Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]([CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:19]([C:21]1[CH:41]=[CH:40][C:24]2[N:25]([CH3:39])[C:26]([CH2:28][NH:29][C:30]3[CH:35]=[CH:34][C:33]([C:36](=[NH:38])[NH2:37])=[CH:32][CH:31]=3)=[N:27][C:23]=2[CH:22]=1)=[O:20].Cl[C:50]([O:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[O:51].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[CH3:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][O:52][C:50](/[N:38]=[C:36](\[NH2:37])/[C:33]1[CH:32]=[CH:31][C:30]([NH:29][CH2:28][C:26]2[N:25]([CH3:39])[C:24]3[CH:40]=[CH:41][C:21]([C:19]([N:18]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=4)[CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[O:20])=[CH:22][C:23]=3[N:27]=2)=[CH:35][CH:34]=1)=[O:51]
Reactant: CCCCCCOC(=O)Cl
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCOC(=O)/N=C(\N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1

Procedure:
55 g of 1-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide tosylate was dissolved in 437 ml of acetone and 273 ml of water. 16.4 g of hexyl chloroformate and 34 g of potassium carbonate was added to it at a temperature of about 15° C. After the end of the reaction, the precipitated product is filtered off and washed with acetone/water. Dissolved the obtained solid in 270 ml of acetone under heating and then filtered. The title product was crystallized by the addition of 220 ml of water. The isolated substance is dried under reduced pressure at 45° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:9](=[NH:22])(C1C=CC=CC=1)[C:10]1C=CC=CC=1.O1CCOCC1.ClCC=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C)C>[Cl:8][C:6]1[CH:5]=[N:4][N:3]2[CH:10]=[CH:9][N:22]=[C:2]2[CH:7]=1
Reactant: Clc1cnnc(Cl)c1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Clc1cnn2ccnc2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
A mixture of 3,5-dichloropyridazine (1.49 g, 10.0 mmol, Maybridge, MO08501), benzophenone imine (2.01 g, 11.1 mmol, Aldrich, Cat. No. 293733), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (208 mg, 0.360 mmol), tris(dibenzylideneacetone)dipalladium(0) (165 mg, 0.180 mmol) and 1,4-dioxane (30 mL) was degassed and recharged with nitrogen for three times, and was heated and stirred at 90° C. overnight. After cooling, the mixture was filtered through a pad of silica gel, and washed with THF. [LCMS (M+H)+: m/z=294.1/296.0 corresponds to 5-chloro-N-(diphenylmethylene)pyridazin-3-amine]. The filtrate was treated with 3 N HCl aq. (6 ml) at RT and stirred for 30 min. The mixture was adjusted with NaOH (2 N) to pH=7. The resulting mixture was concentrated under reduced pressure to about the volume of 30 mL. [LCMS (M+H)+: m/z=130.1/132.0 corresponds to 5-chloropyridazin-3-amine]. Isopropanol (50 mL) and chloroacetaldehyde (10.0 mL, 78.7 mmol) was added to the solution. The mixture was heated and stirred at 90° C. for 5 h. After cooling, the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and extracted with water. The combined aqueous layers were adjusted to about pH=9 with 1 N NaOH aq. Solution. The resulting solution was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product (0.988 g, 64.3%) which was directly used in next step reaction without further purification. LCMS (M+H)+: m/z=153.9/155.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:18]([CH3:38])=[C:19]([CH3:37])[C:20]4[O:24][C:23]([CH3:26])([CH3:25])[C:22]([C:28]5[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=5)(O)[C:21]=4[C:35]=3[CH3:36])[CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>CCCCCC.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]3[C:18]([CH3:38])=[C:19]([CH3:37])[C:20]4[O:24][C:23]([CH3:26])([CH3:25])[CH:22]([C:28]5[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=5)[C:21]=4[C:35]=3[CH3:36])[CH2:15][CH2:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccc(C)cc3)C(C)(C)O4)CC2)cc1OC
Solvent: CO
Solvent: CCCCCC
Product: COc1ccc(C2CCN(c3c(C)c(C)c4c(c3C)C(c3ccc(C)cc3)C(C)(C)O4)CC2)cc1OC
Yield: 51 %

Procedure:
Using 5-(4-(3,4-dimethoxyphenyl)piperidino)-3-(4-methylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Example 78, the title compound was synthesized in the same manner as in Example 46. Yield 51%. mp. 103–105° C. (hexane-methanol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23].[CH3:24][C:25]([OH:29])([CH:27]=[CH2:28])[CH3:26]>C(Cl)Cl>[OH:29][C:25]([CH3:26])([CH3:24])[CH:27]=[CH:28][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23]
Reactant: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccc(Br)cc12
Reactant: C=CC(C)(C)O
Solvent: ClCCl
Product: CC(C)(O)C=Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1

Procedure:
Obtained by a procedure similar to that described in Example 1, using 5-bromo-3-(2-phthalimidoethyl)-1H-indole (which was prepared as described in U.S. Pat. No. 4,252,803) and 2-methylbut-3-en-2-ol, as a foam. Rf 0.10 (SS 8). Found: C,72.31; H,6.09; N,.7.16. C23H22N2O3 ; 0.15 CH2Cl2 requires C,71.82; H,5.81; N,7.23%.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1.[C:13]([NH:18][C@H:19]([C:28]([O:30][CH3:31])=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1)(=[O:17])[CH:14]([CH3:16])[CH3:15].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:13]([NH:18][C@H:19]([C:28]([O:30][CH3:31])=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:12][CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][O:2][CH3:1])=[CH:5][CH:6]=2)=[CH:23][CH:22]=1)(=[O:17])[CH:14]([CH3:15])[CH3:16]
Reactant: COCc1ccc(CCO)cc1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C(C)C
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCc1ccc(CCOc2ccc(C[C@H](NC(=O)C(C)C)C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
2-[4-(Methoxymethyl)phenyl]ethanol (0.6 g, 3.61 mmol) and methyl N-isobutyryltyrosinate (1.15 g, 4.34 mmol) were mixed in dichloromethane (20 ml, dry). 1,1′-(Azodicarbonyl)dipiperidine (1.1 g, 4.36 mmol) and triphenylphosphine (1.14 g, 4.35 mmol) were then added respectively. The mixture was stirred at room temperature overnight and filtered. The filtrate was evaporated in vacuum to dry. Column chromatography of the residue on silica gel using ethyl acetate/heptane (gradient 5:95 to 50:50) as eluant gave 0.71 g desired product, yield 48%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[N:12]1([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[CH:10]=[N:9][CH:8]=[CH:7]3)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: Brc1cccc2ccncc12
Product: c1cc(N2CCNCC2)c2cnccc2c1

Procedure:
8-(Piperazin-1-yl)isoquinoline is prepared from 8-bromoisoquinoline and piperazine using the coupling procedure as described in Step 1 of Preparation 54A to afford about 270 mg (88%). EIS-MS 214.0 M+1
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].CC(C)([O-])C.[K+].[C:13]([O:17][C:18](=[O:29])[C:19]1[CH:24]=[CH:23][C:22](F)=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27])([CH3:16])([CH3:15])[CH3:14].O>O1CCCC1>[C:13]([O:17][C:18](=[O:29])[C:19]1[CH:24]=[CH:23][C:22]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27])([CH3:16])([CH3:14])[CH3:15]
Reactant: CN(C)CCO
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCOc1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
To a solution of 2-dimethylaminoethanol (6.67 mL, 64.8 mmol) in anhydrous tetrahydrofuran (100 mL), at 0° C., potassium tert-butoxide (6.66 g, 59.4 mmol) was added. The mixture was stirred at 0° C. for 1 h, then 4-fluoro-2-nitro-benzoic acid tert-butyl ester (10 g, 41.5 mmol) in anhydrous tetrahydrofuran (50 mL) was added dropwise. After 2 hours at 0° C., the mixture was poured into water (1 L) and extracted with ethyl acetate (4×200 mL). The organic phase was washed with water, brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The crude was purified by flash chromatography, using dichloromethane-methanol-33% NH4OH 9:1:0.01 as eluant, to give the title compound (4.53 g) as yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:15][CH2:16][C@:17]2([CH3:23])[CH2:21][O:20]C(=O)[NH:18]2)[CH:5]=[C:6]([CH3:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].O[Li].O>C(O)C.O>[NH2:18][C@:17]([CH3:23])([CH2:16][CH2:15][C:4]1[CH:5]=[C:6]([CH3:14])[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[C:2]([Br:1])[CH:3]=1)[CH2:21][OH:20]
Reactant: CCCCCOc1c(C)cc(CC[C@]2(C)COC(=O)N2)cc1Br
Agent: [Li]O
Solvent: O
Solvent: CCO
Product: CCCCCOc1c(C)cc(CC[C@@](C)(N)CO)cc1Br
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-4-[2-(3-Bromo-5-methyl-4-pentyloxy-phenyl)-ethyl]-4-methyl-oxazolidin-2-one (58 mg, 0.15 mmol) in ethanol (2 ml) is added a solution of LiOH-hydrate (180 mg, 4.28 mmol) in water (1.5 ml). The mixture is stirred at 90° C. for 2 h. After cooling to RT and extraction with AcOEt (2×20 ml), the organic phase is dried using MgSO4. Evaporation of solvent is followed by reverse phase preparative HPLC (20×250 mm, RP18: 10 μm) using acetonitrile/water/trifluoroacetic acid=900/100/1 as eluent to yield the title compound as white solid. MS (ESI+): m/z=358/360 (MH+).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH2:6])=[S:5])[CH3:2].[CH2:7]=[C:8]1O[C:10](=[O:11])[CH2:9]1>C(O)(=O)C>[CH2:1]([N:3]1[C:8]([CH3:7])=[CH:9][C:10](=[O:11])[N:6]=[C:4]1[SH:5])[CH3:2]
Reactant: C=C1CC(=O)O1
Reactant: CCNC(N)=S
Solvent: CC(=O)O
Product: CCn1c(C)cc(=O)nc1S

Procedure:
18 Grams of N-ethyl-thiourea were dissolved in 50 m. of glacial acetic acid, boiled to reflux and treated dropwise with 17.2 g of diketene. The mixture was then boiled at reflux for 20 minutes and subsequently evaporated to 50 ml. While cooling and stirring, the residue was treated with 50 ml of water. The yellowish crystals which precipitated were filtered off under suction and recrystallized from tetrahydrofuran to give 1-ethyl-1,4-dihydro-2-mercapto-6-methyl-4-oxo-pyrimidine; melting point 190°.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH:4]([O:5][S:13]([CH3:12])(=[O:15])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OC(CCCl)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OC(CCCl)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of the 3-chloro-1-phenyl-propan-1-ol (1.5 g, 8.79 mmol) in DCM at 0° C. (50 mL) was added TEA (1.6 mL, 11.4 mmol) followed by MsCl (0.75 mL, 9.7 mmol). The reaction mixture was stirred 1.5 hours at 0° C., quenched with ice, and partitioned between a saturated solution of NaHCO3 and DCM. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and concentrated at 0° C. The methanesulfonic acid 3-chloro-1-phenyl-propyl ester (95% crude yield, 2.08 g) thus prepared was used in the next step without purification.
Reaction SMILES: [C:1](=[O:26])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH:3]1[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[NH2:14])=[CH:9][N:8]=2)[CH2:4]1.[CH:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([CH3:29])[CH3:28]>C(Cl)Cl>[CH:27]([N:30]1[CH2:35][CH2:34][N:33]([C:1]([O:2][CH:3]2[CH2:4][N:5]([C:7]3[CH:12]=[CH:11][C:10]([C:13](=[O:15])[NH2:14])=[CH:9][N:8]=3)[CH2:6]2)=[O:26])[CH2:32][CH2:31]1)([CH3:29])[CH3:28]
Reactant: CC(C)N1CCNCC1
Reactant: NC(=O)c1ccc(N2CC(OC(=O)Oc3ccc([N+](=O)[O-])cc3)C2)nc1
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)OC2CN(c3ccc(C(N)=O)cn3)C2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 10.1 %

Procedure:
To a solution of 1-(5-carbamoylpyridin-2-yl)-azetidin-3-yl 4-nitrophenyl carbonate (0.36 g, 1 mmol) in DCM (5 mL) under nitrogen was added 1-isopropylpiperazine (0.13 g, 1 mmol). The resulting solution was stirred under N2 at room temperature for 24 h. The reaction mixture was then filtered and the filter cake was washed with DCM. The combined filtrates were concentrated to afford the crude product. After further purified by preparative HPLC, the title compound (35 mg, 10%) was obtained as a yellow solid. [1HNMR (500 MHz, CDCl3) δ8.58 (d, 1H), 7.96 (dd, 1H), 7.76 (s, 1H), 7.77 (s, 1H), 7.15 (s, 1H), 6.41 (d, 1H), 5.21 (m, 1H), 4.32 (m, 2H), 3.92 (m, 2H), 3.41 (m, 4H), 2.65 (m, 1H), 2.40 (m, 4H), 0.95 (d, 6H); LCMS RtA=1.59 min, [M+H]+=348.2].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([OH:18])[CH3:17])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[CH:19](O)=O>O1CCCC1>[NH:8]1[C:7]2[CH:6]=[CH:5][C:4]([O:9][C:10]3[CH:15]=[CH:14][C:13]([CH:16]([OH:18])[CH3:17])=[CH:12][CH:11]=3)=[CH:3][C:2]=2[N:1]=[CH:19]1
Reactant: O=CO
Reactant: CC(O)c1ccc(Oc2ccc(N)c(N)c2)cc1
Solvent: C1CCOC1
Product: CC(O)c1ccc(Oc2ccc3[nH]cnc3c2)cc1

Procedure:
Crude 1-{4-[(3,4-diaminophenyl)oxy]phenyl}ethanol was dissolved in 10 mL of tetrahydrofuran and 5 mL of 88% formic acid and heated at 100 degrees Centigrade for 2 hours. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate and saturated NaHCO3. The organic layer was separated and washed twice with saturated NaHCO3. The organic layer was dried over MgSO4 and concentrated. The residue was dissolved in 10 mL of THF and heated at 100 degrees centigrade with 5 mL of aqueous 10% LiOH for 2 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The organic layers were combined, dried over MgSO4 and concentrated to give crude 1-[4-(1H-benzimidazol-5-yloxy)phenyl]ethanol, which was carried on crude to the next step without further purification. (M+1) 239.0, 1.39 min (LC/MS method B)
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:29][CH3:30])=[C:5]([C:10]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[CH2:24][CH2:25][CH2:26][CH2:27][OH:28])(=[O:16])=[O:15])=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:2].[CH3:31][S:32](Cl)(=[O:34])=[O:33].N1C=CC=CC=1>ClCCl>[CH2:1]([C:3]1[C:4]([O:29][CH3:30])=[C:5]([C:10]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[CH2:24][CH2:25][CH2:26][CH2:27][O:28][S:32]([CH3:31])(=[O:34])=[O:33])(=[O:16])=[O:15])=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1ccc(NS(=O)(=O)c2ccc(F)cc2CCCCO)c(C(=O)OC)c1OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1ccc(NS(=O)(=O)c2ccc(F)cc2CCCCOS(C)(=O)=O)c(C(=O)OC)c1OC
Yield: 96.6 %

Procedure:
A solution of Example 615C (288 mg, 0.66 mmol), methanesulfonyl chloride (188 mg, 1.64 mmol) and pyridine (104 mg, 1.32 mmol) in dichloromethane (5 mL) was stirred at ambient temperature overnight. Dichloromethane (20 mL) was added and the solution was washed with 1N HCl (2×10 mL) and brine (2×10 mL). The solution was then dried (MgSO4), filtered, and concentrated to provide the desired product (0.33 g, 97%).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][C:29]([OH:32])([CH3:31])[CH3:30])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:34]1[CH2:41][CH2:40][CH2:39][C@H:35]1[C:36]([NH2:38])=[O:37]>>[OH:32][C:29]([CH3:31])([CH3:30])[CH2:28][C@@:19]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:18][C:17](=[O:33])[N:16]([C@H:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:34]4[CH2:41][CH2:40][CH2:39][C@H:35]4[C:36]([NH2:38])=[O:37])=[N:7][CH:6]=3)=[CH:9][CH:10]=2)[CH3:15])[CH2:21][CH2:20]1
Reactant: C[C@@H](c1ccc(-c2ccc(F)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: NC(=O)[C@@H]1CCCN1
Product: C[C@@H](c1ccc(-c2ccc(N3CCC[C@H]3C(N)=O)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 30 %

Procedure:
The title compound was prepared from 3-{(S)-1-[4-(6-fluoro-pyridin-3-yl)-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one and L-prolinamide following a procedure analogous to that described in Example 53. Yield: 30% of theory; Mass spectrum (ESI+): m/z=543 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[C:4]([CH3:10])=[N:3]1.C(Cl)(=O)C(Cl)=O.[NH2:17][C:18]1[CH:19]=[C:20]([CH:37]=[CH:38][CH:39]=1)[O:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([CH:28]=[C:29]([NH:31][C:32]([CH:34]3[CH2:36][CH2:35]3)=[O:33])[N:30]=2)[N:27]=1.[OH-].[Na+]>ClCCl.CN(C)C=O.CN1CCCC1=O>[CH:34]1([C:32]([NH:31][C:29]2[N:30]=[C:25]3[CH:24]=[CH:23][C:22]([O:21][C:20]4[CH:19]=[C:18]([NH:17][C:7]([C:5]5[C:4]([CH3:10])=[N:3][N:2]([CH3:1])[CH:6]=5)=[O:8])[CH:39]=[CH:38][CH:37]=4)=[N:27][N:26]3[CH:28]=2)=[O:33])[CH2:35][CH2:36]1
Reactant: Cc1nn(C)cc1C(=O)O
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: Cc1nn(C)cc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 58.4 %

Procedure:
To a suspension of 1,3-dimethyl-1H-pyrazole-4-carboxylic acid (140 mg, 1.0 mmol) in dichloromethane (10 mL) were added N,N-dimethylformamide (2 drops) then oxalyl chloride (0.171 mL, 2.0 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure. The residue was diluted with N-methylpyrrolidone (5 mL), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (155 mg, 0.50 mmol) was added thereto, and the mixture was stirred at room temperature for 6 hr. To the reaction mixture was added 0.5N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→70/30). The objective fraction was concentrated under reduced pressure, and the residue was washed with diisopropyl ether to give the title compound (126 mg, yield 58%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[S:3][CH2:4][C:5](=O)[C:6]([CH3:9])([CH3:8])[CH3:7].Cl.[NH2:14][OH:15]>>[F:1][C:2]([F:12])([F:11])[S:3][CH2:4][C:5](=[N:14][OH:15])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)C(=O)CSC(F)(F)F
Reactant: NO
Agent: Cl
Product: CC(C)(C)C(CSC(F)(F)F)=NO

Procedure:
Using the method of example 2, 1-trifluoromethylthio-3,3-dimethyl-2-butanone was reacted with hydroxylamine hydrochloride to provide the desired oxime, m.p. 94.5° to 96°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[CH2:24]([NH:26][CH2:27][CH:28]1[CH2:30][CH2:29]1)[CH3:25]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:26]([CH2:27][CH:28]4[CH2:30][CH2:29]4)[CH2:24][CH3:25])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1
Reactant: CCNCC1CC1
Reactant: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2
Product: CCN(Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2)CC1CC1

Procedure:
In the manner given in Preparation 29, 8-bromo-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine is treated with ethyl(cyclopropylmethyl)amine to give 8-bromo-1-[[(cyclopropylmethyl)ethylamino]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 32 8-(Trifluoromethyl)-1-[[(cyclopropylmethyl)methylamino]methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][N:36]=1)[C:29]#[N:30].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:30]=[C:29]([C:28]2[CH:31]=[CH:32][C:33]([O:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:42])[F:43])=[CH:37][N:36]=3)=[C:26]([O:25][CH3:24])[CH:27]=2)[N:2]([CH3:1])[N:3]=1
Reactant: COc1cc(C#N)ccc1Oc1ccc(C(F)(F)F)cn1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Agent: Cl[Fe](Cl)Cl
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2nc(-c3c(F)cccc3Cl)nn2C)ccc1Oc1ccc(C(F)(F)F)cn1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (3.75 g), 3-methoxy-4-(5-trifluoromethylpyridine-2-yloxy)benzonitrile (3.03 g), anhydrous iron (III) chloride (1.70 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (300 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent and washed with hexane to give 2.80 g of desired compound.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH:8]([CH3:21])[CH2:9][N:10]2[C:14](=[CH:15][C:16](OCC)=[O:17])[CH2:13][S:12][C:11]=12)=[O:6])([CH3:3])[CH3:2].[CH3:22][NH2:23]>>[CH3:22][NH:23][C:16](=[O:17])[CH:15]=[C:14]1[CH2:13][S:12][C:11]2=[C:7]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH:8]([CH3:21])[CH2:9][N:10]12
Reactant: CN
Reactant: CCOC(=O)C=C1CSC2=C(C(=O)OC(C)C)C(C)CN12
Product: CNC(=O)C=C1CSC2=C(C(=O)OC(C)C)C(C)CN12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.2 g of ethyl (7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo[2,1-b]thiazol-3-ylidene]acetate was suspended in 25 ml of a 40% aqueous solution of monomethylamine and stirred at room temperature for 24 hours. The precipitate was collected by filtration, washed with water and recrystallized from ethanol to thereby give 1.2 g of the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1[N:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:29](O)=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][C:18]=2[F:32])=[CH:13][N:12]=1.[F:33][C:34]([F:39])([F:38])[C@@H:35]([NH2:37])[CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:10][C:11]1[N:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:29]([NH:37][C@@H:35]([CH3:36])[C:34]([F:39])([F:38])[F:33])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][C:18]=2[F:32])=[CH:15][N:16]=1
Reactant: Nc1ncc(-c2ccc(-c3ccccc3C(=O)O)cc2F)cn1
Reactant: C[C@H](N)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1)C(F)(F)F

Procedure:
To a solution of DIPEA (47 mg, 0.36 mmol) in DMF (2 mL) were added 4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid (75 mg, 0.24 mmol), (S)-1,1,1-trifluoropropan-2-amine (30 mg, 0.27 mmol) and HATU (110 mg, 0.290 mmol).