Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:10]=1[CH2:11][NH2:12].[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH:26]=O.C1(C)C=CC(S(N)(=O)=O)=CC=1>O>[F:21][C:22]([F:35])([F:36])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=1)[CH:26]=[N:12][CH2:11][C:10]1[CH:13]=[C:14]([C:17]([F:18])([F:19])[F:20])[CH:15]=[CH:16][C:9]=1[Cl:8]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NCc1cc(C(F)(F)F)ccc1Cl
Agent: Cc1ccc(S(N)(=O)=O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc(C=NCc2cc(C(F)(F)F)ccc2Cl)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a 100 mL round bottom flask, equipped with a Dean Start Trap was charged 50 mL of toluene, 5.0 gm of 2-chloro-5-trifluoromethyl benzyl amine and 5.8 gm of 3,5-bis(trifluoromethyl)benzaldehyde and 50 mg of para-toluenesulfonamide. The reaction was heated until water no longer distilled off about 3 hours, then cooled to ambient temperature and the solvent removed in vacuum. The crude product was used directly in the next step without further purification. 10.0 gm.
Reaction SMILES: [CH:1](/[CH2:9][C:10]([OH:12])=[O:11])=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:13]S(O)(=O)=O.C[O-].[Na+]>CO.C(OC)(OC)OC>[C:3]1(/[CH:2]=[CH:1]/[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)C/C=C/c1ccccc1
Reactant: CS(=O)(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: COC(=O)C/C=C/c1ccccc1

Procedure:
A solution of 3.24 mg (20 mmol) of (E)-styrylacetic acid in 20 ml of methanol,2 ml of trimethyl orthoformate and 192 mg (2 mmol) of methanesulphonic acid was stirred at 50° C. under argon for one hour. For the working-up, the mixture was neutralized with 2 mmol of sodium methylate and subsequently the solvent mixture was distilled off under reduced pressure. There was obtained methyl (E)-4-phenyl-but-3-enoate as a colourless liquid in quantitative yield; MS: 176 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[N:16][CH:17]=2)[NH:14][CH2:13][CH2:12][CH2:11]3)[CH:5]=[N:6][CH:7]=1.[C:18]([N:26]=C=O)(=[O:25])C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[N:16][CH:17]=2)[N:14]([C:18]([NH2:26])=[O:25])[CH2:13][CH2:12][CH2:11]3)[CH:5]=[N:6][CH:7]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Brc1cncc(-c2cnc3c(c2)CCCN3)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC(=O)N1CCCc2cc(-c3cncc(Br)c3)cnc21
Temperature: 50 °C
Reaction time: 16 h
Yield: 70.8 %

Procedure:
6-(5-Bromo-pyridin-3-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine (190 mg, 0.67 mmol) and benzoyl isocyanate (220 mg, 1.3 mmol) are mixed in 3.0 mL of DCM and the mixture is stirred at 50° C. for 2 hrs and room temperature for 16 hrs. Then the solvent is removed and the residue is suspended in 3.0 mL of EtOH. K2CO3 (160 mg, 1.1 mmol) is added and the mixture is heated at 70° C. for 30 min. Then the solvent is removed and the residue is partitioned between water (20 mL) and EtOAc (50 mL). The aqueous layer is separated and extracted with DCM (2×50 mL). The organic layers are combined and concentrated to give the crude product. To the crude product is added EtOAc (10 mL) and the solid formed is filtered, washed again with EtOAc (2×10 mL) and dried to give 158 mg of 6-(5-bromo-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[C@H:2]([C:5]([O:7][CH2:8][C:9]([Cl:12])([Cl:11])[Cl:10])=[O:6])[CH2:3][OH:4].N(C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:31](C(O)=O)[C@@H](C)OC(C)(C)C>>[NH:1]([C:13]([O:15][CH2:16][CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[C:29]1=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:14])[C@H:2]([C:5]([O:7][CH2:8][C:9]([Cl:10])([Cl:11])[Cl:12])=[O:6])[C@@H:3]([CH3:31])[OH:4]
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=C(N[C@@H](CO)C(=O)OCC(Cl)(Cl)Cl)OCC1c2ccccc2-c2ccccc21
Product: C[C@@H](O)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCC(Cl)(Cl)Cl
Yield: 68 %

Procedure:
According to the procedure used for the synthesis of Fmoc-Ser-OTce, Fmoc-Thr(OtBu)-OH (1 g, 2.5 mmol) provided Fmoc-Thr-OTce (0.81 g, 1.7 mmol, 68% overall yield for two steps).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([NH:13]C(=O)OC(C)(C)C)[CH2:10][CH2:11][OH:12].FC(F)(F)C(O)=O>ClCCl>[NH2:13][CH:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1])[CH2:10][CH2:11][OH:12]
Reactant: CC(C)(C)OC(=O)NC(CCO)c1cccc(Cl)c1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(CCO)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Of the compound from Example 85A, 800 mg (2.50 mmol) were dissolved in 20 ml of dichloromethane and admixed at 0° C. with 1.92 ml (25.0 mmol) of trifluoroacetic acid, then stirred at room temperature for 1 hour. The mixture was freed from the solvent and from the trifluoroacetic acid on a rotary evaporator. The crude product was taken up in 20 ml of toluene and again concentrated on a rotary evaporator under reduced pressure. Purification took place by chromatography on silica gel. By elution with ethyl acetate it was possible to separate off apolar impurities. Elution with dichloromethane/methanol/26% strength ammonia solution (10:1:0.1) gave 673 mg (79% of theory) of the target compound.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][N:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[S:27][C:17]=2[N:18]=1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyrazin-2-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH2:11]1.[CH3:20][C:21]([S:24](Cl)=[O:25])([CH3:23])[CH3:22].Cl>C(OCC)(=O)C>[CH3:20][C:21]([S:24]([NH:9][C@@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH2:15]1)=[O:25])([CH3:23])[CH3:22]
Reactant: COC(=O)[C@H]1CC[C@@H](N)CC1
Reactant: CC(C)(C)S(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CC[C@@H](NS(=O)C(C)(C)C)CC1

Procedure:
Triethylamine (272 mL) was added dropwise to a suspension of methyl cis-4-amino-1-cyclohexane carboxylate hydrochloride (7) (151 g, 0.78 mol) and 2-methylpropane-2-sulfinyl chloride (3) (120.8 g, 1.1 eq) in ethyl acetate (755 mL) at 6 to 9° C. The mixture was stirred for an hour at the same temperature and poured into diluted hydrochloric acid. The mixture was extracted with ethyl acetate (750 mL×2) and each of organic layers was washed with water, 5% aqueous solution of sodium bicarbonate, water and brine, successively. The solvent was concentrated under reduced pressure to obtain oily (14) (222.7 g, 1.09%).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5](O)=[O:6].C(OC(Cl)=O)C(C)C.C(N(CC)CC)C.[CH2:43]([NH:61]CCCCCCCCCCCCCCCCCC)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60]>O1CCCC1>[CH2:43]([NH:61][C:5](=[O:6])[CH2:4][CH2:3][CH:2]([CH:8]1[C:12]2([CH3:27])[CH:11]([CH:16]3[CH:15]([CH2:14][CH2:13]2)[C:20]2([CH3:26])[CH:19]([CH2:24][CH:23]([OH:25])[CH2:22][CH2:21]2)[CH2:18][CH2:17]3)[CH2:10][CH2:9]1)[CH3:1])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60]
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCNC(=O)CCC(C)C1CCC2C3CCC4CC(O)CCC4(C)C3CCC12C
Yield: 172.2 %

Procedure:
Lithocholic acid (81) (9.78 g, 26 mmol) was sissolved in anhydrous tetrahydrofuran (60 mL). Isobutylchloroformate (3.55 g, 3.55 mL, 26 mmol) was added followed by the addition of triethylamine (5.26 g, 7.25 mL, 52 mmol) and dioctadecylamine (7 g, 26 g). The reaction mixture was brought to ambient temperature and allowed to stir over night. The reaction mixture was concentrated under vacuum, and the residue was dissolved in dichloromethane (250 mL). The organic layer was washed with 5% sodium bicarbonate, 3% aqueous HCl and water. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure to afford amide 88 (14.5 g) in 89% yield. This was used as such for the next step.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[CH3:13][C:14]([CH3:27])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:15](OCC)=[O:16].[Cl-].[NH4+]>C1COCC1>[CH3:13][C:14]([CH3:27])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:15](=[O:16])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: CCCCCCCC(C)(C)C(=O)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCCCC(C)(C)C(=O)CP(=O)(OC)OC
Reaction time: 0.25 h
Yield: 34.2 %

Procedure:
To a solution of dimethyl methylphosphonate (6.1 ml, 56.0 mmol) in 100 ml anhydrous THF was added dropwise n-butyl lithium (1.61N, 34.7 ml, 55.9 mmol) at -78° C. under argon atmosphere. After stirring the mixture for 15 minutes, ethyl 2,2-dimethylnonanoate (5.00 g, 23.3 mmol) was added dropwise and the mixture was stirred at -78° C. for 20 minutes and then at room temperature for 2 hours. To the reaction mixture was added 20 ml of saturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate (50 ml×4). The ethyl acetate layers were washed with water (50 ml) and with brine (50 ml), dried over anhydrous sodium sulfate, and concentrated. Purification by column chromatography on silica gel (ethyl acetate) gave pure dimethyl 3,3-dimethyl-2-oxodecylphosphonate (2.3312 g, 7.97 mmol, yield 34%). The structure of this product was confirmed by the following data.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH:30]1([CH2:35][CH2:36]O)[CH2:34][CH2:33][CH2:32][CH2:31]1.Cl.[K+].[Br-]>C(Cl)(Cl)Cl>[CH:30]1([CH2:35][CH2:36][O:24][C:23]([C:18]2([C:20]([O:22][CH2:36][CH2:35][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: OCCC1CCCC1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(Cc1ccc2c(c1)OC(C(=O)OCCC1CCCC1)(C(=O)OCCC1CCCC1)O2)NCC(O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 2-cyclopentylethanol according to the procedure of Example 30 as an amber gum (HCl salt); 1H NMR (CDCl3) δ 1.32 (d, J=6.3 Hz, 3H), 1.60 (m, 20H), 2.80 (m, 1H), 2.90 (m, 2H), 3.15 (m, 1H), 3.20 (m, 1H), 3.48 (m, 2H), 4.30 (t, J=6.9 Hz, 4H), 5.50 (bd, 1 H), 6.80 (m, 3H), 7.25 (m, 2H), 7.43 (s, 1H), 8.70 (bs, 1H), 10.10 (bs, 1H); IR (KBr): 1765 cm-1 (C=O); MS (CI) m/z 614 (MH+); [α]D25 -24° (c, 1.0, CHCl3). Anal. Calcd. for C34H44ClNO7 ·HCl: C, 62.77; H, 6.82; N, 2.15; Cl, 10.90. Found: C, 64.04; H, 8.24; N, 1.62; Cl, 8.99.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:9]1[N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:10]1
Reactant: c1ccc(-c2nn[nH]c2-c2ccccc2)cc1
Reactant: BrCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: BrCCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)n1
Yield: 54.3 %

Procedure:
A mixture of 4,5-diphenyltriazole (11 g), 1,8-dibromooctane (67.6 g), and potassium carbonate (10.31 g) in dry butanone (300 ml) was heated at reflux temperature for 24 hours. The mixture was filtered and the solvent evaporated to give an oily residue. Distillation to remove 1,8-dibromooctane and column chromatography on silica gel eluted with a hexane:ethyl acetate gradient gave 2-(8-bromooctyl)-4,5-diphenyl-triazole (11.13 g, 54%) as an oil. NMR d (CDCl3) 1.2-1.5 (8H, m, 4×CH2), 1.84 (2H, m, CH2), 2.05 (2H, m, CH2), 3.37 (2H, t, Br--CH2), 4.47 (2H, t, N--CH2), 7.3-7.6 (10H, m, 2×Ph) ppm
Reaction SMILES: N[C:2]1[S:3][C:4]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:5]([CH3:7])[N:6]=1.[Cu](C#N)[C:19]#[N:20].N(OCCC(C)C)=O>C(#N)C.C(OCC)(=O)C>[CH2:11]([NH:10][C:8]([C:4]1[S:3][C:2]([C:19]#[N:20])=[N:6][C:5]=1[CH3:7])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#C[Cu]C#N
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Agent: CC(C)CCON=O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1nc(C#N)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 29 %

Procedure:
To a solution of 2-amino-N-benzyl-4-methylthiazole-5-carboxamide (0.50 g, 2.02 mmol) in acetonitrile (50 mL) was added copper cyanide (0.36 g, 4.04 mmol) and isoamyl nitrite (0.54 mL, 4.04 mmol). The reaction mixture was heated to reflux for 1 hour, cooled to ambient temperature, diluted with ethyl acetate and washed with water and brine. The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography to afford N-benzyl-2-cyano-4-methylthiazole-5-carboxamide in 29% yield (0.15 g): 1H NMR (300 MHz, CDCl3) δ 7.48-7.18 (m, 5H), 6.87 (br s, 1H), 4.49 (d, J=5.8 Hz, 2H), 2.69 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]([S:9][CH:10]([CH3:12])[CH3:11])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C-:13]#[N:14].[K+]>O.O.[Ni](Cl)Cl.[Mn].CN(C)C=O>[NH2:5][C:4]1[C:3]([S:9][CH:10]([CH3:12])[CH3:11])=[C:2]([CH:8]=[CH:7][CH:6]=1)[C:13]#[N:14]
Reactant: [C-]#N
Reactant: CC(C)Sc1c(N)cccc1Cl
Agent: Cl[Ni]Cl
Agent: [Mn]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Sc1c(N)cccc1C#N
Temperature: 50 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
6 liters of dimethylformamide are added to 50 g of nickel chloride dihydrate, 200 g of BPPFA (1,1'-bisdiphenylphosphine-1-(dimethylaminoethyl)ferrocene) and 49 g of manganese powder, and the mixture is stirred at 50° C. for 2 hours under an inert atmosphere. A brown suspension forms. 1,200 g of 3-chloro-2-isopropylthioaniline and 430 g of KCN are added to the suspension and the mixture is stirred for 16 hours at 50° C. After working up, white crystals of m.p. 82° C. are obtained in a yield of approximately 90%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[N:10]([CH:19]([CH3:21])[CH3:20])[C:9]=2[C:22]([OH:24])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:27])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[N:10]([CH:19]([CH3:21])[CH3:20])[C:9]=2[C:22]([Cl:27])=[O:24])=[CH:4][CH:3]=1
Reactant: CC(C)n1c(C(=O)O)c(-c2ccc(F)cc2)c2ccccc2c1=O
Reactant: O=S(Cl)Cl
Product: CC(C)n1c(C(=O)Cl)c(-c2ccc(F)cc2)c2ccccc2c1=O

Procedure:
A mixture of 4-(4-fluorophenyl)-2-isopropyl-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid (4.9 g) and thionyl chloride (50 ml) was heated at reflux for 90 minutes. The excess thionyl chloride was then removed by evaporation in vacuo (15 mmHg/40° C.) followed three times by treatment with dichloromethane and evaporation in vacuo, to give 4-(4-fluorophenyl)-2-isopropyl-1-oxo-1,2-dihydroisoquinoline-3-carbonyl chloride (4.35 g) in the form of a white solid, m.p.132°-134° C. [Elemental analysis: C,66.4; H,4.4; N,4.04; Cl,10.3%; calculated: C,66.4; H,4.40; N,4.08; Cl,10.31%].
Reaction SMILES: [C:1]1([CH:7]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:8]([OH:11])[CH:9]=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:20]([O:22][CH2:23][CH3:24])=[CH2:21].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>N1C=CC=CC=1.C(Cl)Cl>[C:1]1([CH:7]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:8]([O:11][CH:20]([O:22][CH2:23][CH3:24])[CH3:21])[CH:9]=[CH2:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=COCC
Reactant: C=CC(O)C(NC(=O)OC(C)(C)C)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC(OC(C)OCC)C(NC(=O)OC(C)(C)C)c1ccccc1
Yield: 86.5 %

Procedure:
526 mg (2.0 mmol) of 1-phenyl-1-t-butoxycarbonylamino-2-hydroxybut-3-ene, syn form, 20 cm3 of dry methylene chloride, 1.9 cm3 (20.0 mmol) of distilled ethyl vinyl ether and 50.2 mg (0.2 mmol) of pyridinium p-toluenesulphonate (PPTS) are introduced successively into a 50 cm3 single-necked flask placed under an argon atmosphere and equipped with a magnetic stirring system. The resulting homogeneous reaction mixture is left to react for 4.5 hours at a temperature of about 20° C. When the reaction is complete, 1 drop of pyridine is added and the reaction mixture is then diluted in 60 cm3 of methylene chloride. The organic phase is washed twice with water and twice with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulphate. After filtration, the solvents are driven off under reduced pressure on a rotary evaporator. The residue obtained is purified by passage over a column of silica gel using a hexane/ether mixture (8/2 by volume) as the eluent. 580 mg (1.73 mmol) of 1-phenyl-1-t-butoxycarbonylamino-2-(1-ethoxyethoxy)but-3-ene are obtained with a yield of 87% in the form of two epimers in a ratio of 55/45, said product having the following characteristics:
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19].Cl>C1COCC1>[CH2:15]([C:2]([CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15])([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH2:16][CH2:17][CH:18]=[CH2:19]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=CCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCCC(CCCC=C)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diethyl malonate (25 g, 156 mmol) was dissolved in 150 mL dry THF in a 3 necked round bottom flask, and NaH (18.74 g of 60% dispersion in mineral oil, 469 mmol, 3.0 eq.) was added portionwise. The suspension was magnetically stirred for 30 minutes. Subsequently, 58.1 g 5-bromo-1-pentene (390 mmol, 2.5 eq.) was added in one portion via syringe. The yellow suspension was heated at reflux overnight and cooled to room temperature. Aqueous 1 M HCl was added until the pH of the mixture was ≦7. The THF was removed via rotary evaporation and diethyl ether (300 mL) was added. The mixture was extracted with 2×150 mL aqueous 1 M HCl and 2×150 mL brine. The organic layer was then dried over MgSO4, filtered, and concentrated to give a yellow-brown oil, diethyl di-(4-pentenyl)malonate. This oil was placed in a 500 mL round-bottomed flask and 100 mL ethanol was added, followed by a large excess (30 g, ˜5 eq.) of NaOH, some of which did not dissolve. H2O (5 mL) was added and the resulting mixture was stirred at reflux overnight. Subsequently, the entire mixture was poured into a large beaker, cooled to 0° C. using an ice water bath, and stirred (additional H2O may be added to dissolve any residual solids interfering with stirring). Concentrated aqueous HCl was added portionwise until the pH of the mixture was ≦7; solids were formed upon acidification. Diethyl ether (300 mL) was added to the mixture at room temperature, and the aqueous layer was extracted with 2×150 mL diethyl ether. The combined organic layers were extracted with 4×150 mL 1 M aqueous NaOH. The combined aqueous fractions from the extractions were then transferred to a beaker and acidified with concentrated aqueous HCl until the pH of the mixture was ≦7. Diethyl ether (200 mL) was added. The aqueous layer was extracted with 3×100 mL diethyl ether, and all of the combined organic layers were dried over MgSO4 and filtered. Volatiles were removed to give 2,2-di-(4-pentenyl)malonic acid as a yellow-brown oil. Subsequently, 2,2-di-(4-pentenyl)malonic acid (60 g, 250 mmol) was placed in a large round-bottomed flask equipped with a reflux condenser and heated with vigorous magnetic stirring to 200° C.-210° C. using an oil bath. Gas evolution was observed upon reflux. After a 1 hour period, decarboxylation (evidenced by vigorous frothing) was complete and the mixture was cooled to room temperature and purified by flash chromatography on silica using 15% ethyl acetate:hexanes as mobile phase to give 2-(4-pentenyl)-6-heptenoic acid (23 g, 79%). 1H NMR (CDCl3): δ 11.2-12.2 (br, 1H), 5.6-6.0 (m, 2H), 4.8-5.0 (m, 4H), 2.2-2.4 (m, 1H), 1.9-2.1 (m, 4H), 1.8-1.9 (m, 2H), 1.2-1.8 (m, 6H) ppm.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[S:23]1[C:27]([CH:28]=O)=[CH:26][C:25]2[S:30][CH:31]=[CH:32][C:24]1=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[S:23]1[C:27]([CH2:28][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]=[CH:12][C:11]3=[O:22])[CH2:6][CH2:7]2)=[CH:26][C:25]2[S:30][CH:31]=[CH:32][C:24]1=2
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1cc2sccc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4cc5sccc5s4)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To 6 mL of a chloroform solution containing 270 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 135 mg of thieno[3,2-b]thiophene-2-carbaldehyde, 54 mg of acetic acid were added, and stirred at room temperature for 2 hours. To the reaction mixture, 284 mg of sodium triacetoxyborohydride was added, and stirred for 18 hours. Aqueous saturated sodium hydrogen carbonate solution was added, and the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=10:1], to give 0.31 g of 1-(2-(4-((thieno[3,2-b]thiophen-2-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one as a brown oil.