Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([CH2:7][CH:8]([C:16]([NH:18][S:19]([C:22]2C=C[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)(=[O:21])=[O:20])=[O:17])[C:9](N(CC)CC)=[O:10])=[CH:5][CH:4]=1)#[N:2].C(/S(N)(=O)=[O:43])=C\C1C=CC=CC=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]([C:16](=[O:17])[NH:18][S:19](/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:20])=[O:21])[C:9]([OH:10])=[O:43])=[CH:32][CH:33]=1)#[N:2]
Reactant: NS(=O)(=O)/C=C/c1ccccc1
Reactant: CCN(CC)C(=O)C(Cc1ccc(C#N)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Product: N#Cc1ccc(CC(C(=O)O)C(=O)NS(=O)(=O)/C=C/c2ccccc2)cc1
Yield: 176.7 %

Procedure:
In the same manner as in Example 152 (3), the object compound was obtained using the compound (1.57 g) obtained in Example 111 (2) and trans-β-styrenesulfonamide (1.25 g). This was subjected to hydrolysis in the same manner as in Example 1 (3) to give the title compound (2.30 g) as a white powder.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2Cl)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([C:20]1([CH2:23][CH3:24])[CH2:22][NH:21]1)[CH2:17][CH2:18][CH3:19].O.[SH2:26].[Na]>CS(C)=O.C(OCC)C>[C:1]1([C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[S:26][CH2:22][C:20]([NH2:21])([CH2:23][CH3:24])[CH2:16][CH2:17][CH2:18][CH3:19])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S
Reactant: CCCCC1(CC)CN1
Reactant: O=C(c1ccccc1)c1ccncc1Cl
Agent: [Na]
Solvent: O
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCCCC(N)(CC)CSc1cnccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 27.7 %

Procedure:
A mixture of the product from step (b) (4.3 g), 2-butyl-2-ethylaziridine (2.54 g, Synthetic Example 1(f)), and sodium hydrogen sulfide hydrate (1.48 g) in dimethylsulfoxide was stirred 48 hours at ambient temperature. The reaction mixture was diluted with diethyl ether and washed with aqueous sodium hydroxide, dried, filtered and evaporated to a yellow viscous oil. The oil was chromatographed on silica gel using ethyl acetate-ethanol (3:1) as eluant to give a yellow viscous oil (1.87 g). 1H NMR is consistent with proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]=1[OH:29])[CH:24]=O)[CH3:19].[NH2:33][C:34]([NH2:36])=[O:35].Cl>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:36][C:34](=[O:35])[NH:33][CH:24]([C:23]3[CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]([OH:29])=[C:21]([O:20][CH2:18][CH3:19])[CH:22]=3)[C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(Cc1ccccc1)c1cc(F)cc(F)c1
Reactant: NC(N)=O
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3cc(F)cc(F)c3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 19.9 %

Procedure:
To a solution of 1-(3,5-difluorophenyl)-2-phenylethanone (Intermediate 18) (100 mg, 0.43 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (84.9 mg, 0.43 mmol), and urea (78.6 mg, 1.29 mmol) in 5 mL of ethanol was added 0.2 mL of concentrated HCl, and the mixture was refluxed for 2 days. After the solvent was removed under reduced pressure, the residue was purified by reverse-phase preparatory HPLC (26-53% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 15 min.) to give Compound 46 (40 mg, yield 19.9%). 1H NMR (DMSO-d6 400 MHz) δ 10.27 (s, 1H), 8.81 (s, 1H), 7.56 (s, 1H), 7.41 (s, 1H), 7.31 (m, 2H), 7.14 (s, 1H), 7.11-6.99 (m, 4H), 6.86 (d, J=7.2 Hz, 2H), 5.24 (s, 1H), 4.04 (m, 2H), 1.32 (t, J=7.2 Hz, 3H); MS (ESI): m/z 468.0 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][N:10]1[C:18]2[C:17](Cl)=[N:16][CH:15]=[N:14][C:13]=2[CH:12]=[CH:11]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]([F:40])([F:39])[F:38])[CH:31]=1)[NH2:25]>C(O)(C)C.C(OCC)(=O)C>[CH3:21][C:22]1[CH:23]=[C:24]([NH:25][C:17]2[C:18]3[N:10]([CH2:9][CH2:8][NH:7][C:6](=[O:20])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:11]=[CH:12][C:13]=3[N:14]=[CH:15][N:16]=2)[CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]([F:38])([F:39])[F:40])[CH:31]=1
Reactant: CC(C)(C)OC(=O)NCCn1ccc2ncnc(Cl)c21
Reactant: Cc1cc(N)ccc1Oc1cccc(OC(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Cc1cc(Nc2ncnc3ccn(CCNC(=O)OC(C)(C)C)c23)ccc1Oc1cccc(OC(F)(F)F)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 103.5 %

Procedure:
tert-Butyl[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (297 mg) and 3-methyl-4-[3-(trifluoromethoxy)phenoxy]aniline (425 mg) were dissolved in isopropyl alcohol (2.97 mL), and the mixture was stirred at 80° C. for 16 hrs. After cooling to room temperature, the mixture was diluted with ethyl acetate (60 mL), and washed with aqueous sodium hydrogen carbonate (30 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→0:100) to give the title compound (563 mg) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:40]=[CH:41][N:42]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:37]=[CH:38][CH:39]=3)[C:21]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([C:28]([O:30]C(C)(C)C)=[O:29])=[CH:26][CH:25]=3)=[O:22])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:40]=[CH:41][N:42]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:37]=[CH:38][CH:39]=3)[C:21]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[O:22])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2cc(-c3cccc(C(=O)Nc4ccc(C(=O)OC(C)(C)C)cc4)c3)nn3ccnc23)nc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Nc2cc(-c3cccc(C(=O)Nc4ccc(C(=O)O)cc4)c3)nn3ccnc23)nc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.2 %

Procedure:
A mixture of tert-Butyl 4-(3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamido)benzoate (80 mg, 0.14 mmol) and TFA (3 mL) in dichloromethane (3 mL) was stirred for 2 h at room temperature. The mixture was concentrated and then triturated with MeOH (2 mL) to give the product 4-(3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamido)benzoic acid (28 mg, 39%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.71 (s, 1H), 10.02 (s, 1H), 8.66 (s, 1H), 8.55 (s, 1H), 8.29 (s, 1H), 8.24 (d, 1H, J=7.8 Hz), 8.12 (d, 1H, J=7.5 Hz), 7.97-7.93 (m, 2H), 7.76-7.71 (m, 3H), 7.44 (d, 1H, J=8.1 Hz), 7.13 (d, 1H, J=8.4 Hz), 4.05 (s, 3H), 3.88 (s, 3H). LC-MS: [M+H]+, 510.9, tR=1.505 min, HPLC: 97.21% at 214 nm, 99.12% at 254 nm, tR=6.006 min.
Reaction SMILES: C(=O)([O-])O.[Na+].[NH2:6][C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[CH3:20])[C:10]([CH:21]=[O:22])=[C:9]([SH:23])[N:8]=1.Br[CH2:25][S:26]([NH:29][CH:30]1[CH2:32][CH2:31]1)(=[O:28])=[O:27].C(OCC)(=O)C>CN(C=O)C>[NH2:6][C:7]1[N:8]=[C:9]([S:23][CH2:25][S:26]([NH:29][CH:30]2[CH2:32][CH2:31]2)(=[O:28])=[O:27])[C:10]([CH:21]=[O:22])=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[CH3:20])[N:12]=1
Reactant: O=S(=O)(CBr)NC1CC1
Reactant: Cc1ccc(-c2nc(N)nc(S)c2C=O)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc(N)nc(SCS(=O)(=O)NC3CC3)c2C=O)c(C)c1
Temperature: 85 °C

Procedure:
Sodium hydrogen carbonate was added to a solution of 2-Amino-4-(2,4-dimethylphenyl)-6-mercapto-pyrimidine-5-carbaldehyde in DMF and the suspension stirred. C-bromo-N-cyclopropyl-methane sulphonamide was added, and the mixture heated, ˜85° C., for ˜3 hrs. The resulting suspension was allowed to cool and ethyl acetate added, the mixture was washed with water and saturated aqueous sodium chloride solution. The solution was dried over anhydrous sodium sulphate and concentrated to a pale yellow solid. The crude solid was purified by column chromatography on silica eluting with mixtures of ethyl acetate and hexane.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:28]1[N:29]=[C:30]([NH:33]C(=O)C(F)(F)F)[S:31][CH:32]=1)[C:5]([NH:7][CH:8]1[C:26](=[O:27])[N:10]2[C:11]([C:23]([OH:25])=[O:24])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH3:22])[N:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6].[OH-].[Na+].O.Cl>C(O)C.C(OCC)(=O)C>[CH3:1][O:2][N:3]=[C:4]([C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1)[C:5]([NH:7][CH:8]1[C:26](=[O:27])[N:10]2[C:11]([C:23]([OH:25])=[O:24])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH3:22])[N:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csc(NC(=O)C(F)(F)F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csc(N)n1
Yield: 47.5 %

Procedure:
A solution of 7-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.3 g.) in a 0.1 N aqueous solution of sodium hydroxide (10.5 ml.) was warmed at 45° C. for 6 hours. Water (15 ml.) and ethyl acetate (30 ml.) were added to the reaction mixture and the resulting mixture was adjusted to pH 3.5 with 10% hydrochloric acid. The aqueous layer was separated, washed with ethyl acetate and adjusted to pH 5.0 with an aqueous solution of sodium bicarbonate. The aqueous solution was subjected to column chromatography on Amberlite XAD-2 (20 ml.) (prepared by Rohm & Haas Co.) using 10% ethanol as developing solvent. The eluate containing object compound was collected and lyophilized to give 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.12 g.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:33])[C@@H:11]([CH2:18][C:19]1[C:20]([CH2:28][O:29]C(=O)C)=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][N:23]=[CH:22]2)[CH2:12][C:13]([O:15][CH2:16]C)=[O:14])C>CO>[CH3:7][O:9][C:10](=[O:33])[C@@H:11]([CH2:18][C:19]1[C:20]([CH2:28][OH:29])=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][N:23]=[CH:22]2)[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: CCOC(=O)C[C@H](Cc1ccc2[nH]ncc2c1COC(C)=O)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)C[C@H](Cc1ccc2[nH]ncc2c1CO)C(=O)OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
Potassium carbonate (1.6 g, 11.6 mmol) was added to a solution of 2-(S)-(4-acetoxymethyl-1H-indazol-5-ylmethyl)-succinic acid diethyl ester (2.0 g, 5.5 mmol) in methanol (60 mL). Mixture was stirred at room temperature for 1.5 hours. Reaction was quenched with the addition of 1N hydrochloric acid (30 mL). Methanol was removed from the mixture in vacuo. Remaining aqueous was basified with sodium bicarbonate. Mixture was extracted with ethyl acetate (2×40 mL). Combined organic layers were washed successively with water (30 mL) and brine (30 mL). Organic was dried (magnesium sulfate), filtered then concentrated in vacuo. Desired product was obtained in 92% yield as an amber oil. 1H NMR (300 MHz, CDCl3): δ=8.21 ((s, 1H), 7.34 (d, J=9.2, 1H), 7.17 (d, J=8.8, 1H), 5.02 (dd, J1=12.4, J2=17.9, 1H)3.63 (s, 6H), 3.23 (m, 1H), 2.98 (m, 1H), 2.77 (dd, J1=7.7, J2=16.8, 1H), 2.53 (dd, J1=6.4, J2=16.7, 1H). MS m/e (M+H)−=307.0.
Reaction SMILES: [I-:1].[C:2]([O:6][C:7]([NH:9][C@@H:10]1[C:41](=[O:42])[N:12]2[C:13]([C:25]([O:27][CH:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])=[C:14]([CH2:18][N+:19]3[N:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)[CH2:15][S:16](=O)[C@H:11]12)=[O:8])([CH3:5])([CH3:4])[CH3:3].CN(C)C=O.P(Cl)(Cl)Cl>O>[I-:1].[C:2]([O:6][C:7]([NH:9][C@@H:10]1[C:41](=[O:42])[N:12]2[C:13]([C:25]([O:27][CH:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[O:26])=[C:14]([CH2:18][N+:19]3[N:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)[CH2:15][S:16][C@H:11]12)=[O:8])([CH3:5])([CH3:3])[CH3:4]
Reactant: Cn1ccc[n+]1CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]2S(=O)C1
Agent: [I-]
Solvent: O
Solvent: ClP(Cl)Cl
Solvent: CN(C)C=O
Product: Cn1ccc[n+]1CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]2SC1
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
To a solution of benzhydryl 7β-tert-butoxycarbonylamino-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate 1-oxide iodide (20 g) and N,N-dimethylformamide (100 ml) was stirred at -35° C. Phosphorus trichloride (7.8 g) was added thereto and stirred for 10 minutes at the same temperature. The reaction mixture was added to water (600 ml). The precipitates were collected by filtration and washed with water to give benzhydryl 7β-tertbutoxycarbonylamino-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate iodide (15.4 g).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]([CH3:12])=[C:7]([C:9]([CH3:11])=O)[N:8]=1)[CH2:2][CH3:3].[C:13](OCC)(=[O:16])[NH:14][NH2:15]>C(O)(=O)C.C(O)CCC>[CH3:11][C:9]1[C:7]2[N:8]([C:4]([CH2:1][CH2:2][CH3:3])=[N:5][C:6]=2[CH3:12])[C:13](=[O:16])[NH:14][N:15]=1
Reactant: CCCc1nc(C(C)=O)c(C)[nH]1
Reactant: CCOC(=O)NN
Solvent: CC(=O)O
Solvent: CCCCO
Product: CCCc1nc(C)c2c(C)n[nH]c(=O)n12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 59.7 g. of methyl 2-n-propyl-5-methyl-4-imidazolyl ketone, 41.14 g. of ethyl carbazate, 200 ml. of n-butanol and 4 drops of glacial acetic acid is warmed until solution is complete and then heated under reflux for 5 hours. The solution is concentrated in vacuo to an oily residue, 250 ml. of diphenyl ether are added and the resulting solution is heated with stirring in an oil bath for 30 minutes after the start of gas evolution. The temperature is maintained as closely as possible to the point at which gas evolution starts (150°-250°C.). The reaction is removed from the oil bath, cooled to 50° C. and diluted with 1-2 volumes hexane. The product is collected, washed with petroleum ether and then dissolved in 200 ml. of chloroform. This solution is filtered through 250 ml. of Magnesol® followed by an 800 ml. chloroform wash. The filtrate is concentrated in vacuo and the residue is recrystallized from 250 ml. of ethyl acetate, giving 48.2 g. of the desired product as off-white crystals, m.p. 154°-155° C.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[NH2:5][C:6]1[O:10][C:9]([C:11]([O:13]CC)=O)=[N:8][N:7]=1.[CH2:16]1COC[CH2:17]1>>[NH2:5][C:6]1[O:10][C:9]([C:11]([OH:13])([CH2:1][CH3:2])[CH2:16][CH3:17])=[N:8][N:7]=1
Reactant: CC[Mg]Br
Reactant: C1CCOC1
Reactant: CCOC(=O)c1nnc(N)o1
Product: CCC(O)(CC)c1nnc(N)o1
Reaction time: 0.5 h

Procedure:
To a solution of ethyl magnesium bromide (200 mmol) in 300 mL of THF at 0° C. was added a suspension of ethyl 5-amino-1,3,4-oxadiazol-2-carboxylate (8.00 g, 50.9 mmol; Chemical Abstract, 1966, 64, 3558a) in THF. The reaction mixture was brought to rt and 30 min later quenched with NH4Cl. After extraction with EtOAc and drying over MgSO4, the solvent was removed. The crude product thus obtained was triturated, filtered and dried to yield the title compound.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C@@H:13]([OH:15])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1CCN2C(=NCCC2)CC1.[Cl:29][C:30]([Cl:34])([Cl:33])[C:31]#[N:32]>C(OCC)C>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([C@@H:13]([O:15][C:31](=[NH:32])[C:30]([Cl:34])([Cl:33])[Cl:29])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: N#CC(Cl)(Cl)Cl
Reactant: C[C@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: C[C@H](OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 93.2 %

Procedure:
A solution of 25.82 g (100 mmol) of (1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol in 200 mL dry diethyl ether under nitrogen atmosphere was cooled in an ice/water bath. Neat 3 mL (20 mmol, 0.2 equiv) DBU was added to the reaction flask then the mixture was stirred at 0° C. for ten min. Slowly 15 mL (150 mmol, 1.5 equiv.) trichloroacetonitrile was added dropwise over 15 min. The reaction was stirred at 0° C. for 2 hr. during which time it became deep yellow in color. The volatiles were removed under vacuum using a cool bath (<35° C.) to give a pale brown mobile liquid which was purified by column chromatography on silica gel (3″×10″ pad) in two batches eluting with hexanes/EtOAc (9/1) then hexanes/EtOAc (4/1). The product fractions were combined and the solvent removed under vacuum to give 37.5 g of the title compound as a pale yellow oil. 1H-NMR (CDCl3): δ: 1.74 (3H, d, J=6.5 Hz), 6.07 (1H, q, J=6.5 Hz), 7.82 (1H, s), 7.86 (2H, s), 8.40 (1H, br. s) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1>CN(C=O)C.ClCCl>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:17]=3)[N:12]([CH2:37][O:38][C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=3)[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: ClCOc1ccc(Cl)cc1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(CN3CCOCC3)cc2c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(COc2ccc(Cl)cc2)c2ccc(CN3CCOCC3)cc2c1=O
Temperature: 100 °C
Yield: 71 %

Procedure:
A suspension of N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (0.21 gm) from Preparation No. 40 and cesium carbonate (0.33 gm) in DMF (2 mL) is treated with α,4-dichloroanisole (0.13 gm). The mixture is tightly capped and heated to 100° C. for 3 hrs. The reaction mixture is allowed to cool to room temperature, diluted with dichloromethane (50 mL) and washed with water. The aqueous phase is extracted with two additional portions of dichloromethane. The combined organic phase is washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product is purified by flash column chromatography eluting with 1% to 4% methanol in dichloromethane and then by recrystallization with acetonitrile to afford 0.20 gm of the title compound as a white solid.
Reaction SMILES: [C:1]([CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1)(=O)[CH3:2].C([O-])(C)=O.[NH4+].[BH3-]C#[N:27].[Na+].O>C1COCC1.CO>[NH2:27][CH:1]([CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)C1CN(C(=O)OCc2ccccc2)CCO1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(N)C1CN(C(=O)OCc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 50 h
Yield: 39.8 %

Procedure:
To a solution of benzyl 2-acetylmorpholine-4-carboxylate (5.0 g, 19 mmol) in THF/MeOH (1/5, 100 mL) were added AcONH4 (14.6 g, 190 mmol) and NaBH3CN (11.8 g, 190 mmol). The mixture was stirred at room temperature for 50 hr. The mixture was concentrated to give the crude. Water (20 mL) was added and the mixture was extracted by ethyl acetate (60 mL*3). 1N HCl was added into the combined organic layers. The aqueous layer was concentrated, brought to above pH >8 with 2N NaOH and extracted by ethyl acetate (60 mL*3). The organic layer was washed with brine, dried over sodium sulfate. The mixture was concentrated to give benzyl 2-(1-aminoethyl)morpholine-4-carboxylate (2.0 g, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[CH:18][NH:19][CH:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.[Cl:23][C:24]([Cl:29])([Cl:28])[C:25](Cl)=[O:26]>C(Cl)Cl>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[C:18]([C:25](=[O:26])[C:24]([Cl:29])([Cl:28])[Cl:23])[NH:19][CH:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Fc1ccccc1C1=NCc2c[nH]cc2-c2ccc(Cl)cc21
Solvent: ClCCl
Product: O=C(c1[nH]cc2c1CN=C(c1ccccc1F)c1cc(Cl)ccc1-2)C(Cl)(Cl)Cl

Procedure:
A mixture of 0.7 g (2.2 mmol) of 8-chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine and 2.0 ml (18 mmol) of trichloroacetyl chloride in 20 ml of methylene chloride was refluxed for 7 days. The resulting precipitate was collected by filtration and partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a white solid mp 240°-245° (dec).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15]Br)[CH:7]=1.[OH:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=[O:24].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[C:3]([CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[O:12][CH2:13][CH2:14][CH2:15][O:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=[O:24])([OH:2])=[O:19]
Reactant: O=C(O)c1ccccc1O
Reactant: COC(=O)C(Cc1cccc(OCCCBr)c1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COC(Cc1cccc(OCCCOc2ccccc2C(=O)O)c1)C(=O)O

Procedure:
The title compound was prepared from 3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester (Example 323, Step 1) and 2-hydroxy-benzoic acid via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (example 285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) for C20H22O7 [M+H]+: 375.2.
Reaction SMILES: C1(C2CC2C(Cl)=O)C=CC=CC=1.[C:13]1([CH:19]2[CH2:21][CH:20]2[C:22]([N:24]=[C:25]=[S:26])=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][C:34]=1[O:35][C:36]1[C:45]2[C:40](=[CH:41][C:42]([O:48][CH3:49])=[C:43]([O:46][CH3:47])[CH:44]=2)[N:39]=[CH:38][CH:37]=1)[NH2:31].C1(C)C=CC=CC=1>C(O)C>[C:13]1([CH:19]2[CH2:21][CH:20]2[C:22]([N:24]=[C:25]=[S:26])=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl:27][C:28]1[CH:29]=[C:30]([NH:31][C:25]([NH:24][C:22]([CH:20]2[CH2:21][CH:19]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:23])=[S:26])[CH:32]=[CH:33][C:34]=1[O:35][C:36]1[C:45]2[C:40](=[CH:41][C:42]([O:48][CH3:49])=[C:43]([O:46][CH3:47])[CH:44]=2)[N:39]=[CH:38][CH:37]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)C1CC1c1ccccc1
Agent: O=C(N=C=S)C1CC1c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)C4CC4c4ccccc4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
2-Phenyl-1-cyclopropanecarbonyl isothiocyanate was prepared using commercially available 2-phenyl-1-cyclopropanecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2-Phenyl-1-cyclopropanecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were 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 (48 mg, yield 60%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH2:7]([N:14]=[C:15]=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1COCC1>CN(C1C=CN=CC=1)C.CN1C(=O)CCC1>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1][C:15]([NH:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:16]
Reactant: O=C=NCc1ccccc1
Reactant: Nc1nccs1
Agent: CN(C)c1ccncc1
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)Nc1nccs1

Procedure:
A 2-amino-thiazole derivative is condensed with a benzylisocyanate by heating with a basic catalyst (typically DMAP) in an inert organic solvent (typically THF or NMP) to afford the corresponding 1-(thiazol-2-yl)-3-benzyl-urea, which is purified by silica gel chromatography.