Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2.[CH3:23][NH:24][C:25](=[O:41])[C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>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>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[C:29]3[CH:30]=[CH:31][C:26]([C:25]([NH:24][CH3:23])=[O:41])=[N:27][CH:28]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1ccc2c(c1)c1c(n2-c2ccccc2Br)CCN(C)C1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: CNC(=O)c1ccc(-c2ccccc2-n2c3c(c4cc(C)ccc42)CN(C)CC3)cn1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a de-aerated solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.28 mmol), N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (148 mg, 0.56 mmol) and K2CO3 (115 mg, 0.84 mmol) in DME-water (2:1) was added Pd(PPh3)4 (16 mg, 0.014 mmol). The reaction mixture was stirred at 90° C. for 2 h, additional Pd (PPh3)4 (16 mg, 0.014 mmol) was added into the reaction mixture and stirring continued at 90° C. for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (30 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-(2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)phenyl)-N-methylpicolinamide as an off-white solid. 1H NMR (TFA salt, CD3OD) d (ppm): 8.21 (d, 1H), 7.82 (d, 1H), 7.76 (m, 3H), 7.6 (d, 2H), 7.23 (s, 1H), 6.9 (d, 2H), 4.7 (m, 1H), 4.3 (m, 1H), 3.63 (m, 1H), 3.42 (m, 1H), 2.8-3.1 (m, 7H), 2.6 (m, 1H), 2.4 (s, 3H).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C1(N=C=NC2CCCCC2)CCCCC1.[F:43][C:44]1[C:49](O)=[C:48]([F:51])[C:47]([F:52])=[C:46]([F:53])[C:45]=1[F:54]>C(OCC)(=O)C>[CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([O:27][C:49]4[C:48]([F:51])=[C:47]([F:52])[C:46]([F:53])=[C:45]([F:54])[C:44]=4[F:43])=[O:26])=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccc(-c2ccc(-c3ccc(C(=O)O)cc3)cc2)cc1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CCCCCOc1ccc(-c2ccc(-c3ccc(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 4"-(n-pentyloxy)-[1,1':4',1"-terphenyl]-4-carboxylic acid (10.5 mmol) and dicyclohexylcarbodiimide (10.5 mmol) in ethyl acetate at 0° C. is added pentafluorophenol (11.5 mmol). The mixture is stirred at 25° C. for a period of 18 h, producing a precipitate. The mixture is filtered. The filtrate is washed with water and brine and dried with magnesium sulfate. The solvent is removed in vacuo to obtain pentafluorophenyl 4"-(n-pentyloxy)-[1,1':4',1"-terphenyl]-4-carboxylate, C30H23F5O3, M.W.=526.5.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:15]I.C[O-].[Na+]>CO>[CH3:15][O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CI
Reactant: O=C(O)c1cc(O)cc(C(F)(F)F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(=O)O)cc(C(F)(F)F)c1

Procedure:
This product is prepared according to the procedure of Example 5 and comprises contacting 3-hydroxy-5-trifluoromethylbenzoic acid with methyl iodide in methanol containing sodium methoxide as the base, m.p. 131°-135° C.
Reaction SMILES: [CH2:1]([C:3]([C:16]1[CH:29]=[CH:28][C:19]([O:20][CH2:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[C:18]([CH3:30])[CH:17]=1)([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:8]=2[CH:7]=1)[CH2:4][CH3:5])[CH3:2].CCN(CC)CC.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:26][C:23]([CH3:25])([CH3:24])[C:22](=[O:27])[CH2:21][O:20][C:19]1[CH:28]=[CH:29][C:16]([C:3]([C:6]2[S:10][C:9]3[CH:11]=[CH:12][C:13]([O:15][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:14][C:8]=3[CH:7]=2)([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:17][C:18]=1[CH3:30]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(O)ccc2s1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(OS(C)(=O)=O)ccc2s1
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
A solution of 1-{4-[1-ethyl-1-(5-hydroxy-benzo[b]thiophen-2-yl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one (260 mg, 0.612 mmol) in CH2Cl2 (20 mL) at RT is treated with Et3N (0.40 mL) and methanesulfonyl chloride (140 mg, 1.22 mmol). The mixture is stirred for 30 min and quenched with water (1.0 mL). The organic layer is concentrated and purified using silica gel column chromatography (25% EtOAc/Hex) to afford the title compound (190 mg, 62%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.[CH3:14][NH2:15]>C(O)C>[CH3:14][NH:15][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: CN
Reactant: BrCCCn1ccc2ccccc21
Solvent: CCO
Product: CNCCCn1ccc2ccccc21
Reaction time: 6 h

Procedure:
3 g of 1-(3-bromopropyl)indole were treated with a 33% solution of methylamine in ethanol. The resulting solution was stirred for 6 hours. The solvent was evaporated and the residue was dissolved in 50 ml of dichloromethane and washed with a saturated sodium bicarbonate solution. The organic phase was dried and evaporated to give 2.30 g of 1-(3-methylaminopropyl)indole.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][CH2:10][OH:11])=[C:4]([O:12]C)[CH:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[F:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([OH:12])=[C:5]([CH2:9][CH2:10][OH:11])[CH:6]=1
Reactant: COc1cc(F)c(F)cc1CCO
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: OCCc1cc(F)c(F)cc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.7 %

Procedure:
To a solution of 2-(4,5-difluoro-2-methoxyphenyl)ethanol (800 mg, 4.25 mmol) in DCM (25 mL) at 0° C. was added 1M BBr3 (17.01 mL, 17.01 mmol) solution and the resulting mixture was allowed to warm to room temp and stir for 4 h. Then, water (dropwise) was added and after the bubbling stops mixture was diluted with DCM and washed with water, dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (5-70%, EtOAc/hexane) to afford 4,5-difluoro-2-(2-hydroxyethyl)phenol (450 mg, 2.58 mmol, 60.8% yield) as clear viscous oil. 1H NMR (500 MHz, CDCl3) δ 6.93-6.84 (m, 1H), 6.75 (dd, J=11.5, 7.1 Hz, 1H), 4.03-3.96 (m, 2H), 2.85 (t, J=5.2 Hz, 2H).
Reaction SMILES: [Li+].C[Si]([N-][Si:7]([CH3:10])(C)C)(C)C.Br[CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH3:16].CC=C[CH2:20][CH3:21].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.[Li+].[B-](CC)(CC)CC>C1COCC1.C(Cl)Cl>[SiH:7]([CH2:15][CH3:16])([CH2:20][CH3:21])[CH2:10][CH3:23].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.[CH3:12][CH:13]=[CH:14][CH2:15][CH3:16]
Reactant: CC/C=C\CBr
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: CC=CCC
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: C1CCNC1
Product: CC[SiH](CC)CC

Procedure:
To a stirred solution of 7a (9.47 g, 29.7 mmol, 1 equiv) in anhydrous THF at −78° C. under N2 was added a 1 M solution of LiHMDS in THF (33 mmol, 33 mL, 1.1 equiv) followed by cis-1-bromo-2-pentene (4.21 mL, 35.6 mmol, 1.2 equiv), afforded a mixture of diastereomers of the lactam 7b (R9′=2-pentene) (43.2%) after silica gel purification. The lactam 7b (3.96 g, 10.22 mmol) was reduced to the pyrrolidine 7c (R9′=2-pentene) by the two-step sequence involving superhydride® reduction of the lactam to the hemiaminal, at −78° C. in anhydrous THF, and the subsequent reduction of the hemiaminal with Et3SiH/BF3OEt2 in anhydrous DCM at −78° C., affording 7c (R9′=2-pentene) (71%) after silica gel purification. The pyrrolidine 7c (2.71 g, 7.26 mmol) and 10% palladium on carbon (560 mg) in anhydrous methanol (30 mL) was subjected to Parr hydrogenolysis at 50 psi for 5 h. The reaction mixture was filtered through a celite pad and washed several times with methanol. The combined washings and filtrate were evaporated to dryness, affording, without further purification, a colorless oil 7d (R9=pentyl) (1.68 g, 80%); TLC: Rf=0.3 [Solvent system: DCM:hexanes:MeOH (6:5:1)]. MS (ESNEG): 284.5 [M−H]−.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C@@H:11]([CH2:28][N:29]2[CH:34]3[CH2:35][CH:36]([OH:38])[CH2:37][CH:30]2[CH2:31][O:32][CH2:33]3)[CH2:10]1)(=[O:8])=[O:7].[CH2:39]1COCC1.[H-].[Na+].IC>CO>[F:23][C:22]([F:25])([F:24])[C:21]([C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH2:13][CH2:14][N:9]([S:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)(=[O:7])=[O:8])[CH2:10][C@@H:11]2[CH2:28][N:29]2[C@H:30]3[CH2:37][CH:36]([O:38][CH3:39])[CH2:35][C@@H:34]2[CH2:33][O:32][CH2:31]3)=[CH:16][CH:17]=1)([OH:27])[CH3:26]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2C3COCC2CC(O)C3)cc1)C(F)(F)F
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: COC1C[C@H]2COC[C@@H](C1)N2C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 25-mL round-bottomed flask was charged with 9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) (50 mg, 0.087 mmol, Example 107) and THF (3 mL). Sodium hydride (60% dispersion in mineral oil, 34.7 mg, 0.869 mmol, Sigma-Aldrich, St. Louis, Mo.) was added at room temperature. After gas evolution had ceased iodomethane (0.054 mL, 0.87 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. The reaction was stirred at room temperature for 20 min, then MeOH (20 mL) was added and then the reaction concentrated onto silica gel and purified via column chromatography (12 g silica gel, 0 to 100% hexanes in EtOAc) to give 1,1,1-trifluoro-2-(4-((2S)-2-(((1R,5S)-7-methoxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (endo) (10 mg) as a mixture of two isomers.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][C:9]1([CH3:30])[CH2:15][O:14][C:13]2[CH:16]=[C:17](/[CH:20]=[CH:21]/[C:22]([O:24]C(C)(C)C)=[O:23])[CH:18]=[N:19][C:12]=2[NH:11][C:10]1=[O:29]>C(Cl)Cl>[CH3:8][C:9]1([CH3:30])[CH2:15][O:14][C:13]2[CH:16]=[C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])[CH:18]=[N:19][C:12]=2[NH:11][C:10]1=[O:29]
Reactant: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)OCC(C)(C)C(=O)N2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)COc2cc(/C=C/C(=O)O)cnc2NC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
TFA (3 mL) was added to a cooled solution of (E)-tert-butyl 3-(3,3-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-8-yl)acrylate (1 g, 3 mmol) in CH2Cl2 (5 mL) and stirred for 30 min at rt. The mixture was evaporated and HCl/dioxane (4M, 5 mL) was added. The precipitate that formed was washed with ether and dried to afford the title compound (530 mg, 66%). 1H NMR (300 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.28 (s, 1H), 7.82 (d, J=15.5 Hz, 1H), 6.84 (d, J=20 Hz, 1H), 4.05 (s, 2H), 1.47 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][C@@H:10]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(C(C)C)C(C)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:8][C:6]1[CH:7]=[C:2]2[NH:1][C:32](=[O:34])[N:9]([C@@H:10]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]3)[C:3]2=[N:4][CH:5]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ncc(Cl)cc2N)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](n2c(=O)[nH]c3cc(Cl)cnc32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 189 %

Procedure:
A stirred solution of (R)-tert-butyl 3-(3-amino-5-chloropyridin-2-ylamino)pyrrolidine-1-carboxylate (680 mg, 2.2 mmol) and i-Pr2NEt (1.2 mL, 6.6 mmol0 in CH2Cl2 (50 mL) was cooled in an ice bath and solid triphosgene (213 mg, 0.72 mmol) was added. The ice bath was allowed to melt and the mixture was stirred overnight at rt. The mixture was concentrated to leave a black solid which was purified by chromatography on a 12-g silica cartridge eluted with a 0-100% EtOAc in hexanes gradient to afford (R)-tert-butyl 3-(6-chloro-2-oxo-1H-imidazo[4,5-b]pyridin-3(2H)-yl)pyrrolidine-1-carboxylate (461 mg, 62%) as a black solid. LC-MS Method 1 tR=1.65 min, m/z=339, 283.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH2:13][C:12]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)=[N:11]1.CN(C)C=O.[Br:33]Br>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([Br:33])[C:12]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)=[N:11]1
Reactant: O=C(NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1)c1cccc([N+](=O)[O-])c1
Reactant: BrBr
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1Br)c1cccc([N+](=O)[O-])c1
Yield: 96.6 %

Procedure:
428 g (1.0 mol) of 1-(2,4,6-trichlorophenyl)-3-(3-nitrobenzamido)-5-oxo-2-pyrazoline was added to 2.2l of dimethylformamide and the mixture was stirred under cooling with ice. Next, 160 g (1.0 mol) of bromine was added dropwise, followed by stirring for about 1 hour. The reaction solution was then poured into 9 l of water, and thereafter the precipitated crystals were filtered to obtain 489.5 g (96.6 %) of 1-(2,4,6-trichlorophenyl)-3-(3-nitrobenzamido)-4-bromo-5-oxo-2-pyrazoline.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([O-])=[O:26])=[CH:23][CH:22]=4)[CH:15]=3)[CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)(C)C(Cl)=O.[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(=O)(O)[O-].[Na+]>C1COCC1.C(N(CC)CC)C>[C:38]1([NH:37][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([CH2:20][O:19][C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[CH2:10][CH:9]([CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:18][CH2:17]4)=[CH:29][CH:28]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Nc1ccccc1
Reactant: O=C([O-])c1ccc(COc2ccc3c(c2)CCC(CCN2CCCCC2)C3)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)c1ccc(COc2ccc3c(c2)CCC(CCN2CCCCC2)C3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
Triethylamine (0.11 ml) was added to THF suspension (3 ml) of 4-[[2-(2-piperidinoethyl)-6-tetralinyl]oxymethyl]benzoate (300 mg). Further, THF solution (0.5 ml) of trimethylacetyl chloride (92 mg) was added dropwise under ice-cooling, which was stirred for 30 minutes. The temperature of the reaction mixture was raised to room temperature, which was stirred for 1 hour. THF solution (0.5 ml) of aniline (85 mg) was added dropwise to the reaction mixture under ice-cooling, which was stirred for 1 hour. After the reaction mixture was stirred for 24 hours at room temperature, saturated sodium bicarbonate solution was added, and extraction was conducted using a mixed solution of ethyl acetate and THF. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was recrystallized from THF-methanol-IPE to give the titled compound (150 mg).
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[C:11]([OH:23])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[CH3:35][C:36]([CH3:43])([CH3:42])[CH2:37][CH2:38][C:39](Cl)=[O:40]>>[C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[C:11]([O:23][C:39]([CH2:38][CH2:37][C:36]([CH3:43])([CH3:42])[CH3:35])=[O:40])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(Oc2ccc(C(=O)CNC(C)(C)C)cc2O)cc1
Reactant: CC(C)(C)CCC(=O)Cl
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: Cc1ccc(Oc2ccc(C(=O)CNC(C)(C)C)cc2OC(=O)CCC(C)(C)C)cc1

Procedure:
Following a procedure similar to that described in Example 2A above, when 3-hydroxy-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is interacted with 3,3-dimethylbutanecarbonyl chloride there is obtained 3-(3,3-dimethylbutanecarbonyloxy)-4 -(p-toluyloxy)phenyl tert-butylaminomethyl ketone which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 2B, there is obtained 3-(3,3-dimethylbutane carbonyloxy)-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [Si]([N:5]=[N+:6]=[N-:7])(C)(C)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[C:11]([O:18][CH:19]([CH3:21])[CH3:20])[CH:10]=1>CCOC(C)=O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:16](=[O:17])[NH:7][N:6]=[N:5]2)=[C:11]([O:18][CH:19]([CH3:21])[CH3:20])[CH:10]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)Oc1cc(F)ccc1N=C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(F)ccc1-n1nn[nH]c1=O
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 81 %

Procedure:
This reaction with TMS-N3 was performed behind a blast shield. The crude 4-fluoro-1-isocyanato-2-isopropoxybenzene was placed under argon and trimethylsilylazide (16 mL, 118.2 mmol, 2 equiv) was added. The reaction mixture was heated to refluxed for ON under argon. After cooling to RT, the reaction mixture was concentrated under vacuum, and the residue was charged with saturated NaHCO3 (100 mL) and stirred vigorously for 5-10 min, then the basic reaction mixture was diluted with EtOAc. The layers were separated, and the organic layer was monitored by TLC to confirm that all the product had been extracted by the saturated NaHCO3 solution. EtOAc was added to the combined basic aqueous extracts, and the pH was adjusted to <3 using 6N HCl. The aqueous and organic layers were partitioned, and the aqueous layer was extracted with EtOAc 3×. The combined organic layers were dried over Na2SO4, filtered, and the solvent removed under vacuum to provide 1-(4-fluoro-2-isopropoxyphenyl)-1H-tetrazol-5(4H)-one (11.4 g, 81%) as a brown oil that was used without further purification. 1H NMR (300 MHz; d6-DMSO) δ 7.47-7.52 (dd, 1H, J=6.0 Hz, 8.4 Hz), 7.19-7.24 (dd, 1H, J=2.7 Hz, 12 Hz), 6.87-6.94 (td, 1H, J=2.7 Hz, 8.1 Hz), 4.63-4.75 (d, 6H, J=6.0 Hz), 1.17-1.19 (d, 6H, J=6.0 Hz); 19F NMR (282 MHz; d6-DMSO) δ −107.2 (q); m/z=238 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([F:21])([F:20])([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:6][CH:7]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.[Na+]>CN(C)C=O>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH2:2][C:3]2[N:4]=[C:5]([CH:8]=[CH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16]([F:21])([F:20])([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[O:6][CH:7]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: O=S([O-])c1ccc(Br)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(Cc1coc(C=Cc2ccc(S(F)(F)(F)(F)F)cc2)n1)c1ccc(Br)cc1

Procedure:
A solution of 4-chloromethyl-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole (0.30 g, 1.28 mmol) and sodium 4-bromobenzenesulfinate (0.717 g, 2.57 mmol) in N,N-dimethyl formamide (20 ml) was stirred for 3 h at 60° C. After cooling the mixture was poured onto water, extracted with ethyl acetate (3×50 ml), the combined organic layers were washed with water, dried over sodium sulfate, concentrated in vacuo and crystallized from ether/isohexane yielding 4-(4-bromo-benzenesulfonylmethyl)-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole as white crystalline product. Yield 0.345 g (51%).
Reaction SMILES: [OH:1][C@@H:2]([C:6]([O:19][CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O-:5])=[O:4].Cl[C@H](C1C=CC(Cl)=CC=1)C[NH3+].CC(C)([O-])C.[K+].[CH3:38][C:39]1[CH:44]=[C:43]([CH3:45])[N:42]=[C:41](S(C)(=O)=O)[N:40]=1.O>CN(C=O)C>[CH3:45][C:43]1[CH:44]=[C:39]([CH3:38])[N:40]=[C:41]([O:1][C@@H:2]([C:6]([O:19][CH3:20])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]([OH:5])=[O:4])[N:42]=1
Reactant: COC(c1ccccc1)(c1ccccc1)[C@H](O)C(=O)[O-]
Reactant: Cc1cc(C)nc(S(C)(=O)=O)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [NH3+]C[C@H](Cl)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(c1ccccc1)(c1ccccc1)[C@H](Oc1nc(C)cc(C)n1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a 25 mL three neck flask with stirring arrangement, (1 gm) (R)-2,4-dichlorophenylethyl ammonium (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionate and (0.726 gm) potassium tertiary butoxide (6.488 mmol) in 10 ml DMF at 25° C. were taken and stirred for 5 min. (0.604 gm) 4,6-dimethyl-2-(methylsulfonyl)pyrimidine (3.244 mmol) was added to the reaction mixture in one lot. The reaction mixture was stirred at room temperature for 6 hours and subsequently dumped into cold water and washed the aqueous layer with toluene. Aqueous layer was collected and acidified with HCl to pH 2. The solid was extracted with ethyl acetate, and wash the ethyl acetate layer with water followed by brine. Dry over sodium sulphate and concentrated on Buchi Rotavapor.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O:16][C:17]([C:19]1[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[C:20]=1[CH3:26])=O)C.C(OCCOCCO)CCC.CO.C[O-].[Na+]>O.CCCCCCC>[O:16]=[C:17]([C:19]1[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[C:20]=1[CH3:26])[CH:11]([C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)[C:12]#[N:13]
Reactant: CC(C)(C)c1ccc(CC#N)cc1
Reactant: CCOC(=O)c1c(C)c(C)nn1C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCCC
Solvent: O
Product: Cc1nn(C)c(C(=O)C(C#N)c2ccc(C(C)(C)C)cc2)c1C
Temperature: 92.5 °C
Yield: 85.4 %

Procedure:
In a 2000 ml-reaction flask equipped with a rectification column and a separating tank, 83.7 g (483 mmol) of 4-tert-butylphenylacetonitrile, 80.0 g (439 mmol) of 1,3,4-trimethylpyrazol-5-carboxylic acid ethyl ester, 640 g of heptane, and 160 g of diethylene glycol monobutyl ether were added, the atmosphere was substituted with nitrogen, then azeotropic dehydration was carried out by heating at 90 to 95° C. for 1 hour. The temperature was maintained, 93.2 g (482 mmol) of 28% sodium methoxide methanol solution was added dropwise over 3 hours, and the resulting mixture was further reacted for 10 hours. After cooling to 30° C. or less, 600 g of water was added to separate out heptane phase, and the resulting aqueous phase was washed with 160 g of heptane and 400 g of toluene was added, then pH was adjusted to 7 with 35% hydrochloric acid. After separating into phases, the toluene phase was washed two times with 160 g of water to obtain a toluene solution containing 116 g (yield 85.1%) of 3-oxo-2-(4-tert-butylphenyl)-3-(1,3,4-trimethylpyrazol-5-yl) propionitrile. Toluene was distilled off under a reduced pressure, then 120 g of di-n-butyl ether was added and completely dissolved therein at a temperature of 120° C. Thereafter, the solution was cooled to 20° C., the resulting crystal was further dispersed in 150 g of di-n-butylether, 200 g of n-hexane was added therein and stirred at 10° C. for 1 hour. The resulting crystal was filtered and washed with 150 g of n-hexane to obtain 92.3 g of 3-oxo-2-(4-tert-butylphenyl)-3-(1,3,4-trimethylpyrazol-5-yl) propionitrile (melting point 178° C.).