Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:5]1[CH:14]=[CH:13][C:8]2[C:9](=[O:12])[O:10][CH2:11][C:7]=2[C:6]=1[CH3:15])[CH3:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].O>C(Cl)Cl>[CH3:15][C:6]1[C:7]2[CH2:11][O:10][C:9](=[O:12])[C:8]=2[CH:13]=[CH:14][C:5]=1[CH:3]([CH3:4])[CH:2]=[O:1]
Reactant: Cc1c(C(C)CO)ccc2c1COC2=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1c(C(C)C=O)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(2-Hydroxy-1-methylethyl)-4-methyl-2-benzofuran-1(3H)-one (161 mg, 0.781 mmol, 1.0 eq) was dissolved in DCM (6 ml). To above solution was added Dess-MartinPeriodinane (397 mg, 0.937 mmol, 1.2 eq). The reaction was stirred at rt for 2 hr. To the reaction was added DCM (10 Ml), Na2S2O3 (6 mL) and H2O (6 mL). The mixture was stirred at r.t. for 30 minutes and formed two layers. The bottom layer was separated and washed with aqueous NaHCO3, brine and water, dried over Na2SO4, filtered, and concentrated to dryness. The crude product was used to next step without purification. 1H NMR (500 MHz, CDCl3, δ in ppm): 9.70 (1H, s, CHO), 7.79 (1H, d, J=7.8 Hz), 7.28 (1H, d, J=7.8 Hz), 5.28 (2H, s), 3.27 (1H, m), 2.32 (3H, s), 1.50 (3H, d, J=7.2 Hz).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([OH:10])=[CH:7][CH:8]=[CH:9][C:2]1=2.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[C:11]([O:10][C:6]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH:9]=[CH:8][CH:7]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1cccc2sccc12
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(Oc1cccc2sccc12)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of benzo[b]thiophen-4-ol (4 g), benzoyl chloride (3.3 ml) and pyridine (10 ml) was heated under reflux under nitrogen for 3 hours, then cooled to ambient temperature and poured onto ice-water (130 ml). The product was extracted into ether (3×50 ml), the combined extracts were washed with 5% aqueous sodium hydrogencarbonate solution (50 ml), 2M hydrochloric acid (50 ml) and water (3×50 ml), then they were dried (MgSO4) and the solvent was removed in vacuo to give benzo[b]thiophen-4-yl benzoate (6.7 g) as a cream solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:9](=[O:28])[C@:10]3([C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][CH2:13][C:12](=[O:23])[N:11]3[CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:5]2=[CH:4][CH:3]=1.[Li+].[CH3:38][CH:39]([N-]C(C)C)[CH3:40].C(Br)C=C>C1COCC1>[CH2:40]([C@@H:13]1[C:12](=[O:23])[N:11]([CH2:24][CH:25]2[CH2:26][CH2:27]2)[C@:10]2([C:5]3[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:8]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:9]2=[O:28])[C@@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[CH2:14]1)[CH:39]=[CH2:38]
Reactant: C[Si](C)(C)CCOCN1C(=O)[C@@]2(c3ccc(Cl)cc31)[C@@H](c1cccc(Cl)c1)CCC(=O)N2CC1CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@]2(C(=O)N(COCC[Si](C)(C)C)c3cc(Cl)ccc32)N(CC2CC2)C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of (rac) (2′S,3′R)-6-chloro-3′-(3-chlorophenyl)-1′-(cyclopropylmethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)spiro[indoline-3,2′-piperidine]-2,6′-dione (Example 62, Step I) (97 mg, 0.178 mmol) in THF (1 mL) at −78° C. under Ar was added freshly prepared LDA (1.0 M in THF) (178 μL, 0.178 mmol). The reaction color turned yellowish orange. The reaction was stirred at −78° C. for 30 min then distilled allyl bromide (15.39 μL, 0.178 mmol) was added. The reaction was stirred at −78° C. for 10 min then warmed to 0° C. The reaction was quenched with sat. NH4Cl and warmed to room temperature. The mixture was diluted with EtOAc and the layers were separated. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 0 to 25% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:22]([O:24]C4C=CC=CC=4)=O)[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:31])=[N:9]2)=[CH:4][CH:3]=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>C(#N)C>[CH3:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:22]([N:36]4[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]4)=[O:24])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:31])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2ccc(N3C(=O)c4ccccc4C3OC(=O)Oc3ccccc3)nc2n1
Reactant: CN1CCNCC1
Solvent: CC#N
Product: Cc1ccc2ccc(N3C(=O)c4ccccc4C3OC(=O)N3CCN(C)CC3)nc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 22.1 %

Procedure:
Following the procedure of Example 11 but starting with 2-(7-methyl-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-1-one (4.9 g.) and 4-methylpiperazine (6 g.) in acetonitrile (40 cc.) and stirring the reaction mixture for 24 hours at 25° C., a crude product (4.2 g.) is obtained. This product is triturated in diethyl ether (42 cc.) and then recrystallised from diisopropyl ether (300 cc.). 2-(7-Methyl-1,8-naphthyridin-2-yl)-3-(4-methylpiperazin-1-yl)carbonyloxy-isoindolin-1-one (1.1 g.), melting at 190° C., is thus obtained.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:35])/[C:23](/[F:34])=[C:24](\[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=2)/[CH3:25])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:42]([O:45][CH2:46]Br)(=[O:44])[CH3:43]>CN(C=O)C.C(OCC)(=O)C>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([N:21]([C:22](=[O:35])/[C:23](/[F:34])=[C:24](\[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=2)/[CH3:25])[CH2:43][C:42]([O:45][CH3:46])=[O:44])=[CH:17][CH:16]=1)(=[O:7])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C/C(=C(\F)C(=O)Nc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)c1cccc(C#N)c1
Reactant: CC(=O)OCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CN(C(=O)/C(F)=C(/C)c1cccc(C#N)c1)c1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.8 %

Procedure:
To a solution of (2E)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3-cyanophenyl)-2-fluorobut-2-enamide (230 mg, 0.47 mmol) in 15 ml DMF was added cesium carbonate (460 mg, 1.41 mmol) and bromomethyl acetate (355 mg, 2.35 mmol). The reaction mixture was stirred at room temperature for 4 hours then diluted with 25 ml of ethyl acetate. Organic was washed with 3×25 ml water, 3×25 ml saturated brine solution, dried over magnesium sulfate, filtered and concentrated in vacuo to give methyl 2-{(2E)-N-[4-(2-{[(tert-butyl)amino]-sulfonyl}phenyl)phenyl]-3-(3-cyanophenyl)-2-fluorobut-2-enoylamino}acetate (230 mg, 86%) as yellow foam. ES-MS (M+H+): 563.2.
Reaction SMILES: C1C=C[NH+]=CC=1.[Br:7][Br-]Br.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([C:22]1[CH:35]=[CH:34][C:25]([O:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:24][CH:23]=1)=[CH:17][CH2:16][CH2:15]2>C1COCC1>[Br:7][C:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][CH3:10])[CH:13]=2)[C:18]=1[C:22]1[CH:35]=[CH:34][C:25]([O:26][CH2:27][CH2:28][N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1
Reactant: COc1ccc2c(c1)CCC=C2c1ccc(OCCN2CCCC2)cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC(Br)=C2c1ccc(OCCN2CCCC2)cc1
Reaction time: 60 h
Yield: 82.9 %

Procedure:
Pyridinium bromide perbromide (21.22 g, 60.55 mmol) was added portionwise to a solution of 1-{2-[4-(6-methoxy-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine (23 g, 72 mmol) in THF (700 mL). The reaction was stirred for 60 h. The precipitate was filtered through a Celite pad with the aid of THF. The off-white solid was dissolved in CH2Cl2 and MeOH and was filtered away from the Celite. The organic solution was washed with 0.5 N aq HCl followed by satd NaHCO3 (aq). The organic solution was dried (MgSO4), filtered, and concentrated to provide a brown solid (21.5 g, 83%). 1H NMR (250 MHz, CDCl3): δ7.14 (d, J=8.7 Hz, 2H), 6.97 (d, J=8.8 Hz, 2H), 6.71 (d, J=2.2 Hz, 1H), 6.55 (m, 2H), 4.17 (t, J=6.0 Hz, 2H), 3.77 (s, 3H), 2.96 (m, 4H), 2.66 (m, 4 H), 1.85 (m, 4H).
Reaction SMILES: [CH2:1](OCC=O)CC(CCC=C(C)C)C.[CH3:15][C:16]1([CH3:31])[C:24]2[CH:23]=[C:22]3[O:25][CH2:26][C:27](=[O:30])[CH2:28][O:29][C:21]3=[CH:20][C:19]=2[CH2:18][CH2:17]1>>[CH3:31][CH:16]([CH2:15][CH3:1])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]2[O:25][CH2:26][C:27](=[O:30])[CH2:28][O:29][C:21]=2[CH:20]=1
Reactant: CC1(C)CCc2cc3c(cc21)OCC(=O)CO3
Reactant: CC(C)=CCCC(C)CCOCC=O
Product: CCC(C)CCc1ccc2c(c1)OCC(=O)CO2

Procedure:
Odor: Marine, animalic, civet-like, floral-aldehyde odor, also somewhat reminiscent of citronelloxyacetaldehyde ([3,7-dimethyl-6-octenyl]oxy-acetaldehyde).—IR (film): ν=1502/1435/1460/1580 cm−1 (ν C═C, Ar), 1265/1304/1202 cm−1 (ν ring), 1051 cm−1 (ν C—O—C), 1741 cm−1 (ν C═O).—1H-NMR (CDCl3): δ=0.87 (t, J=7.2 Hz, 3H, 5′-H3), 0.91 (d, J=6.4 Hz, 3H, 3′-Me), 1.18 (mc1 1H, 2′-Hb), 1.34–1.43 (m, 3H, 2′-Ha, 4′-H2), 1.56–1.62 (m, 1H, 3′-H), 2.48 (ddd, J=14.0, 10.0, 6.4 Hz, 1H, 1′-Ha), 2.56 (ddd, J=14.0, 10.4, 5.2 Hz, 1H, 1′-Hb), 4.67 (d, J=2.4 Hz, 4H, 2-,4-H2), 6.78 (dd, J=8.2, 2.4 Hz, 1H, 8-H), 6.82 (d, J=2.0 Hz, 1H, 6-H), 6.90 (d, J=8.4 Hz, 1H, 9-H).—13C-NMR (CDCl3): δ=11.14 (q, C-5′), 18.93 (q, 3′-Me), 29.18 (t, C-4′), 32.42 (t, C-1′), 33.84 (d, C-3′), 38.23 (t, C-2′), 22.38 (t, C-4′), 30.90/31.26 (2t, C-2′, -3′), 75.35/75.64 (2t, C-2,-4), 120.27/120.51 (2d, C-6,-9), 123.45 (d, C-8), 139.11 (s, C-7), 146.00/147.86 (2s, C-5a,-9a), 204.72 (s, C-3).—MS (EI): m/z (%)=77 (21) [C8H5+], 92 (14) [C7H8+], 135 (11) [M+-C5H11—C2H2O], 149 (16) [M+-C5H11—CO], 177 (100) [M+-C5H11], 191 (4) [M+-C4H9], 205 (7) [M+-C3H7], 248 (45) [M+].
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>CN(C)C1C=CN=CC=1.CC(C)=O>[C:19]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:22])[CH:20]=[CH2:21]
Reactant: C=CC(=O)Cl
Reactant: O=[N+]([O-])c1ccccc1CO
Agent: CN(C)c1ccncc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: C=CC(=O)OCc1ccccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
153.2 g (1.0 mole) of 2-nitrobenzyl alcohol, 95.7 g (0.94 mole) of triethylamine and 12.9 g (0.11 mole) of 4-(dimethylamino)pyridine were dissolved in 600 ml of acetone and to the resulting solution, there was dropwise added a solution of 95.0 g (1.05 mole) of acryloyl chloride in 150 ml of acetone at 0° C. over one hour with stirring. Then the stirring was continued for additional one hour. After filtering off the resulting salt, the filtrate was concentrated and purified by column chromatography (packed material: silica gel: eluent: hexane/ethyl acetate=10/1). Thus, 141 g of an oily liquid was recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1Cl)[C:5]#[N:6].[F-:11].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:11])[C:5]#[N:6]
Reactant: N#Cc1ccc(Cl)c(Cl)c1
Reactant: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(F)c(Cl)c1
Temperature: 170 °C
Yield: 92 %

Procedure:
172 g of 3,4-dichlorobenzonitrile, 200 g of dimethylsulfoxide, 69.6 g of potassium fluoride, and 3.95 g of (N,N-dimethylimidazolidino)tris-(diethylamino)phosphazenium chloride were placed in a 1 liter four-neck flask equipped with anchor stirrer, thermometer, and reflux condenser with bubble counter. The mixture was then heated with stirring to 170° C. and this temperature was maintained for 6 hours. The mixture was then cooled to room temperature, water was added to the reaction mixture in a volumetric ratio of 1:1, and the 3-chloro4-fluorobenzonitrile that precipitated was isolated by filtration, washing, and drying. 3-Chloro4-fluorobenzo-nitrile was obtained in a yield of 92% of theory.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]2=[O:20])([O-])=O.[F:21][C:22]1[CH:27]=[CH:26][C:25]([O-:28])=[CH:24][CH:23]=1.[Na+].Cl>CN(C=O)C>[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:11]2[CH:12]=[CH:4][CH:5]=[C:6]3[C:10]=2[C:9](=[O:13])[N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]3=[O:20])=[CH:24][CH:23]=1
Reactant: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1c1ccccc1
Reactant: [O-]c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2cccc(Oc3ccc(F)cc3)c2C(=O)N1c1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
5-Nitro-2-phenylisoindole-1,3-dione (5.9 g, 22 mmol) was dissolved in DMF (40 ml) and sodium 4-fluorophenolate (3.1 g, 23.1 mmol) was added. The resulting mixture was stirred at 100° C. for 2 hours under an argon atmosphere. The mixture was allowed to cool to RT then poured into 4% aqueous HCl. The yellow precipitate which formed was filtered off, washed with water and recrystallised (DCM/TBME) to yield (4-fluorophenoxy)-2-phenylisoindol-1,3-dione (2.4 g, 41%);
Reaction SMILES: Cl.[CH2:2]([S:4]([CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][C@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1)(=[O:6])=[O:5])[CH3:3].[CH:24]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH2:25].C(N(CC)CC)C>CN(C)C(=O)C>[CH2:2]([S:4]([CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][C@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH2:25][CH2:24][S:26]([CH3:29])(=[O:28])=[O:27])(=[O:6])=[O:5])[CH3:3]
Reactant: C=CS(C)(=O)=O
Reactant: CCS(=O)(=O)CCc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)CCc1ccc2[nH]cc(C[C@H]3CCCN3CCS(C)(=O)=O)c2c1
Temperature: 100 °C
Yield: 54.4 %

Procedure:
5-(2-Ethylsulphonylethyl)-3-(2(R)-pyrrolidinylmethyl)-1H-indole hydrochloride (Preparation 5; 200 mg, 0.56 mmol) was dissolved in N,N-dimethylacetamide (4 ml) under nitrogen at room temperature, then methyl vinyl sulphone (0.06 ml, 0.69 mmol) and triethylamine (0.2 ml) were added. The resulting mixture was heated at 100° C. for 18 hours, allowed to cool, then partitioned between ethyl acetate and water. The organic phase was separated, washed with water, dried (Na2SO4) and evaporated under reduced pressure. The resulting crude material was purified by column chromatography on silica gel, eluting with a gradient of ethanol in dichloromethane (0 to 5% ethanol), to afford the title compound as a gum (130 mg). Rf 0.70 (SS 4). [α]D25 +43° (c=0.1, CH3OH). Found: C,55.38; H,7.12; N,6.50. C20H30N2O4S2 ; 0.10 CH2Cl2 requires C,55.48; H,7.00; N,6.44%. δ(CDCl3): 1.38(3H,t), 1.50-1.90(5H,m), 2.22(1H,m), 2.60-2.80(3H,m), 2.90-3.35(12H,m), 3.48(1H,m), 5.30(0.20H,s,CH2Cl2), 6.98-7.10(2H,m), 7.30(1H,d), 7.44(1H,s), 8.22(1H,br s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][C:13](=[CH2:19])[C:12]2=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][CH:13]([CH2:19][N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)[C:12]2=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1c[nH]cn1
Reactant: C=C1COc2ccc(OCc3ccccc3)cc2C1=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2cc(OCc3ccccc3)ccc2OCC1Cn1ccnc1
Yield: 64.6 %

Procedure:
A solution of 3.7 g of 6-benzyloxy-3-methylene-4-chromanone and 3.7 g of imidazole in 50 cc of DMF was heated at 60° C. for 1.5 hours. The reaction was allowed to cool, then poured into water and extracted with ethyl acetate. The combined organic layers were dried over Na and evaporated to give 4 g of crude product which was purified by recrystallization from CH2Cl2 /ether to give 3 g of title product, m.p. 108°-110° C. MS calculated for C20H18N2O3 : 334.1317; found: 334.1317.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[CH2:11][CH2:12][N:13]([CH2:16][C:17]2[C:18]([NH2:24])=[N:19][C:20]([CH3:23])=[N:21][CH:22]=2)[CH2:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1.[Pt](=O)=O>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[C:18]([NH2:24])=[N:19][C:20]([CH3:23])=[N:21][CH:22]=2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ncc(CN2CC=C(COCc3ccccc3)CC2)c(N)n1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: Cc1ncc(CN2CCC(COCc3ccccc3)CC2)c(N)n1
Reaction time: 5 h
Yield: 70.3 %

Procedure:
A suspension of 0.040 g of platinum dioxide in 2 ml of tetrahydrofuran was treated with a solution of 0.11 g (0.00034 mol) of [5-(4-benzyloxymethyl-3,6-dihydro-2H-pyridin-1-ylmethyl)-2-methyl-pyrimidin-4-yl]-amine in 3.5 ml of tetrahydrofuran and the mixture was hydrogenated under normal pressure for 5 hours. The catalyst was filtered off, the filtrate was concentrated and the residue was chromatographed on silica gel with ethyl acetate as the eluent. 0.078 g (70%) of [5-(4-benzyloxymethyl-piperidin-1-ylmethyl)-2-methyl-pyrimidin-4-yl]-amine was obtained as colourless crystals; m.p. 106°-108°.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][C:11]([CH3:13])=O.Cl.O>C1C=CC=CC=1>[CH2:16]([O:15][C:9](=[O:14])[CH:10]=[C:11]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([I:1])[CH:3]=1)[CH3:13])[CH3:17]
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1cccc(I)c1
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C=C(C)Nc1cccc(I)c1
Reaction time: 4 h

Procedure:
A mixture of 47.79 g 3-iodoaniline, 27.7 ml ethyl acetoacetate and 0.13 ml 37% hydrochlorid acid in 65 ml benzene is boiled under a reflux condenser fitted with a water separator. After 4 h. 4 ml of water have been collected. The solvent is removed at reduced pressure and the residual oil dried in vacuo 3-(3-iodo-phenylamino)-but-2-enoic acid ethyl ester is obtained as a light brown oil. MS (ISP): 332.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]#[N:18])=[C:7]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].IC.[C:23]([O-])(O)=O.[Na+]>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]#[N:18])=[C:7]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[N:8]2[CH3:23])=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: N#Cc1c(-c2cccnc2)[nH]c2cc(F)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(-c2cccnc2)c(C#N)c2ccc(F)cc21
Reaction time: 1 h

Procedure:
A flask is charged with 6-fluoro-2-pyridin-3-yl-1H-indole-3-carbonitrile (Example 140, 50 mg, 0.21 mmol) and DMF (2 mL), and 60% sodium hydride (25 mg, 0.63 mmol) is added. The mixture is stirred at room temperature for 30 min before addition of iodomethane (45 mg, 0.315 mmol). After 1 h, saturated NaHCO3 aqueous solution (3 mL) is added to quench the reaction and the mixture is filtered and purified on Xbridge C18 eluting with a 9:1 to 1:9 water-acetonitrile gradient to give 6-fluoro-1-methyl-2-pyridin-3-yl-1H-indole-3-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.77 (s, 3H), 7.19-7.26 (m, 1H), 7.66-7.76 (m, 3H), 8.14-8.19 (m, 1H), 8.80 (dd, J=4.9, 1.6 Hz, 1H), 8.89 (dd, J=2.3, 0.8 Hz, 1H). HRMS (ESI) m/z 293.1210 [(M+H+CH3CN)+ calcd for C17H14FN4: 293.1203].
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Cl:8])[N:7]=1.[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])([O:13][CH3:14])=[O:12]>ClCCCl>[Cl:8][C:6]1[N:7]=[C:2]([NH:1][C:25]([NH:24][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:11]([O:13][CH3:14])=[O:12])(=[O:23])=[O:22])=[O:26])[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: Cn1cc(Cl)nc(N)c1=O
Solvent: ClCCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(Cl)cn(C)c1=O

Procedure:
To a mixture of 3-amino-5-chloro-1-methyl-2(1H)-pyrazinone (0.40 g, 0.0025 mol) in anhydrous 1,2-dichloroethane (4 mL) under nitrogen was added a solution of 2-carbomethoxybenzenesulfonyl isocyanate (0.84 g, 0.0035 mol) in anhydrous 1,2-dichloromethane (3 mL). The mixture was heated at reflux for 2 hours. The solvent was rotary evaporated, and the residue was purified by chromatography on a column of silica gel using a solvent mixture of 1:1 hexanes-acetone containing a little acetic acid as eluant. Rotary evaporation of the appropriate fractions left 0.34 g of methyl 2-[[(6-chloro-3,4-dihydro-4-methyl-3-oxo-2-pyrazinylamino)carbonylamino]sulfonyl]benzoate as a crystalline powder melting at 173°-176° C.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[CH2:13]([OH:17])[C:14]#[C:15][CH3:16]>>[CH2:13]([O:17][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)[C:14]#[C:15][CH3:16]
Reactant: CC#CCO
Reactant: CCOC(=O)c1ccc(Cl)nc1
Product: CC#CCOc1ccc(C(=O)O)cn1
Yield: 38 %

Procedure:
The title compound was synthesized as described for Intermediate example I-92 in 38% yield starting from ethyl 6-chloronicotinate and 2-butyn-1-ol; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.61-8.76 (m, 1 H), 8.03-8.23 (m, 1 H), 6.83-6.98 (m, 1 H), 4.94-5.05 (m, 2 H), 1.74-1.91 (m, 3 H); MS (ESI) m/z 192[M+H+], m/z 190[M−H+].
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH3:27])([CH3:26])[C@H:7]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:8]([O:10]CC1C=CC=CC=1)=[O:9])(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([O:4][CH2:5][C:6]([CH3:27])([CH3:26])[C@H:7]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(C)(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)OCC(C)(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.8 %

Procedure:
To a solution of (S)-benzyl 4-acetoxy-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoate (0.26 g) in MeOH (10 mL) was added 10% Pd/C (0.020 g) under N2. The reaction mixture was stirred under H2 at rt for 16 h. The reaction was filtered through diatomaceous earth (Celite®), washed with EtOAc and concentrated to yield (S)-4-acetoxy-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoic acid (0.18 g). LC/MS (Cond. N-1): [M+Na]+ 312.21, RT=3.12 min.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CCN(C(C)C)C(C)C.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1>[CH2:21]([NH:28][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: NCc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(F)cc1NCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
2,4-Difluoronitrobenzene E-1.1′″ (3.448 ml; 31.429 mmol) is dissolved in dioxane (35.000 ml). DIPEA (6.601 ml; 40.857 mmol) and benzylamine (3.429 ml; 31.429 mmol) are added. The reaction mixture is stirred at 50° C. overnight. The reaction mixture is concentrated under reduced pressure. The residue crystallises after some minutes. It is triturated with diethyl ether to give the pure crystalline compound.