after chromatography over silica gel using toluene/ethyl acetate(1:1) as eluant, as a viscous oil. According to 1H-NMR spectroscopy, the oil is pure.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].O>[Pd].C(O)(C)C>[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=Cc1ccc(Br)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 81.5 °C
Reaction time: 17.5 h
Yield: 85.4 %

Procedure:
5% Palladium on carbon, type 58, 50% paste (0.94 kg, 0.22 moles Pd) was added to a mixture of 4-bromobenzaldehyde (3.34 kg, 17.69 moles), 4-trifluoromethylphenyl boronic acid (3.50 kg, 18.06 moles) and sodium carbonate (3.75 kg, 35.38 moles) in process water (36 L). Isopropanol (36 L) was added and the resultant mixture heated to reflux (80-83° C.) for ca. 2.5 hours. The catalyst was removed from the hot suspension by filtration through celite (1.5 kg). The celite bed was washed with a hot (ca. 70° C.) isopropanol (10 L)/water (10 L) mixture then the combined filtrate and wash were cooled to 23° C., process water (18 L) was added and the mixture stirred at 20-25° C. for ca. 17.5 hours. The solid was collected by filtration, washed with process water (1×27 L, 2×18 L) then dried at 39° C. for 24 hours to give the title compound (3.78 kg, 85%) as a white solid. 1H NMR (CDCl3) δ 7.75 (4H, s), 7.78 (2H, d) 7.98 (2H, d), 10.10 (1H, s)
Reaction SMILES: C(N(CC)CC)C.O[C:9]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[C:21](=[O:35])[NH:22][C:23](=[O:34])[C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=2)=[CH:15][CH:14]=1)=[O:10].Cl.[NH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:45](=[O:47])[CH3:46].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(N(CC)C=O)C.C(OCC)(=O)C>[C:45]([NH:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][NH:37][C:9]([CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[C:21](=[O:35])[NH:22][C:23](=[O:34])[C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=2)=[CH:17][CH:18]=1)=[O:10])(=[O:47])[CH3:46]
Reactant: CC(=O)NCCCCCCN
Reactant: O=C(O)CCc1ccc(NC2=C(c3cccc([N+](=O)[O-])c3)C(=O)NC2=O)cc1
Agent: CCN(C=O)CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)NCCCCCCNC(=O)CCc1ccc(NC2=C(c3cccc([N+](=O)[O-])c3)C(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of triethylamine (81 mg, 0.8 mmol) in dry N,N-diethylformamide (5 mL) was added to a mixture of 3-[4-[2-(hydroxycarbonyl)ethyl]phenylamino]-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione (Example A763, 152 mg, 0.4 mmol), N-(6-aminohexyl)acetamide hydrochloride (78 mg, 0.4 mmol), 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (77 mg, 0.4 mmol) and 1-hydroxybenzotriazole (54 mg, 0.4 mmol) and the resulting mixture stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate (25 mL) and washed successively with water (2×25 mL), saturated aqueous sodium bicarbonate solution (25 mL), water (2×25 mL), brine (25 mL), dried over magnesium sulphate and concentrated. The residue was redissolved in dichloromethane-methanol (1:1 v/v), filtered and evaporated to afford the title compound as a foam.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13])[CH:5]=[CH:4][C:3]=1[C:16](=[O:18])[CH3:17].Br.[CH:20]([NH:23][C:24]1[S:25][CH:26]=[C:27]([C:29](O)=[O:30])[N:28]=1)([CH3:22])[CH3:21].P(Cl)(Cl)(Cl)=O.O>N1C=CC=CC=1>[C:16]([C:3]1[C:2]([NH:1][C:29]([C:27]2[N:28]=[C:24]([NH:23][CH:20]([CH3:22])[CH3:21])[S:25][CH:26]=2)=[O:30])=[C:7]([Cl:8])[C:6]([O:9][CH2:10][CH:11]([O:12][CH3:13])[O:14][CH3:15])=[CH:5][CH:4]=1)(=[O:18])[CH3:17]
Reactant: CC(C)Nc1nc(C(=O)O)cs1
Reactant: COC(COc1ccc(C(C)=O)c(N)c1Cl)OC
Agent: Br
Solvent: c1ccncc1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(COc1ccc(C(C)=O)c(NC(=O)c2csc(NC(C)C)n2)c1Cl)OC
Temperature: 0 °C
Reaction time: 4 h
Yield: 85.7 %

Procedure:
To a mixture of 1-[2-amino-3-chloro-4-(2,2-dimethoxyethoxy)phenyl]ethanone (13 g, 47.5 mmol) and isopropylaminothiazole-4-carboxylic acid hydrobromide (prepared as described in Ivanov, V., et. al.; EP1881001A1, p. 62-63; 12.6 g, 47.5 mmol) in pyridine (150 ml) was slowly added phosphorus oxychloride (9.47 g, 61.8 mmol) at −40° C. The mixture was then stirred at 0° C. for 4 h. Upon completion of the reaction, H2O (30 ml) was added dropwise to the mixture. The mixture was then stirred at 0° C. for another 15 min. The mixture was concentrated in vacuo. The residue was diluted with EtOAc, washed with a sat. NaHCO3 aqueous solution. The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in CH2Cl2, hexanes was added slowly to the solution, and a yellow solid started to crash out. More hexanes were added precipitation was complete to afford 2-isopropylaminothiazole-4-carboxylic acid [6-acetyl-2-chloro-3-(2,2-dimethoxyethoxy)phenyl]amide (18 g, 85% yield).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([Cu])#[N:12].[NH4+].[OH-]>CN1C(=O)CCC1>[NH2:12][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#C[Cu]
Reactant: Cc1ccc(C#N)c(Br)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc(C#N)c(N)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
A solution of 2-bromo-4-methylbenzonitrile (2.0 g, 10.7 mmol) and CuCN (1.92 g, 21.4 mmol) in NMP (10 mL) was reacted in a microwave for 20 min at 200° C. Upon completion the reaction was cooled to 0° C., and 15% aqueous NH4OH (215 mL) was slowly added. The mixture was stirred at rt for 30 min, then extracted with CH2Cl2. The organic layer was washed with H2O, brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (3:1 Hexane:EtOAc) to provide 2-amino-4-methylbenzonitrile (1.24 g, 88%). 1H NMR (400 MHz, CDCl3) δ 1.45 (s, 3H), 5.70 (m, 1H), 5.84 (m, 1H), 6.41 (d, J=8.0 Hz, 1H).
Reaction SMILES: COC1C=C(C(Cl)=O)C=CC=1OC.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][C:30]=1[F:36].[CH3:37][O:38][C:39]1[CH:40]=[C:41]([C:47]([N:49]=[C:50]=[S:51])=[O:48])[CH:42]=[CH:43][C:44]=1[O:45][CH3:46]>C1(C)C=CC=CC=1.C(O)C>[CH3:37][O:38][C:39]1[CH:40]=[C:41]([C:47]([N:49]=[C:50]=[S:51])=[O:48])[CH:42]=[CH:43][C:44]=1[O:45][CH3:46].[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[C:47]([NH:49][C:50]([NH:33][C:32]1[CH:34]=[CH:35][C:29]([O:28][C:19]2[C:18]3[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=3)[N:22]=[CH:21][CH:20]=2)=[C:30]([F:36])[CH:31]=1)=[S:51])=[O:48]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: COc1ccc(C(=O)Cl)cc1OC
Agent: COc1ccc(C(=O)N=C=S)cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(F)c2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
3,4-Dimethoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3,4-dimethoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3,4-dimethoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (54 mg, yield 63%).
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[NH:6][CH2:5][CH2:4][O:3]1.C(N(CC)CC)C.[Cl:15][CH:16]([Cl:24])[C:17]([O:19][CH2:20][C:21](Cl)=[O:22])=[O:18].O>C(Cl)Cl>[CH3:1][C:2]1([CH3:7])[N:6]([C:21](=[O:22])[CH2:20][O:19][C:17](=[O:18])[CH:16]([Cl:24])[Cl:15])[CH2:5][CH2:4][O:3]1
Reactant: O=C(Cl)COC(=O)C(Cl)Cl
Reactant: CC1(C)NCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)OCCN1C(=O)COC(=O)C(Cl)Cl
Temperature: 25 °C
Yield: 69.1 %

Procedure:
A solution was made by combining while cooling in an ice bath, 1.51 g (0.015 mole) of 2,2-dimethyloxazolidine, 1.6 g (0.015 mole) of triethylamine, and 100 ml of methylene chloride. A second solution containing 3.08 g (0.015 mole) of dichloroacetoxyacetyl chloride dissolved in 10 ml of methylene chloride was added dropwise to the first solution. The mixture was stirred in the ice bath for ten minutes. After refluxing for one hour, it was allowed to cool to room temperature. The reaction product was water washed twice and dried over magnesium sulfate. It was decolorized with a decolorizing agent and charcoal. The solvent was removed by reduced pressure evaporation leaving 2.8 g (69% yield) of 2,2-dimethyl-3-dichloroacetoxyacetyloxazolidine. The structure was confirmed by IR.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1([OH:13])[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([NH:4][CH2:5][C:6]1([OH:13])[CH2:7][CH2:8][N:9]([CH3:12])[CH2:10][CH2:11]1)[CH3:2]
Reactant: CC(=O)NCC1(O)CCN(C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNCC1(O)CCN(C)CC1
Reaction time: 72 h
Yield: 33.2 %

Procedure:
4-acetamidomethyl-4-hydroxy-1-methylpiperidine (3.4 g, 0.018 mole) in dry THF was refluxed in the presence of lithium aluminium hydride (4 g). After 3 days, the mixture was poured into an ice-water bath and filtered through Celite. The solvent was evaporated and after addition of water the solution was extracted with chloroform, and the extract was dried with magnesium sulfate and evaporated to yield 1.03 g (33% yield) crude material. The product thus obtained, 4-ethylaminomethyl-4-hydroxy-1-methylpiperidine, was used without further purification.
Reaction SMILES: [CH2:1]([CH:8]1[CH:14]([N:15](CC2C=CC=CC=2)CC2C=CC=CC=2)[C:13](=[O:30])[NH:12][C:11]2[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:10]=2[O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[NH2:15][CH:14]1[C:13](=[O:30])[NH:12][C:11]2[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:10]=2[O:9][CH:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Nc2cc(F)ccc2OC(Cc2ccccc2)C1N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC1C(=O)Nc2cc(F)ccc2OC1Cc1ccccc1

Procedure:
The title compound was prepared by hydrogenation of (+)-(6R,7R or 6S,7S)-6-benzyl-7-dibenzylamino-2-fluoro-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one in methanol with Pd/C (10%), MS m/e (%): 287.1 (M+H+, 100).
Reaction SMILES: [CH2:1]1[CH:7](O)[NH:6][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[O:3][CH2:2]1.[CH:16]1([NH3+:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[SH:23][CH2:24][CH2:25][S:26]([O-:29])(=[O:28])=[O:27].ClC(Cl)(Cl)C(O)=O>O>[CH:16]1([NH3+:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[Cl:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][Cl:15])[P:4]1(=[O:5])[NH:6][CH:7]([S:23][CH2:24][CH2:25][S:26]([O-:29])(=[O:28])=[O:27])[CH2:1][CH2:2][O:3]1
Reactant: O=S(=O)([O-])CCS
Reactant: O=P1(N(CCCl)CCCl)NC(O)CCO1
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: [NH3+]C1CCCCC1
Solvent: O
Product: O=P1(N(CCCl)CCCl)NC(SCCS(=O)(=O)[O-])CCO1
Reaction time: 72 h

Procedure:
5.6 g (20 mmol) of 4-hydroxycyclophosphamide (i.e., 2-(bis-(2-chloroethyl)-amino)-4-hydroxy-tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide) and 4.8 g (20 mmol) of cyclohexylammonium-2-mercaptoethanesulphonate were dissolved in 100 ml of distilled water, mixed with some trichloroacetic acid and left to stand in a refrigerator for 3 days at 0° C. The solvent was then removed under high vacuum, the residue was taken up in acetone, re-concentrated, crystallised from acetone and recrystallised from isopropanol.