Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:14]([C:16]2[C:17]([CH3:28])=[N:18][O:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=2)[OH:15])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:38]=[CH:39][C:40]([C:24]3[CH:23]=[CH:22][C:21]([C:20]4[O:19][N:18]=[C:17]([CH3:28])[C:16]=4[CH:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:9]=4)[OH:15])=[CH:26][CH:25]=3)=[CH:41][CH:42]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cccc(Cc2ccccc2)c1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cccc(Cc5ccccc5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 17, Step 1, using (3-benzyl-phenyl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-])=O.C1C(=O)N([Br:25])C(=O)C1>CO.C(Cl)Cl.[Pd]>[Br:25][C:5]1[CH:6]=[C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:8]=[CH:9][C:4]=1[NH2:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1ccc(CCN2CCOCC2)cc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc(CCN2CCOCC2)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.9 %

Procedure:
To a solution 4-[2-(4-nitro-phenyl)-ethyl]-morpholine (0.70 g, 2.97 mmol) (as prepared in the previous step) in 15 mL of MeOH was added 10% Pd/C (30 mg) and the mixture hydrogenated under 20 psi of H2 for 2 h. The mixture was filtered though Celite and concentrated. The residue was dissolved in DCM (20 mL) and NBS (0.53 g, 2.97 mmol) was added and the reaction stirred for 20 min at RT. The reaction was diluted with DCM (20 mL) and washed with NaHCO3 (2×40 mL) and the organic layer dried over Na2SO4 and concentrated. The title compound was eluted from a 20-g SPE with 100% EtOAc to give 0.49 g (58%) of a light yellow oil. Mass spectrum (ESI, m/z): Calcd. for C12H17BrN2O, 285.0 (M+H). found 285.0.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10][CH2:9]1)C1C=CC=CC=1.C1CCCCC=1>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCN1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCCCCCCCCN1CCNCC1

Procedure:
A mixture of 1-benzyl-4-nonylpiperazine (0.54 g, 1.80 mmol) (prepared by reacting 1-benzylpiperazine, Aldrich, with 1-bromononane, Aldrich, and NaH in DMF), palladium hydroxide on carbon (0.14 g) and cyclohexene (7 mL) in ethanol (15 mL) was heated at reflux overnight. After filtration, the filtrate was concentrated in vacuo to dryness to give 1-nonylpiperazine as an oil, 0.38 g, 100%.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])=[C:4]([C:17]2[CH:18]=[N:19][C:20](S(CCC)(=O)=O)=[N:21][CH:22]=2)[CH:3]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([C:17]2[CH:22]=[N:21][C:20]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[N:19][CH:18]=2)[CH:3]=1
Reactant: CCCS(=O)(=O)c1ncc(-c2cc(Cl)ccc2OCC(=O)OC(C)(C)C)cn1
Reactant: C1COCCN1
Product: O=C(O)COc1ccc(Cl)cc1-c1cnc(N2CCOCC2)nc1

Procedure:
The title compound was prepared from the product of example 20 step (iv) and morpholine by the method of example 20 step (v).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])=[CH:6][CH:5]=1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH:18]([O:17][CH:11]([CH2:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][O:1][C:28](=[O:29])[NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:9][CH:8]=1)[C:12]([OH:14])=[O:13])([CH3:19])[CH3:20]
Reactant: O=C=Nc1ccccc1
Reactant: CCOC(=O)C(Cc1ccc(CCO)cc1)OC(C)C
Product: CC(C)OC(Cc1ccc(CCOC(=O)Nc2ccccc2)cc1)C(=O)O

Procedure:
Using ethyl 3-[4-(2-hydroxyethyl)phenyl]-2-isopropoxypropanoate and phenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)=[CH:5][CH:4]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][NH2:28])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][NH:28][CH:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:10]2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: COc1ccc2c(c1)CC(=O)CC2
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1ccc2c(c1)CC(NCC1CCN(C(=O)OC(C)(C)C)CC1)CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.9 %

Procedure:
To a solution of 7-methoxy-3,4-dihydro-1H-naphthalen-2-one (1.0 g, 5.67 mmol) and 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.34 g, 6.23 mmol) in dichloroethane (50 mL) under a nitrogen atmosphere was added sodium triacetoxyborohydride (3.0 g, 14.2 mmol, 2.5 eq.) in a single portion. The reaction was stirred at room temperature for 24 h. The reaction was concentrated in vacuo and partitioned between EtOAc (100 mL) and 5% aq. KOH (50 mL). The aqueous layer was extracted twice more with ethyl acetate (2×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. Flash chromatography on silica gel eluting with 5% methanol/methylene chloride afforded 4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester as an oil (2.1 g).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:23][O:24][C:25](=[O:39])[C@@H:26]1[CH2:30][C@@H:29]([NH2:31])[CH2:28][N:27]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].Cl.[CH3:41][N:42]([CH3:47])[CH2:43][C:44](O)=[O:45]>ClCCl.C(N(CC)CC)C>[CH3:23][O:24][C:25](=[O:39])[C@@H:26]1[CH2:30][C@@H:29]([NH:31][C:44](=[O:45])[CH2:43][N:42]([CH3:47])[CH3:41])[CH2:28][N:27]1[C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33]
Reactant: COC(=O)[C@@H]1C[C@@H](N)CN1C(=O)OC(C)(C)C
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](NC(=O)CN(C)C)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 74.2 %

Procedure:
Triethylamine (362 μL), 1-hydroxybenzotriazole (160 mg), and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (249 mg) were added to a mixture of N-tert-butoxycarbonyl-trans-4-amino-L-proline methyl ester(Compound D101 (M), 264 mg) and N,N-dimethylglycine hydrochloride (181 mg) in dichloromethane (10 mL) at 0° C. After stirring at 0° C. for 30 min and at room temperature for 18 hr, the solvent was removed in vacuo. The residue was diluted with saturated sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform then chloroform:methanol=50:1 to 30:1, v/v) to afford the title compound (264 mg) as a pale yellow oil. The compound appears as a mixture of rotamers: 1H NMR (400 MHz, CDCl3) δ 1.42 and 1.46 (each s, total 9H), 2.28 (s, 6H), 2.13-2.40 (m, 2H), 2.94 (s, 2H), 3.22-3.43 (m, 1H), 3.74 (s, 3H), 3.75-3.88 (m, 1H), 4.28-4.48 (m, 1H), and 4.50-4.62 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:4][C:3]=1[O:20][CH3:21].[C:22]([O:27][CH2:28][CH:29]1[O:31][CH2:30]1)(=[O:26])[C:23]([CH3:25])=[CH2:24].O>CN(C)C(=O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:21][O:20][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:6]=[CH:7][C:2]=1[O:1][CH2:30][CH:29]([OH:31])[CH2:28][O:27][C:22](=[O:26])[C:23]([CH3:25])=[CH2:24]
Reactant: COc1cc(C=Cc2ccc3ccccc3n2)ccc1O
Reactant: C=C(C)C(=O)OCC1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: C=C(C)C(=O)OCC(O)COc1ccc(C=Cc2ccc3ccccc3n2)cc1OC
Yield: 50 %

Procedure:
In 5 cm3 of N,N-dimethylacetamide, 2.77 g of the produced quinoline derivative was dissolved and 1.42 g of glycidyl methacrylate and 0.10 g of tetrabutylammonium chloride were added thereto. The resultant mixture was reacted by maintaining it at 90° to 100° C. for 5 hours. The reaction product was mixed with water. The oily substance separated consequently was extracted via ethyl acetate, washed thoroughly with water, and dried. The dry product was distilled to expel the solvent and then separated and purified by silica gel chromatography, to afford 2-{2-[3-methoxy-4-(2-hydroxy-3-methacryloyloxypropyloxy)-phenyl]-ethenyl}-quinoline in a yield of 50%. When this product was recrystallized via ethyl acetatehexane, there was obtained a pure product having a melting point of 119° C. It was identified by elementary analysis and infrared absorption spectrometry.
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.[CH2:13]([C@@H:15]1[C@@H:20]([C:21](=[O:23])[CH3:22])[C@@H:19]([CH3:24])[CH:18]=[CH:17][CH2:16]1)[CH3:14].C(=O)C.Cl>O1CCCC1>[CH2:13]([C@@H:15]1[C@@H:20]([C:21](=[O:23])/[CH:22]=[CH:1]/[CH3:2])[C@@H:19]([CH3:24])[CH:18]=[CH:17][CH2:16]1)[CH3:14]
Reactant: CC(C)NC(C)C
Reactant: CC[C@H]1CC=C[C@H](C)[C@@H]1C(C)=O
Agent: CC=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C/C=C/C(=O)[C@@H]1[C@@H](CC)CC=C[C@@H]1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 55.9 %

Procedure:
At −78° C., a solution of diisopropylamine (6.6 g, 34 mmol) in tetrahydrofuran (23 ml) was treated with n-butyl lithium (21 ml, 1.6M in hexane, 34 mmol). The resulting solution was warmed to 0° C., cooled to −78° C., and treated with a solution of 1-(rel-(1R,2S,6S)-6-ethyl-2-methylcyclohex-3-enyl)ethan-1-one (4.5 g, 27 mmol) in tetrahydrofuran (23 ml). The resulting solution was stirred 20 min. at −20° C., cooled to −78° C. and treated with a solution of acetaldehyde (1.8 g, 41 mmol) in tetrahydrofuran (23 ml). After 1 h stirring, aqueous 1N HCl (50 ml) was added and the reaction mixture warmed to 20° C. The aq. phase was extracted with diethyl ether and the combined org. phases dried (MgSO4), and concentrated. A solution of the residue (4.9 g) in toluene (4.9 ml) was treated with para-toluene sulfonic acid monohydrate (20 mg) and refluxed overnight. The reaction mixture was cooled, treated with a saturated aqueous solution of NaHCO3 and the aqueous phase was extracted with diethyl ether. The combined organic phases were dried (MgSO4) and concentrated. FC (550 g SiO2, hexane/diethyl ether 9:1) of the crude product gave (2E)-1-(rel-(1R,2S,6S)-6-ethyl-2-methylcyclohex-3-enyl)but-2-en-1-one (2.9 g, 56%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](Cl)[CH:6]=[C:5]([O:10][CH3:11])[N:4]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[C:5]([O:10][CH3:11])[N:4]=1
Reactant: C1CNCCN1
Reactant: COc1cc(Cl)cc(OC)n1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1cc(N2CCNCC2)cc(OC)n1

Procedure:
2.5 g (13 mmol) 2,6-dimethoxy-4-chloro-pyridine and 6.21 g (65 mmol) piperazine were heated at reflux in 22 ml anhydrous pyridine for 20 hours. After cooling (precipitation was detected) 50 ml of toluene was added and the suspension was filtered. The filtrate was concentrated under reduced pressure, piperazine and pyridine were azeotropically removed by repeated evaporation with toluene (five times). The residue was triturated with diethylether/petrolether (1:1) and dried in vacuo. The product was obtained as yellow solid and used directly in the next step.
Reaction SMILES: [C:1]([N:8]1[CH2:31][CH2:30][C@@:15]23[C:16]4[CH:17]=[C:18]([O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:20][C:21]=4[CH2:22][C@@H:9]1[C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14]3)(OC(C)(C)C)=O.O1CCOCC1.Cl.C(Br)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:1]([N:8]1[CH2:31][CH2:30][C@@:15]23[C:16]4[CH:17]=[C:18]([O:23][C:24](=[O:29])[C:25]([CH3:27])([CH3:26])[CH3:28])[CH:19]=[CH:20][C:21]=4[CH2:22][C@@H:9]1[C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14]3)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(OC(=O)C(C)(C)C)cc13
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)Oc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(Cc1ccccc1)CC3
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
To a solution of compound 31 (5 mg, 0.012 mmol) in dry CH2Cl2 (0.2 ml) was added 4 M HCl dioxane solution (0.5 mL) and the mixture stirred for 2 h at 0° C. Solvent was evaporated under reduced pressure. The crude amine salt 32 was dissolved in CH2Cl2 (0.5 ml) and to it were slowly added benzyl bromide (2 μL, 0.020 mmol) and TEA (9 μL, 0.064 mmol) at 0° C. After 4 h stirring, the reaction mixture was concentrated under reduced pressure. The crude product was purified on a silica gel column chromatography (3:1 n-Hexane/EtOAc) to give a colorless oil (4 mg, 80% yield): 1H NMR (300 MHz, CDCl3) 0.91˜1.74 (m, 18H); 1.89 (m, J=12.6 Hz, 1H); 2.07˜2.21 (m, 1H), 2.29˜2.48 (m, 2H); 2.63˜2.69 (m, 1H); 2.87 (s, 1H); 3.09 (d, J=18.3 Hz, 1H); 3.68 (dd, J=13.4 Hz, 2H); 6.82˜6.93 (m, 2H); 7.15 (d, J=8.3 Hz, 1H); 7.25˜7.38 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH3:30])[C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH3:28])([CH3:27])[C:21]=3[CH:29]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH:31]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH3:30])[C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH3:27])([CH3:28])[C:21]=3[CH:29]=2)=[O:31])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(SCCCCOc2cc(C)c3c(c2)C(C)(C)OC(=O)N3)cc1OC
Reactant: OO
Product: COc1ccc(S(=O)CCCCOc2cc(C)c3c(c2)C(C)(C)OC(=O)N3)cc1OC

Procedure:
Prepared analogously to Example 2 from 6-[4-(3,4-dimethoxy-phenylmercapto)-butoxy]-4,4,8-trimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=[CH:23][CH:24]=2)[CH:14]=[CH:15][CH:16]=1>>[Br:1][C:2]1[C:3]([NH:10][C:11]2[CH:12]=[C:13]([CH2:17][CH2:18][C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH:22]=[CH:23][CH:24]=3)[CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCc2cccc(N)c2)c1
Product: CC(C)(C)OC(=O)Nc1cccc(CCc2cccc(Nc3nc(Cl)ncc3Br)c2)c1
Yield: 70 %

Procedure:
This compound was prepared according to the procedure of Example B5, step G using 5-bromo-2,4-dichloropyrimidine and tert-butyl {3-[2-(3-aminophenyl)ethyl]phenyl}carbamate as the starting materials in 70% yield. LCMS calculated for C23H25BrClN4O2 (M+H)+: m/z=503.1, 505.1.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12](Cl)=[N:11][CH:10]=1.[NH:34]1[CH:38]=[N:37][CH:36]=[N:35]1>>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([N:34]2[CH:38]=[N:37][CH:36]=[N:35]2)=[N:11][CH:10]=1
Reactant: c1nc[nH]n1
Reactant: Cc1ccccc1-c1cc(Cl)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: Cc1ccccc1-c1cc(-n2cncn2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 130 °C
Reaction time: 36 h
Yield: 87.3 %

Procedure:
A mixture of 1.00 g (2.05 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-chloro-N-methyl-4-o-tolyl-nicotinamide and 1.42 g (20.5 mmol) 1,2,4-triazole was stirred at 130° C. for 36 h. After cooling to room temperature the crude mixture was purified by flash chromatography to give 0.93 g (87%) of the title compound as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](I)[CH3:8].[F:10][C:11]1[C:12]([O:25][CH3:26])=[C:13]([CH:21]=[CH:22][C:23]=1[F:24])[NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17]>CN(C)C=O>[F:10][C:11]1[C:12]([O:25][CH3:26])=[C:13]([CH:21]=[CH:22][C:23]=1[F:24])[N:14]([CH2:7][CH3:8])[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17]
Reactant: COc1c(NC(=O)C(F)(F)F)ccc(F)c1F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(C(=O)C(F)(F)F)c1ccc(F)c(F)c1OC
Temperature: 70 °C
Reaction time: 5 h
Yield: 99.4 %

Procedure:
5.66 g (0.041 mole) of potassium carbonate and 6.39 g (0.041 mole) of ethyl iodide were added to a solution of 7.0 g (0.027 mole) of 3,4-difluoro-2-methoxy-N-(trifluoroacetyl)aniline (XI) [prepared as described in Preparation 15 (C1)] dissolved in 130 ml of dimethylformamide. The mixture was then stirred at 70° C. for 5 hours, after which the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, and then subjected to column chromatography through silica gel eluted with toluene, to give 7.6 g of 3,4-difluoro-N-ethyl-2-methoxy-N-(trifluoroacetyl)aniline (XII, R9' =ethyl) as a reddish-brown oil.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][CH:20]([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])[CH:13]=3)=[CH:10][C:9]([NH2:29])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:30]=[C:31]1[NH:35][CH2:34][C@@H:33]([C:36](O)=[O:37])[CH2:32]1.CCN=C=NCCCN(C)C.Cl.O>CN(C)C(=O)C>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][CH:20]([C:21]([F:22])([F:23])[F:24])[C:25]([F:28])([F:26])[F:27])[CH:13]=3)=[CH:10][C:9]([NH:29][C:36]([C@H:33]3[CH2:32][C:31](=[O:30])[NH:35][CH2:34]3)=[O:37])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C[C@H](C(=O)O)CN1
Reactant: Nc1cc(-c2cccc(COC(C(F)(F)F)C(F)(F)F)c2)n(-c2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C1C[C@H](C(=O)Nc2cc(-c3cccc(COC(C(F)(F)F)C(F)(F)F)c3)n(-c3ccccc3)n2)CN1
Reaction time: 8 h
Yield: 54.6 %

Procedure:
To a solution of 1-phenyl-5-[3-(2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (78 mg) in N,N-dimethylacetamide (1.0 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid (29 mg) prepared according to the same procedures as Preparation 5 and WSC.HCl (44 mg) at room temperature, and the mixture was stirred overnight. To this reaction mixture was added water, and then the precipitated solid was collected by filtration. The resulting solid was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=9/1). To the resulting solid were added water and a small amount of methanol, and the mixture was stirred. A solid was collected from this suspension by filtration, and was dried under reduced pressure to give the titled compound (54 mg).
Reaction SMILES: [C:1]([N:8]([CH2:21][CH2:22][C:23]#[CH:24])[S:9]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)(=[O:11])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:25]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=1I)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[C:4]([O:3][C:1]([N:8]([CH2:21][CH2:22][C:23]#[C:24][C:40]1[CH:41]=[C:42]([Cl:45])[CH:43]=[CH:44][C:39]=1[NH:38][CH:25]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[S:9]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)(=[O:11])=[O:10])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: C#CCCN(C(=O)OC(C)(C)C)S(=O)(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: Clc1ccc(NC(c2ccccc2)c2ccccc2)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CCC#Cc1cc(Cl)ccc1NC(c1ccccc1)c1ccccc1)S(=O)(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 55 °C
Yield: 93.8 %

Procedure:
A warm (45° C.) solution of N-BOC-N-but-3-ynyl-(3,4-dichloro-phenyl)-methanesulfonamide (347 g, 0.885 mol), dichlorobis(triphenylphosphine)palladium (II) (3.50 g, 4.99 mmol), and DMF (700 mL) was added slowly over 8 h to a warm (55° C.), stirred mixture of benzhydryl-(4-chloro-2-iodo-phenyl)-amine (350 g, 0.833 mol), dichlorobis(triphenylphosphine)palladium (II) (3.5 g, 4.99 mmol), copper (I) iodide (20.0 g, 0.105 mol), triethylamine, (259 g, 2.56 mol), and DMF (250 mL). The reaction mixture was stirred and maintained at 55° C. for 30 m after complete addition. The reaction mixture was distilled at reduced pressure using a heating bath temperature of 40-45° C. to remove triethylamine. The reaction mixture was filtered through a celite pad. The pad was washed with DMF (40 mL). 2-Propanol (280 mL) was added to the filtrate. The mixture was warmed to 55° C. Water (280 mL) was added slowly over 1 h to the stirred mixture. The stirred mixture was maintained at 55° C. for 30 m after complete water addition. The mixture was cooled to 10° C. The solid product was collected by filtration and washed with cold 1/1 (v/v) IPA/water (2×300 mL). The solid was vacuum dried at <50° C. to give N-t-butoxycarbonyl-N-{4-[2-(benzhydryl-amino)-5-chloro-phenyl]-but-3-ynyl}-C-(3,4-dichlorophenyl)-methanesulfonamide (534.5 g, 94%) with 98% purity (as determined by HPLC).
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.[NH:12]1[CH:16]=[C:15]([C:17](=[S:19])[NH2:18])[N:14]=[CH:13]1>>[NH:12]1[CH:16]=[C:15]([C:17]2[S:19][C:2]3[CH2:10][C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[C:3]=3[N:18]=2)[N:14]=[CH:13]1
Reactant: NC(=S)c1c[nH]cn1
Reactant: O=C1c2ccccc2CC1Br
Product: c1ccc2c(c1)Cc1sc(-c3c[nH]cn3)nc1-2

Procedure:
Starting compounds: 2-bromo-1-indanone, 4-imidazole carbothioamide
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:5]=1[OH:11])[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:17].C(=O)([O-])[O-].[K+].[K+]>>[Br:10][C:6]1[C:5]2[O:11][CH:2]([CH2:3][OH:17])[CH2:1][C:4]=2[CH:9]=[CH:8][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1cccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OCC1Cc2cccc(Br)c2O1
Yield: 74.3 %

Procedure:
Treatment of 2-allyl-6-bromophenol (61.4 g 0.288 mol) with 3-chloroperoxybenzoic acid (77%, 149.18 g, 0.864 mol)) followed by potassium carbonate (99.56 g, 0.72 mol) generally according to the procedure described for Intermediate 9 provided 49.00 g (78%) (86%) of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methanol as an amber oil. Rf=0.66 (silica, ethyl acetate:hexanes 1:9) 1H NMR (DMSO-d6) δH 7.23 (dd, 1H); 7.14 (dd, 1H); 6.71 (t, 1H); (5.01 m, 1H); 4.85 (m, 1H); 4.99 (m, 2H); 3.36 (d, 2H).