Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([O:5]N1C(=O)CCC1=O)=O.[NH2:23][C@H:24]([C:31]([OH:33])=[O:32])[CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1.[OH-].[Na+]>O.O1CCOCC1>[N:1]1([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([NH:23][C@H:24]([C:31]([OH:33])=[O:32])[CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1)=[O:5]
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)ON1C(=O)CCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O

Procedure:
1.25 g of Boc-Pro-OSu [G. W. Anderson et al., J. Amer. Chem. Soc. 86, 1839 (1964)] and 0.68 g of H-His-OH are suspended in 4 ml of H2O and 2 ml of dioxan. While stirring vigorously, 2N NaOH is added by means of a pH stat at a pH value of 9.0. After 45 minutes the absorption of NaOH ceases. The now clear solution is stirred for a further 10 minutes, the pH value is adjusted subsequently to 5.0 with 4N HCl, and the whole is concentrated to approximately 5 ml. After the addition of 20 ml of H2O, the whole is again concentrated to approximately 5 ml and then purified by chromatography over a column of absorber resin, diaion HP-20 (φ=1.6 cm; length=20 cm). The bulk of this product is eluted with 20% isopropanol in H2O. The fractions that are pure according to thin layer chromatography are combined, concentrated almost to dryness and, after the addition of H2O, lyophilised, yielding Boc-Pro-His-OH in the form of an amorphous powder; Rf (E)=0.45; Rf (A)=0.21.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[O:8][N:9]=[C:10]([OH:11])[C:5]2=[CH:4][CH:3]=1.[N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:13]=[O:14]>C1COCC1>[CH2:15]([NH:12][C:13]([N:9]1[C:10](=[O:11])[C:5]2[C:6](=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[O:8]1)=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Cc1ccc2c(O)noc2n1
Reactant: CCCCCCN=C=O
Solvent: C1CCOC1
Product: CCCCCCNC(=O)n1oc2nc(C)ccc2c1=O

Procedure:
In analogy to example 1c, 50 mg (0.33 mmol) of 6-methylisoxazolo[5,4-b]pyridin-3-ol were reacted with 50.8 mg (0.4 mmol) of 1-isocyanatohexane in THF. Yield: 30 mg (32%), M+H+: 278.1.
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])OCC.B(F)(F)F.[O:15]=[C:16]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[O:34][C:18]2([CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:20][CH2:19]2)[CH2:17]1.C(N(C(C)C)C(C)C)C>ClCCl>[CH2:9]([O:8][CH:1]([O:5][CH2:6][CH3:7])[CH:17]1[C:18]2([CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])[CH2:20][CH2:19]2)[O:34][C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:16]1=[O:15])[CH3:10]
Reactant: CCOC(OCC)OCC
Reactant: O=C1CC2(CCN(C(=O)OCc3ccccc3)CC2)Oc2ccccc21
Agent: FB(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(OCC)C1C(=O)c2ccccc2OC12CCN(C(=O)OCc1ccccc1)CC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.7 %

Procedure:
To a solution of triethyl orthoformate (71 mL, 0.43 mol)] in dichloromethane (250 mL) at −10° C. under nitrogen was added boron trifluoride diethyletherate (54 mL, 0.43 mol) dropwise over 30 minutes. The mixture was allowed to warm to 0° C. and stirring was continued at 0° C. for 15 minutes. The mixture was then cooled to −78° C. and a solution of benzyl 4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (50 g, 0.14 mol) in dichloromethane (250 mL) was added dropwise over 1 hour, followed by N-ethyl-N-isopropylpropan-2-amine (87 mL, 0.50 mol) over 1 hour at −78° C. The mixture was continued to stir at −78° C. for 30 minutes and then at 25° C. for 15 hours. The reaction mixture was diluted with dichloromethane (750 mL) and then partitioned with saturated sodium bicarbonate solution (500 mL). The organic phase was washed with water (500 mL), saturated sodium chloride solution (500 mL), dried over magnesium sulfate and concentrated under reduced pressure. Purification by silica gel flash chromatography (0-50% ethyl acetate in hexane) afforded benzyl 3-(diethoxymethyl)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (50 g, 78%) as a yellow oil. ESI-MS m/z calc. 453.2, found 408.5 (M+1-OEt)+; Retention time: 2.08 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:12]([CH3:18])([CH3:17])[C:13]([O:15]C)=[O:14])[C:7](=[O:19])[C:6]3([CH3:24])[CH2:20][O:21][CH2:22][CH2:23][N:5]3[C:4]=2[N:3]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:12]([CH3:18])([CH3:17])[C:13]([OH:15])=[O:14])[C:7](=[O:19])[C:6]3([CH3:24])[CH2:20][O:21][CH2:22][CH2:23][N:5]3[C:4]=2[N:3]=1
Reactant: COC(=O)C(C)(C)N1C(=O)C2(C)COCCN2c2nc(Cl)ncc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C(=O)O)N1C(=O)C2(C)COCCN2c2nc(Cl)ncc21
Reaction time: 48 h

Procedure:
To a suspension of methyl 2-(2-chloro-6a-methyl-6-oxo-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-2-methylpropanoate (82.6 mg, 0.233 mmol) in THF (6 ml) and MeOH (3 ml) was added 1 N NaOH aqueous solution (0.698 ml, 0.698 mmol), and the mixture was stirred for 2 days. After further addition of THF (20 ml) and MeOH (10 ml), the mixture was stirred for 16 hours and concentrated in vacuo to give a crude 2-(2-chloro-6a-methyl-6-oxo-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-2-methylpropanoic acid which was used in the next step without further purification. MS [M+H] found 341.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[O:6][C@@H:5]([C@H:7]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:8]([O:10]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[C:4](=[O:26])[O:3]1.ONC(=O)[C@@H](O)[C@@H](C(N1CCN(C2C=CC=CN=2)CC1)=O)CC(C)C.C(N(CC)CC)C.[CH3:60][C@H:61]1[NH:66][CH2:65][CH2:64][N:63]([C:67]2[CH:72]=[C:71]([C:73]([F:76])([F:75])[F:74])[CH:70]=[CH:69][N:68]=2)[CH2:62]1>CN(C=O)C>[CH3:27][C:2]1([CH3:1])[O:3][C:4](=[O:26])[C@H:5]([C@@H:7]([C:8]([N:66]2[CH2:65][CH2:64][N:63]([C:67]3[CH:72]=[C:71]([C:73]([F:76])([F:74])[F:75])[CH:70]=[CH:69][N:68]=3)[CH2:62][C@H:61]2[CH3:60])=[O:10])[CH2:22][CH:23]([CH3:24])[CH3:25])[O:6]1
Reactant: CC(C)C[C@H](C(=O)Oc1c(F)c(F)c(F)c(F)c1F)[C@@H]1OC(C)(C)OC1=O
Reactant: C[C@@H]1CN(c2cc(C(F)(F)F)ccn2)CCN1
Agent: CC(C)C[C@H](C(=O)N1CCN(c2ccccn2)CC1)[C@H](O)C(=O)NO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](C(=O)N1CCN(c2cc(C(F)(F)F)ccn2)C[C@H]1C)[C@@H]1OC(C)(C)OC1=O

Procedure:
To a 55/45 diastereoisomeric mixture of pentafluorophenyl (2S)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoate and pentafluorophenyl (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoate (Intermediate 1, 484.8 mg; 1.22 mmol; 1.0 eq.) and triethylamine (339.13 μl; 2.45 mmol; 2.0 eq.) in DMF (10.0 mL) was added (3R)-3-methyl-[4-(trifluoromethyl)pyridin-2-yl]piperazine (Intermediate 9, 300 mg; 1.22 mmol; 1.0 eq.). After 14 h of reaction at RT, the solvent was evaporated and the residue dissolved in ether and extracted with water (3×). The combined organic layers were dried and evaporated to give an oil. This residue was purified by chromatography to give the title product (170 mg; 30.4% as a mixture of 2 diastereoisomers). M+(ESI): 458.4. HPLC (Condition A): Rt: 4.1 min (HPLC purity: 91.8%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Cl:10][CH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[CH2:11][Cl:10])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(N)cccc1Br
Reactant: O=C(Cl)c1ccccc1CCl
Solvent: ClCCl
Product: Cc1c(Br)cccc1NC(=O)c1ccccc1CCl
Yield: 44 %

Procedure:
A solution of 3-bromo-2-methylaniline (10 g, 53.7 mmol) in DCM (200 mL) at 0° C. was treated with TEA (14.98 mL, 107 mmol), followed by dropwise addition of 2-(chloromethyl)benzoyl chloride (10.16 g, 53.7 mmol) in DCM (50 mL) over 1 h. The mixture was diluted with DCM (ca. 1 L), washed with NaHCO3 (aq) and water, and concentrated to remove most of the solvent. The precipitate was collected by filtration and washed with DCM (2×10 mL) to provide N-(3-bromo-2-methylphenyl)-2-(chloromethyl)benzamide as a white solid (8.0 g). The filtrate was concentrated further, resulting in additional precipitate which was collected by filtration and washed with DCM (2×10 mL) to provide additional N-(3-bromo-2-methylphenyl)-2-(chloromethyl)benzamide as a white solid (3.06 g), for a combined yield of 61%. Mass spectrum 338, 340, 342 The filtrate was concentrated and purified by column chromatography (hexane-EtOAc) to provide 2-(3-bromo-2-methylphenyl)isoindolin-1-one as a yellow solid (2.0 g, 12%). A solution of the N-(3-bromo-2-methylphenyl)-2-(chloromethyl)benzamide (11.06 g, 32.7 mmol) in DMF (50 mL) was cooled to 0° C. and treated with a mixture of sodium hydride (60% oil dispersion, pre-washed with hexane, 1.70 g, 42.5 mmol) and DMF (10 mL). The mixture was stirred at 0° C. for 1.5 h, then was treated with water. The precipitate was collected by filtration, dried and combined with the material purified by column chromatography (see above) to provide 2-(3-bromo-2-methylphenyl)isoindolin-1-one as a yellow solid (9.41 g, 95%). 1H NMR (400 MHz, chloroform-d) δ 7.96 (1 H, d, J=7.5 Hz), 7.58-7.67 (2 H, m), 7.49-7.57 (2 H, m), 7.20-7.25 (1 H, m), 7.15 (1 H, t, J=7.9 Hz), 4.72 (2 H, s), 2.31 (3 H, s). Mass spectrum m/z 302, 304 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O-:3])=[O:2].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:28][CH:27]=1>>[C:29]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:28]=[CH:27][C:26]([CH2:25][N:9]2[C:10]3[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=3)[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:8]2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:31][CH:30]=1
Reactant: CCOC(=O)c1[nH]c2ccc([N+](=O)[O-])cc2c1-c1ccccc1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1c(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1Cc1ccc(-c2ccccc2)cc1

Procedure:
Ethyl 1-(1,1′-biphenyl-4-ylmethyl)-5-nitro-3-phenyl-1H-indole-2-carboxylate was prepared from ethyl 5-nitro-3-phenyl-1H-indole-2-carboxylate and 4-bromomethylbiphenyl according to the procedure of Example 1 Step 1 as a yellowish solid: 1H NMR (DMSO-d6) δ 0.95 (t, J=7.0 Hz, 3H, 4.13 (q, J=7.0 Hz, 2H, 5.96 (s, 2H, 7.30-7.32 (m, 14H, 7.62 (d, J=2.3 Hz, 1H, 8.25 (d, J=2.8 Hz, 1H, 8.36 (s, 1H; MS (ESI) m/z 477 (MH+); HRMS calcd for C30H25N2O4: 477.1815; found (ESI+): 477.1806; Anal. calcd for C30H24N2O4: C, 75.62; H, 5.08; N, 5.88. Found: C, 75.25; H, 5.18; N, 5.47.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]#[CH:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=O.C([N:31]=[C:32]=[S:33])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH:20]([C:17]1[CH:18]=[CH:19][C:14]([C:12]2[C:3]3[C:2](=[CH:7][CH:6]=[C:5]([O:8][CH2:9][C:10]#[CH:11])[CH:4]=3)[NH:1][C:32](=[S:33])[N:31]=2)=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: C#CCOc1ccc(N)c(C(=O)c2ccc(C(C)C)cc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#CCOc1ccc2[nH]c(=S)nc(-c3ccc(C(C)C)cc3)c2c1
Reaction time: 18 h

Procedure:
A solution of 0.5 g (1.71 mmol) (2-amino-5-prop-2-ynyloxy-phenyl)-(4-isopropyl-phenyl)-methanone and 0.23 ml (1.71 mmol) benzoyl isothiocyanate in 5 ml THF is stirred for 3 h at r.t. before 0.235 g potassium carbonate and 5 ml methanol are added. After stirring for 18 h, the reaction mixture is acidified with 0.1 M aqueous hydrochloric acid and extracted with dichloromethane. After evaporation of the organic phases, the residue is triturated with diethyl ether to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[C:10]([NH:18]C(=O)C)[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)[CH2:4][CH2:3]1.N1(CCCC2C=C(N)C=C(C(F)(F)F)C=2)CCCCC1>>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[CH:9]=[C:10]([NH2:18])[CH:11]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:13]=2)[CH2:6][CH2:7]1
Reactant: CC(=O)Nc1cc(C2CCN(C)CC2)cc(C(F)(F)F)c1
Agent: Nc1cc(CCCN2CCCCC2)cc(C(F)(F)F)c1
Product: CN1CCC(c2cc(N)cc(C(F)(F)F)c2)CC1

Procedure:
3-(1-Methylpiperidin-4-yl)-5-trifluoromethyl-phenylamine was prepared from N-[3-(1-methylpiperidin-4-yl)-5-trifluoromethyl-phenyl]-acetamide similar to the procedure described in the preparation of 3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenylamine.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].O.[F:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[C:25]([F:27])[CH:26]=1>O1CCCC1>[C:15]([O:14][C:12]([NH:7][C@H:6]([CH2:10][CH2:9][C:8]([C:23]1[CH:22]=[C:21]([F:20])[CH:26]=[C:25]([F:27])[CH:24]=1)=[O:11])[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: Fc1cc(F)cc([Mg]Br)c1
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@H](CCC(=O)c1cc(F)cc(F)c1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (3.0 g) in tetrahydrofuran (70 mL), 3,5-difluorophenylmagnesium bromide (0.5 M solution in tetrahydrofuran; 25.7 mL) was added dropwise at −40° C. over 10 minutes, and the reaction solution was stirred at −40° C. to 0° C. for one hour. Water was added to the solution in small portions at 0° C., followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 3.0 g of the title compound as a pale yellow oil. The property values of the compound are as follows.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]3[CH:20]=[C:19]([C:21](O)=O)[CH:18]=[CH:17][N:16]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:36]([S:41](N)(=[O:43])=[O:42])[CH2:37][CH2:38][CH2:39][CH3:40].N12CCCN=C1CCCCC2.Cl.C[N:58](C)[CH:59]=[O:60]>>[CH2:36]([S:41]([NH:58][C:59]([CH2:21][C:19]1[CH:18]=[CH:17][N:16]=[C:15](/[CH:14]=[CH:13]/[C:10]2[CH:11]=[CH:12][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][CH:9]=2)[CH:20]=1)=[O:60])(=[O:43])=[O:42])[CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccnc(/C=C/c2ccc(-c3ccccc3)cc2)c1
Reactant: CCCCCS(N)(=O)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCS(=O)(=O)NC(=O)Cc1ccnc(/C=C/c2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(E)-2-(2-(4-phenylphenyl)ethenyl)pyridine-4-carboxylic acid (277 mg) was dissolved in 2.8 ml of dried dimethylformamide, and 194 mg of carbonyldiimidazole was added thereto. The mixture was stirred at room temperature for 1.5 hours and then stirred at 100° C. for 30 minutes. After being cooled to room temperature, the mixture was mixed with 209 mg of pentanesulfonamide and 210 mg of 1,8-diazabicyclo[5.4.0]undec-7-ene and stirred at 100° C. for 48 hours. The reaction mixture was cooled with ice, and then its pH was adjusted to 5 using 1N hydrochloric acid. The resulting precipitate was collected by filtration and washed with water. The partially purified material thus obtained was further purified by silica-gel thin-layer chromatography (eluent, chloroform:methanol:water=65:25:4) to yield 67 mg of brown powder of (E)-N-(n-pentanesulfonyl)-2-(2-(4-phenylphenyl)ethenyl)pyridine-4-carboxyamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4](I)[CH:3]=1.C([Mg]Cl)(C)C.[CH2:15]([O:18][CH2:19][C:20](N(OC)C)=[O:21])[CH:16]=[CH2:17].[NH4+].[Cl-]>C1COCC1.O>[CH2:15]([O:18][CH2:19][C:20]([C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[F:8])=[O:21])[CH:16]=[CH2:17]
Reactant: Fc1ccc(Br)cc1I
Reactant: C=CCOCC(=O)N(C)OC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOCC(=O)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Scheme 1, steps C and D: To 4-bromo-1-fluoro-2-iodobenzene (0.95 equiv.) in THF (4.6 mL/g) at 0° C. is added isopropylmagnesium chloride (1.0 equiv, 20 weight percent in THF). After about 60 minutes at 0° C., a solution of 2-(allyloxy)-N-methoxy-N-methylacetamide (1.0 equiv.) (Volumes for this stage are in mL/g of this compound) in THF (2.2 mL/g) is added over about 60 minutes. The reaction mixture is quenched into a solution of NH4Cl (4.3 equiv.) in water (5.8 mL/g) at 0° C. Heptanes (7.2 mL/g) is added as the mixture is warmed to room temperature, and the layers are separated. The organic layer is washed with water (7.2 mL/g). The organic layer is concentrated while additional heptanes (4 mL/g) is added to remove water and THF. The intermediate, 2-allyloxy-1-(5-bromo-2-fluoro-phenyl)ethanone is obtained as a solution in heptanes (approximately 20-25 weight %).
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:19]([O:22][C@@H:23]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[O:32][C@@H:24]1OC(=N)C(Cl)(Cl)Cl)(=[O:21])[CH3:20]>ClCCl>[C:19]([O:22][C@@H:23]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[O:32][C@H:24]1[O:1][C:2]1[C:10]2[C:9]([CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Oc1cccc2scc(CCc3ccccc3)c12
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3scc(CCc4ccccc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
To a solution of 4-hydroxy-3-(2-phenylethyl)benzo-[b]thiophene (80 mg), 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose (0.17 g) in dichloromethane (3 mL) was added boron trifluoride-diethyl ether complex (0.044 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1-3/2) to give the title compound (75 mg).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:13][C:14]1[CH:50]=[CH:49][CH:48]=[CH:47][C:15]=1[CH2:16][NH:17][C:18]([C@@H:20]1[C:24]([CH3:26])([CH3:25])[S:23][CH2:22][N:21]1[C:27](=[O:46])[C@@H:28]([OH:45])[C@@H:29]([NH:37][C:38](=[O:44])[C@H:39]([CH:41]([CH3:43])[CH3:42])[NH2:40])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:19].C(OCC)(=O)C>C(Cl)Cl>[CH3:13][C:14]1[CH:50]=[CH:49][CH:48]=[CH:47][C:15]=1[CH2:16][NH:17][C:18]([C@@H:20]1[C:24]([CH3:26])([CH3:25])[S:23][CH2:22][N:21]1[C:27](=[O:46])[C@@H:28]([OH:45])[C@@H:29]([NH:37][C:38](=[O:44])[C@@H:39]([NH:40][S:2]([CH3:1])(=[O:4])=[O:3])[CH:41]([CH3:43])[CH3:42])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:19]
Reactant: Cc1ccccc1CNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@@H](N)C(C)C)CSC1(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccccc1CNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@@H](NS(C)(=O)=O)C(C)C)CSC1(C)C
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (25 μl) and triethylamine (46 μl) were added to a solution of H-Val-Apns-Dmt-NHBzl(2-Me) (162 mg) in methylene chloride (3 ml) and the mixture was stirred for two hours. After the addition of ethyl acetate, the reaction mixture was washed with 3% Na2CO3, 1N HCl, and 5% NaCl and dried over MgSO4. After filtration and concentration, the residue was purified using silica gel column chromatography and reprecipitated from ethyl acetate/n-hexane to obtain the title compound (127 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13].[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH:18]=O.CC(OC)(C)C.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([O:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])[CH:4]=1
Reactant: COC(C=O)OC
Reactant: CN(C)CCOc1cc(N)ccc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: COC(CNc1ccc(Cl)c(OCCN(C)C)c1)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a suspension of 4-chloro-3-(2-dimethylaminoethoxy)aniline (1.22 g, 0.006 mol) in MeOH (30 ml) containing dimethoxyethanal in MTBE (1.76 g, 0.17 mol) and glacial acetic acid (1.71 g) was added sodium cyanoborohydride (1.78 g, 0.03 mol ) portionwise at 0° C. The reaction was left to stir at room temperature for 1 hour, and then 10% aq. NaOH was added and the mixture was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), and concentrated in vacuo to give a brown oil. Purification by FCC, eluting with CH2Cl2 gave the title compound (1.49 g, 87%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:3]=1.[Br:24]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([Br:24])=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:3]=1
Reactant: N#Cc1c(OCCc2ccccn2)nc(N)nc1-c1ccco1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: N#Cc1c(OCCc2ccccn2)nc(N)nc1-c1ccc(Br)o1

Procedure:
From 2-amino-4-furan-2-yl-6-(2-pyridin-2-yl-ethoxy)-pyrimidine-5-carbonitrile and N-bromosuccinimide in DMF. ES-MS m/e (%): 388 (M{81Br}+H+, 100), 386 (M{79Br}+H+, 95).
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[CH:6]([O:15][CH:16]1[CH2:19][NH:18][CH2:17]1)[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[CH:30]1([N:36]=[C:37]=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C(Cl)Cl>[F:25][C:3]([F:2])([F:24])[C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[CH:6]([O:15][CH:16]1[CH2:19][N:18]([C:37]([NH:36][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:38])[CH2:17]1)[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1
Reactant: O=C=NC1CCCCC1
Reactant: CSc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CSc1ccc(C(OC2CN(C(=O)NC3CCCCC3)C2)c2ccccc2C(F)(F)F)cc1

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-(methylthio)benzhydryloxy]azetidine hydrochloride (118) (100 mg, 0.26 mmol) in anhydrous DCM (5 mL) was added MP-carbonate (3.10 mmol/g; 250 mg, 0.84 mmol) and cyclohexyl isocyanate (33 μL, 0.26 mmol). The resultant mixture was shaken at ambient temperature for 16 h, after which time it was poured onto a DCM-wetted SCX-2 (1 g) cartridge. The sample was eluted with DCM (18 mL), then evaporated to afford the desired product as a white, crystalline solid (65 mg, 52%).