Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:21]4=[CH:22][C:23]5[O:27][CH2:26][O:25][C:24]=5[CH:28]=[C:20]4[O:19][CH2:18]3)[C:10]2=[O:29])[CH2:4][CH2:3]1.Br[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.C1CCN2C(=NCCC2)CC1.O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[N:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:21]4=[CH:22][C:23]5[O:27][CH2:26][O:25][C:24]=5[CH:28]=[C:20]4[O:19][CH2:18]3)[C:10]2=[O:29])[CH2:4][CH2:3]1
Reactant: Brc1ccccn1
Reactant: O=C1N(CC2CCNCC2)c2ccccc2C12COc1cc3c(cc12)OCO3
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1N(CC2CCN(c3ccccn3)CC2)c2ccccc2C12COc1cc3c(cc12)OCO3
Temperature: 120 °C
Yield: 24.9 %

Procedure:
A mixture of 1′-(piperidin-4-ylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one hydrobromide (0.20 g, 0.44 mmol), 2-bromopyridine (0.16 mL, 0.65 mmol), tetrabutyl ammonium iodide (0.05 g) and DBU (0.16 mL, 1.09 mmol) in DMF (5.00 mL) was heated at 120° C. for 15 hrs. After cooling down to ambient temperature, water (30.0 mL) was added. The above mixture was extracted twice with ethyl acetate (50.0 mL), the combined organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to flash chromatography eluting with 30% ethyl acetate in hexane to give a white solid (0.05 g, 27%): mp 95-97° C.; 1H NMR (300 MHz, CDCl3) δ 8.17 (d, 1H), 7.47 (td, 1H), 7.31 (t, 1H), 7.18 (d, 1H), 7.06 (t, 1H), 6.92 (d, 1H), 6.66 (d, 1H), 6.59 (dd, 1H), 6.52 (s, 1H), 6.12 (s, 1H), 5.91-5.84 (m, 2H), 4.91 (d, 1H), 4.66 (d, 1H), 4.42-4.27 (m, 2H), 3.82-3.53 (m, 2H), 2.85 (t, 2H), 2.22-2.05 (m, 1H), 1.85-1.70 (m, 2H), 1.53-1.35 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 177.9, 158.8, 156.1, 149.0, 147.4, 142.8, 142.5, 138.0, 132.4, 129.1, 124.2, 123.5, 119.5, 112.9, 108.8, 107.7, 103.1, 101.7, 93.8, 80.7, 58.3, 46.0, 45.5, 45.4, 35.2, 29.8, 29.7; MS (ES+) m/z 456 (M+1).
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]3[S:19][C:20]([CH2:23][NH2:24])=[CH:21][N:22]=3)[CH:13]=2)[O:8]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[O:55]1[C:59]([C:60](O)=[O:61])=[CH:58][CH:57]=[N:56]1>CN(C=O)C.O>[C:1]1([CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]3[S:19][C:20]([CH2:23][NH:24][C:60]([C:59]4[O:55][N:56]=[CH:57][CH:58]=4)=[O:61])=[CH:21][N:22]=3)[CH:13]=2)[O:8]1
Reactant: Cc1ccccc1C1CCc2cc(Oc3ncc(CN)s3)ccc2O1
Reactant: O=C(O)c1ccno1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccccc1C1CCc2cc(Oc3ncc(CNC(=O)c4ccno4)s3)ccc2O1
Reaction time: 16 h
Yield: 58.2 %

Procedure:
To a solution of [2-(2-o-tolyl-chroman-6-yloxy)-thiazol-5-ylmethyl]amine (150 mg, 0.43 mmol) in DMF (2 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (114 mg, 0.60 mmol, 1.4 eq), 1-hydroxy-benzotriazole (81 mg, 0.60 mmol, 1.4 eq) and N-methylmorpholine (107 mg, 1.07 mmol, 2.5 eq) and isoxazole-5-carboxylic acid (72 mg, 0.64 mmol, 1.5 eq) were added. The mixture was stirred for 16 h, then diluted with water, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with a diluted aqueous solution of sodium carbonate and brine, dried over sodium sulfate and filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, ethyl acetate/methanol gradient). Isoxazole-5-carboxylic acid [2-(2-o-tolyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide (112 mg, 59%) was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=1[Cl:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:39])[F:40])[CH:33]=2)[CH2:19][N:20]2[C:21](=[O:30])[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]2=[O:29])=[O:15])[S:10][C:11]=1[Cl:12]
Reactant: N[C@@H](Cc1cccc(C(F)(F)F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1ncc(Br)c1-c1cc(C(=O)O)sc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Br)c1-c1cc(C(=O)N[C@@H](Cc2cccc(C(F)(F)F)c2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxylic acid (183 mg, 0.54 mmol) [prepared according to the procedure of Example 167], 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (201 mg, 0.52 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine (4.98 g, 15.0 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (298 mg, 0.64 mmol) in chloroform (5 mL). DIEA (470 μL, 2.69 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (246 mg, 0.36 mmol, 69%): LC-MS (ES) m/z=653 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([CH3:16])[CH:8]=1.[CH3:18][C:19]1[C:20]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:21][C:22]([CH3:26])=[C:23]([CH3:25])[CH:24]=1>>[O:17]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:30]2[CH2:31][CH2:32][N:27]([C:20]3[C:19]([CH3:18])=[CH:24][C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=3)[CH2:28][CH2:29]2)=[O:13])=[C:9]([CH3:16])[CH:8]=1
Reactant: Cc1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Product: Cc1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2nc(C)c(C)cc2C)CC1
Yield: 59 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methylbenzoic acid (128 mg) described in Preparation Example 29 and 1-(3,5,6-trimethylpyridin-2-yl)piperazine (103 mg) described in Preparation Example 92 and by the reaction and treatment in the same manner as in Example 87, the title compound (131 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)=O.P(Cl)(Cl)(Cl)(Cl)[Cl:12]>>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([Cl:12])=[CH2:1])=[CH:5][CH:6]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(=O)c1ccc(Br)cc1
Product: C=C(Cl)c1ccc(Br)cc1

Procedure:
Initially, 4-bromoacetophenone (3) can be treated with powdered phosphorous pentachloride to produce 1-(4-bromophenyl)-1-chloroethylene (4). Compound 4 was then treated with potassium hydroxide to produce 4-bromophenylacetylene (5) at a 60% yield. Treatment of compound 5 with ethyl magnesium bromide was followed by reaction with chlorotrimethylsilane. The resulting product (4-bromophenylethynyl) trimethylsilane (6) was recovered with a 90% yield. Compound 6 was then treated with ethyl magnesium bromide, followed by reaction with carbon dioxide to produce (4-carboxyphenylethynyl) trimethylsilane (7) in 89% yield. Compound 7 was then deprotected using KOH in methanol to form 4-ethynylbenzoic acid (8) in 96% yield. Compound 8 is a useful building block for forming a variety of molecular switches in accordance with the present invention, and was used in forming molecular switches of the following examples.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[C:15]([CH3:21])=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.O1CCOCC1.[Al].CC(C)=O>O=[Mn]=O.CCCCCC>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[C:15]([CH3:21])=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:29][CH:30]=1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: O=[Mn]=O
Agent: [Al]
Solvent: CC(C)=O
Solvent: C1COCCO1
Solvent: CCCCCC
Product: COc1nc2ccc(C(=O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
To a 100 mL flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanol (1.51 g, 3.1 mmol, Intermediate 12: step e) was added 1,4-dioxane (50 mL) followed by activated MnO2 (1.3 g, 15 mmol) and the mixture was heated to reflux in an aluminum heating mantle under N2. After 1 hour, TLC (25% acetone:hexane) indicated that the reaction was complete. The contents were filtered while still hot through Celite® and rinsed with THF. The resulting light yellow solution was concentrated and chromatographed by passing through a silica gel column (10% acetone-hexane increasing to 25% acetone) to give the title compound as a light yellowish amorphous solid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][NH:7][C:8](=[O:40])[C@@H:9]([CH3:39])[NH:10][C:11](=[O:38])[C@H:12]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:37])=[CH:24][CH:23]=1)[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].Cl>CC(C)=O>[C:17]([O:16][C:14]([NH:13][C@H:12]([C:11]([NH:10][C@@H:9]([C:8]([NH:7][CH2:6][C:5]([OH:41])=[O:4])=[O:40])[CH3:39])=[O:38])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30]2[C:31]([Cl:37])=[CH:32][CH:33]=[CH:34][C:35]=2[Cl:36])=[CH:26][CH:27]=1)=[O:15])([CH3:18])([CH3:19])[CH3:20]
Reactant: COC(=O)CNC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C[C@@H](NC(=O)[C@H](Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O

Procedure:
Aqueous 1 N sodium hydroxide (12 ml.) is added to a suspension of t-butoxycarbonyl-O-(2,6-dichlorobenzyl)-L-tyrosyl-D-alanylglycine methyl ester (Step 2, 4.7 g.) in acetone (25 ml.) stirred with a magnetic stirrer. After 41/2 hours the solution is acidified to pH 2 with 4 N hydrochloric acid. After an hour a white precipitate is removed by filtration and dried under vacuum to give t-butoxycarbonyl-O-(2,6-dichlorobenzyl)-L-tyrosyl-D-alanylglycine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.[F:20][C:21]([F:31])([F:30])[C@H:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[NH2:23]>>[F:31][C:21]([F:20])([F:30])[C@@H:22]([NH:23][C:8]([C:5]1[CH:4]=[C:3]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)c1cc(Cc2ccc(F)cc2)c(Cl)cn1
Reactant: N[C@@H](c1cccnc1)C(F)(F)F
Agent: Cl
Product: O=C(N[C@@H](c1cccnc1)C(F)(F)F)c1cc(Cc2ccc(F)cc2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 12d, using 5-chloro-4-(4-fluorobenzyl)-pyridine-2-carboxylic acid and (αS)-α-(trifluoromethyl)-3-pyridinemethanamine hydrochloride (1:1) (CAN 749839-26-7) as starting materials and isolated (23 mg, 71%) as colorless oil; MS (ESI, m/z): 424.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10](Cl)[C:9]=2Cl)=[C:6]([CH3:17])[N:5]=[C:4]([N:18]([CH3:20])[CH3:19])[N:3]=1.[Cl:21]C1C=C(CC#N)C=CC=1Cl>>[CH3:19][N:18]([CH3:20])[C:4]1[N:3]=[C:2]([NH2:1])[C:7]([C:8]2[CH:9]=[CH:10][C:11]([Cl:21])=[C:12]([Cl:14])[CH:13]=2)=[C:6]([CH3:17])[N:5]=1
Reactant: Cc1nc(N(C)C)nc(N)c1-c1cc(Cl)cc(Cl)c1Cl
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Product: Cc1nc(N(C)C)nc(N)c1-c1ccc(Cl)c(Cl)c1

Procedure:
This compound was made in an analogous manner to the compound of Example 13 from 3,4-dichlorophenylacetonitrile.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=[O:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH3:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH2:25][NH:24][CH2:23][CH2:22]2.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[F:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH2:25][N:24]([C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=[O:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH3:17])[CH:3]=1)[CH2:23][CH2:22]2
Reactant: Cc1cc(Br)nc(C)c1NC(=O)CC(C)(C)C
Reactant: Fc1ccc2c(c1)CCNC2
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3cc(F)ccc3C2)nc(C)c1NC(=O)CC(C)(C)C
Temperature: 100 °C
Yield: 73.5 %

Procedure:
In a tube, a mixture of 1d (0.65 g, 2.15 mmol), 6-fluoro-1,2,3,4-tetrahydroisoquinoline (0.348 g, 2.6 mmol) in toluene (15 ml) was degassed by nitrogen flow for 15 minutes. To this mixture was added tris(dichlorobenzylidenacetone)palladium (0) (0.052 g, 0.055 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.08 g, 0.2 mmol) and potassium tert-butoxide (0.437 g, 3.9 mmol). The tube was heated under microwave irradiation (Biotage Initiator®) for 6 hour at 100° C. The reaction mixture was cooled to room temperature, washed with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, concentrated and chromatographed to yield the title compound (0.584 g, 1.58 mmol, 73%). 1H NMR (CDCl3, 400 MHz) δ 1.14 (s, 9H), 2.19 (s, 3H), 2.27 (s, 2H), 2.35 (s, 3H), 2.91 (t, J=6.2 Hz, 2H), 3.82 (t, J=6.2 Hz, 2H), 4.62 (s, 2H), 6.38 (s, 1H), 6.50 (bs, 1H), 6.85-6.92 (m, 2H), 7.09-7.16 (m, 1H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.[C:18]([N:25]1[CH:29]=[CH:28]N=[CH:26]1)(N1C=CN=C1)=[O:19].[CH:30]([C:32]1C=[CH:39][CH:38]=[C:37]2[C:33]=1CNC2)=[CH2:31].S(=O)(=O)(O)[O-].[K+]>CN(C=O)C.O>[CH:38]([C:37]1[CH:33]=[CH:32][CH:30]=[C:31]2[C:28]=1[CH2:29][N:25]([C:18]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1)=[O:19])[CH2:26]2)=[CH2:39]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: C=Cc1cccc2c1CNC2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1cccc2c1CN(C(=O)O[C@@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1)C2
Temperature: 60 °C
Yield: 81 %

Procedure:
A solution of 1-tert-butyl 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (1.0 eq.) in DMF (0.5 M) under nitrogen was cooled to 0° C. Solid 1,1′-carbonyldiimidazole (1.0 eq.) was added to the reaction. The contents of the reaction flask were warmed to RT and after 2 h a solution of 4-vinylisoindoline (1.0 eq.) in DMF (4 M) was added. The reaction was heated in a 60° C. oil bath for 2 h then cooled and poured into water and 5% potassium bisulfate. The resulting mixture was extracted with EtOAc. Combined organics were washed with brine, dried with anhydrous sodium sulfate, filtered and evaporated. Flash column chromatography eluting with hexane/EtOAc 70/30 gave the title compound as a white foam (81%). LRMS (ESI) m/z 417 (M+H).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH:6]2[CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.[CH:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>ClCCl>[CH:24]1([C:30]([N:4]2[CH2:3][C:2](=[O:1])[N:7]3[CH2:8][CH2:9][O:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[CH:6]3[CH2:5]2)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: O=C1CNCC2c3ccccc3OCCN12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CCCCC1)N1CC(=O)N2CCOc3ccccc3C2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Oxo-1,2,3,6,7,12b-hexahydropyrazino[1,2-d][1,4]benzoxazepine (0.9 g) and triethylamine (1 g) were dissolved in dichloromethane (20 ml), cooled in ice and cyclohexanoyl chloride (0.7 g, 1.1 equiv.) added. The mixture was stirred at room temperature for 3 h, then washed with dilute aqueous hydrochloric acid, followed by dilute aqueous ammonia solution. Evaporation of the dichloromethane gave an oil which was purified by column chromatography (SiO2 /chloroform) and crystallised from ether/40°-60° petroleum ether to give white crystals of the title compound m.p. 92°-3°;
Reaction SMILES: [Br:1]Br.O.[NH2:4][C:5]1[C:12]([F:13])=[CH:11][C:8]([C:9]#[N:10])=[C:7]([F:14])[CH:6]=1>CC(O)=O>[NH2:4][C:5]1[C:12]([F:13])=[CH:11][C:8]([C:9]#[N:10])=[C:7]([F:14])[C:6]=1[Br:1]
Reactant: BrBr
Reactant: N#Cc1cc(F)c(N)cc1F
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cc(F)c(N)c(Br)c1F
Reaction time: 16 h
Yield: 71 %

Procedure:
A mixture of 1.65 mL of Br2, 2 mL of H2O and 5 g of 4-amino-2,5-difluorobenzonitrile in 50 mL of AcOH is stirred at 20°-25° for 16 hours. The solvents are removed in vacuo and the residue partitioned between 100 mL of H2O and 3×200 ml of CH2Cl2. The CH2Cl2 extracts are washed with H2O, saturated NaHCO3, H2O (100 mL each), dried with Na2SO4 and evaporated in vacuo to give 6.89 g of crude 4-amino-3-bromo-2,5-difluorobenzonitrile. This is purified by dry-column chromatography using SiO2 to give 5.38 g (71% yield). Recrystallization from CH2Cl2 /hexane affords analytically pure material, m.p. 106°-108° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][N:9]=[C:10]([C:15](=[O:19])[CH2:16][O:17][CH3:18])[C:11]([O:13][CH3:14])=[O:12].[CH3:20]OC(OC)N(C)C>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:20]=[C:16]([O:17][CH3:18])[C:15](=[O:19])[C:10]([C:11]([O:13][CH3:14])=[O:12])=[N:9]1
Reactant: COCC(=O)C(=NNc1ccccc1F)C(=O)OC
Reactant: COC(OC)N(C)C
Product: COC(=O)c1nn(-c2ccccc2F)cc(OC)c1=O
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of methyl 2-[(2-fluorophenyl)hydrazono]-4-methoxy-3-oxobutanoate (5.02 g, 18.7 mmol) in N,N-dimethylformamide dimethyl acetal (35 mL) was refluxed for 1 h. After cooling to room temperature, the precipitate was collected by filtration and washed with hexane/AcOEt (2/1) to give the title compound (4.70 g, 90% yield) as off-white crystals: mp 155-157° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.91 (3H, s), 3.97 (3H, s), 7.29-7.36 (2H, m), 7.44-7.51 (1H, m), 7.65 (1H, dt, J=1.9, 7.9 Hz), 7.77 (1H, d, J=2.3 Hz). Anal. Calcd for C13HH FN2O4: C, 56.12; H, 3.98; N, 10.07. Found: C, 56.17; H, 3.97; N, 10.25.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:15])([F:14])[F:13].[Cl:19][S:20](O)(=[O:22])=[O:21]>>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:20]([Cl:19])(=[O:22])=[O:21])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:14])([F:15])[F:13]
Reactant: O=S(=O)(O)Cl
Reactant: C[C@@](O)(C(=O)Nc1cccc(Cl)c1Cl)C(F)(F)F
Product: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)Cl)c(Cl)c1Cl)C(F)(F)F
Temperature: 85 °C
Yield: 45.2 %

Procedure:
(R)-N-{2,3-Dichlorophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 74) (5.0 g, 16.6 mmol) was added in portions to cooled (0° C.) chlorosulphonic acid (5.3 ml, 81 mmol) over 15 mins and then the mixture was heated to 85° C. for 4.5 hours. The reaction mixture was cooled in an ice bath and then poured slowly onto a stirred ice-water mixture (60 ml). The mixture was extracted with DCM (2×75 ml), the DCM washed with brine, dried and evaporated. The residue was chromatographed on silica with 20% EtOAc in hexane as eluent to give the title compound as a solid (3.0 g, 7.5 mmol). NMR (CDCl3): 1.8 (s, 3H), 3.4 (s, 1H), 8.15 (d, 1H), 8.65 (d, 1H) and 9.55 (brs, 1H); m/z 400.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1.C(OC(N1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])=O)C>ClC>[CH2:7]([N:4]1[CH2:5][CH2:6][CH:2]([N:1]2[C:23](=[O:24])[C:22]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]3[C:20]2=[O:29])[CH2:3]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NC1CCN(Cc2ccccc2)C1
Agent: CCl
Product: O=C1c2ccccc2C(=O)N1C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 10 h
Yield: 73.3 %

Procedure:
10.0 g of 3-amino-1-benzylpyrrolidine was dissolved into 10 ml of chloromethane, to which 12.4 g of N-ethoxycarbonylphthalimide was added and stirred at a room temperature for 10 hours. The solvent was distilled off, diethyl ether was added and insoluble matters were filtered out. The filtrate was concentrated and purified on silica gel column chromatography, to obtain 12.70 g of the above-captioned compound (yield: 73%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.[N:21]([CH2:24][C:25](OCC)=[O:26])=[C:22]=[O:23]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:25](=[O:26])[CH2:24][NH:21][C:22]2=[O:23])=[CH:16][CH:15]=1
Reactant: CCOC(=O)CN=C=O
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(N)cc2)C1
Solvent: CC#N
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(N3C(=O)CNC3=O)cc2)C1
Reaction time: 4 h
Yield: 118 %

Procedure:
4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (95 mg; preparation as described in WO2004085404) was dissolved in acetonitrile (2 ml) and ethyl isocyanatoacetate (30 mg) was added dropwise with stirring. After 4 hours, the solution was concentrated and the residue purified by means of preparative HPLC. The fractions comprising product were combined, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with potassium carbonate and extracted three times with ethyl acetate. Drying over magnesium sulfate was followed by concentration to dryness. The residue was taken up with aqueous hydrochloric acid and freeze-dried. 107 mg of the desired compound were obtained.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4](S([O-])=O)=[CH:3][CH:2]=1.[Na+].C([CH2:19][CH2:20][NH:21][C:22]1C=CC(C=O)=C[CH:23]=1)C1C=CC=CC=1>>[CH2:22]([N:21]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:10]=[C:20]1[CH3:19])[CH3:23]
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: O=Cc1ccc(NCCCc2ccccc2)cc1
Agent: [Na+]
Product: CCn1c(C)cc2ccccc21
Yield: 86.1 %

Procedure:
Following a procedure similar to that described in Example 4A but employing 6.5 g. of 81.9% sodium p-toluenesulfinate, 6.3 g. of 95% 4-(benzylethylamino)benzaldehyde and 3.8 g. of 86.1% 1-ethyl-2-methyl-1H-indole, there was obtained 15.3 g. of 3-{[4-(benzylethylamino)phenyl](4-methylphenylsulfonyl)methyl}-1-ethyl-2-methyl-1H-indole as a gray tar-like product.