Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[N:13]=[CH:12][C:11]([C@@H:14]([OH:36])[CH2:15][N:16]([CH2:24][C@H:25]3[CH2:34][CH2:33][C:32]4[C:27](=[CH:28][CH:29]=[C:30]([I:35])[CH:31]=4)[O:26]3)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[CH3:37][C:38]([Si:41](Cl)([CH3:43])[CH3:42])([CH3:40])[CH3:39].N1C=CN=C1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Si:41]([O:36][C@H:14]([C:11]1[CH:12]=[N:13][C:8]([N:3]2[C:4]([CH3:7])=[CH:5][CH:6]=[C:2]2[CH3:1])=[CH:9][CH:10]=1)[CH2:15][N:16]([CH2:24][C@H:25]1[CH2:34][CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([I:35])[CH:31]=2)[O:26]1)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([C:38]([CH3:40])([CH3:39])[CH3:37])([CH3:43])[CH3:42]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc(C)n1-c1ccc([C@@H](O)CN(C[C@H]2CCc3cc(I)ccc3O2)C(=O)OC(C)(C)C)cn1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1ccc(C)n1-c1ccc([C@H](CN(C[C@H]2CCc3cc(I)ccc3O2)C(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73 %

Procedure:
A mixture of tert-butyl (2R)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]-2-hydroxyethyl{[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate (Example 357, 7.5 g, 12.4 mmol), TBDMSCl (2.25 g, 14.9 mmol), and imidazole (2.10 g, 30.9 mmol) in DMF (10 mL) was stirred at room temperature under argon for 24 hours. The reaction mixture was then poured into a saturated NaHCO3 solution (50 mL). The mixture was extracted with ether (100 mL×2). The ether layer was washed with water (50 mL) and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo afforded a near white syrup which was purified by column chromatography (silica gel, hexanes/ethyl acetate (5/1, v/v)) and gave the desired compound as a colorless oil (6.5 g, 72%).
Reaction SMILES: [Br:1]Br.[CH:3]1([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:16][CH:15]=3)=[CH:12][C:11]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>CC(O)=O>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:9]([CH:3]3[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]3)[N:10]=[C:11]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:12]=2[Br:1])=[CH:15][CH:16]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1
Reactant: BrBr
Solvent: CC(=O)O
Product: CCOC(=O)c1nn(C2CCCCC2)c(-c2ccc(OCc3ccccc3)cc2)c1Br
Temperature: 25 °C
Reaction time: 17 h
Yield: 61.4 %

Procedure:
Bromine (82 μL, 1.61 mmol) was added to pyrazole 1.3 (500 mg, 1.24 mmol) in AcOH (5 ml) at 0° C. and the reaction mixture was stirred at rt for 17 h. Upon concentration, the crude product was purified by SiO2 chromatography (stepwise gradient: 20 to 25% EtOAc/hexanes) to afford 368 mg (62%) of bromide 8.1. MS (ESI) 483.4 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:40])[CH:10]=[CH:11][CH:12]([OH:39])[CH2:13][O:14][C:15](=[O:38])[C@H:16]([CH:35]([CH3:37])[CH3:36])[NH:17][C:18]([O:20][CH2:21][CH:22]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:47](Cl)(=[O:65])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64].C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:8][C:9](=[O:40])[CH:10]=[CH:11][CH:12]([O:39][C:47](=[O:65])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[CH2:13][O:14][C:15](=[O:38])[C@H:16]([CH:35]([CH3:37])[CH3:36])[NH:17][C:18]([O:20][CH2:21][CH:22]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCC(O)C=CC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)OC(C=CC(=O)OCc1ccccc1)COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 8 h

Procedure:
To a solution of benzyl-5-(N-FMOC-L-valyloxy)-4-hydroxy-2-pentenoate (6.5 g, 12 mmol) and pyridine (2.0 g, 25 mmole) in 100 ml dichloromethane at 10° C. was added dropwise a solution of stearoylchloride (4.55 g, 15 mmol) in 25 ml dichloromethane. The mixture was stirred overnight. 100 ml of 5% sodium hydrogencarbonate solution was added and the mixture was stirred for 30 minutes. The organic phase was separated and the water phase was extracted two times with dichloromethane. The combined organic phases were dried with sodium sulfate and concentrated in vacuo. The product was isolated by silica gel column chromatography Yield: 7.8 g=80%
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[Br:17][CH2:18][CH2:19][CH2:20]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[O:15][CH2:20][CH2:19][CH2:18][Br:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccc(O)c1NC(=O)OC(C)(C)C
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc(OCCCBr)c1NC(=O)OC(C)(C)C
Temperature: 55 °C

Procedure:
To (2-hydroxy-6-methyl-phenyl)-carbamic acid tert-butyl ester (5.5 g, 24.6 mmol) in acetonitrile (200 mL) was added 1,3-dibromopropane (17.5 mL, 172 mmol), and potassium carbonate (27.0 g, 196 mmol). The mixture was heated at 55° C. for 2.5 hrs, followed by a filtration to remove solids. The filtrate was concentrated and repartitioned with ethyl acetate (250 mL) and water (150 mL). The organic layer was then washed with brine (150 mL), dried over MgSO4, and evaporated affording [2-(3-bromo-propoxy)-6-methyl-phenyl]-carbamic acid tert-butyl ester (quantitative yield). MS: 243.8 (M+H-Boc)+; tR=2.62 min (method 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[N:16]2[CH:17]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[CH:19]=[CH:20][C:15]2=[N:14][N:13]=1.[Cl:29][Sn]Cl.C([O-])([O-])=O.[Na+].[Na+].Cl>C(OCC)(=O)C.O>[ClH:29].[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([C:12]2[N:16]3[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[CH:19]=[CH:20][C:15]3=[N:14][N:13]=2)=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: Cl[Sn]Cl
Reactant: COc1ccc(-c2ccc3nnc(-c4ccc([N+](=O)[O-])cc4OC)n3c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc3nnc(-c4ccc(N)cc4OC)n3c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.1 %

Procedure:
A mixture of 3-(2-methoxy-4-nitrophenyl)-6-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine (50 mg, 0.13 mmol) and SnCl2 (120 mg, 0.65 mmol) in ethyl acetate (25 mL) was heated to reflux for 6 h under Argon. The reaction mixture was cooled to room temperature and basified to pH=10 with saturated aqueous Na2CO3. The biphasic solution was separated and the aqueous layer was extracted with ethyl acetate (40 mL). The combined organic layers were washed with brine and concentrated. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=2:1 to 0:1) to give crude product as yellow oil. The oil was stirred in a solution of HCl in ethyl acetate (2M, 20 mL) at room temperature, and then was mixed with water (30 mL). The aqueous phase was washed with ethyl acetate (30 mL), basified with saturated aqueous Na2CO3 to pH>10 and extracted with ethyl acetate (30 mL). The organic phase was stirred with a solution of HCl in ethyl acetate (2M, 10 mL) at room temperature for 2 h and concentrated in vacuo to give the title compound as yellow solids (16 mg, 30% yield). 1H NMR (DMSO-d6): 8.32 (s, 1H), 8.19 (dd, J=9.6 and 1.2 Hz, 1H), 8.09 (d, J=9.6 Hz, 1H), 7.72 (d, J=8.7 Hz, 2H), 7.36 (d, J=8.4 Hz, 1H), 7.08 (d, J=8.7 Hz, 2H), 6.61 (d, J=1.5 Hz, 1H), 6.52 (dd, J=8.4 and 1.5 Hz, 1H), 3.82 (s, 3H), 3.79 (s, 3H). MS: m/z 347.1 [M+H+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.C([Li])CCC.Cl>O1CCCC1.CCCCCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([B:17]([OH:22])[OH:18])=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc(Br)ccc1OCc1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
Under nitrogen stream, 1-(benzyloxy)-4-bromo-2-fluorobenzene (12.0 g, 43 mmol) was dissolved in tetrahydrofuran, followed by addition of triisopropyl borate (11.8 mL, 51 mmol), and then the mixture was cooled to −78° C. Butyl lithium (1.55M hexane solution) (30 mL, 47 mmol) was slowly added dropwise, and the mixture was stirred for 1 hour at −78° C. A 1N aqueous hydrochloric acid solution (100 mL) was added to the reaction mixture, and the mixture was stirred for 1 hour at room temperature. The solvent was distilled off under reduced pressure. The aqueous phase was extracted with ethyl acetate, the extracted solution was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue obtained was suspended in hexane, and was then collected by filtration to give the title compound (9.27 g, 88%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[NH:11][CH:10]=1.[OH-].[Na+].C(Cl)(Cl)Cl>O1CCOCC1>[F:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:8][CH2:7][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Fc1ccc2[nH]cc(CCBr)c2c1
Reactant: C1CCNC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Fc1ccc2[nH]cc(CCN3CCCC3)c2c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Pyrrolidine (2.94 g, 3.4 ml, 41.3 mmol) was dissolved in abs dioxane (100 ml), 3-(2-bromo-ethyl)-5-fluoro-1H-indole (5.00 g, 20.7 mmol) was added at RT and the mixture was stirred at 70° C. for 8 h. The solution was concentrated, the residue was taken up in CHCl3 (150 ml) and the mixture was washed with water (2×50 ml). The organic phase was dried over Na2SO4, filtered and concentrated i. vac. The residue obtained was purified by flash chromatography with 500 g of silica gel and chloroform/methanol (20:1→9:1→4:1→methanol. Only with methanol was a salt of the compound obtained, and it was then possible to liberate this by stirring with 2N NaOH and CHCl3. The phases were separated, the aqueous phase was extracted twice with CHCl3 and the combined organic phases were dried over Na2SO4, filtered and concentrated i. vac. The chloroform used was probably contaminated with HCl.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:50]1[CH:55]=[CH:54][C:53]([NH2:56])=[N:52][CH:51]=1>CN(C)C=O>[N:50]1[CH:55]=[CH:54][C:53]([NH:56][C:23]([C:18]2[C:19](=[O:22])[O:20][C:21]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH3:10])=[O:25])=[N:52][CH:51]=1
Reactant: Nc1ccncn1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3ccncn3)c(=O)oc12
Temperature: 25 °C
Yield: 11.2 %

Procedure:
DIEA (0.044 mL, 0.25 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.030 g, 0.14 mmol) and HATU (0.095 g, 0.25 mmol) in 1 mL of dimethylformamide (DMF) with constant stirring at room temperature until a clear solution resulted. Subsequently, pyrimidin-4-ylamine (0.009 g, 0.09 mmol) was added and allowed to react overnight, when a solid precipitated out of solution. The precipitate was filtered and dried under suction and then in vacuo to give 0.003 g of 1541E in an 11% yield: LCMS (ESI) m/z 298 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])[CH:3]=1.[CH3:31][C:32]1([CH3:38])[O:36][C:35](=[O:37])[NH:34][CH2:33]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:34]4[CH2:33][C:32]([CH3:38])([CH3:31])[O:36][C:35]4=[O:37])=[CH:3][C:4]=3[N:24]3[CH2:28][CH2:27][CH2:26][S:25]3(=[O:30])=[O:29])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Reactant: CC1(C)CNC(=O)O1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)(C)OC4=O)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 32.8 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (247 mg) described in Preparation Example 118 and 5,5-dimethyloxazolidin-2-one (57.6 mg) described in Preparation Example 43, the title compound (86.6 mg) was obtained.
Reaction SMILES: [C:1]([CH:7]([OH:26])[C@H:8]1[O:12][C@@H:11]([N:13]2[CH:24]=[C:19]([C:20]([F:23])([F:22])[F:21])[C:17](=[O:18])[NH:16][C:14]2=[O:15])[CH2:10][C@@H:9]1[OH:25])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1>N1C=CC=CC=1>[N:31]1[CH:32]=[CH:33][CH:34]=[C:29]([C:28]([C@@:9]2([OH:25])[C@@H:8]([CH:7]([C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[OH:26])[O:12][C@@H:11]([N:13]3[CH:24]=[C:19]([C:20]([F:21])([F:22])[F:23])[C:17](=[O:18])[NH:16][C:14]3=[O:15])[CH2:10]2)=[O:35])[CH:30]=1
Reactant: CC(C)(C)C(=O)C(O)[C@H]1O[C@@H](n2cc(C(F)(F)F)c(=O)[nH]c2=O)C[C@@H]1O
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)C(O)[C@H]1O[C@@H](n2cc(C(F)(F)F)c(=O)[nH]c2=O)C[C@@]1(O)C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 87.1 %

Procedure:
To a stirring solution of 450 mg of 5'-pivaloyltrifluorothymidine in 10 mL of pyridine was added 1.0 g of nicotinoyl chloride hydrochloride under ice-cooling. The reaction mixture was stirred at room temperature for 3 days, then was poured into 100 mL of ice water and extracted with 100 mL of ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and then evaporated in vacuo to give an oil. Crystallization from n-hexane afforded 500 mg (87%) of colorless needles melting at 175°-177° C. The product had the structure ##STR133## as further confirmed by NMR spectral analysis.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.Cl[CH:14]([O:16]C(Cl)Cl)Cl.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[O:16])[C:5]2[O:9][CH2:8][C:7]([CH3:10])([CH3:11])[C:6]=2[CH:12]=1
Reactant: CC1(C)COc2ccc(Br)cc21
Reactant: ClC(Cl)OC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC1(C)COc2c(C=O)cc(Br)cc21
Temperature: 25 °C
Yield: 62.4 %

Procedure:
To a stirred, cooled (ice-bath) solution of 5-bromo-3,3-dimethyl-2,3-dihydrobenzofuran (Intermediate 2, 0.4 g, 1.57 mmol) in anhydrous dichloromethane(4 mL), titanium tetrachloride (0.172 mL, 1.57 mmol) was added followed by dichloromethyl ether (0.14 mL, 1.57 mmol). The reaction mixture was allowed to warm to room temperature and at the end of 3 hr, the reaction mixture was poured into iced water and extracted with diethyl ether. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to a residue that on flash column chromatography using 2.5% ethyl acetate in hexane as the eluent afforded the title compound (0.25 g, 63%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[K+].[K+].[CH:12]1([C:15]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[O:16])[CH2:14][CH2:13]1>CC(C)=O>[Br:1][CH2:2][CH2:3][CH2:4][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]([CH:12]2[CH2:13][CH2:14]2)=[O:16])=[CH:22][CH:21]=1
Reactant: BrCCCBr
Reactant: O=C(c1ccc(O)cc1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(c1ccc(OCCCBr)cc1)C1CC1
Reaction time: 8 h

Procedure:
To a stirred and heated mixture of 1,3-dibromopropane (5 mmol) and potassium carbonate (3.4 mmol) in acetone (40 ml) was added dropwise a solution of 4-cyclopropanecarbonylphenol (5 mmol) in acetone (20 ml). The reaction was allowed to continue overnight. The mixture was filtered hot and the solvent removed under reduced pressure to leave an oil. The oil was purified by column chromatography on silica gel eluting with petroleum ether/ethyl acetate (15:1).
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1.C(=O)=O.Cl>N1C=CC=CC=1>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:14][C:15]([OH:17])=[O:16])=[CH:6][CH:5]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(OC(F)F)cc1
Agent: Cl
Agent: O=C=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc(OC(F)F)cc1
Temperature: 25 °C

Procedure:
A mixture of 10.0 g (7.68 ml, 58.1 mmol) 4-difluoromethoxy-benzaldehyde, 6.65 g (63.9 mmol) malonic acid, 0.21 g (2.50 mmol) piperidine and 50 ml pyridine was kept at reflux temperature until carbon dioxide development ceased (3 h). After cooling to room temperature the reaction mixture was poured onto 200 g ice and 100 ml 6N HCl. The precipitate was isolated, washed with water and dried. Yield: 8.8 g (71%) 3-(4-Difluoromethoxy-phenyl)-acrylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH3:10][O-:11].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:11][CH3:10])[N:3]=1
Reactant: C[O-]
Reactant: Cc1cc(Cl)nc(Cl)c1
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)cc(Cl)n1
Yield: 63.5 %

Procedure:
A solution of 2,6-dichloro-4-methyl-pyridine (250 mg, 1.5 mmol) in methanol (2 mL) was added to a solution of sodium methoxide (prepared from sodium (71 mg, 3.0 mmol) and anhydrous methanol (20 mL)) and heated at reflux for 48 h. The solvent was evaporated and the residue partitioned between water and dichloromethane. The organic layer was separated, washed with water, brine, dried over anhydrous sodium sulfate and concentrated to afford 2-chloro-6-methoxy-4-methyl-pyridine (150 mg, 61%) as a pale orange oily liquid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:13])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[CH2:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[C:23]#[N:24])=[O:17].C(N(CC)CC)C>ClCCl>[OH:13][CH:4]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][NH:2][CH2:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[C:23]#[N:24])=[O:17]
Reactant: NCC(O)COc1ccccc1
Reactant: N#CC1CCCN1C(=O)CCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CC1CCCN1C(=O)CNCC(O)COc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.7 %

Procedure:
A solution of 1-amino-3-phenoxypropan-2-ol hydrochloride (7.9 g, 38.8 mmol) and 1-(2-chloroacetyl)pyrrolidine-2-carbonitrile (6.1 g, 35.3 mmol) in DCM (250 mL) was added triethylamine (15 mL, 106 mmol). The mixture was stirred at room temperature overnight. After the TLC showed that the reaction was complete, the mixture was washed by brine. The aqueous solution was extracted with dichloromethane (DCM) (3×100 mL) and the combined DCM solution was concentrated to give a crude product, which was purified by column chromatography to give 3.5 g of 1-(2-(2-hydroxy-3-phenoxypropylamino)acetyl)pyrrolidine-2-carbonitrile (as shown at 6). Yield was 33.6%.
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:15][CH2:16][NH2:17])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH3:21][N:22]=[C:23]=[O:24]>C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH2:18]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:15][CH2:16][NH:17][C:23]([NH:22][CH3:21])=[O:24])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:19][CH3:20]
Reactant: CN=C=O
Reactant: CCCN(CCC)C1CCc2cccc(CCN)c2C1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCN(CCC)C1CCc2cccc(CCNC(=O)NC)c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.3 g (4.7 mmol) of 2-dipropylamino-8-(2-aminoethyl)-1,2,3,4-tetrahydronaphthalene were initially introduced into 20 ml of toluene. The reaction was catalyzed using 3 drops of triethylamine, and 0.31 ml (5.17 mmol) of methyl isocyanate were then added dropwise. The mixture was stirred overnight at room temperature, and then evaporated. After subsequent chromatography over silica gel 60, 40-63 μm, using diisopropyl ether/ethanol/triethylamine, the product was stirred with petroleum ether and a little diisopropyl ether, and filtered off under suction.
Reaction SMILES: N#N.[F:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[NH:12][CH:13]([CH2:16][OH:17])[CH2:14][CH3:15])[C:7]#[N:8].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O[CH:32](O)[C:33]([F:36])([F:35])[F:34])C>C1(C)C=CC=CC=1>[CH2:14]([CH:13]1[CH2:16][O:17][CH:32]([C:33]([F:36])([F:35])[F:34])[N:12]1[C:11]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[F:3])[CH3:15]
Reactant: CCOC(O)C(F)(F)F
Reactant: CCC(CO)Nc1ccc(C#N)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Solvent: Cc1ccccc1
Product: CCC1COC(C(F)(F)F)N1c1ccc(C#N)cc1F
Temperature: 125 °C
Yield: 82.4 %

Procedure:
A 25 mL round bottom flask fitted with a Dean-Stark trap, reflux condenser, and N2 line was charged with 245.3 mg (1.17 mmol) of 3-Fluoro-4-(1-hydroxymethyl-propylamino)-benzonitrile. p-Toluenesulfonic acid (27.4 mg, 0.144 mmol) was then added, along with trifluoroacetaldehyde ethyl hemiacetal (859.2 mg, 5.96 mmol) in 4 mL toluene. Toluene was then added to the Dean-Stark trap and the reaction was heated in an oil bath at 125° C. overnight. The reaction was cooled to room temperature, poured onto water, and the water extracted with EtOAc (2×). The organic layers were combined, washed with brine, dried (MgSO4), and concentrated. The resulting residue was purified via silica gel chromatography (10% EtOAc/Hexanes) to afford 277.8 mg (82%) of 4-(4-Ethyl-2-trifluoromethyl-oxazolidin-3-yl)-3-fluoro-benzonitrile as a mixture of diastereomers. This was dissolved in 8 mL CHCl3 (8 mL) and Et3SiH (0.62 mL, 3.88 mmol) was then added via syringe and the resulting solution was cooled to −78° C. TiCl4 (1M in dichloromethane, 1.95 mL) was then added dropwise via syringe. The reaction was slowly warmed to room temperature and stirred for 18 hours. The reaction mixture was poured onto water, and the water extracted with EtOAc (2×). The organic layers were combined, washed with brine, dried (MgSO4), and concentrated. The resulting residue was purified via silica gel chromatography (gradient from 5% EtOAc/Hexanes to 15% EtOAc/Hexanes followed by 50% EtOAc/Hexanes) to afford 99.8 mg (36% yield) of 4-(N-(2,2,2-trifluoroethyl)-N-(1-hydroxybut-2-yl)amino)-3-fluorobenzonitrile. 1H NMR (CDCl3, 500 MHz) δ: 7.39-7.34 (m, 2H), 7.32 (m, 1H), 4.05 (m, 1H), 3.83 (m, 1H), 3.73 (m, 1H), 3.65 (m, 1H), 3.46 (m, 1H), 1.96 (m, 1H), 1.55 (m, 2H), 0.94 (t, J=7.4 Hz, 3H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[S:11](=[O:14])(=[O:13])[N:10]([CH2:15]CN(CC)CC)[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.CI>O1CCCC1>[Br:3][C:4]1[C:12]2[S:11](=[O:14])(=[O:13])[N:10]([CH3:15])[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CCN(CC)CCN1Cc2cccc(Br)c2S1(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1Cc2cccc(Br)c2S1(=O)=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 57.2 %

Procedure:
To sodium hydride (40 mg, 1.0 mmol) in tetrahydrofuran (10 mL) at 0° C. was added 7-bromo-N,N-diethyl-1,2-benzisothiazole-2(3H)-ethanamine 1,1-dioxide (0.26 g, 1.0 mmol). The reaction was stirred for 20 min and treated with methyl iodide (0.06 mL, 1.3 mmol). The resulting mixture was stirred at ambient temperature over 18 h, poured into ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by a flush chromatography ((ethyl acetate/hexane, 1:4) to afford 7-bromo-2,3-dihydro-2-methyl-1,2-benzisothiazole 1,1-dioxide (0.15 g, 56%). LRMS (ES−): 262.0 (M−H)+.