Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N+:3]=1[O-].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:13]>ClCCl>[OH:13][CH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc[n+]([O-])c(C)c1
Solvent: ClCCl
Product: Cc1ccnc(CO)c1
Reaction time: 8 h

Procedure:
A mixture of 2,4-dimethylpyridine N-oxide (10.9 g, 88.5 mmol) and trifluoroacetic anhydride (31 mL, 219 mmol) in dichloromethane (75 mL) was stirred at room temp. overnight. The product mixture was concentrated under vacuum. The residue was dissolved in a mixture of dichloromethane (75 mL) and aqueous sodium carbonate (225 mL, 2M), and stirred vigorously for 4 h. The resultant mixture was diluted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 1-2% methanol in chloroform gradient. Collection and concentration of appropriate fractions provided 2-hydroxymethyl-4-methylpyridine as clear oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C[Al](C)C.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[N:19]1[C:24]2[N:25]=[C:26]([NH:37][CH2:38][C:39](OC)=[O:40])[N:27]=[C:28]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[CH3:36])[C:23]=2[CH:22]=[CH:21][C:20]1=[O:43]>ClCCl.CCOC(C)=O>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[N:19]1[C:24]2[N:25]=[C:26]([NH:37][CH2:38][C:39]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:40])[N:27]=[C:28]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[CH3:36])[C:23]=2[CH:22]=[CH:21][C:20]1=[O:43]
Reactant: C1COCCN1
Reactant: COC(=O)CNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: C[Al](C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1nc(NCC(=O)N2CCOCC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 16 h
Yield: 31.2 %

Procedure:
Under Ar, a soln of morpholine (58 mg, 0.66 mmol) and trimethylaluminum (2M in toluene) (0.33 mL, 0.66 mmol) in dichloromethane was stirred for 10 min. A soln of the product of Example 190 (100 mg, 0.22 mmol) in dichloromethane (2 mL) was added. The resulting mixture was stirred for 16 h, diluted with EtOAc and washed with H2O to give the crude material. Purification by Flash chromatography on silica gel, eluting with EtOAc/hexane/triethylamine (70/30/2, v/v/v), followed by recrystallization from dichloromethane and hexane, gave the desired product (35 mg, 31%). LC-MS: 510.10 (MH+, m/z), 1.96 (Rt, min).
Reaction SMILES: [CH3:1][O:2][C:3]([O:11][Si](C)(C)C)=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.F[B-](F)(F)F.[C:21]1([N+:27]#[N:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1.C(OCC)C>[C:5]1([C:4](=[N:28][NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3]([O:2][CH3:1])=[O:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=Cc1ccccc1)O[Si](C)(C)C
Reactant: N#[N+]c1ccccc1
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: c1ccncc1
Product: COC(=O)C(=NNc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
1.0 mmol of (1-methoxy-2phenylethenyl)oxytrimethylsilane was placed in a 20-ml flask, followed by the addition of 3 ml of pyridine as a solvent. 1.3 mmol of benzenediazonium tetrafluoroborate was added to the flask. The obtained mixture was stirred at 0° C. in a nitrogen atmosphere for 2 hours. The reaction mixture was diluted with diethyl ether and washed with 1.5N hydrochloric acid, water and a saturated aqueous solution of common salt successively. The obtained organic phase was dried over magnesium sulfate and distilled under a reduced pressure to remove the solvent. The obtained oily mixture was subjected to silica gel thin-layer chromatography to obtain 0.84 mmol of methyl 2-phenyl-2-phenylhydrazonoacetate.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:8]2[CH:41]=[CH:40][CH:39]=[CH:38][C:9]=2[C:10]([NH:12][C:13]2[CH:37]=[CH:36][C:16]([C:17]([N:19]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4/[C:23](=[CH:30]/[C:31](O)=[O:32])/[C:22]([F:35])([F:34])[CH2:21][CH2:20]3)=[O:18])=[CH:15][CH:14]=2)=[O:11])[CH:5]=[CH:6][N:7]=1)[CH3:2].[CH:42]1([NH2:45])[CH2:44][CH2:43]1>>[CH:42]1([NH:45][C:31](/[CH:30]=[C:23]2\[C:22]([F:34])([F:35])[CH2:21][CH2:20][N:19]([C:17]([C:16]3[CH:36]=[CH:37][C:13]([NH:12][C:10](=[O:11])[C:9]4[CH:38]=[CH:39][CH:40]=[CH:41][C:8]=4[N:4]4[CH:5]=[CH:6][N:7]=[C:3]4[CH2:1][CH3:2])=[CH:14][CH:15]=3)=[O:18])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]\2=3)=[O:32])[CH2:44][CH2:43]1
Reactant: CCc1nccn1-c1ccccc1C(=O)Nc1ccc(C(=O)N2CCC(F)(F)/C(=C\C(=O)O)c3ccccc32)cc1
Reactant: NC1CC1
Product: CCc1nccn1-c1ccccc1C(=O)Nc1ccc(C(=O)N2CCC(F)(F)/C(=C\C(=O)NC3CC3)c3ccccc32)cc1

Procedure:
Using 0.5 g of (Z)-[1-[4-[2-(2-ethyl-1H-imidazol-1-yl)benzoylamino]benzoyl]-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ylidene]acetic acid and 0.074 ml of cylopropylamine, a similar procedure as in Example 11 was repeated to obtain 325 mg of (Z)-4'-[[5-[(N-cyclopropylcarbamoyl)methylene]-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl]-2-(2-ethyl-1H-imidazol-1-yl) benzanilide.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([NH:17][N:18]=[CH:19][CH:20]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)[C:21](OCC)=[O:22])=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([NH:8][C:9](=[O:10])[C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:21]([OH:22])=[C:20]([C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=3)[CH:19]=[N:18]2)=[N:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C=NNc1ccc(C(=O)NCc2ccccc2)cn1)c1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)NCc4ccccc4)cn3)c2O)cc1
Yield: 6.2 %

Procedure:
Combined ethyl 3-(2-(5-(benzylcarbamoyl)pyridin-2-yl)hydrazono)-2-(4-cyanophenyl)propanoate (90 mg, 0.204 mmol) and potassium carbonate (42.3 mg, 0.306 mmol) in ethanol (2 mL) and heated for 1 hour at 60° C. The reaction mixture was evaporated to give a residue which was purified by HPLC (ZQ9, Prep-TFA-50-55, Rt 4.54 min) to give the title compound (5 mg, 6%) as an off-white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 4.69 (d, J=5.56 Hz, 2 H), 6.37 (br. s., 1 H), 7.30-7.42 (m, 5 H), 7.62-7.69 (m, 2 H), 7.77-7.83 (m, 2 H), 7.91 (s, 1 H), 8.02 (d, J=8.08 Hz, 1 H), 8.32 (dd, J=8.84, 2.27 Hz, 1 H), 8.80 (d, J=1.77 Hz, 1 H). MS m/z [M+H]+ 396.3.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26]Cl>CN(C=O)C>[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26][N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=[C:3]1[CH2:2][OH:1]
Reactant: OCc1nc2ccccc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1c(CO)nc2ccccc21
Temperature: 60 °C
Yield: 43.7 %

Procedure:
To a stirred solution of 2-hydroxymethylbenzimidazole (31.94, 0.216 mol) in dry DMF (450 mL) was added N,N-diisopropylethylamine (90 mL, 0.52 mol) followed by 2-(trimethylsily)ethoxymethyl chloride (75% in pentane, 55 g, 0.25 mol) and the mixture heated to 60° C. for 2 h. The mixture was cooled to room temperature, concentrated under reduced pressure and partitioned between EtOAc (400 mL) and distilled water (700 mL). The phases were separated and the aqueous layer extracted with EtOAc (2×200 mL). The combined organic extracts were washed with brine (1×400 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. Purification of the crude oil by column chromatography on silica gel (4% MeOH/CH2Cl2) afforded the desired 1-(2-trimethylsilylethoxymethyl)-2-hydroxymethylbenzimidazole (26.28 g, 44%) as a yellow oil. 1H NMR (CDCl3) δ −0.04 (s, 9H), 0.89 (t, 2H, J=9 Hz), 1.75 (br s, 1H), 3.55 (t, 2H, J=9 Hz), 4.94 (s, 2H), 7.26-7.30 (m, 2H), 7.43-7.45 (m, 1H), 7.70-7.72 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[Br:10][CH2:11][CH2:12]Br.[OH-].[Na+]>>[Br:10][CH2:11][CH2:12][O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1]
Reactant: Oc1cccc(Cl)c1Cl
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Product: Clc1cccc(OCCBr)c1Cl
Yield: 60.2 %

Procedure:
To a mixture of 2,3-dichlorophenol (20 g, 0.123 mol) and 1,2-dibromoethane (30.5 g, 0.162 mol) was added a sodium hydroxide solution (5 g, 0.125 mol in 125 ml of water), and the mixture was heated under reflux for 8 h. The mixture was allowed to cool and extracted with chloroform (2×100 ml). The combined extracts were washed with 1N aqueous sodium hydroxide solution (100 ml), dried, filtered and concentrated in vacuo. The residue was distilled at 106° C./0.3 mm of mercury to afford on cooling to room temperature the title compound as a yellow solid (20 g, 60%).
Reaction SMILES: CN(C)CCN[C:6]([C@@H:8]([NH:20][C:21]([C:23]1[CH:42]=[CH:41][C:26]2[N:27]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:28]([C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=2)[NH:12][CH:11]=1)=[O:7].[NH2:44][C:45]([CH3:49])([CH3:48])[CH2:46][OH:47]>>[OH:47][CH2:46][C:45]([NH:44][C:6]([C@@H:8]([NH:20][C:21]([C:23]1[CH:42]=[CH:41][C:26]2[N:27]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:28]([C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=2)[NH:12][CH:11]=1)=[O:7])([CH3:49])[CH3:48]
Reactant: CN(C)CCNC(=O)[C@H](Cc1c[nH]c2ccc(O)cc12)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Reactant: CC(C)(N)CO
Product: CC(C)(CO)NC(=O)[C@H](Cc1c[nH]c2ccc(O)cc12)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1

Procedure:
The carboxylic acid of example 133 was coupled to 2-amino-2-methyl-1-propanol under standard TBTU conditions to yield the title compound of example 139.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[NH:8][CH2:9]2)=[CH:4][CH:3]=1.[C:20]([O:24][C:25]([N:27]([CH2:38][CH:39]=O)[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[N+:35]([C:32]1[CH:31]=[CH:30][C:29]([CH2:28][N:27]([CH2:38][CH2:39][N:8]2[CH:7]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[CH2:6][C:5]3[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:9]2)[C:25](=[O:26])[O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:34][CH:33]=1)([O-:37])=[O:36]
Reactant: Fc1ccc(CC2Cc3ccc(F)cc3CN2)cc1
Reactant: CC(C)(C)OC(=O)N(CC=O)Cc1ccc([N+](=O)[O-])cc1
Product: CC(C)(C)OC(=O)N(CCN1Cc2cc(F)ccc2CC1Cc1ccc(F)cc1)Cc1ccc([N+](=O)[O-])cc1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 117-d) using 7-fluoro-3-(4-fluorobenzyl)-1,2,3,4-tetrahydroisoquinoline obtained in Example 56-c) and [N-(tert-butoxycarbonyl)-N-4-nitrobenzylamino]acetaldehyde to obtain a title compound as a light yellow oily substance.
Reaction SMILES: C([O:8][CH:9]1[CH2:13][CH2:12][CH2:11][C:10]1([NH:17][C:18](=[O:37])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][C:30]2[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=2)[CH:20]=1)[C:14]([OH:16])=[O:15])C1C=CC=CC=1>C(O)C.[Pd].[H][H]>[OH:8][CH:9]1[CH2:13][CH2:12][CH2:11][C:10]1([NH:17][C:18](=[O:37])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][C:30]2[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=2)[CH:20]=1)[C:14]([OH:16])=[O:15]
Reactant: COc1ccc(C(=O)NC2(C(=O)O)CCCC2OCc2ccccc2)cc1OCCc1cccc(C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C(=O)NC2(C(=O)O)CCCC2O)cc1OCCc1cccc(C)c1

Procedure:
Diastereomer 1 and diastereomer 2 of the compound of example 66 were separately dissolved in ethanol and hydrogenated with palladium 10% on charcoal at room temperature with 1 bar hydrogen pressure until completion of the reaction. After filtration, the solutions were evaporated to dryness and the residues purified by RP HPLC (water/ACN gradient) to yield the two diastereomers of the title compound separately.
Reaction SMILES: Cl/[CH:2]=[CH:3]/[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:27]=[CH:26][S:25][CH:24]=3)[CH:18]=2)[CH:10]=1)[CH2:6][CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N)CCC.[CH3:52][CH:53]([CH2:56][CH3:57])[C:54]#[CH:55]>O1CCCC1.[Pd](Cl)Cl.[Cu]I>[CH3:52][CH:53]([CH2:56][CH3:57])[C:54]#[C:55]/[CH:2]=[CH:3]/[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:27]=[CH:26][S:25][CH:24]=3)[CH:18]=2)[CH:10]=1)[CH2:6][CH3:7]
Reactant: C#CC(C)CC
Reactant: CCN(C/C=C/Cl)Cc1cccc(OCc2cccc(-c3ccsc3)c2)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCN
Product: CCC(C)C#C/C=C/CN(CC)Cc1cccc(OCc2cccc(-c3ccsc3)c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 71 %

Procedure:
To a solution of 100 mg (0.25 mmol) of (E)-N-(3-chloro-2-propenyl)-N-ethyl-3-[3-(3-thienyl)benzyloxy]benzylamine in 2 ml of tetrahydrofuran were added 6.0 mg (0.023 mmol) of triphenylphosphine, 4.0 mg (0.023 mmol) of palladium chloride, 6.0 mg (0.032 mmol) of copper (I) iodide, 100 μl (1 mmol) of n-butylamine and 0.5 ml (5.12 mmol) of 3-methyl-1-pentyne. The mixture was stirred for 48 hours at room temperature, and concentrated under reduced pressure. The residue was treated with a mixture of ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (n-hexane→n-hexane/ethyl acetate=9/1). The desired fractions were put together and concentrated under reduced pressure. The residue was subjected to thin layer chromatography to obtain 79 mg (yield: 71%) of the above identified compound as a brown oil.
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:17])=[C:10]([Cl:16])[CH:11]=[C:12]2[Cl:15])=[N:7]1)[C:3]#[N:4].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[S:26])=[CH:23][CH:22]=1>>[C:3]([C:2]([NH:1][C:25](=[S:26])[C:24]1[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=1)([CH3:18])[CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:17])=[C:10]([Cl:16])[CH:11]=[C:12]2[Cl:15])=[N:7]1)#[N:4]
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Product: CC(C#N)(Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (60 mg, described in Example 147) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (40 mg, 40%). Rf=0.65 (1:1 EA/heptane). 1H NMR: (400 MHz, DMSO-d6): 1.70 (s, 3H), 5.11 (d, 1H), 5.25 (d, 1H), 7.47 (s, 1H), 7.79-7.80 (m, 4H), 8.73 (s, 1H) and 9.00 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −42.0 (s, 3F).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([OH:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH:25]([CH:27](OS(C)(=O)=O)[CH3:28])[CH3:26])(=O)=O>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]3[O:13][CH:25]([CH3:26])[CH:27]([CH3:28])[N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1cc(-c2ccc(F)cc2)n[nH]1
Reactant: CC(OS(C)(=O)=O)C(C)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1Oc2cc(-c3ccc(F)cc3)nn2C1C
Temperature: 60 °C
Reaction time: 16 h
Yield: 71.8 %

Procedure:
To a solution of 3-(4-fluorophenyl)-1H-pyrazol-5-ol (3 g, 16.8 mmol) in DMF (15 mL) was added K2CO3 (9.3 g, 67.4 mmol) and butane-2,3-diyl dimethanesulfonate (4.8 g, 18.5 mmol) (prepared as described in US2010/41748) at room temperature and then stirred for 16 h at 60° C. Thereafter, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to get the crude product. Purification by column chromatography over silica gel (eluent 5-10% ethyl acetate in petrol ether) yielded 6-(4-fluorophenyl)-2,3-dimethyl-2,3-dihydropyrazolo[5,1-b][1,3]oxazole (2.8 g, 71%) as yellow oil and a mixture of diastereoisomers.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:7]([F:16])=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9](O)=[O:10]>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:5][C:6]1[C:7]([F:16])=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9]([Cl:3])=[O:10]
Reactant: O=C(O)c1ccc(F)c(Cl)c1F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc(F)c(Cl)c1F

Procedure:
Thionyl chloride is metered at 70° C. to a suspension of 235 g (1.22 mol) of 3-chloro-2,4-difluorobenzoic acid in 800 ml of toluene and 3 ml of dimethylformamide until a clear solution has formed and evolution of gas is no longer observed. The toluene and excess thionyl chloride are then distilled off, and the product is subsequently obtained by distillation.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]([CH3:16])([CH3:15])[CH2:13]O>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][CH2:13][C:12]([CH3:16])([CH3:15])[N:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CC(C)(N)CO
Solvent: ClCCl
Product: CC1(C)COC(c2ccc(Br)cc2)=N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-Bromobenzoyl chloride (20.02 g, 91 mmol) was dissolved in dichloromethane (180 ml) and added dropwise to a solution of 2-amino-2-methyl-1-propanol (19.20 g, 216 mmol) in dichloromethane (90 ml) at ambient temperature. The mixture was stirred for 24 hours at ambient temperature, followed by filtration and removal of the solvent at reduced pressure. Thionyl chloride (90 ml) was added dropwise and the mixture was stirred for 30 minutes at ambient temperature. Excess thionyl chloride was removed at reduced pressure and the residue was added to an aqueous HCl-solution (5%, 500 ml). The solution was washed with ether (2×100 ml) and aqueous NaOH (50%) was added to pH 9. The basic solution was extracted with ether (3×100 ml), and the combined ether solution was washed with water (50 ml) and saturated aqueous NaCl-solution. The dried (MgSO4) ether solution was evaporated and the title compound isolated by distillation. Yield 14.14 g (61%), b.p. 128-130° C. (1 mm Hg).
Reaction SMILES: N[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2.N([O-])=[O:14].[Na+].[OH-].[Na+]>OS(O)(=O)=O.O>[OH:14][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2
Reactant: O=N[O-]
Reactant: Cc1ccc2ncc(N)cc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2ncc(O)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.6 %

Procedure:
A solution of 3-Amino-6-methylquinoline [(1.21 g, 7.65 mmol), prepared according to J. Chem. Soc. 2024-2027(1948) Morley, J. S.; Simpson, J. C. E.] in 6N H2SO4 (25 ml) was cooled in an ice bath. To the solution NaNO2 (560 mg, 8.10 mmol) in water (2 ml) was added and stirred for 30 min at 0 degrees. Separately 5% H2SO4 was refluxed and above Diazo reaction mixture was added to this refluxing solution. After 30 min the reaction mixture was cooled to room temperature, and was neutralized by 6N NaOH. The resulting insoluble material was collected by filtration. This solid was recrystallized by CHCl3/AcOEt to afford compound (308) (348 mg, 29%).
Reaction SMILES: [C:1](#[N:3])[CH3:2].[C:4]([OH:13])(=[O:12])[C@@H:5]([C@H:7]([C:9]([OH:11])=[O:10])[OH:8])[OH:6]>C(O)(=O)C>[C:9]([CH:7]([CH:5]([C:4]([O-:13])=[O:12])[OH:6])[OH:8])([O-:11])=[O:10].[C:1](#[N:3])[CH3:2]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CC#N
Solvent: CC(=O)O
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Temperature: 50 °C
Reaction time: 8 h

Procedure:
In 80 volume parts of acetic acid are dissolved 19 parts of TRH monohydrate and 7.5 parts of L-tartaric acid, and while the solution is warmed to 50°C, 240 volume parts of acetonitrile is added in installments. The temperature is gradually brought down to room temperature, at which temperature the solution is allowed to stand overnight. The resultant crystals are harvested by filtration, washed with acetonitrile and dried under reduced pressure. The procedure yields 25.7 parts of TRH tartrate-acetonitrile as crystals melting at 145°C-148°C. [α]D22 =-47.1° (c=1.0 in water)
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[F:24])[CH2:4]1.Cl[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[CH3:1][N:2]([CH3:25])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:19]([O:22][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)=[CH:18][CH:17]=3)=[CH:10][C:9]=2[F:24])[CH2:4]1
Reactant: Clc1ccccn1
Reactant: CN(C)[C@@H]1CCN(c2ccc(NC(=O)c3ccc(O)cc3)cc2F)C1
Product: CN(C)[C@@H]1CCN(c2ccc(NC(=O)c3ccc(Oc4ccccn4)cc3)cc2F)C1

Procedure:
(R)-N-[4-(3-Dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-4-hydroxybenzamide was reacted with 2-chloropyridine by method R. This resulted in the product with the molecular weight of 434.52 (C25H27N4O2); MS (ESI): 435 (M+H+).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:20])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:26]=[CH:25][N:24]([CH2:27][CH2:28][CH2:29][OH:30])[N:23]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:20])[C:8]([NH:21][C:22]2[CH:26]=[CH:25][N:24]([CH2:27][CH2:28][CH2:29][OH:30])[N:23]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccn(CCCO)n1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2ccccc2C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccn(CCCO)n1)[C@H](CC1CCCC1)N1Cc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.4 %

Procedure:
To a solution of (S)-3-cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared as in Example 9, 80 mg, 0.29 mmol) and 3-(3-amino-pyrazol-1-yl)-propan-1-ol (prepared as in US 20080021032, Example 23, 49 mg, 0.35 mmol) and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (Chemimpex, 0.15 g, 0.35 mmol) in methylene chloride (8 mL) was added N,N-diisopropylethylamine (0.15 mL, 0.88 mmol) dropwise and the resulting solution stirred at room temperature for 4 h. The solution was diluted with methylene chloride, washed with a 1 N hydrochloric acid solution (25 mL), a saturated sodium bicarbonate solution (25 mL) dried over magnesium sulfate. The mixture was filtered and evaporated and the resulting material purified via automated flash chromatography (Analogix, SF4-12 g column, 50-70% ethyl acetate/hexanes) to afford (S)-3-cyclopentyl-N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide (28 mg, 24%) as an off white solid: HR-ES(+) m/e calcd for C22H28N4O3 [M+H]+ 397.2234, observed 397.2233; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.94-2.34 (m, 7H), 4.04 (t, J=6.79 Hz, 3H), 4.37-5.28 (m, 6H), 6.39 (s, 2H), 7.31-7.90 (m, 8H), 10.86 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[Cl:13][CH2:12][CH2:11][CH2:10][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: ClCCCBr
Reactant: Oc1ccc(F)cc1
Product: Fc1ccc(OCCCCl)cc1

Procedure:
Prepared by Procedure U and Scheme AK using 4-fluorophenol and 1-bromo-3-chloropropane.