Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:68])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:24]([O:62][CH3:63])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:60][CH3:61])[C@@H:34]([CH3:59])[C:35]([NH:37][C@@H:38]([CH2:49][C:50]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[NH:52][CH:51]=1)[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].[O:69]=[C:70]1[CH:74]=[CH:73][C:72](=[O:75])[N:71]1[CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][C:81]([NH:83][NH2:84])=[O:82].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:75]=[C:72]1[CH:73]=[CH:74][C:70](=[O:69])[N:71]1[CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][C:81]([NH:83][NH:84][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:68])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:24]([O:62][CH3:63])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:60][CH3:61])[C@@H:34]([CH3:59])[C:35]([NH:37][C@@H:38]([CH2:49][C:50]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[NH:52][CH:51]=1)[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:82]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9 mg (9.5 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(benzyloxy)-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 72) were dissolved in 1000 μl of DMF and then admixed with 10 mg (38 μmol) of commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide, 7.2 mg (19 μmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and 8 μl of N,N-diisopropylethylamine, and the reaction mixture was stirred at RT for 1 h. Subsequently, the solvent was removed under reduced pressure and the remaining residue was purified by means of preparative HPLC. The corresponding fractions were concentrated and, by lyophilization, 6.4 mg (58% of theory) of the title compound were obtained as a colourless foam.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[CH3:19][N:20]1[CH:24]=[CH:23][C:22]([C:25](O)=[O:26])=[N:21]1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:25]([C:22]3[CH:23]=[CH:24][N:20]([CH3:19])[N:21]=3)=[O:26])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: Cn1ccc(C(=O)O)n1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: Cn1ccc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OCC3(F)F)c2)n1

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 1-methyl-1H-pyrazole-3-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=368.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[O:14][C:15]([CH3:27])([CH3:26])[CH2:16][CH:17]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:11]3=[CH:10][C:9]=2[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[C:4]([Cl:35])[CH:3]=1.CN(C=O)C.CC1(C)C(C)(C)OB([C:49]2[CH:50]=[N:51][N:52](C(OC(C)(C)C)=O)[CH:53]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCO.O>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([C:9]2[CH:10]=[C:11]3[C@H:17]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:16][C:15]([CH3:26])([CH3:27])[O:14][C:12]3=[N:13][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([C:49]3[CH:50]=[N:51][NH:52][CH:53]=3)=[CH:3][C:4]=2[Cl:35])=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)OC(=O)NC1CC(C)(C)Oc2nc(-c3ccc(Br)cc3Cl)c(-c3ccc(Cl)cc3)cc21
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CC(C)(C)Oc2nc(-c3ccc(-c4cn[nH]c4)cc3Cl)c(-c3ccc(Cl)cc3)cc21
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To a solution of Example 314 (1.5 g, 2.59 mmol) in a mixed solvent of 9.0 mL of DMF, 1.0 mL of H2O, and 2.0 mL of EtOH was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.53 g, 5.19 mmol), Na2CO3 (830 mg, 7.78 mmol), and tetrakis(triphenylphosphino)palladium(0) (150 mg, 0.13 mmol). The mixture was stirred at 120° C. under microwave irradiation for 30 min. After cooling, the mixture was diluted with EtOAc (200 mL) and washed with H2O (50 mL) and brine (50 mL). The organic layer was separated, dried over MgSO4, and concentrated. Chromatography on a Biotage 40+M cartridge using 1:1 v/v EtOAc/hexanes as the eluant afforded the product: 1H NMR δ 1.49 (s, 3H), 1.52 (s, 9H), 1.58 (s, 3H), 1.84 (t, J=12.7, 1H), 2.33 (dd, J=6.2, 13.2, 1H), 4.78 (m, 1H), 5.15 (m, 1H), 7.09 (d, J=8.4, 2H), 7.20 (d, J=8.5, 2H), 7.26-7.41 (m, 3H), 7.74 (s, 1H), 7.85 (s, 2H).
Reaction SMILES: C12N(C3C=NC4C(=CC=CC=4)N=3)CC1CCNC2.[CH:19]12[CH2:25][NH:24][CH:23]1[CH2:22][N:21]([C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[N:38]=[CH:37][CH:36]=[N:35]1)=[O:27])[CH2:20]2.Cl[C:40]1[N:45]=[C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:43]=[CH:42][N:41]=1>>[C:46]1([C:44]2[CH:43]=[CH:42][N:41]=[C:40]([N:24]3[CH2:25][CH:19]4[CH:23]3[CH2:22][N:21]([C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N:34]3[N:38]=[CH:37][CH:36]=[N:35]3)=[O:27])[CH2:20]4)[N:45]=2)[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: Clc1nccc(-c2ccccc2)n1
Reactant: O=C(c1ccccc1-n1nccn1)N1CC2CNC2C1
Agent: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Product: O=C(c1ccccc1-n1nccn1)N1CC2CN(c3nccc(-c4ccccc4)n3)C2C1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using Intermediate 25 and 2-chloro-4-phenyl-pyrimidine. MS (ESI) mass calcd. for C24H21N7O, 423.48; m/z found, 424.2 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:6]([NH2:7])[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.C(N(CC)CC)C.[C:22](Cl)(Cl)=[O:23]>ClCCl>[O:23]=[C:22]1[NH:1][CH:2]2[CH2:3][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH:6]2[NH:7]1
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@@H](N)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2NC(=O)NC2C1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl cis-3,4-diaminopyrrolidine-1-carboxylate (the product in Intermediate 11, Step C; 140 mg) and triethylamine (0.29 mL) in dichloromethane (10 mL) was added phosgene (20% in benzene, 0.4 mL) at 0° C. and the reaction mixture allowed to warm up to room temperature. The solution was evaporated after stirring for one h and purified on a Biotage Horizon® system (silica gel, 10-20% gradient of methanol containing 10% ammonium hydroxide in dichloromethane). The tert-butyl 2-oxohexahydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate obtained was dissolved in trifluoroacetic acid/dichloromethane (2 mL, 1:1) and eluted through Strata-X-C™ ion exchange resin. The desired product was eluted with a solution of concentrated ammonium hydroxide in methanol (5%) and evaporated under reduced pressure.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[N+:14]([O-])=O)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9](=[O:22])[C:8]2([CH3:24])[CH3:23])([CH3:3])[CH3:2]>CN(C)C=O.[Pd]>[NH2:14][C:13]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:24])([CH3:23])[C:9](=[O:22])[N:10]2[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:6][C:5]=1[NH:4][CH:1]([CH3:2])[CH3:3]
Reactant: CCCCCN1C(=O)C(C)(C)c2cc(NC(C)C)c([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CN(C)C=O
Product: CCCCCN1C(=O)C(C)(C)c2cc(NC(C)C)c(N)cc21
Yield: 98.9 %

Procedure:
5-Isopropylamino-3,3-dimethyl-6-nitro-1-pentyl-1,3-dihydro-indol-2-one (200 mg) is dissolved in N,N-dimethylformamide (10 ml) and hydrogenated at RT at 3 bar for 12 h using Pd/C (10%; 0.1 g) as catalyst. After completion of the reaction the mixture is filtered and evaporated to give the compound (180 mg).
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[CH:5][C:4]([O:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH2:13])=O)=[CH:3]1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[O:1]=[C:2]1[NH:7][N:6]=[CH:5][C:4]([O:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]#[N:13])=[CH:3]1
Reactant: NC(=O)c1ccccc1Oc1cn[nH]c(=O)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccccc1Oc1cn[nH]c(=O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.1 %

Procedure:
A solution of 2-(6-oxo-1,6-dihydro-pyridazin-4-yloxy)-benzamide (31.1 g, 0.14 mol) in methylene chloride and triethylamine (65.5 g, 0.65 mol) was treated dropwise with trifluoroacetic anhydride (62.2 g, 0.30 mol). The resulting solution was stirred at 25° C. for 5 min. After this time, the reaction was washed with a 2N aqueous hydrochloric acid solution and a saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered, rinsed and concentrated in vacuo to afford 2-(6-oxo-1,6-dihydro-pyridazin-4-yloxy)-benzonitrile (25.1 g, 87%) as a white solid; ESI-MS 214 [M+H+]; HPLC: >95% (purity). 1H-NMR (300 MHz, CDCl3) δ 11.75 (s, 1H), 7.91 (s, 1H), 7.71-7.81 (m, 2H), 7.44-7.49 (m, 1H), 7.28-7.30 (m, 1H), 5.98 (s, 1H).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH3:13])=[CH:8][CH:7]=1.F>>[CH3:5][C:6]1[CH:7]=[C:8]([C:2](=[S:1])[NH2:3])[C:9]([S:12][CH3:13])=[CH:10][CH:11]=1
Reactant: N#C[S-]
Reactant: CSc1ccc(C)cc1
Agent: F
Agent: [K+]
Product: CSc1ccc(C)cc1C(N)=S
Temperature: 25 °C
Reaction time: 10 h

Procedure:
At a temperature and in the manner as indicated in Example 1, 39 g of potassium thiocyanate (0.4 mol) and 46 g of 4-methyl-thioanisol (0.33 mol) are stirred with 0.3 l of 98% hydrofluoric acid. The mixture is then stirred first for 10 hours at room temperature and then for 3 hours in a steel autoclave at 40° - 50° C, subsequently cooled, the reaction mixture is poured onto ice, the 4-methyl-thioanisol-2-thiocarboxylic acid amide precipitated is suction-filtered and dried. The yield (54 g) is 81% of the theoretical yield, relative to the 4-methyl-thioanisol used. After recrystallization of the product from chlorobenzene, the melting point is 160° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][CH:30]=[CH:29]3)=[CH:22][C:21]=1[CH:35]=O.[CH3:37][N:38]1[CH2:43][CH2:42][CH:41]([NH2:44])[CH2:40][CH2:39]1>ClCCCl.ClCCl>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][CH:30]=[CH:29]3)=[CH:22][C:21]=1[CH2:35][NH:44][CH:41]1[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]1
Reactant: O=Cc1cc(-c2ccc3[nH]ccc3c2)ccc1F
Reactant: CN1CCC(N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: CN1CCC(NCc2cc(-c3ccc4[nH]ccc4c3)ccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 117.6 %

Procedure:
Sodium triacetoxyborohydride (400 mg, 1.88 mmol) and then enough acetic acid to bring the pH to 5 were added to a solution of 5-(4-fluoro-3-formylphenyl)-1H-indole (150 mg, 0.63 mmol) and 1-methyl-piperidin-4-ylamine (144 mg, 1.23 mmol) in 15 mL of 1,2-dichloroethane. The mixture was stirred at ambient temperature overnight, and then it was diluted with dichloromethane and washed with water. The aqueous phase extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated to leave the crude product, which was eluted through an SCX cation exchange column (elution with methanol, followed by 2M ammonia in methanol) to give 250 mg of product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][N:12]=2)[CH2:7][CH2:6]1>O1CCCC1.CO.[Pd]>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][N:12]=2)[CH2:9][CH2:10]1
Reactant: COC(=O)CC1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CC1CCN(c2ccc(N)cn2)CC1
Reaction time: 1 h

Procedure:
To a solution of (5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid methyl ester (279 mg, 1 mmol) from above in a mixture of tetrahydrofuran (10 mL) and methanol (50 mL) was added 10% palladium on carbon (50 mg). The mixture was hydrogenated at 50 psi for 1 hr. The mixture was filtered and the solvents were evaporated to give (5′-amino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid methyl ester that was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][C:16]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:15]4)=[N:9][N:10]=2)[CH:7]=1.N#N.C([Sn](CCCC)(CCCC)[C:35]([O:37][CH2:38][CH3:39])=[CH2:36])CCC>O1CCOCC1.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>[CH2:38]([O:37][C:35]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][C:16]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:15]4)=[N:9][N:10]=2)[CH:7]=1)=[CH2:36])[CH3:39]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1ccc2nnc(Sc3ccc4ncc(N5CCOCC5)cc4c3)n2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Solvent: C1COCCO1
Product: C=C(OCC)c1ccc2nnc(Sc3ccc4ncc(N5CCOCC5)cc4c3)n2c1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
The solution of (77.1) (110 mg, 0.249 mmol) and PdCl2(PPh3)2 (17.45 mg, 0.025 mmol) in 1,4-dioxane (4 ml) was bubbled by N2 for 5 min. Tributyl(1-ethoxyvinyl)stannane (135 mg, 0.373 mmol) was added. The reaction tube was flushed by N2 for 5 min again and sealed. The sealed-tube was stirred at 120° C. for 2 h. The reaction was evaporated to dryness and the residue was directly used in the next step. LCMS (method A): [M+H]+=433.6, tR=2.54 min.
Reaction SMILES: [C:1]([O:7][CH:8]([C:13]([Cl:16])([Cl:15])[Cl:14])[CH:9]=[C:10]([CH3:12])[CH3:11])(=[O:6])[CH2:2]C(C)=O.C(N(CC)CC)C.S([N:34]=[N+:35]=[N-])(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+]>C(#N)C>[N+:34](=[CH:2][C:1]([O:7][CH:8]([C:13]([Cl:16])([Cl:15])[Cl:14])[CH:9]=[C:10]([CH3:12])[CH3:11])=[O:6])=[N-:35]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(=O)CC(=O)OC(C=C(C)C)C(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)=CC(OC(=O)C=[N+]=[N-])C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 3-methyl-1-trichloromethyl-2-butenyl acetoacetate (5.75 g, 0.02 mole) and triethylamine (2.02 g, 0.02 mole) in 50 ml of acetonitrile was added a solution of tosyl azide (3.94 g, 0.02 mole, prepared according to the method of Organic Synthesis Collective Volume V, page 179A) in acetonitrile dropwise over a period of 10 minutes. The resultant mixture, containing the thus produced 3-methyl-1-trichloromethyl-2-butenyl-2-diazoacetoacetate, was stirred at room temperature for two hours and then poured into 60 ml (0.06 mole) of 1N aqueous sodium hydroxide. The resulting mixture was stirred at room temperature for 30 minutes and then extracted with about 100 ml of ether. After phase separation, the aqueous layer was extracted with an additional 150 ml portion of ether, and the ether extracts were combined. The ethereal solution was then washed ten times with 50 ml portions of 3% aqueous potassium hydroxide containing sodium chloride and then three times with 50 ml portions of saturated aqueous sodium chloride. The washed ethereal solution was dried over magnesium sulfate, and the ether was removed by evaporation, affording a brown oily residue. The residue was purified by column chromatography on silica gel using benzene as the eluent, to give 3-methyl-1-trichloromethyl-2-butenyl diazoacetate (4.63 g, 85% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][Si@H:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[CH:2].I[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[CH2:15]([Si@H:12]1[CH2:11][CH2:10][C@H:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:24]3[CH:25]=[CH:26][C:21]([CH2:20][CH3:19])=[CH:22][CH:23]=3)=[CH:4][CH:5]=2)[CH2:14][CH2:13]1)[CH2:16][CH3:17]
Reactant: C#Cc1ccc([C@H]2CC[Si@H](CCC)CC2)cc1
Reactant: ICCc1ccccc1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCC[Si@H]1CC[C@H](c2ccc(C#Cc3ccc(CC)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
100 mg of tetrakis (triphenylphosphine) palladium (0) and 50 mg of copper (I) iodide were added to a mixture of 1.21 g (5.00 mmol) of trans-4-(p-ethynylphenyl)-1-n-propyl-1-silacyclohexane, 1.50 g (6.46 mmol) of p-iodoethylbenzene and 30 ml of triethylamine. The reaction mixture was stirred for 20 hours at room temperature. After a conventional after treatment, purification was conducted by means of silica-gel column chromatography to obtain 1.30 g (yield 75%) of the target product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1.[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][C@H:28]([C:32](Cl)=[O:33])[CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OCC)(=O)C>ClCCl.CN(C)C1C=CN=CC=1.CCCCCC>[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][C@H:28]([C:32](=[O:33])[NH:15][C:11]2[CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:14]=[CH:13][N:12]=2)[CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Reactant: COc1ccccc1-c1cc(N)ncn1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1ccccc1-c1cc(NC(=O)[C@H]2CCCN(C(=O)OCc3ccccc3)C2)ncn1
Reaction time: 2 h
Yield: 53.8 %

Procedure:
To a solution of 6-(2-methoxy-phenyl)-pyrimidin-4-ylamine (XXIV) (7.80 g, 39.1 mmol) in 90 ml of dichloromethane was added 4-dimethylaminopyridine (5.70 g, 47.0 mmol) followed by dropwise addition of N—(S)-3-chlorocarbonyl-piperidine-1-carboxylic acid benzyl ester (XXXIII) (11.0 g, 39.1 mmol) at room temperature. The reaction mixture was stirred for 2 hours and washed with water. The organic layer was separated, dried over sodium sulfate and concentrated. The obtained crude residue was passed through a pad of silica gel eluting with 25% ethyl acetate in hexane to provide (S)-3-[6-(2-methoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (XXXIV) (9.4 g, 54%).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:9]=2)[O:6][C:5](=[O:7])[NH:4][CH2:3]1.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:9]=2)[O:6][C:5](=[O:7])[N:4]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:3]1
Reactant: COc1ccc(C2(C)CNC(=O)O2)cc1OCC1CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C2(C)CN(Cc3ccccc3)C(=O)O2)cc1OCC1CC1
Reaction time: 2 h
Yield: 52.6 %

Procedure:
500 mg (1.8 mmol) of 5-methyl-5-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxazolidinone was first agitated with 75 mg (3.1 mmol) of sodium hydride in 17 ml of dimethylformamide for 30 minutes and, after adding 0.32 ml (2.7 mmol) of benzyl bromide, for 2 hours at room temperature. The procedure was continued analogously to Example 10, thus obtaining 348 mg of 5-methyl-5(3-cyclopropylmethoxy-4-methoxyphenyl)-3-benzyl-2-oxazolidinone as an oil.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:24][CH:25]=[CH2:26])[CH3:23])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=O)(C)(C)C.O.[OH-].[Na+]>C(O)C>[CH2:24]([N:22]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][CH:9]=[CH:10]2)[CH3:23])[CH:25]=[CH2:26]
Reactant: C=CCN(C)CCCCCc1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCN(C)CCCCCc1ccc2[nH]ccc2c1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 100.3 %

Procedure:
To 1.3 g (3.5 mmol) 5-[5-(Allyl-methyl-amino)-pentyl]-indole-1-carboxylic acid tert-butyl ester in 20 ml ethanol were added 1.5 ml water and 3 ml conc. NaOH, and stirred at 60° C. for 1.5 h. The slurry was concentrated and dissolved in ether/water. The organic layer was washed with water and dried over Na2SO4 and evaporated to yield 900 mg (quantitative) Allyl-[5-(1H-indol-5-yl)-pentyl]-methyl-amine as light yellow oil, MS: 257 (MH+).
Reaction SMILES: [OH:1][CH:2]([CH3:9])[C:3]([O:5][CH2:6][CH:7]=[CH2:8])=[O:4].[CH:10](O)=[O:11].CNC1(NC)C=CN=CC1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCCl>[CH:10]([O:1][CH:2]([CH3:9])[C:3]([O:5][CH2:6][CH:7]=[CH2:8])=[O:4])=[O:11]
Reactant: C=CCOC(=O)C(C)O
Reactant: O=CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CNC1(NC)C=CN=CC1
Solvent: ClCCCl
Product: C=CCOC(=O)C(C)OC=O
Reaction time: 0.5 h
Yield: 54 %

Procedure:
5.00 g (41 mmol) of 2-propenyl 2-hydroxypropionate, 2.48 g (54 mmol) of formic acid, and 1.00 g (8 mmol) of 4,4-dimethylaminopyridine (nucleating agent) were dissolved in 30 g of 1,2-dichloroethane (solvent), and a mixed solution of 12.00 g (171 mmol) of N,N′-dicyclohexylcarbodiimide (dehydrating agent) and 20 g of 1,2-dichloroethane (solvent) was added thereto at 10° C., taking 30 minutes. These were reacted at room temperature for 3 hours, the reaction liquid was filtered to remove N,N′-dicyclohexylurea, and the filtrate was concentrated. The concentrate was purified through silica gel column chromatography, and from the fraction taken with hexane/ethyl acetate=8/1, 3.5 g (yield 54%) of 2-propenyl 2-(formyloxy)propionate was obtained.