Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8][CH2:9][CH:10]([F:12])[F:11])[C@H:3]1[C:14]([OH:16])=[O:15].[C:18]([C@H:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)#[N:19]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8][CH2:9][CH:10]([F:11])[F:12])[C@H:3]1[C:14]([O:16][C@@H:20]([C:18]#[N:19])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:22]=1)=[O:15]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C\C(=O)OCC(F)F
Reactant: N#C[C@H](O)c1cccc(Oc2ccccc2)c1
Solvent: ClC(Cl)Cl
Product: CC1(C)[C@H](C(=O)O[C@@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OCC(F)F

Procedure:
Using the procedure of Step F of Example 9, (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2,2-difluoroethoxy)-1-propenyl]-cyclopropane-carboxylic acid and (R)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain (R)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2,2-difluoroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+117.5°±3° (c=0.6% in chloroform).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1F.C(N(C(C)C)CC)(C)C>CS(C)=O>[Cl:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1[N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2Cl)CC1
Temperature: 25 °C

Procedure:
A solution of t-butyl 1-piperazinecarboxylate 38 (1.0 g., 5.37 mmole), 3-chloro-4-fluoronitrobenzene (0.94 g., 5.37 mmole) and diisopropylethylamine (0.70 g., 5.4 mmole) in DMSO (30 mL.) was heated 16 hours at 100°, cooled to r.t. and poured into ice water (300 mL.). The suspension was extracted with ethyl acetate (2×60 mL.). The combined organic layers were washed with water (3×40 mL.), dried over Na2SO4 and evaporated to dryness to give an orange solid which was recrystallized twice from methanol to give the title compound, 1.2 g. MS (M+H)+ 342.0
Reaction SMILES: C([O:3][C:4]([CH:6]([NH:15][C@H:16]([C:18]([N:20]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[C:28]([OH:30])=[O:29])=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[C:4]([CH:6]([NH:15][C@H:16]([C:18]([N:20]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[C:28]([OH:30])=[O:29])=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)N1CCCCCC[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](NC(CCc1ccccc1)C(=O)O)C(=O)N1CCCCCC[C@H]1C(=O)O
Reaction time: 3 h

Procedure:
To a solution of 1-[N-(1-ethoxycarbonyl-3-phenylpropyl) (S)-alanyl]azacyclooctane-2(S)-carboxylic acid (prepared as described in Example 41) in ethanol, add 0.25N sodium hydroxide. After three hours, concentrate the reaction mixture and absorb it on an XAD-2 resin column and elute with water and then with methanol. Concentrate the methanol eluant to give a residue and absorb this residue on a silica gel column and elute with chloroform:methanol: 14% ammonium hydroxide 1:1:1. Concentrate the desired eluant fractions to obtain the title compound.
Reaction SMILES: [N:1]1([CH:6]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>N1C=CC=CC=1.O1CCCC1>[N:1]1([CH:6]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:19](=[O:22])[CH2:20][CH3:21])[CH3:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCC(=O)Cl
Reactant: CC(c1cccc(OCCCN)c1)N1CCCC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCC(=O)NCCCOc1cccc(C(C)N2CCCC2)c1
Yield: 71.3 %

Procedure:
211.8 mg of 3-[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]propylamine was dissolved in 2 ml of dry pyridine, and the solution was stirred under ice cooling. A solution of 87 mg of propionyl chloride in 2 ml of dry tetrahydrofuran was added dropwise in small portions. After the addition, the reaction temperature was adjusted to room temperature, and the mixturwe was stirred for 2 hours. The solvent was distilled off, and 10 ml of water was added. Furthermore, 300 mg of potassium carbonate was added. The precipitated oily product was extracted with 30 ml of chloroform. The extract was dried over anhydrous potassium carbonate, and the solvent was distilled off. The residue was purified by TLC (developing solvent: chloroform/methanol=9/l) to afford 185 mg of N-[3-[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]propyl] propionamide as an oil.
Reaction SMILES: [N:1]1[N:2]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[O:22])=[CH:13][CH:12]=2)[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=12.[C:23]1(=O)[CH2:27][CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH:23]1([N:8]2[CH2:9][CH2:10][C:4]3=[CH:3][N:2]([C:11]4[CH:12]=[CH:13][C:14]([N:17]5[CH2:21][CH2:20][CH2:19][C:18]5=[O:22])=[CH:15][CH:16]=4)[N:1]=[C:5]3[CH2:6][CH2:7]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCCC1
Reactant: O=C1CCCN1c1ccc(-n2cc3c(n2)CCNCC3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: O=C1CCCN1c1ccc(-n2cc3c(n2)CCN(C2CCCC2)CC3)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-[4-(5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)phenyl]-2-pyrrolidinone (may be prepared as described in Description 22) (45 mg, 0.15 mmol) in dichloromethane (3 ml) was added cyclopentanone (26 mg, 0.30 mmol) and acetic acid (2 drops). The resulting mixture was stirred at room temperature, under argon, for 20 minutes. Sodium triacetoxyborohydride (64 mg, 0.30 mmol) was added and stirring continued for 1.5 hours. The resulting crude mixture was diluted with methanol and then purified by SCX, eluting with methanol and then with 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo. Crude product was triturated with ether to afford the title compound (E24). MS (ES+) m/e 365 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[F:11])#[N:2].[C:12]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[CH:17]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][C:4]=1[F:11])#[N:2]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(C=O)cc1F
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1ccc(C#N)c(F)c1

Procedure:
A solution of the product from Step A (970 mg, 6.5 mmol) and (carbethoxymethylene)triphenylphosphorane (2.3 g, 6.5 mmol) was heated at reflux in 50 mL of toluene overnight. The reaction was concentrated in vacuo, triturated with ether, and filtered. The filtrate was concentrated in vacuo, and purified by flash column chromatography on silica gel (15% EtOAc/hexane) to yield the desired product as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[I-:13].O>N1C=CC=CC=1>[OH:1][C:2]1[C:12]([I:13])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1ccc(O)nc1
Reactant: [I-]
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1cnc(O)c(I)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
Ethyl 6-hydroxynicotinate (2.0 g, 12.0 mmol) was dissolved in pyridine (60 mL), which was then added with iodide (6.07 g, 23.9 mmol) and stirred at 60° C. overnight. The reaction solution was then added with water at room temperature and extracted with ethyl acetate. Subsequently, the organic layer was washed with a saturated aqueous solution of sodium sulfite and brine, and dried over sodium sulfate. The obtained residue was purified using column chromatography (chloroform/methanol) and concentrated in vacuo. Ethyl 6-hydroxy-5-iodonicotinate (2.9 g, yield 83%) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9](OS(C(F)(F)F)(=O)=O)[CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+].B1([C:49]2[CH:54]=[CH:53][CH:52]=[N:51][CH:50]=2)OCCCO1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([C:49]2[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=2)[CH:8]=1
Reactant: COC(=O)c1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1OS(=O)(=O)C(F)(F)F
Reactant: c1cncc(B2OCCCO2)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1-c1cccnc1
Temperature: 95 °C
Reaction time: 16 h
Yield: 99.1 %

Procedure:
To a solution of methyl 4-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(trifluoromethanesulfonyl)oxybenzoate (333 mg, 0.6555 mmol) in toluene (6 ml) were added tetrakistriphenylphosphine palladium (23 mg, 0.0199 mmol), aqueous solution of sodium carbonate (2M aqueous solution, 1.00 ml), lithium chloride (56 mg, 1.3241 mmol) and ethanolic solution (1.3 ml) of pyridine-3-boronic acid 1,3-propanediol cyclic ester (159 mg, 0.9814 mmol) and the mixture was heated with stirring at 95° C. for 16 hours. The reaction solution was diluted with ethyl acetate (100 ml), washed with water and dried and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the title compound (284 mg, 0.6498 mmol, 99%).
Reaction SMILES: [CH3:1][C:2]([CH3:58])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:55])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:54])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42]([NH:44][C@@H:45]([C:47]4[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=4)[CH3:46])=[O:43])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:57])[CH3:56])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[Cl:53][C:50]1[CH:49]=[CH:48][C:47]([C@H:45]([NH:44][C:42](=[O:43])/[CH:41]=[CH:40]/[C@:23]23[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]2[C@@H:25]2[C@@:20]([CH3:54])([CH2:21][CH2:22]3)[C@@:19]3([CH3:55])[C@@H:28]([C@:29]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:56])([CH3:57])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:58])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]4)[CH2:27][CH2:26]2)[CH3:46])=[CH:52][CH:51]=1
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@H](C)c2ccc(Cl)cc2)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@H](C)c2ccc(Cl)cc2)CC1=O
Temperature: 25 °C
Yield: 72.7 %

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-(((R)-1-(4-chlorophenyl)ethyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (2.5 g, 3.05 mmol) in Dichloromethane (20 mL) was added TFA (13 mL, 3.05 mmol). The reaction mixture was stirred at r.t. for 2 hs and evaporated in vacuo to afford crude product, which was diluted with DCM, washed with water, saturated NaHCO3 twice, water, 2 M HCl, water, and the organic layer was concentrated, diluted with MeOH/H2O (1:5, 36 mL) and freeze-dried under high vacuo to give the product 4-(((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-(((R)-1-(4-chlorophenyl)ethyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (1.7 g, 2.217 mmol, 72.6%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) d=12.34-12.04 (m, 1H), 8.43 (d, J=7.8 Hz, 1H), 7.53-7.18 (m, 4H), 6.63 (d, J=15.8 Hz, 1H), 5.92 (d, J=15.8 Hz, 1H), 4.94 (quin, J=7.0 Hz, 1H), 4.39 (dd, J=4.6, 10.9 Hz, 1H), 3.18 (dt, J=6.7, 13.7 Hz, 1H), 2.70 (dd, J=4.3, 10.5 Hz, 2H), 2.58-2.52 (m, 1H), 2.34-1.99 (m, 3H), 1.99-0.56 (m, 48H); LC/MS: m/z calculated 761.4. Found 762.3 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[C:17](F)[CH:16]=1>CN(C)C=O.[Cl-].[NH4+]>[F:14][C:15]1[CH:16]=[C:17]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccnc1
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)cc(Oc2cccnc2)c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a solution of 3-hydroxypyridine (3.25 g) in dimethylformamide (75 ml), 6.75 g of potassium carbonate and 5.0 g of 1,3-difluoro-5-nitrobenzene were added, and the reaction solution was stirred at 100° C. for 6 hours. The reaction solution was cooled, thereafter diluted with a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The combined organic layers were washed with water and a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified by silica gel chromatography to yield the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([F:23])=[CH:9][CH:10]=2)[N:5]([CH3:24])[C:4]1=[O:25])[CH3:2].B(Cl)(Cl)Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([F:23])=[CH:9][CH:10]=2)[N:5]([CH3:24])[C:4]1=[O:25])[CH3:2]
Reactant: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(OC)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 88.6 %

Procedure:
To a stirred solution of (3R)-3-ethyl-7-fluoro-4-(4-methoxybenzoyl)-1-methyl-3,4 dihydroquinoxalin-2(1H)-one (0.19 g, 0.55 mmol) and tetrabutylammonium iodide (0.41 g, 1.1 mmol) in methylene chloride (5 mL), under nitrogen, at −78° C., was added a 1.0 M solution of boron trichloride in methylene chloride (2.8 mL, 2.8 mmol). Stirring was continued at −78° C. for 5 minutes, and the reaction was warmed to 0° C. where it was stirred for 5 h. The reaction was quenched by the addition of ice water, and the resulting mixture was stirred for 10 min. The layers were separated. The organic layer was washed with water and brine and dried over magnesium sulfate. Evaporation of the solvent and purification by eluting it through a short plug of silica gel with 75% hexane/EtOAc gave 0.16 g (88%) of (3R)-3-ethyl-7-fluoro-4-(4-hydroxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one. [α]D25=−300° (c=0.009 G/ML, DMSO); MS (ESI) m/z 329 ([M+H]+); MS (ESI) m/z 327 ([M−H]−); HRMS: calcd for C18H17FN2O3, 328.1223; found (ESI+), 329.13036; Anal. Calcd for C18H17FN2O3: C, 65.85; H, 5.22; N, 8.53. Found: C, 65.73; H, 5.46; N, 8.28.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[CH:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([CH3:20])[CH3:19]>>[CH:18]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[N:3]=[N:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH2:23][CH2:22]1)([CH3:20])[CH3:19]
Reactant: CC(C)N1CCNCC1
Reactant: CC(=O)Nc1ccc(-c2ccc(Cl)nn2)cc1
Product: CC(=O)Nc1ccc(-c2ccc(N3CCN(C(C)C)CC3)nn2)cc1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 3-chloro-6-(4-acetylaminophenyl)pyridazine and 1-isopropylpiperazine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][C:9]2[S:11][CH:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[Cl:14]N1C(=O)CCC1=O>C(O)(=O)C.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[NH:10][C:9]2[S:11][C:12]([Cl:14])=[CH:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cc2ccsc2[nH]1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2cc(Cl)sc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
Using a modified procedure by R. M. Kellogg et al. (J. Org. Chem., 33: 2902-290 (1968)), to a 0° C. solution of 6H-thieno[2,3-b]pyrrole-5-carboxylic acid ethyl ester (Eras, J.; Galvez, C.; Garcia, F., J. Heterocycl. Chem., 21: 215-217 (1984); 1.45 g, 7.44 mmol) in acetic acid (15 mL) and CHCl3 (15 mL) was added N-chlorosuccinimide (1.04 g, 7.81 mmol) over 2 h. The reaction mixture was slowly allowed to warm to room temperature over several hours, stirred overnight, concentrated to remove the chloroform, diluted with water, basified with 5 N NaOH, and extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous NaHCO3, dried over MgSO4, and concentrated. The product was purified by chromatron chromatography (radial) using 90:10 hexanes/diethyl ether and then then then the product obtained was recrystallized using hexanes/diethyl ether (90:10). Last, the product of the recrystallization was further purified by flash column chromatography using 90:10 petroleum ether/isopropyl ether. The resulting product was obtained as a white solid (824 mg, 48%).
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[N:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][CH2:28][OH:29])[CH:20]=3)[N:12]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:14]=2)C=CC=CC=1.[N:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)=[CH:33][CH:32]=1>C1COCC1>[C:15]([C:13]1[CH:14]=[C:10]([NH:9][C:8]([NH:44][C:41]2[CH:40]=[CH:39][C:38]([O:37][C:34]3[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=3)=[CH:43][CH:42]=2)=[O:30])[N:11]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][CH2:28][OH:29])[CH:20]=2)[N:12]=1)([CH3:17])([CH3:18])[CH3:16]
Reactant: Nc1ccc(Oc2ccncc2)cc1
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2cccc(OCCCO)c2)n1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2cccc(OCCCO)c2)n1
Temperature: 60 °C

Procedure:
To a solution of {5-tert-butyl-2-[3-(3-hydroxy-propoxy)-phenyl]-2H-pyrazol-3-yl}-carbamic acid phenyl ester (200 mg, 0.49 mmol) in THF was added 4-(pyridin-4-yloxy)-phenylamine (109 mg, 0.59 mmol). The reaction mixture was heated at 60° C. for 16 h. The reaction mixture was cooled to room temperature, concentrated at reduced pressure, and the residue was dissolved in DMF and methanol. The product was isolated by preparative HPLC, and the HPLC fraction containing the desired product was concentrated at reduced pressure and then partitioned between EtOAc (20 mL) and saturated aq Na2CO3 (10 mL). The organic layer was dried over Na2SO4 and evaporated to give 1-{5-tert-butyl-2-[3-(3-hydroxy-propoxy)-phenyl]-2H-pyrazol-3-yl}-3-[4-(pyridin-4-yloxy)-phenyl]-urea (51.3 mg, 21%). 1H-NMR (DMSO-d6) δ 7.50 (d, 2H), 7.10 (m, 5H), 6.90 (d, 2H), 6.70 (m, 3H), 6.40 (s, 1H), 4.0 (t, 2H), 3.60 (t, 3H), 1.80 (m, 2H), 1.30 (s, 9H); MS LC-MS [M+H]+=502.1, RT=2.36 min.
Reaction SMILES: C1(C)C=CC=CC=1.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[S:13][CH2:14][CH2:15][C:16]([OH:18])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH-].[Na+]>C(OCC)(=O)C.CCCCCC.O>[S:8]1[C:9]2[S:13][CH2:14][CH2:15][C:16](=[O:18])[C:10]=2[CH:11]=[CH:12]1
Reactant: O=C(O)CCSc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCCCCC
Solvent: O
Product: O=C1CCSc2sccc21
Reaction time: 1.5 h

Procedure:
In a 2-L reactor fitted with an overhead mechanical stirrer, thermometer, addition funnel, reflux condenser, and nitrogen bubbler vented through an acid-vapor scrubber was placed the toluene solution of product from Step A (130.7 g, 695 mmol). The reaction mixture was brought to an initial temperature of 20° C. and trifluoroacetic anhydride (161 g, 765 mmol) was added over 5 minutes to the stirred solution. The reaction was then heated to 35°-38° C. and stirred for about 1.5 hours. The reaction mixture was then slowly added to water (500 mL) maintaining the temperature at <25° C. A pH probe was placed in the vessel and the mixture was titrated to pH 7.0 with 50% sodium hydroxide (123 g, 1.53 mole). The layers were separated and the aqueous phase was extracted once with toluene (200 mL), The combined organic extracts were then concentrated under vacuum (43 mBar) to a volume of 200 mL and then diluted to 1.2 L with ethyl acetate for the next step (oxidation). A small sample was chromatographed to obtain the following data: Rf =0.29 (85:15 hexane:ethyl acetate). m.p. 61°-62° C. 1H NMR: δ 7.42 (d, J=5.4, H2); 6.98 (d, J=5.4 H3); 3.33 (m, C5H2); 2.82 (m, C6H2). 13C NMR; δc 188.9 (C4), 150.9, 135.0 (C3a, C7a), 126.1, 121.8 (C2, C3), 38.1 (C6), 30.0 (C5). Anal Calcd for C7H6OS2 : C, 49.39; H, 3.55; S, 37.66. Found: C, 49.56; H, 3.58; S, 37.68.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.C(N(CC)CC)C.[Cl:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][N:40]=1>O1CCCC1>[Cl:38][C:39]1[CH:47]=[CH:46][C:42]([C:43]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:29])[C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=5)[CH:12]=4)=[N:6][N:5]3[CH:30]=2)=[O:44])=[CH:41][N:40]=1
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)c4ccc(Cl)nc4)cn3n2)c1)c1cccc(C(F)(F)F)c1
Yield: 77.4 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.362 mmol), triethylamine (76 μL, 0.544 mmol), 6-chloronicotinoyl chloride (76 mg, 0.435 mmol) and tetrahydrofuran (5 mL) as starting materials and in the same manner as in Example 388, the title compound (155 mg, 77%) was obtained as a pale-yellow powder.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11].C[O-].[Na+].[CH3:15][O:16][N:17]=[C:18]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29]Br)[C:19]([O:21][CH3:22])=[O:20]>CO.CN(C)C=O.C(OCC)(=O)C>[CH3:15][O:16][N:17]=[C:18]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:4]=[N:3][O:2][CH3:1])[C:19]([O:21][CH3:22])=[O:20]
Reactant: CON=Cc1ccccc1O
Reactant: CON=C(C(=O)OC)c1ccccc1CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CO
Product: CON=Cc1ccccc1OCc1ccccc1C(=NOC)C(=O)OC
Temperature: 100 °C
Reaction time: 5 h

Procedure:
3.0 g (20 mmol) of 2-hydroxybenzaldehyde O-methyloxime are dissolved in 20 ml of methanol, and 3.6 g (20 mmol) of sodium methanolate (30% strength in methanol) are added. The mixture is refluxed for four hours and then concentrated. The residue is taken up in 100 ml of dimethylformamide, and 6.5 g (23 mmol) of methyl 2-bromomethylphenylglyoxylate O-methyloxime in 50 ml of dimethylformamide are added. The mixture is stirred at 100° C. for 5 hours, the solvent is stripped off, and the residue is taken up in ethyl acetate. The organic phase is washed with water, dried and concentrated. The residue is triturated with pentane to induce crystallization. 4.8 g (67% of theory) of the title compound are obtained in the form of colorless crystals (melting point 73°-76° C., compound no. 2).