Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=1.[F:27][C:28]1[C:33](B(O)O)=[CH:32][CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:27][C:28]1[C:33]([C:2]2[N:6]([S:7]([C:10]3[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=3)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=2)=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: OB(O)c1cccnc1F
Reactant: Cc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2cccnc2F)cn1
Temperature: 105 °C
Reaction time: 1 h
Yield: 40.7 %

Procedure:
A suspension of tert-butyl ({5-bromo-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (206 mg), (2-fluoropyridin-3-yl)boronic acid (80 mg), sodium carbonate (119 mg) and tetrakis(triphenylphosphine)palladium (80 mg) in 1,2-dimethoxyethane (5 mL) and water (2.5 mL) was stirred under a nitrogen atmosphere at 105° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a pale-yellow oil (yield 87 mg, 41%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[Al].[Br:14]N1C(=O)CCC1=O>O>[Br:14][C:4]1[C:3]([O:2][CH3:1])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)CCC2=O
Agent: [Al]
Solvent: O
Product: COc1ccc2c(c1Br)CCC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Methoxy-indane-1-one (17.2 g, 106.05 mmol) is suspended in 100 mL of water. The flask is covered with an aluminium foil to create a dark environment. N-Bromo-succinimide (18.87 g, 106.05 mmol) is added portionwise and the reaction mixture is stirred at room temperature overnight. The reaction mixture is extracted with 200 mL of ethyl acetate, the organic phase is collected, dried over sodium sulfate and concentrated under vacuum. The crude product obtained (20 g) is used in the next step without any further treatment.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].N1C=CC=CC=1.Cl[C:17]([O:19][CH3:20])=[O:18]>C(Cl)(Cl)Cl>[CH3:20][O:19][C:17](=[O:18])[NH:5][C:4]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([Cl:1])[CH:3]=1
Reactant: Cc1ccc(N)cc1Cl
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1ccc(C)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 10.0 grams (0.071 mole) of 3-chloro-4-methylaniline in 100 ml of chloroform was added 16.7 grams (0.212 mole) of pyridine. Methyl chloroformate, 8.0 grams (0.085 mole), was then added dropwise during a 20 minute period. During the addition the reaction mixture temperature was held between 25°-30° C. with external cooling. Upon completion of addition the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was washed into a separatory funnel with 50 ml of chloroform; and the solution was washed with two 100 ml portions of water and 100 ml of aqueous 5% hydrochloric acid. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a waxy solid residue. The residue was recrystallized from hexane/ethyl acetate to give 10.9 grams of methyl(3-chloro-4-methylphenyl)carbamate; m.p. 80°-81.5° C.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[CH:18]([NH2:21])([CH3:20])[CH3:19].CCN(C(C)C)C(C)C>C(#N)C>[F:11][C:4]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:2]([NH:21][CH:18]([CH3:20])[CH3:19])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ccccn2)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)Nc1c([N+](=O)[O-])ccc(F)c1-c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
A mixture of 2-(2,6-difluoro-3-nitrophenyl)pyridine (0.85 g, 3.6 mmol), isopropylamine (0.31 mL, 3.6 mmol) and DIPEA (0.63 mL, 3.6 mmol) in acetonitrile (10 mL) was stirred overnight at RT. The mixture was concentrated in vacuo and the resulting residue was purified by chromatography (Si—PPC, gradient 0-50% EtOAc/cyclohexane) to afford the title compound as a yellow oil (0.49 g, 50%). 1H NMR (CDCl3, 400 MHz): δ 8.76 (1H, ddd, J=6.5, 3.7, 2.4 Hz), 8.26 (1H, dd, J=12.7, 8.1 Hz), 7.86 (1H, br s), 7.81 (1H, td, J=10.4, 2.5 Hz), 7.46 (1H, dq, J=10.5, 1.5 Hz), 7.34 (1H, ddd, J=10.2, 6.5, 1.6 Hz), 6.57 (1H, dd, J=12.7, 10.8 Hz), 2.70-2.54 (1H, m), 0.93 (6H, d, J=8.4 Hz)
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].CN(C)C=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:42]12([C:48]3[C:49]([O:53][C:54]4[N:59]=[CH:58][C:57]([NH2:60])=[CH:56][CH:55]=4)=[CH:50][CH:51]=[CH:52][C:47]=3[O:46][CH2:45]1)[CH2:44][CH2:43]2>>[C:42]12([C:48]3[C:49]([O:53][C:54]4[N:59]=[CH:58][C:57]([NH:60][C:10]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:13][CH3:14])=[O:12])=[CH:56][CH:55]=4)=[CH:50][CH:51]=[CH:52][C:47]=3[O:46][CH2:45]1)[CH2:44][CH2:43]2
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.5 %

Procedure:
To a solution of (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (94 mg, 0.462 mmol) in dry N,N-Dimethylformamide (2 mL) DIPEA (0.115 mL, 0.661 mmol) and then TBTU (159 mg, 0.496 mmol) were added and the reaction mixture was stirred for 15 minutes at room temperature. 6-(spiro[1-benzofuran-3,1′-cyclopropan]-4-yloxy)-3-pyridinamine (Reference Intermediate 216, 84 mg) was added and the reaction mixture was stirred for 6 hours at the same temperature. The reaction was quenched with brine (2 ml), diluted with water (5 ml) and extracted with ethyl acetate (2×10 ml). The organic layer was washed with ice cold brine (2×5 ml), dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 7:3 as eluents affording the title compound as a colourless oil (130 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:14]([F:21])=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:16]/[C:15]3[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[C:14]=3[F:21])/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Cl)c1F
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccc(Cl)c1F
Temperature: 50 °C
Yield: 89 %

Procedure:
To the mixture of 6-chloro-2-oxindole (11 g, 65.6 mmol) (Crescent) and 3-chloro-2-fluorobenzaldehyde (12 g, 75.7 mmol) (Aldrich) in methanol (140 mL) was added piperidine (5.59 g, 65.6 mmol) (Aldrich) dropwise. The mixture was then heated at 50° C. for 3 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 18 g, 89%).
Reaction SMILES: [NH2:1][C:2]1[CH2:3][C@@H:4]2[C@@H:11]([C@H:12]([OH:14])[CH3:13])[C:10](=[O:15])[N:5]2[C:6]=1[C:7]([O-:9])=[O:8].[Na+:16].C(=O)(O)[O-].[Na+].[C:22](Cl)(=[O:24])[CH3:23].S(=O)(=O)(O)O>O.O1CCOCC1>[C:22]([NH:1][C:2]1[CH2:3][C@@H:4]2[C@@H:11]([C@H:12]([OH:14])[CH3:13])[C:10](=[O:15])[N:5]2[C:6]=1[C:7]([O-:9])=[O:8])(=[O:24])[CH3:23].[Na+:16]
Reactant: CC(=O)Cl
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(N)C[C@H]12
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)NC1=C(C(=O)[O-])N2C(=O)[C@H]([C@@H](C)O)[C@H]2C1

Procedure:
A solution of sodium (5R,6S)-2-amino-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate (23 mg, 0.1 mmol) in water (2.5 ml) is cooled in an ice-bath, stirred, and treated with sodium bicarbonate (84 mg, 1 mmol) and dioxane. The resulting solution is stirred in the cold while a solution of acetyl chloride (11 μl, 0.15 mmol) in dioxane (0.5 ml) is added dropwise over 10 minutes. After stirring an additional 30 minutes, the solution is acidified to pH 6.8 with 1M sulfuric acid and extracted with diethyl ether (3×10 ml). The aqueous phase is layered with ethyl acetate (2.5 ml) and vigorously stirred in an ice-bath while acidifying to pH 2.3 with 1M sulfuric acid. The aqueous phase is separated and extracted with more ethyl acetate (2×2 ml). The combined ethyl acetate solution is washed with brine, then layered with water (5 ml) and stirred vigorously in an ice-bath while the pH is brought to 7 with 1N sodium hydroxide. The aqueous phase is separated, concentrated under vacuum, and lyophilized to yield sodium (5R,6S)-2-acetamido-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate (32).
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:30][CH2:29][C:17]3([CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[CH2:16][CH2:15]2)[CH:9]=1>C(Cl)Cl>[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:30][CH2:29][C:17]3([CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:16][CH2:15]2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(c3cccnc3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cncc(N2CCC3(CCNC3)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TFA (2 ml) was added to a solution of tert-butyl 8-(pyridine-3-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (1.14 mmol, 1.0 eq.) in methylene chloride (6 ml) at 0° C. and the reaction mixture was stirred at 25° C. for 2 h. When the reaction was complete, the solvent was concentrated in vacuo in order to obtain the desired amine (AMN-24).
Reaction SMILES: CC1C=C(C(O)=O)C=CC=1C1C=CC=CC=1C(F)(F)F.Br[C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[O:32][CH3:33].[CH3:34][C:35]1[C:36](B(O)O)=[CH:37][S:38][CH:39]=1>>[CH3:33][O:32][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][C:22]=1[C:36]1[C:35]([CH3:34])=[CH:39][S:38][CH:37]=1)[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)c1ccc(Br)c(OC)c1
Reactant: Cc1cscc1B(O)O
Agent: Cc1cc(C(=O)O)ccc1-c1ccccc1C(F)(F)F
Product: COC(=O)c1ccc(-c2cscc2C)c(OC)c1

Procedure:
The title compound was prepared following procedure described for Intermediate 5, step 1, but starting from methyl 4-bromo-3-methoxybenzoate (Combi-Blocks, 2.50 g; 10.20 mmol; 1 eq.) and 4-methyl-3-thiopheneboronic acid (1.59 g; 11.22 mmol; 1.10 eq.), and was isolated as a brown oil. It was used in the next step without further purification. LC/MS (Method A): 262.8 (M+H)+. HPLC (Method A) Rt 4.79 min.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:12])(=[O:10])=[O:9])=[N:6][CH:7]=1.[CH3:22][O:23][CH2:24][C@H:25]([CH3:45])[O:26][C:27]1[CH:28]=[C:29]([OH:44])[CH:30]=[C:31]([C:33]2[NH:34][C:35]([C:38]3[O:39][C@@H:40]([CH3:43])[CH2:41][N:42]=3)=[CH:36][CH:37]=2)[CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:11]([CH3:12])[S:8]([C:5]2[CH:4]=[CH:3][C:2]([O:44][C:29]3[CH:30]=[C:31]([C:33]4[NH:34][C:35]([C:38]5[O:39][C@@H:40]([CH3:43])[CH2:41][N:42]=5)=[CH:36][CH:37]=4)[CH:32]=[C:27]([O:26][C@@H:25]([CH3:45])[CH2:24][O:23][CH3:22])[CH:28]=3)=[CH:7][N:6]=2)(=[O:10])=[O:9])=[CH:15][CH:16]=1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Reactant: COc1ccc(CN(C)S(=O)(=O)c2ccc(Cl)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N(C)Cc3ccc(OC)cc3)nc2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
5-Chloro-N-(4-methoxybenzyl)-N-methylpyridine-2-sulfonamide (228 mg, 0.70 mmol) synthesized in Example (121b) and 3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (220 mg, 0.67 mmol) synthesized in Example (116d) were dissolved in N,N-dimethylformamide (3 mL), and cesium carbonate (434 mg, 1.33 mmol) was added, followed by stirring at 100° C. for 3 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (20 mL) was added, and extraction was carried out twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0.5%-5%) to afford the desired compound (293 mg, yield 71%) as a white solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[OH:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:9]=[O:10].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:9]=[O:10]
Reactant: BrCCBr
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C=O)cc1OCCBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.3 %

Procedure:
1,2-Dibromoethane (56 mL, 0.66 moles) was added to a mixture of 3-hydroxy-4-methoxybenzaldehyde (10 g, 66 mmoles) and potassium carbonate (45 g, 328 mmoles) in DMF (170 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (0.5 L) and extracted with ethyl acetate (3×200 mL). The combined organic phases were washed with saturated sodium chloride (500 mL), dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel (800 mL) eluting with a mixture of ethyl acetate and heptane (1:1) to afford 9.8 g (58%) of 3-(2-bromoethoxy)-4-methoxybenzaldehyde.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]([O:27]CC2C=CC(OC)=CC=2)=[O:26])[CH2:21][CH2:20]1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(COC(=O)C2CCC(OC(=O)[C@@H](NC(=O)OCc3ccccc3)C(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OC1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-methoxybenzyl 4-(N-benzyloxycarbonyl-L-valyloxy)-cyclohexanoate (12 g, 24.1 mmole) in dichloromethane (100 ml) was added trifluoroacetic acid (20 ml) and the mixture was stirred for 3 hours at room temperature. The solution was evaporated under reduced pressure and coevaporated two times with toluene. The residue was stirred 1 hour with about 100 ml ethanol and the white solid was filtered (byproduct). The solution was evaporated under reduced pressure and the product was isolated by silica gel column chromatography with toluene/acetone. Yield: 6.8 g=74%. The product can be activated and esterified directly to a drug or firer modified as described below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15](O)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1.S(Cl)([Cl:20])=O.CCOC(C)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([Cl:20])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: OC1c2ccc(Cl)cc2CCc2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Clc1ccc2c(c1)CCc1cccnc1C2Cl
Yield: 71.6 %

Procedure:
To a mixture of 13.3 g (54 mmol) of 8-chloro-6,11-dihydro-11-hydroxy-5H-benzo[5,6]cyclohepta[1,2-b]pyridine in 290 mL of toluene at -15° C. and under an atmosphere of nitrogen was added via syringe pump over a period of 1 hour 6.20 mL (85.7 mmol) of thionyl chloride. The extent of reaction was monitored by TLC (50% EtOAc in hexanes). When completed the mixture was poured into 300 mL of 1.0N aqueous NaOH and extracted with EtOAc (5×). The combined organic portions were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was taken up in EtOAc, quickly filtered through basic alumina, and concentrated again to yield a product which was triturated with pentane to yield 10.22 g of the title compound as a tan solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:21][CH2:22][CH3:23])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:16]2[O:17][CH:18]=[CH:19][N:20]=2)[CH:15]=1)[C:10](O)=[O:11])=[O:6])[CH2:2][CH3:3].C([N:27](CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[O:17]1[CH:18]=[CH:19][N:20]=[C:16]1[C:14]1[CH:15]=[C:7]([C:5]([N:4]([CH2:21][CH2:22][CH3:23])[CH2:1][CH2:2][CH3:3])=[O:6])[CH:8]=[C:9]([CH:13]=1)[C:10]([NH2:27])=[O:11]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCCN(CCC)C(=O)c1cc(C(N)=O)cc(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 148.5 %

Procedure:
A solution of 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoic acid 38 (120 mg, 0.38 mmol) in methylene chloride (3.8 mL) containing N,N-diisopropylethylamine (132 μL, 0.76 mmol) and HBTU (151 mg, 0.40 mmol) was stirred at room temperature for 0.5 h. To the above solution was added a solution of the orange oil from step 7 (207 mg, 0.57 mmol) in methylene chloride (3.8 mL) containing N,N-diisopropylethylamine (132 μL, 0.76 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then diluted with additional methylene chloride and washed with saturated sodium bicarbonate and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure to yield an oily residue. Purification by flash column chromatography (silica, 90:10 methylene chloride/methanol) gave N1-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[({2-(dimethylamino)methyl]pyridin-4-yl}methyl)amino]-2-hydroxypropyl}-5-(1,3-oxazol-2-yl)-N3,N3-dipropylisophthalamide (178 mg): mp 63-66° C.; ESI MS m/z 663 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:7]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:8][C@@H:9]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[S:5][CH:6]=1.[CH3:36][C:37]([OH:41])([C:39]#[CH:40])[CH3:38]>CCN(CC)CC.Cl[Pd-2](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>[OH:41][C:37]([CH3:38])([CH3:36])[C:39]#[C:40][C:2]1[N:3]=[C:4]([N:7]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:8][C@@H:9]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[S:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CN(C(=O)OC(C)(C)C)c1nc(Br)cs1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1csc(N(C[C@H](Cc2ccc(C(F)(F)F)cc2)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 91.6 %

Procedure:
(S)-tert-butyl 1-(N-(4-bromothiazol-2-yl)-tert-butoxylcarbonylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.25 g, 0.43 mmol) was taken up in 4 mL of Et3N. 2-Methylbut-3-yn-2-ol (0.21 mL, 2.2 mmol), dichlorobis(triphenylphosphino)-palladium(II) (0.030 g, 0.043 mmol), and copper(I) iodide (0.025 g, 0.13 mmol) were added. The mixture was stirred for 20 minutes. No reaction was observed, and the mixture was heated to 60° C. for 1 hour. The reaction was judged to be complete by LC/MS, the solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (5% to 30% EtOAc/hexanes), to provide (S)-tert-butyl 1-(N-(4-(3-hydroxy-3-methylbut-1-ynyl)thiazol-2-yl)-tert-butoxylcarbonylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.23 g, 91% yield): LCMS (M+H) 584 calc. for C28H37F3N3O5S 583.6.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH3:13])[C:3]=1[CH:4]=O.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(Cl)Cl.O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH3:13])[C:3]=1[CH2:4][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNCC1
Reactant: COc1cc(Cl)c(C=O)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1cc(Cl)c(CN2CCCCC2)c(OC)c1
Yield: 90.6 %

Procedure:
To a pre-stirred solution of 2-chloro-4,6-dimethoxybenzaldehyde (2.7 g, 13.5 mmol) and piperidine (1.46 mL, 14.9 mmol) in DCM (50 mL) at 0° C. was added sodium triacetoxyborohydride (4.29 g, 20.0 mmol) in portions. The reaction mixture was then allowed to warm to ambient and stirred for an additional 3 h before the addition of water (50 mL). The pH of the aqueous phase was adjusted to 2 by the addition of hydrochloric acid and then washed with DCM (50 mL). The pH of the aqueous phase was then adjusted to 9 by the addition of saturated aqueous sodium carbonate and then the organic component was extracted into DCM (50 mL), dried over sodium sulfate and evaporated under reduced pressure to afford the title compound as a beige solid (3.3 g, 91%) that was used without further purification. 1H NMR (CDCl3, 300 MHz): 6.60 (d, J=2.4 Hz, 1H), 6.43 (d, J=2.4 Hz, 1H), 4.35 (s, 2H), 3.90 (s, 3H), 3.83 (s, 3H), 3.6-2.57 (v br m, 4H), 2.29-1.88 (br m, 4H), 1.71-1.40 (br m, 2H).
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:12]O.P(Br)(Br)[Br:15].O>C(OCC)C>[Br:15][CH2:12][C:3]1[C:4]([C:8]([F:11])([F:10])[F:9])=[N:5][N:6]([CH3:7])[C:2]=1[F:1]
Reactant: Cn1nc(C(F)(F)F)c(CO)c1F
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: O
Product: Cn1nc(C(F)(F)F)c(CBr)c1F
Temperature: -30 °C
Reaction time: 12 h
Yield: 67.3 %

Procedure:
A solution of 35.4 g (178.7 mmoles) of 5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-methanol dissolved in 500 ml of diethyl ether was cooled to −30° C. Thereto was added 54.0 g (199.5 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with diethyl ether. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 31.4 g (yield: 80.8%) of 4-bromomethyl-5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole.