Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C@H:3]1[O:11][C@H:10]2[C@H:6]([N:7]=[C:8]([CH2:12][CH2:13][CH3:14])[S:9]2)[C@@H:5]([OH:15])[C@@H:4]1[OH:16].S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>N1C=CC=CC=1.C(Cl)Cl>[N:28]([CH2:2][C@H:3]1[O:11][C@H:10]2[C@H:6]([N:7]=[C:8]([CH2:12][CH2:13][CH3:14])[S:9]2)[C@@H:5]([OH:15])[C@@H:4]1[OH:16])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CN=[N+]=[N-])O[C@@H]2S1
Temperature: 25 °C
Yield: 81.6 %

Procedure:
(3aR,5R,6S,7R,7aR)-5-(hydroxymethyl)-2-propyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (200 mg, 0.81 mmol) was dissolved in pyridine (2 mL) and CH2Cl2 (2 mL) and cooled to 0° C. Tosyl chloride (230 mg, 1.2 mmol) was then added and the solution allowed to warm to room temperature over 1 h. The mixture was diluted with CH2Cl2 (10 mL) and washed with water (2×5 mL), dried (MgSO4), filtered and concentrated. The resultant colourless residue (280 mg) was taken up in DMF (3 mL) and NaN3 (158 mg, 2.4 mmol) was added. The resultant mixture was stirred at 55° C. for 2 days. Concentration of the mixture gave a residue which was taken up in CH2Cl2 (20 mL) and washed with water (2×5 mL), dried (MgSO4), filtered and concentrated. Flash chromatography of the residue on silica gel (MeOH:EtOAc, 1:9) gave 180 mg (82% yield) of (3aR,5R,6S,7R,7aR)-5-(azidomethyl)-2-propyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (50) as a colourless oil. 1H NMR (500 MHz, methanol-d4): δ 0.98 (t, 3H, J=7.3 Hz), 1.63-1.67 (m, 2H), 2.46-2.50 (m, 2H), 3.33 (m, 1H), 3.54 (dd, 1H, J=4.3, 9.5 Hz), 3.44 (dd, 1H, 2.3, 12.0 Hz), 3.55 (dd, 1H, J=6.2, 12.0 Hz), 4.06 (dd, 1H, J=4.4, 4.6 Hz), 4.29 (m, 1H, J=4.3 Hz), 6.31 (d, 1H, J=6.9 Hz).
Reaction SMILES: C(NC1SC(S(Cl)(=O)=O)=C(C)N=1)(=O)C.C[O:16][C:17](=[O:78])[C@@H:18]([NH:32][C:33]([CH:35]1[CH2:44][C:43]2[CH:42]=[C:41]3[O:45][CH2:46][C@H:47]([C:49]4[CH:54]=[CH:53][C:52]([O:55][CH2:56][C:57]5[CH:62]=[CH:61][C:60]([Cl:63])=[C:59]([Cl:64])[CH:58]=5)=[CH:51][CH:50]=4)[O:48][C:40]3=[CH:39][C:38]=2[CH2:37][N:36]1[S:65]([C:68]1[S:72][C:71]([NH:73]C(=O)C)=[N:70][C:69]=1[CH3:77])(=[O:67])=[O:66])=[O:34])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=1>>[NH2:73][C:71]1[S:72][C:68]([S:65]([N:36]2[CH:35]([C:33]([NH:32][C@@H:18]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:22][CH:21]=3)[C:17]([OH:78])=[O:16])=[O:34])[CH2:44][C:43]3[CH:42]=[C:41]4[O:45][CH2:46][C@H:47]([C:49]5[CH:54]=[CH:53][C:52]([O:55][CH2:56][C:57]6[CH:62]=[CH:61][C:60]([Cl:63])=[C:59]([Cl:64])[CH:58]=6)=[CH:51][CH:50]=5)[O:48][C:40]4=[CH:39][C:38]=3[CH2:37]2)(=[O:67])=[O:66])=[C:69]([CH3:77])[N:70]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Product: Cc1nc(N)sc1S(=O)(=O)N1Cc2cc3c(cc2CC1C(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Yield: 46.5 %

Procedure:
The methyl ester hydrochloride salt (36 mg) was reacted with 2-acetylamino-4-methyl thiazole-5-sulfonyl chloride (26 mg) according to General Procedure E. The resulting (S)-2-({(S)-7-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl-]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-biphenyl-4-yl-propionic acid methyl ester (32 mg) was hydrolyzed according to General Procedures N and B to give the title compound (14 mg). LCMS: (m/z) 887.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=C)[C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[O:14].[O:31]=[O+][O-]>C(Cl)Cl.CO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=[O:31])[C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:19])([CH3:21])[CH3:20])=[O:14]
Reactant: O=[O+][O-]
Reactant: C=Cc1ccccc1CC(C(=O)OCC[Si](C)(C)C)N1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: CO
Product: C[Si](C)(C)CCOC(=O)C(Cc1ccccc1C=O)N1C(=O)c2ccccc2C1=O
Temperature: -78 °C
Yield: 100 %

Procedure:
Dissolve 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(2-vinyl-phenyl)-propionic acid, 2-trimethylsilanyl-ethyl ester (2.61 g, 6.19 mmol) in methylene chloride (70 mL) and methanol (75 mL). Cool to -78° C. and treat with ozone until a blue color persists. Purge with nitrogen and add dimethylsulfide (7 mL) and pyridine (0.35 mL). Allow to warm to room temperature gradually overnight. Partition between methylene chloride (100 mL) and water (40 mL). Extract the aqueous with methylene chloride (50 mL), dry (Na2 SO4) and purify by silica gel chromatography (2.5:1 hexane/ethyl acetate) to give the title compound as a colorless viscous oil (2.65 g, 100%).
Reaction SMILES: Cl.Cl.N[CH2:4][CH2:5][C:6]1[N:10]([CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([F:20])[CH:13]=2)[C:9]([CH3:21])=[N:8][CH:7]=1.CC[N:24](CC)CC.[C:29]([N:33]=[C:34]=[O:35])([CH3:32])([CH3:31])[CH3:30]>CN(C=O)C>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([CH2:11][N:10]2[C:6]([CH2:5][CH2:4][N:33]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:34]([NH2:24])=[O:35])=[CH:7][N:8]=[C:9]2[CH3:21])=[CH:13][C:14]=1[F:20])#[N:17]
Reactant: Cc1ncc(CCN)n1Cc1ccc(C#N)c(F)c1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)N=C=O
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ncc(CCN(C(N)=O)C(C)(C)C)n1Cc1ccc(C#N)c(F)c1

Procedure:
To a solution of 4-[5-(2-amino-ethyl)-2-methyl-imidazol-1-ylmethyl]-2-fluoro-benzonitrile dihydrochloride (as described in Example 34, Step A) (0.3 g, 0.97 mmol) in DMF (5.0 mL) was added NEt3 (0.41 mL, 2.97 mmol) and t-butyl-isocyanate (0.125 mL, 1.07 mmol). After ½ hr the DMF was removed in vacuo and the residue partitioned between EtOAc and saturated NaHCO3. The organic layer was separated, washed with brine and dried (MgSO4). Filtration and concentration in vacuo gave the title compound as an oil.
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].[Li].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.[Cl-].[NH4+]>O1CCCC1.C1CCCCC1>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]([OH:14])[CH2:2][C:1]([O:4][CH2:5][CH3:6])=[O:3])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCOC(=O)CC(O)c1ccc(Br)cc1
Reaction time: 0.25 h
Yield: 80 %

Procedure:
Ethyl acetate (5.8 ml) was dissolved in tetrahydrofuran (80 ml), to which was then added 1.5M lithium diisoprypylamide/cyclohexane solution (43 ml) in nitrogen atmosphere at −70° C., and then the mixture was stirred for 15 min. 4-Bromobenzaldehyde (10.151 g)/tetrahydrofuran (10 ml) solution was added to the reaction mixture, which was then stirred for 30 min. A saturated aqueous solution of ammonium chloride was added thereto, and then it was extracted with in ethyl acetate. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by (NH) silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a yellow oil (11.906 g, yield; 80%).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:5]([C:7]1[CH:15]=[CH:14][C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=1)=[O:6].[C:22]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)#[N:23].C(N(CC)CC)C.O>ClCCl>[O:11]1[C:10]2[CH:14]=[CH:15][C:7]([C:5](=[O:6])[CH:4]([NH:3][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:24]([C:22]#[N:23])=[CH:25][CH:26]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:8][C:9]=2[O:13][CH2:12]1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: NC(C(=O)c1ccc2c(c1)OCO2)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1ccc(C(=O)NC(C(=O)c2ccc3c(c2)OCO3)c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.8 %

Procedure:
2-Amino-1-benzo[1,3]dioxol-5-yl-2-pyridin-2-yl-ethanone dihydrochloride (1 g, 3 mmol) was added to a stirring solution of 4-cyano-benzoyl chloride (0.459 g, 3 mmol) in dichloromethane (10 ml). Triethylamine (2 ml, 14 mmol) was added dropwise and the reaction was stirred at ambient temperature for 18 hours. Water was (50 ml) added the organics were extracted into dichloromethane. Chromatographic purification using a dichloromethane solution of ammonia in methanol (0.5% c. ammonia: 4.5% methanol: 95% dichloromethane) yielded the title compound as a pale yellow oil (0.9 g, 76%); m/z (API) 386 (M+H+, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([O:12][C:13](=[O:15])[CH3:14])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:16][C:17](=[O:19])[CH3:18])[CH:3]=1.[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.BrN1C(=O)CCC1=O>[Br:20][CH2:1][C:2]1[CH:3]=[C:4]([O:16][C:17](=[O:19])[CH3:18])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:10]([O:12][C:13](=[O:15])[CH3:14])[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(OC(C)=O)cc(C)cc1OC(C)=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(OC(C)=O)cc(CBr)cc1OC(C)=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 61.6 %

Procedure:
Methyl 4-methyl-2,6-diacetoxybenzoate (14.9 grams, 56.0 mmoles) was dissolved in carbon tetrachloride (200 mL), and N-bromosuccinimide (11.1 grams, 62.2 mmoles) and benzoyl peroxide (0.2 grams, 0.8 mmoles) were added. The mixture was refluxed under nitrogen. After 3.5 hours, an additional portion (0.2 grams) of N-bromosuccinimide was added. Reflux was continued for an additional hour. The reaction mixture was cooled to room temperature and then in ice for 1 hour, and the solid removed by filtration. The filtrate was evaporated to dryness. Hexanes (250 mL) was added to the residue, and the mixture was boiled until dissolution was obtained. The hexanes solution was concentrated to about 75 mL when a solid just began to precipitate. The mixture was heated to dissolve the solid, and the solution was allowed to cool slowly to room temperature. White crystals formed slowly, and the mixture was chilled in ice for 2 hours to complete crystallization. The solid was filtered, washed with cold hexanes (100 mL), and dried in vacuo to afford 11.9 grams (62% yield) of methyl 4-bromomethyl-2,6-diacetoxy-benzoate (m.p. 93°-95° C., open capillary, uncorrected). The product was contaminated with a small amount of methyl 2,6-diacetoxy-4-dibromomethylbenzoate, which did not interfere with subsequent reactions.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH:14]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[OH:15])[C:11](O)=[O:12])=[CH:4][C:3]=2[O:2]1.Cl.[NH2:23][C@H:24]([C:35]([O:37][CH3:38])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.O>[CH3:38][O:37][C:35](=[O:36])[C@H:24]([CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)[NH:23][C:11](=[O:12])[CH:10]([C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)[CH:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[OH:15]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=C(O)C(c1ccc2c(c1)OCO2)C(O)C1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C(c1ccc2c(c1)OCO2)C(O)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
To a solution of (2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionic acid (100 mg), HCl.H-L-Trp-OMe (136 mg) and HOBT (55 mg) in dimethylformamide (6 ml) was added WSCD (64 mg) under ice-bath cooling. After being stirred overnight at room temperature, the mixture was poured into water (20 ml) and extracted with ethyl acetate (20 ml). The organic layer was washed with 5% hydrochloric acid solution, 1M aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo to afford N-[(2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-tryptophane methyl ester (165 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH2:16][OH:17])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[Si:19](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CN=C1.CN(C)C=[O:45]>>[CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH2:16][OH:17])[N:5]([O:45][Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Product: COC(=O)[C@H](CO)N(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 99 %

Procedure:
Subsequently, to a solution of N-carbobenzyloxy-L-serine methyl ester (4.40 g, 16.7 mmol) in dimethylformamide (210 ml) were added t-butyldiphenylsilyl chloride (5.20 ml, 20.0 mmol) and imidazole (1.36 g, 20.0 mmol) in an ice bath, and the mixture was stirred at room temperature for 3 days. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (8:1→6:1) as the eluant to afford t-butyldiphenylsilyloxy-N-carbobenzyloxy-L-serine methyl ester (18.8 g, 99%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1.[CH2:18]1[CH2:22]OC[CH2:19]1>>[Cl:11][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:12][C:13]2[NH:14][N:15]=[C:16]([CH:19]3[CH2:18][CH2:22]3)[CH:17]=2)[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: C1CCOC1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Reactant: Nc1cc[nH]n1
Product: O=[N+]([O-])c1c(Cl)ncnc1Nc1cc(C2CC2)n[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4,6-dichloro-5-nitro-pyrimidine (100 mg, 0.52 mmol) in anhydrous THF (2 mL) was added aminopyrazole (76 mg, 0.62 mmol). The solution was stirred at RT for 2 hrs and was filtered via short silica gel column. The filtrate that contained product and the unreacted starting pyrrimidine was concentrated under vacuum. The resulting residue was used directly without further purification.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:24]1([Li])[CH:29]=CC=C[CH:25]=1.[C:31]([C:33]1[CH:38]=[CH:37][C:36]([C@H:39]2[CH2:44][CH2:43][C@H:42](CC=O)[CH2:41][CH2:40]2)=[CH:35][CH:34]=1)#[N:32]>O1CCCC1.C1(C)C=CC=CC=1>[CH3:2][O:3][CH:40]1[CH:39]([C:36]2[CH:35]=[CH:34][C:33]([C:31]#[N:32])=[CH:38][CH:37]=2)[CH2:44][CH2:43][CH2:42][CH:41]1[CH:25]=[CH:24][CH3:29]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]c1ccccc1
Reactant: N#Cc1ccc([C@H]2CC[C@H](CC=O)CC2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC=CC1CCCC(c2ccc(C#N)cc2)C1OC
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
Commercially available methoxymethyltriphenylphosphonium chloride (15.7 g, 0.0458 mol) was added to tetrahydrofuran (100 ml), followed by dropwise adding a 25% by weight toluene solution (23 ml) of phenyllithium in argon atmosphere with stirring at -10° C. over 10 minutes, agitating the reaction mixture at 0° C. for 30 minutes, dropwise adding a tetrahydrofuran solution (90 ml) of trans-4-(4-cyanophenyl)cyclohexylacetaldehyde (7.3 g, 0.032 mol) obtained in Example 2 (i) at -10° C. over 10 minutes, agitating the reaction mixture at 0° C. for 2 hours, washing by adding toluene (100 ml) and water (200 ml), further three times washing the toluene solution with water (200 ml), drying over anhydrous sodium sulfate, separating the drying agent, distilling off toluene, dissolving the residue in ethyl acetate (20 ml) on heating, allowing the solution to stand at room temperature for one day, filtering off deposited crystals, concentrating the mother liquor, dissolving the concentrate in heptane, purifying by silica gel column chromatography to obtain trans-1-(3-methoxy-2-propenyl-4-(4-cyanophenyl)cyclohexane (4.4 g, 0.017 mol), adding to the total quantity, tetrahydrofuran (70 ml) and 2N-hydrochloric acid (18 ml), heating the mixture for 1h. under reflux with stirring, cooling the reaction mixture, adding diethyl ether (50 ml) and water (50 ml), three times washing the resulting diethyl ether solution with water (50 ml), drying it over anhydrous sodium sulfate, separating the drying agent, and distilling off diethyl ether to obtain 3-[trans-4-(4-cyanophenyl)cyclohexyl]-1-propanal (4.2 g, 0.017 mol).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[CH2:11]([S:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)[CH3:12]>>[CH2:11]([S:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=2)[CH:17]=[CH:16][CH:15]=1)[CH3:12]
Reactant: CCSc1cccc(B(O)O)c1
Reactant: Nc1c(F)cc(Br)cc1F
Product: CCSc1cccc(-c2cc(F)c(N)c(F)c2)c1
Yield: 70.7 %

Procedure:
The title compound (900 mg) was prepared from 4-bromo-2,6-difluoroaniline (1 g, 4.8 mmol) and 3-(ethylthio)phenylboronic acid (1.13 g, 6.24 mmol) as a colourless liquid.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH3:4].C(NC(C)C)(C)C.Br[C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=1>C(#N)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:19][C:17]1[CH:16]=[N:15][CH:14]=[C:13]([C:1]#[C:2][CH2:3][CH3:4])[CH:18]=1
Reactant: C#CCC
Reactant: Brc1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: CCC#Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
But-1-yne (g) was during 5 min gently bubbled through anhydrous acetonitrile cooled in an ice-water bath. The resulting solution contained about 170 mg but-1-yne per mL. The solution of but-1-yne (4.57 mL, 14.36 mmol) and diisopropylamine (3.72 mL, 26.11 mmol) were added sequentially to a mixture of 3,5-dibromopyridine (3.09 g, 13.06 mmol), bis(triphenylphosphine)-palladium(II) chloride (0.458 g, 0.65 mmol) and CuT (0.249 g, 1.31 mmol) in acetonitrile (15 mL) under an argon atmosphere. The resulting mixture was stirred at r.t. overnight, diluted with EtOAc and passed through a short plug of silica. The solvents were evaporated and the residue was purified by flash chromatography on silica (gradient elution 0-20% EtOAc in heptane) to give 2.40 g of the title compound (87% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17 (t, 4H), 2.47 (q, 3H), 8.11 (t, 1H), 8.57 (d, 1H), 8.65 (d, 1H); MS (ES+) m/z 210 [M+H]+.
Reaction SMILES: O1C2(CCC(C3C4C(=CC=CC=4)NC=3)CC2)OCC1.[O:20]1[C:24]2([CH2:29][CH2:28][C:27]([C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[C:36]([C:39]#[N:40])[CH:37]=4)[NH:32][CH:31]=3)=[CH:26][CH2:25]2)[O:23][CH2:22][CH2:21]1>>[O:23]1[C:24]2([CH2:29][CH2:28][CH:27]([C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[C:36]([C:39]#[N:40])[CH:37]=4)[NH:32][CH:31]=3)[CH2:26][CH2:25]2)[O:20][CH2:21][CH2:22]1
Reactant: N#Cc1ccc2[nH]cc(C3=CCC4(CC3)OCCO4)c2c1
Agent: c1ccc2c(C3CCC4(CC3)OCCO4)c[nH]c2c1
Product: N#Cc1ccc2[nH]cc(C3CCC4(CC3)OCCO4)c2c1
Yield: 94.8 %

Procedure:
This compound was prepared in the manner described above for intermediate 2a by replacing 3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-1H-indole with 3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-5-cyano-1H-indole (54.6 g) ) to afford 52.12 g (95%) of the title compound as a white solid in 95% (52.12 g) yield as a white solid: mp 153-155° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([OH:9])[C:6]([Br:10])=[CH:5][C:3]=1[OH:4].[N+]([O-])([O-])=O.[NH4+].[Ce]>C(#N)C.O>[Br:1][C:2]1[C:3](=[O:4])[CH:5]=[C:6]([Br:10])[C:7](=[O:9])[CH:8]=1
Reactant: Oc1cc(Br)c(O)cc1Br
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: O=C1C=C(Br)C(=O)C=C1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 0.1 %

Procedure:
To a solution of 2,5-dibromohydroquinone (1) (5 g, 18.6 mol) in acetonitrile (250 ml) was added cerium ammonium nitrate (21.4 g, 39.0 mmol), in small portions. The clear orange solution was stirred for 10 min at room temperature, diluted with water (80 ml) and extracted with chloroform (3×200 ml). The combined chloroform layers were dried over sodium sulphate and evaporated, yielding 3.5 g (71%) of the quinone (2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[C:5]([CH3:12])[C:4]=1[CH3:13].[CH3:14]I.[CH2:16]([NH2:19])[CH2:17][NH2:18]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:16])[C:10]#[N:11])=[C:5]([CH3:12])[C:4]=1[CH3:13].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:14]2[NH:18][CH2:17][CH2:16][N:19]=2)[CH3:10])=[C:5]([CH3:12])[C:4]=1[CH3:13]
Reactant: COc1ccc(CC#N)c(C)c1C
Reactant: CI
Reactant: NCCN
Product: COc1ccc(C(C)C#N)c(C)c1C
Product: COc1ccc(C(C)C2=NCCN2)c(C)c1C

Procedure:
rac-2-(4-Methoxy-2,3-dimethyl-phenyl)-propionitrile which was prepared from 2-(4-methoxy-2,3-dimethyl-phenyl)-acetonitrile and methyl iodide in analogy to Example 65a) was reacted with ethylenediamine to form rac-2-[1-(4-methoxy-2,3-dimethyl-phenyl)-ethyl]-4,5-dihydro-1H-imidazole in analogy to Example 19b; isolated as hydrochloride: white powder; MS (EI): 233.3 ((M+.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]([OH:16])=O.[NH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2>>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]([NH:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2)=[O:16]
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1Br
Reactant: Nc1ccc2[nH]ccc2c1
Product: O=C(/C=C/c1ccc(C(F)(F)F)cc1Br)Nc1ccc2[nH]ccc2c1

Procedure:
Analogous to the procedure used to prepare Example 1, (2E)-3-[2-bromo-4-(trifluoromethyl)phenyl]prop-2-enoic acid, Example 97(e), (140 mg, 0.48 mmol) and 5-aminoindole (75 mg, 0.57 mmol, Aldrich) provided, after purification by silica gel chromatography (gradient: 0-25% EtOAc in hexane), the title compound as a yellow solid. MP 205-207° C. MS (ESI, pos. ion) m/z: 409 (M+1).
Reaction SMILES: C([O:3][CH:4]1[CH:8]([NH:9][C:10]([CH2:12][N:13]2[CH2:19][CH:18]=[CH:17][CH2:16][CH:15]([NH:20][C:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][N:24]=3)=[O:22])[C:14]2=[O:33])=[O:11])[CH2:7][C:6](=[O:34])[O:5]1)C.FC(F)(F)C(O)=O>CC#N.O>[OH:3][CH:4]1[CH:8]([NH:9][C:10]([CH2:12][N:13]2[CH2:19][CH:18]=[CH:17][CH2:16][CH:15]([NH:20][C:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][N:24]=3)=[O:22])[C:14]2=[O:33])=[O:11])[CH2:7][C:6](=[O:34])[O:5]1
Reactant: CCOC1OC(=O)CC1NC(=O)CN1CC=CCC(NC(=O)c2nccc3ccccc23)C1=O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(CN1CC=CCC(NC(=O)c2nccc3ccccc23)C1=O)NC1CC(=O)OC1O
Reaction time: 0.5 h

Procedure:
To a solution of isoquinoline-1-carboxylic acid {1-[(2-ethoxy-5-oxo-tetra-hydrofuran-3-ylcarbamoyl)methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl} amide, 6, from above in CH3CN/H2O is added trifluoroacetic acid. After stirring for 30 minutes the solution is concentrated in vacuo and the crude product purified by preparative reverse phase HPLC to afford the desired product.