Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]([CH2:14][C:15]1[C:23]2[C:18](=[C:19]([F:24])[CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)([NH:11]C=O)C(OCC)=O)C.[OH-].[Na+].C(O)(=O)C>C1COCC1>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[NH:17][CH:16]=[C:15]2[CH2:14][C@@H:5]([C:4]([OH:25])=[O:3])[NH2:11]
Reactant: CCOC(=O)C(Cc1c[nH]c2c(F)cccc12)(NC=O)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N[C@@H](Cc1c[nH]c2c(F)cccc12)C(=O)O
Temperature: 25 °C
Yield: 52 %

Procedure:
A solution of 2-(7-Fluoro-1H-indol-3-ylmethyl)-2-formylamino-malonic acid diethyl ester in THF was treated with NaOH (300 mg in 10 mL water) at room temperature for 24 hr. The mixture was slowly acidified with acetic acid (5 mL) and then refluxed for 24 hr. The reaction mixture was concentrated under vacuum, and treated with dil. HCl (10 mL, 3M) and then again refluxed for ˜16 h. The reaction was allowed to cool to room temperature. The pH was adjusted to 6.0 with 2M KOH. The white solid that formed was filtered, washed with water, and dried under vacuum to give 7-fluoro-tryptophan (282 mg, 52%): mp 256-261° C., 1H NMR (500 MHz, DMSO-d6): 2.92-2.97 (dd, J=8.5 and 15 Hz, 1H), 3.25-3.29 (dd, J=4.0 and 15 Hz, 1H), 3.38-3.41 (dd, J=4.0 and 8.5 Hz, 1H), 6.87-6.96 (m, 2H), 7.25 (s, 1H), 7.37 (d, J=7.5 Hz, 1H), 11.36 (s, 1H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([S@:7]([N:9]=[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=2)[CH2:12][CH2:11]1)=[O:8])([CH3:6])[CH3:5].C1COCC1.CO>C(=O)=O>[CH3:6][C:4]([S@:7]([NH:9][C@H:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:17]=2)[CH2:12][CH2:11]1)=[O:8])([CH3:3])[CH3:5]
Reactant: CC(C)(C)[S@@](=O)N=C1CCc2ccc(C(F)(F)F)cc21
Agent: O=C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)[S@@](=O)N[C@@H]1CCc2ccc(C(F)(F)F)cc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 26.7 %

Procedure:
Sodium borohydride (756 mg, 20.0 mmol) was stirred in a round-bottomed flask under argon at −40 to −50° C. The reaction mixture of Intermediate 4A was added dropwise to the flask, and THF was added to the reaction mixture (ca. 0.6 M). The resulting mixture was allowed to warm up to 0° C. during 1.5 h period. The reaction mixture was cooled in dry ice and MeOH was added dropwise until gas evolution stopped. The mixture was stirred at rt for 20 min, filtered through Celite and rinsed with EtOAc then CH2Cl2. The filtrate was washed with brine (2×) and dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (hexanes/EtOAc) to give Intermediate 4B (370 mg, 1.21 mmol, 26.7% yield) as colorless crystals. LC-MS (ESI) 306.0 (M+H), RT=2.10 min (Method B).
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)=[N:4][CH:5]=[C:6]([CH:17]=1)[C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])=[O:8].[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[CH:20]1([CH2:19][O:18][C:3]2[C:2]([C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]([F:23])([F:35])[F:36])=[CH:31][CH:30]=3)=[CH:17][C:6]([C:7]([NH:9][C@@H:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]3[OH:16])=[O:8])=[CH:5][N:4]=2)[CH2:22][CH2:21]1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCC2CC2)c(Br)c1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCC2CC2)c(-c2ccc(OC(F)(F)F)cc2)c1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 23, using 5-bromo-6-cyclopropylmethoxy-N-(trans-2-hydroxy-cyclohexyl)-nicotinamide and 4-trifluoromethoxyphenylboronic acid (commercially available) as starting materials. MS (m/e): 451.3 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]3[N:21]([CH2:22][CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:20](=[O:31])[C@H:19]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:18]3)=[C:11]([N+:37]([O-])=O)[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].CN(C)C=O>C(O)C.[Pd]>[NH2:37][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH2:16][C@H:17]1[N:21]([CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20](=[O:31])[C@H:19]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:18]1
Reactant: COC(=O)C[C@@H]1C[C@@H](COc2ccc(-c3ccc(C#N)cc3)cc2[N+](=O)[O-])N(CCCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: COC(=O)C[C@@H]1C[C@@H](COc2ccc(-c3ccc(C#N)cc3)cc2N)N(CCCc2ccccc2)C1=O

Procedure:
4 g of (3S,5S)-5-[(4'-cyano-3-nitro-4-biphenylyl)oxymethyl]-3-[(methoxycarbonyl)methyl]-1-(3-phenylpropyl)-2-pyrrolidinone are hydrogenated in 40 ml of ethanol and 10 ml of dimethylformamide with 1.5 g of palladium (10% on activated charcoal) under a hydrogen pressure of 3 bar at ambient temperature. After 40 minutes the catalyst is removed by suction filtering and the filtrate is evaporated down. The residue is divided between water and methylene chloride, the organic phase is separated off, dried with magnesium sulphate and evaporated down. Column chromatography on silica gel with methylene chloride/ethyl acetate (4:1) yields 2.9 g (77% of theory) of the desired compound. Melting point: 111°-112° C. Rf value: 0.37 (silica gel; 1,2-dichloroethane/ethyl acetate=3:1) Calculated: C 72.41 H 6.28 N 8.45 Found: 72.31 6.54 8.27
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:24])=[C:6]([C:8]23[CH2:15][CH:14]2[CH2:13][CH2:12][S:11][C:10]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:9]3)[CH:7]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32](O)=[O:33])=[N:30][CH:31]=1>>[Cl:24][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:32](=[O:33])[C:29]2[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][N:30]=2)=[CH:7][C:6]=1[C:8]12[CH2:15][CH:14]1[CH2:13][CH2:12][S:11][C:10]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[N:9]2
Reactant: CC(C)(C)OC(=O)NC1=NC2(c3cc(N)ccc3Cl)CC2CCS1
Reactant: O=C(O)c1ccc(Cl)cn1
Product: CC(C)(C)OC(=O)NC1=NC2(c3cc(NC(=O)c4ccc(Cl)cn4)ccc3Cl)CC2CCS1
Yield: 54.4 %

Procedure:
Prepared in an analogous manner as described for intermediate rac-A9a from tert-butyl (1SR,7SR)-1-(5-amino-2-chlorophenyl)-4-thia-2-azabicyclo[5.1.0]oct-2-en-3-ylcarbamate (intermediate rac-A8b) (56 mg, 152 μmol) and 5-chloro-2-pyridinecarboxylic acid to give the tert-butyl (1SR,7SR)-1-(2-chloro-5-(5-chloropicolinamido)phenyl)-4-thia-2-azabicyclo[5.1.0]oct-2-en-3-ylcarbamate (42 mg, 82.8 μmol, 54.4% yield) as a light brown oil. MS (ISP): m/z=407.2 [(M-Boc+H)+], 409.2 [(M-Boc+2+H)+] and 411.0 [(M-Boc+4+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH:28]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:30]1[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][N:30]3[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CC=O)cn(C)c34)no2)cc1Cl
Reactant: O=C(O)C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCN5CC(C(=O)O)C5)cn(C)c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 3 h
Yield: 29.8 %

Procedure:
To a stirred solution of [7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]acetaldehyde (D88) (50 mg), 3-azetidinecarboxylic acid (25 mg) and acetic acid (0.1 mL) in DCM (10 mL) was added sodium triacetoxyborohydride (78 mg). The reaction was stirred at 20° C. for 3 h. The mixture was concentrated and the residue was partitioned between ethyl acetate (25 mL) and aqueous HCl (2 M, 25 mL). The organic phase was washed with water (25 mL) and brine (25 mL), dried over sodium sulphate and evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford 1-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl}-3-azetidinecarboxylic acid (E67) (18 mg, TFA salt). δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 3.00 (2H, t), 3.47 (2H, t), 3.60 (1H, m), 3.65 (3H, s), 4.22 (4H, m), 4.88 (1H, m), 7.22 (1H, t), 7.31 (1H, s), 7.47 (2H, m), 7.87 (1H, dd), 8.12 (1H, dd), 8.19 (1H, d). MS (ES): C26H27ClN4O4 requires 494; found 495.2 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]2[CH:11]=[CH:10][CH:9]=[CH:8]2)=[C:5]([C:12]([OH:14])=O)[CH:4]=[N:3]1.N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:23]>ClCCl>[CH3:1][N:2]1[C:6]([N:7]2[CH:11]=[CH:10][CH:9]=[CH:8]2)=[C:5]([C:12]([F:23])=[O:14])[CH:4]=[N:3]1
Reactant: Fc1nc(F)nc(F)n1
Reactant: Cn1ncc(C(=O)O)c1-n1cccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1ncc(C(=O)F)c1-n1cccc1
Reaction time: 2 h

Procedure:
To a stirred solution of 1-methyl-5-pyrrol-1-yl-1H-pyrazole-4-carboxylic acid (7.65 g, 40 mmol) in dry dichloromethane (150 mL) and pyridine (3.2 mL, 40 mmol) under a nitrogen atmosphere was added cyanuric fluoride (5.4 g, 40 mmol) at 0° C. The reaction mixture was stirred for two hours during which time the reaction temperature was allowed to rise to room temperature. Crushed ice was then added along with additional dichloromethane. The organic layer was separated and the aqueous layer was extracted twice with dichloromethane. Concentration of the combined organic layers under reduced pressure gave 1-methyl-5-pyrrol-1-yl-1H-pyrazole-4-carbonyl fluoride which was used in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH2:15])[N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]1([CH3:33])[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30](Cl)=[O:31]>>[C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH:15][C:30](=[O:31])[CH2:29][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[CH3:33])[N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1CC(=O)Cl
Reactant: Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Product: Cc1ccccc1CC(=O)Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12

Procedure:
The title compound, MS m/e (%): 420 (M+H+, 100), was prepared in accordance with the general method of example 31 from 2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin ylamine and o-tolylacetyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20](Cl)=[O:21]>>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:21]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3c(F)cccc3F)c2)CC1

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 2,6-difluorobenzoyl chloride (29 μL, 0.229 mmol) and mixing for 24 h, 46.6 mg (>100%) of the title compound were recovered.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[C:25]([N:15]1[CH2:16][CH2:17][CH2:18][C@H:14]1[CH2:13][O:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([NH2:1])=[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:4]([CH3:19])=[N:5]2)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H]3CCCN3)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H]3CCCN3C(C)=O)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-2-methyl-5-(pyrrolidin-2-ylmethoxy)quinoline-3-carboxylate (Example 89b) and acetic anhydride as brown solid (31%). MS 372 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[CH2:21]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[OH-].[Na+]>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:35][C:32]2[CH:33]=[CH:34][C:29]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:30][CH:31]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: CCCCCCCCc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCc1ccc(OCCCOc2ccc(C[C@H](OC)C(=O)O)cc2)cc1

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 4-Octyl-phenol under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C27H38O5 [M+Na]+: 466.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[I:10]N1C(=O)CCC1=O.C(OCC)(=O)C>CN(C=O)C>[NH2:1][C:2]1[C:7]([I:10])=[N:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(Cl)ncc1N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Cl)nc(I)c1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.3 %

Procedure:
5-Amino-2-chloro-4-methylpyridine (1.35 g) was dissolved in DMF (20 mL), N-iodosuccinimide (2.59 g) was added and the reaction mixture was stirred at room temperature for 12 hours. Ethyl acetate was added and the organic layer was washed 3× with water, washed with brine, dried over MgSO4 and concentrated in vacuum. The residue was purified by column chromatography (silica 60, hexane/ethyl acetate=3:1, Rf=0.30) to afford 1.38 g of the title compound of the formula
Reaction SMILES: [CH3:1][CH2:2][O:3][CH2:4][CH2:5][O:6][C:7](=[O:21])[CH2:8][N:9]([C:15]([S:17][CH2:18][C:19]#[CH:20])=[O:16])[CH2:10][P:11](Cl)(Cl)=[O:12].C(Cl)Cl.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(OCC)C>[CH3:1][CH2:2][O:3][CH2:4][CH2:5][O:6][C:7](=[O:21])[CH2:8][N:9]([C:15]([S:17][CH2:18][C:19]#[CH:20])=[O:16])[CH2:10][P:11]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:12]
Reactant: C#CCSC(=O)N(CC(=O)OCCOCC)CP(=O)(Cl)Cl
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCOCC
Product: C#CCSC(=O)N(CC(=O)OCCOCC)CP(=O)(N1CCOCC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(2-Ethoxy)ethyl-N-[(propargylthio)carbonyl]-N-[dichlorophosphinylmethyl]glycinate (10.5 g.; 0.028 mol.) was dissolved in 50 ml. of diethyl ether and 50 ml. of methylene chloride. To the solution was added a solution of morpholine (9.7 g.; 0.11 mol.) in 100 ml. of diethyl ether. The resulting mixture was stirred for 16 hours at 25° C., then filtered. The filtrate was washed with 3% ammonium hydroxide, brine, 5% hydrochloric acid and again with brine. The ether layer was separated, dried and concentrated in vacuo. The residue was purified using a silica gel column with acetonitrile as the eluent to yield (2-ethoxy)ethyl-N-[(propargylthio)carbonyl]-N-[bis(morpholino)phosphinylmethyl]glycinate, dihydrate as an oil (nD25 =1.5200) having the following analysis:
Reaction SMILES: Br[CH2:2][C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C)C=O>[N:17]([CH2:2][C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: BrCc1c2ccccc2cc2ccccc12
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1c2ccccc2cc2ccccc12
Temperature: 25 °C
Yield: 87.5 %

Procedure:
A solution of 9-bromomethyl-anthracene (7.85 g, 29.0 mmol) and sodium azide (7.79 g, 120 mmol) in dimethylformamide (DMF, 190 mL) was heated at 50° C. for 30 minutes. The mixture was cooled to room temperature, and extracted with ether, and the ether layers were washed with water, dried over MgSO4 and concentrated to give 9-azidomethyl-anthracene as yellow crystals (5.92 g, 87% yield). 1H NMR (CDCl3) δ 8.53 (1H, s), 8.31 (2H, d), 8.07 (2H, d), 7.61 (2H, dd), 7.53 (2H, dd), 5.35 (2H, s).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:18])[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=2)=[CH:5][CH:4]=1>C(O)(=O)C.Br.O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:18])[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nc(C(F)(F)F)cn2C)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Cn1cc(C(F)(F)F)nc1-c1ccc(O)cc1

Procedure:
9.3 g of 2-(4-methoxyphenyl)-1-methyl-4-(trifluoromethyl)-imidazole are dissolved in a mixture of 46.1 ml of acetic acid and 46.5 ml of 48% strength hydrobromic acid and the solution is heated under reflux for 48 hours. The solution is concentrated in a rotary evaporator to form a thick paste which is diluted with water; the pH is adjusted to 11 with concentrated ammonia and finally extraction is carried out several times with ethyl acetate. After drying the organic phase and filtration, concentration is carried out in a rotary evaporator until a thick suspension is produced. After cooling, the suspension is filtered and the crystallisate is dried in vacuo, yielding the 2-(4-hydroxyphenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole having a melting point of 220°-221°.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[C:15]([Cl:16])=[C:14]([Cl:17])[CH:13]=[CH:12][C:11]=1[S:18](Cl)(=[O:20])=[O:19]>>[Cl:9][C:10]1[C:15]([Cl:16])=[C:14]([Cl:17])[CH:13]=[CH:12][C:11]=1[S:18]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:20])=[O:19]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1Cl
Product: Cc1noc(NS(=O)(=O)c2ccc(Cl)c(Cl)c2Cl)c1Br
Yield: 66 %

Procedure:
2,3,4-Trichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2,3,4-trichlorobenzenesulfonyl chloride according to the procedures described in Example 45. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 110°-113° C., yield 66%.
Reaction SMILES: [C:1]1([S:7]([OH:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Ca+2].[Cl-].[F:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][CH2:19][C@H:20]2[O:25][CH:24](O)[CH2:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1>C(Cl)Cl>[C:1]1([S:7]([CH:24]2[CH2:23][CH2:22][CH2:21][C@@H:20]([CH2:19][O:18][C:17]3[CH:16]=[CH:15][C:14]([F:13])=[CH:28][CH:27]=3)[O:25]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC1CCC[C@@H](COc2ccc(F)cc2)O1
Reactant: O=S(O)c1ccccc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)C1CCC[C@@H](COc2ccc(F)cc2)O1
Temperature: 0 °C
Reaction time: 4 h
Yield: 76.7 %

Procedure:
25% HCl was added dropwise to benzenesulfinic acid sodium salt (0.6 g), until the solid dissolved. This mixture was extracted with ethyl acetate (15 ml) dried (Na2SO4) and concentrated to give benzenesulfinic acid (0.4 g). To an ice-cooled mixture of benzenesulfinic acid (0.32 g, 2.23 mmol) and calcium chloride (0.25 g, 2.23 mmol) in dry CH2Cl2 a solution of (2RS,6S)-6-(4-fluorophenoxymethyl)-2-hydroxy-tetrahydropyran (0.42 g, 1.86 mmol) in dry CH2Cl2 (5 ml) was added. The reaction mixture was stirred for 4 h, filtered through celite and washed with CH2Cl2. The combined organic layers were washed with saturated aqueous Na2CO3, water, brine and dried (Na2SO4). The solvent was removed under vacuum and the residue was purified on a silica gel column using light petroleum-ethyl acetate (4:1) as eluent to afford pure (2RS,6S)-2-benzenesulfonyl-6-(4-fluorophenoxymethyl)-tetrahydropyran (0.5 g, 70%) as a viscous liquid. TLC:ethyl acetate-light petroleum (1:3), Rf=0.4. 1H NMR (CDCl3, 200 MHz): δ 1.5 (m, 2H), 1.75-2.0 (m, 2H), 2.2-2.4 (m, 1H), 2.6-2.8 (m, 1H), 3.75-3.9 (m, 2H), 4.65 (d, 1H), 4.85-5.0 (m, 1H), 6.7-7.0 (m, 4H), 7.5-7.7 (m, 3H), 7.95 (d, J=5.4 Hz, 2H).
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][C:5]1[C:20]([Cl:21])=[CH:19][C:8]([C:9]([NH:11][CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:10])=[C:7]([OH:22])[CH:6]=1.Br[CH2:24][C:25]([O:27][CH3:28])=[O:26]>CN(C=O)C>[NH2:4][C:5]1[C:20]([Cl:21])=[CH:19][C:8]([C:9]([NH:11][CH2:12][CH2:13][N:14]([CH2:15][CH3:16])[CH2:17][CH3:18])=[O:10])=[C:7]([O:22][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:6]=1
Reactant: COC(=O)CBr
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCC(=O)OC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 67.6 %

Procedure:
To a stirred suspension of sodium hydride (420 mg of 60%, 10.5 mmoles) in DMF (10 ml) was added 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride (1.612 g, 5 mmoles) and the mixture stirred for 20 minutes, followed by cooling (ice water) and addition of methyl bromoacetate (832 mg, 5.44 mmoles). The mixture was stirred for 20 minutes in the cold and another 10 minutes at ambient temperature followed by pouring into 70 ml of ice-cold water. A separated solid was filtered and dried to give 1.58 g of crude product mp 92°-94°. This was recrystallized from methylene chloride-ether to give 1.21 g of the title compound as a white crystalline solid, mp 94°-95° (67.6% yield). The NMR spectrum (90 MHz) in CDCl3 gave the following resonances: δ 8.2 (s, 1H); 6.16 (s, 1H); 4.7 (s, 2H); 4.40 (bs, 2H); 3.86 (s, 3H); 3.54 (m, 2H); 2.6 (m, 6H); 1.04 (t, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[C:7]([Cl:13])=[N:8][CH:9]=[C:10](Br)[CH:11]=1)[CH3:2].CC1(C)C(C)(C)OB([C:23]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:24]=2[CH:25]=[O:26])O1>>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[C:7]([Cl:13])=[N:8][CH:9]=[C:10]([C:23]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:24]=2[CH:25]=[O:26])[CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cc(Br)cnc1Cl
Reactant: CC1(C)OB(c2ccc(C(F)(F)F)cc2C=O)OC1(C)C
Product: CCOC(=O)Cc1cc(-c2ccc(C(F)(F)F)cc2C=O)cnc1Cl

Procedure:
(5-Bromo-2-chloro-pyridin-3-yl)-acetic acid ethyl ester and 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzaldehyde were reacted as described in Example 3, Step 6 to provide [2-chloro-5-(2-formyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:19])[CH2:14][S:15][CH:16]([CH3:18])[CH3:17])[CH2:9]1)=O)(C)(C)C.[H-].[Na+].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25](F)[C:24]=1[C:30]([F:33])([F:32])[F:31].CCO>CN(C=O)C.Cl>[Cl:22][C:23]1[C:24]([C:30]([F:31])([F:32])[F:33])=[C:25]([CH:26]=[CH:27][CH:28]=1)[O:19][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][S:15][CH:16]([CH3:17])[CH3:18]
Reactant: CC(C)SC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1cccc(Cl)c1C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)SC[C@H](Oc1cccc(Cl)c1C(F)(F)F)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((R)-1-Hydroxy-2-isopropylsulfanylethyl)pyrrolidine-1-carboxylic acid t-butyl ester (10 mg, 0.030 μmol) was dissolved in DMF (166 μL). NaH (1.7 mg, 69.1 μmol) was added and the mixture was stirred at room temperature for 15 minutes. 2-Chloro-6-fluorobenzotrifluoride (20.6 mg, 104 μmol) was added and the mixture was stirred at 100° C. for 1 hour. The mixture was cooled to room temperature, concentrated then dissolved in 1.2M HCl in EtOH (1.0 mL, 1.2 mmol) and stirred overnight at room temperature. The product was concentrated and the crude product was dissolved in 1:1 AcOH/H2O (1.5 mL) then purified by preparative HPLC to yield the title compound as a mono-TFA salt (9.2 mg, purity 94%). MS m/z: [M+H]+ calcd for C16H21ClF3NOS, 368.10; found 368.0.