Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:15][CH2:16][CH2:17][CH2:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:19]([CH2:18][CH2:17][CH2:16][Cl:15])(=[O:21])=[O:20])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(CCCCl)Nc1ccc(Br)cc1
Reaction time: 4 h
Yield: 76.8 %

Procedure:
4-Bromoaniline (0.86 g, 5.0 mmol) was dissolved in CH2Cl2 (15 mL), pyridine (0.5 mL) was added, and 3-chloropropanesulfonyl chloride (0.6 mL, 5.0 mmol) was added. The mixture was stirred for 4 hours, diluted with ethyl acetate, and then washed with water, 2N HCl, brine, dried over MgSO4, and concentrated. The crude product was purified via Isco chromatography (the Redisep® column, silica, gradient 5-60% ethyl acetate in hexane) to afford 1.2 g (77%) N-(4-bromophenyl)-3-chloropropane-1-sulfonamide.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]=C(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1)#[N:2].[CH:24]([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.CI>CCCCCC.CCOCC.O.O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:7]([NH2:8])[CH3:24])=[CH:22][CH:23]=1)#[N:2]
Reactant: CC(C)[N-]C(C)C
Reactant: N#Cc1ccc(CN=C(c2ccccc2)c2ccccc2)cc1
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: CC(N)c1ccc(C#N)cc1
Reaction time: 0.25 h

Procedure:
20.7 g (0.07 mol) of benzophenone N-(p-cyanobenzyl)imine were added dropwise to a solution of lithium diisopropylamide, prepared from 8.15 g (0.08 mol) of diisopropylamine and 48.3 ml (0.08 mol) of a 15% strength solution of butyllithium in hexane, in 100 ml of abs. tetrahydrofuran at -70° C., and the mixture was left to stir for 15 minutes. Then 9.94 g (0.07 mol) of methyl iodide were added dropwise, and the temperature of the reaction mixture was allowed to rise to room temperature. After addition of 100 ml of water and several extractions with ether, the ether phase was washed with 5% strength citric acid solution, 5% strength NaHCO3 solution and water and was dried over Na2SO4, and the ether was distilled off. The residue was dissolved in 150 ml of tetrahydrofuran, 100 ml of 1 N HCl were added, and the mixture was stirred at room temperature overnight. The tetrahydrofuran was distilled out of the reaction mixture under reduced pressure, the remaining acid phase was extracted several times with ether to remove the benzophenone, and then the acid phase was made alkaline with aqueous K2CO3 solution while cooling in ice, and the oily base was extracted with methylene chloride. The extract was dried over K2CO3. 9.7 g (95%) of a yellowish oil remained after stripping-off the methylene chloride and were used without further purification in the next reaction.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O)=O.[CH3:13][NH:14][NH2:15]>CCO>[CH3:13][N:14]1[C:10](=[O:12])[CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:1]=[N:15]1
Reactant: O=Cc1ccccc1CC(=O)O
Reactant: CNN
Solvent: CCO
Product: CN1N=Cc2ccccc2CC1=O
Yield: 50 %

Procedure:
To a solution of ortho-formylphenylacetic acid (10 g, 61 mmol) (Bleasdale, et al., J. Chem. Soc. Perkin Trans., 1991, 1683) in 60 mL of EtOH was added N-methylhydrazine (4.2 g, 91 mmol) and refluxed for 1 h. The reaction mixture cooled, solvent removed and transferred the crude reaction mixture to a vacuum sublimation apparatus. The imine was heated at 140° C. under high vacuum for 1 h and collected the cyclized product by extracting with hot 20% ethyl acetate in hexane (Nagarajan, et al., J. Med. Chem., 1972, 15 (10), 1091). The product was crystallized from 20% ethyl acetate in hexane. 4,5-dihydro-3-methyl-3H-2,3-benzodiazepin-4-one was obtained in 50% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=O)=[CH:4][N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)[NH2:11])=[CH:6][CH:7]=1
Reactant: Cc1ccc(N(CCc2ccc(C)nc2)N=O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(N(N)CCc2ccc(C)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Crude 2-methyl-5-(N-nitroso-2-p-tolylaminoethyl)pyridine (612 mg, 2.4 mmol) was dissolved in dry THF (20 cm3) in a dry 3-neck flask under an argon atmosphere and cooled until the internal temperature was between 0-5° C. Solid LiAlH4 (290 mg, 7.7 mmol) was added and the reaction allowed to warm to room temperature. Following 2 hours stirring at room temperature, the reaction was again cooled to 0° C., and quenched with MeOH until no further gas evolution was observed (˜3 cm3). Saturated NaOH solution was then added (3 cm3), followed by H2O (3 cm3), and the medium extracted with CHCl3 (3×50 cm3), the combined extracts were dried (MgSO4), and solvent removed in vacuo to yield a crude orange oil. This could be carried forward to the next step if desired, or stored below 5° C. until required.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Cl)=[N:8][C:7]=1[C:12](=[O:16])[N:13]([CH3:15])[CH3:14])=[O:5])[CH3:2].[CH2:17]([NH:19][C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1)=[O:21])[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C(OCC)(=O)C.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>[CH3:14][N:13]([CH3:15])[C:12]([C:7]1[N:8]=[C:9]([C:26]2[CH:25]=[N:24][C:23]([NH:22][C:20]([NH:19][CH2:17][CH3:18])=[O:21])=[CH:28][CH:27]=2)[S:10][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:16]
Reactant: CCOC(=O)c1sc(Cl)nc1C(=O)N(C)C
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
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: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)Nc1ccc(-c2nc(C(=O)N(C)C)c(C(=O)OCC)s2)cn1
Temperature: 100 °C
Yield: 33.8 %

Procedure:
In a 10 mL of microwave vial, 2-chloro-4-dimethylcarbamoyl-thiazole-5-carboxylic acid ethyl ester (Intermediate 26, 0.1 g, 0.37 mmol), N-ethyl-N′-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-urea (Intermediate1, 0.11 g, 0.37 mmol), cesium carbonate (0.12 g, 0.37 mmol), Tetrakis (triphenyl phosphino) palladium (0) (0.044 g, 0.037 mmol) in 4 mL of 4:1 dioxane:H2O was degassed for 30 min, then heated to 100° C. for 30 min. The reaction mixture was diluted with ethyl acetate (25 mL), then washed with water (10 mL). The organic layer was dried and concentrated to yield crude residue, which was purified by column chromatography over silica gel to afford 0.049 g (36.5%) of the title compound as a pale yellow solid. MS (APCI): 357 (M+H+) for C17H21N5O4S; NMR: δ 1.25 (t, 3H), δ 1.38 (t, 3H), δ 2.91 (s, 3H), δ 3.18 (s, 3H), δ 3.42 (q, 2H), δ 4.36 (q, 2H), δ 6.92 (d, 1H), δ 8.14 (d, 1H), δ 8.78 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:15]([CH2:19][C:20]([NH:22][CH3:23])=[O:21])[CH:16]=[CH:17][N:18]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:26][C:27]([OH:44])([CH3:43])[CH2:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1>>[OH:44][C:27]([CH3:43])([CH3:26])[CH2:28][N:29]1[CH:33]=[C:32]([C:2]2[CH:25]=[CH:24][C:5]3[C:6]4[N:7]([CH:11]=[C:12]([C:14]5[N:15]([CH2:19][C:20]([NH:22][CH3:23])=[O:21])[CH:16]=[CH:17][N:18]=5)[N:13]=4)[CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)[CH:31]=[N:30]1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CNC(=O)Cn1ccnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Product: CNC(=O)Cn1ccnc1-c1cn2c(n1)-c1ccc(-c3cnn(CC(C)(C)O)c3)cc1OCC2

Procedure:
Following the procedure for 214, 2-(2-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1H-imidazol-1-yl)-N-methylacetamide and 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol were reacted under Suzuki conditions to give 221. MS: (ESI+)=462.2. 1H NMR (400 MHz, DMSO) δ 8.38 (d, J=8.4 Hz, 1H), 8.18 (s, 1H), 8.06-7.99 (m, 1H), 7.96 (s, 1H), 7.69 (s, 1H), 7.33 (dd, J=8.4, 1.8 Hz, 1H), 7.26 (d, J=1.7 Hz, 1H), 7.11 (d, J=1.1 Hz, 1H), 6.90 (d, J=1.1 Hz, 1H), 5.18 (s, 2H), 4.76 (s, 1H), 4.49 (s, 4H), 4.04 (s, 2H), 2.65 (d, J=4.6 Hz, 3H), 1.10 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:6]=[CH:7][CH:8]=1.Cl[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=2)[CH:26]=1>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=3)[CH:26]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: COc1ccccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Product: COc1ccccc1N(Cc1ccnc(-c2cc(OC)c(OC)c(OC)c2)c1)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
4-(o-Anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=2[CH3:17])=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:63]=[CH:62][C:53]2[NH:54][C:55]([C@@H:57]([NH2:61])[CH2:58][S:59][CH3:60])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:49][C:50]1[CH:63]=[CH:62][C:53]2[NH:54][C:55]([C@@H:57]([NH:61][C:12](=[O:14])[C:11]3[CH:15]=[CH:16][C:8]([C:6]([N:1]4[CH2:2][CH:3]=[CH:4][CH2:5]4)=[O:7])=[C:9]([CH3:17])[CH:10]=3)[CH2:58][S:59][CH3:60])=[N:56][C:52]=2[CH:51]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CC=CC1
Reactant: CSC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCO
Product: CSC[C@H](NC(=O)c1ccc(C(=O)N2CC=CC2)c(C)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 43 %

Procedure:
Prepared analogously to Example 1g from 4-(2,5-dihydropyrrol-1-ylcarbonyl)-3-methylbenzoic acid, TBTU, diisopropylethylamine, and (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methylsulfanylethylamine in tetrahydrofuran. Yield: 43%; Rf value: 0.47 (silica gel: dichloromethane/ethanol=9:1); C23H23ClN4O2S (454.98); mass spectrum: (M+H)+=455/457 (chlorine isotope).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([CH2:11]Br)[CH:5]=1.[I:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([CH2:11][O:21][C:18]2[CH:19]=[CH:20][C:15]([I:14])=[CH:16][CH:17]=2)[CH:5]=1
Reactant: Oc1ccc(I)cc1
Reactant: COC(=O)c1ccc(F)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(F)c(COc2ccc(I)cc2)c1
Yield: 74.5 %

Procedure:
3-Bromomethyl-4-fluorobenzoic acid methyl ester (3.0 g, 12.1 mmol) was mixed with 4-iodophenol (3.2 g, 14.6 mmol) in acetone (75 mL) containing dry potassium carbonate (2.5 g, 18 mmol). The mixture was refluxed for 6 hrs and then filtered. The filtrate was concentrated and extracted with ether and water. The organic layer was dried over sodium sulfate and solvents were evaporated. The residue was purified through flash column chromatography (120 g silica gel, 0% to 20% ethyl acetate in hexanes over 40 minutes) to give clear oil as 4-fluoro-3-(4-iodophenoxy)methylbenzoic acid methyl ester (3.48 g, 74.4%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:22]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[CH:29]1[C:34]([N+:35]([O-:37])=[O:36])=[CH:33][CH:32]=[C:31](O)[CH:30]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:22]([NH:24][CH2:25][C:26]([O:28][C:31]1[CH:30]=[CH:29][C:34]([N+:35]([O-:37])=[O:36])=[CH:33][CH:32]=1)=[O:27])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CN)C(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CN)C(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 3 h
Yield: 76 %

Procedure:
4.6 g (1.0×10-2 mol) of MA-Gly-Phe-Leu-Gly-OH was esterified with p-nitrophenol (1.1×10-2 mol) in 55 ml of THF by means of dicyclohexylcarbodiimide (DCC) (1.1×10-2 mol). After 3 hours at 15° C. and 12 hours at 25° C., the dicyclohexylurea was filtered off and the remaining solution was evaporated under reduced pressure. The residue was solidified by adding dry ethyl ether and after recrystalisation from acetone:ether (3:1) gave MA-Gly-Phe-Leu-Gly-ONp in 76% yield which was analytically pure; m.p. 124°-8° C. Aminoacid analysis gave Gly:Leu:Phe of 2.0:1.0:0.99.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21](=[O:51])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[O:30][C:29]2[CH:31]=[C:32]([CH:35]([O:43][Si](C(C)(C)C)(C)C)[CH2:36][CH2:37][C:38]3[S:39][CH:40]=[CH:41][CH:42]=3)[CH:33]=[CH:34][C:28]=2[O:27]1>C1COCC1.CCOC(C)=O>[CH3:19][O:20][C:21](=[O:51])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[O:30][C:29]2[CH:31]=[C:32]([CH:35]([OH:43])[CH2:36][CH2:37][C:38]3[S:39][CH:40]=[CH:41][CH:42]=3)[CH:33]=[CH:34][C:28]=2[O:27]1
Reactant: COC(=O)CCCCC1Oc2ccc(C(CCc3cccs3)O[Si](C)(C)C(C)(C)C)cc2O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CCCCC1Oc2ccc(C(O)CCc3cccs3)cc2O1
Yield: 99.6 %

Procedure:
Tetrabutylammonium fluoride (0.58 mL of a 1.0M solution in THF, 0.58 mmol) was added to (±)-methyl-5-[[6-(1-t-butyldimethylsilyloxy-3-(2-thienyl)propyl)]-1,3-benzodioxolyl]pentanoate (Compound E, 178 mg, 0.36 mmol) in THF (4.5 mL). After 16 hours the reaction was diluted with EtOAc and washed with H2O. The organic portion was dried (MgSO4) filtered and concentrated in vacuo. Flash column chromatography (silica gel, 2:1 hex/EtOAc) gave 135 mg (99%) of the title compound. 1H NMR (300 MHz, CDCl3) δ7.14 (d, J=5.1 Hz, 1H), 7.01 (s, 1H), 6.93 (dd, J=3.3, 5.1 Hz, 1H), 6.83 (d, J=3.3 Hz, 1H), 6.60 (s, 1H), 5.92 (s, 2H), 4.88-4.91 (m, 1H), 3.67 (s, 3H), 2.96-3.03 (m, 2H), 2.43-2.49 (m, 2H), 2.29 (t, J=6.9 Hz, 2H), 1.88-2.20 (m, 2H), 1.80 (d, J=3.0 Hz, 1H), 1.44-1.66 (m, 4H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH:18]=[C:17]2[C@@H:7]([CH2:8][C:9]3[C:19]4[C:12](=[CH:13][CH:14]=[CH:15][C:16]2=4)[NH:11][CH:10]=3)[N:5]([CH3:6])[CH2:4]1>[Pd].CN(C)C=O>[OH:1][CH2:2][C@@H:3]1[CH:18]=[C:17]2[C@@H:7]([CH2:8][CH:9]3[C:19]4[C:12](=[CH:13][CH:14]=[CH:15][C:16]2=4)[NH:11][CH2:10]3)[N:5]([CH3:6])[CH2:4]1
Reactant: CN1C[C@H](CO)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Agent: [Pd]
Solvent: CN(C)C=O
Product: CN1C[C@H](CO)C=C2c3cccc4c3C(CN4)C[C@H]21
Yield: 97.2 %

Procedure:
A mixture of Lysergol (1.5 g) and Palladium on carbon (5%, 50% wet, 75 mg) in N,N-dimethylformamide (15 mL) is hydrogenated at 50-60° C. and 40-50 psi until the theoretical volume of hydrogen has been absorbed. The reaction mixture is cooled, filtered and the insoluble material is washed with more N,N-dimethylformamide. The filtrate is evaporated to dryness and suspended with water. The resulting suspension is filtered, washed with more water. The solid is dried under vacuum to give 1.47 g of dihydrolysergol in 97% yield.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][C:11]([C:15](=[O:27])[NH:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[O:23][CH2:24][CH2:25][O:26][C:18]=23)([OH:14])[CH2:10][CH2:9]1)(C)(C)C.CO>C(OCC)(=O)C>[O:26]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][C:17]=2[NH:16][C:15]([C:11]2([OH:14])[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]2)=[O:27])[O:23][CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)NC1CCC(O)(C(=O)Nc2ccnc3c2OCCO3)CC1
Solvent: CO
Solvent: CCOC(C)=O
Product: NC1CCC(O)(C(=O)Nc2ccnc3c2OCCO3)CC1
Yield: 31.9 %

Procedure:
This was prepared from carbamate (b) (105 mg) by the procedure of Example (1m) with the exception that the crude material was subjected to chromatography on silica eluting with a 0-30% methanol in ethyl acetate gradient affording an oil (25 mg, 32%).
Reaction SMILES: [Cl:1][C@H:2]1[C@H:6]([CH2:7][CH2:8][CH2:9][C:10]2[S:14][C:13]([C:15]([O:17]C)=[O:16])=[CH:12][CH:11]=2)[C@@H:5](/[CH:19]=[CH:20]/[C@@H:21]([OH:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[C@H:4]([OH:29])[CH2:3]1.Cl[C@H]1[C@H](CCCC2SC(C(O)=O)=CC=2)[C@@H](/C=C/[C@@H](O)CC(O)CCC)[C@H](O)C1>>[Cl:1][C@H:2]1[C@H:6]([CH2:7][CH2:8][CH2:9][C:10]2[S:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][CH:11]=2)[C@@H:5](/[CH:19]=[CH:20]/[C@@H:21]([OH:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[C@H:4]([OH:29])[CH2:3]1
Reactant: COC(=O)c1ccc(CCC[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCCO)[C@H](O)C[C@H]2Cl)s1
Agent: CCCC(O)C[C@H](O)/C=C/[C@@H]1[C@@H](CCCc2ccc(C(=O)O)s2)[C@H](Cl)C[C@H]1O
Product: O=C(O)c1ccc(CCC[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCCO)[C@H](O)C[C@H]2Cl)s1
Yield: 82 %

Procedure:
Compound 22 (31.8 mg) was prepared in 82% yield using compound 21 according to the procedures described for compound 14 (see Schemes 1-3).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)=[CH:15][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Br-].[Zn+2].[Br-]>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[N:14]=[CH:15][C:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)=[CH:17][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cnc(NCCCOCc3ccccc3)nc2)C(OCc2ccc3ccccc3c2)C1
Agent: [Br-]
Agent: [Zn+2]
Product: c1ccc(COCCCNc2ncc(C3CCNCC3OCc3ccc4ccccc4c3)cn2)cc1

Procedure:
In an analogous manner to that described in Example 125 (h), from tert-butyl (3RS,4RS)-4-[2-(3-benzyloxy-propylamino)-pyrimidin-5-yl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate by cleavage of the BOC group by means of anhydrous zinc bromide there was obtained (3-benzyloxy-propyl)-{5-[(3RS,4RS)-3-(naphthalen-2-ylmethoxy)-piperidin-4-yl]-pyrimidin-2-yl}-amine in the form of a brownish gum; MS: 483 (M+H)+.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][C:8]([O-:10])=[O:9])([O:5][CH3:6])=[O:4].[K+].Br[CH2:13][N:14]1[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([Cl:23])[C:16]([C:24]#[N:25])=[C:15]1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1>CN(C)C=O.O>[CH3:1][O:2][P:3]([CH2:7][C:8]([O:10][CH2:13][N:14]1[C:15]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[C:16]([C:24]#[N:25])[C:17]([Cl:23])=[C:18]1[C:19]([F:22])([F:20])[F:21])=[O:9])([O:5][CH3:6])=[O:4]
Reactant: COP(=O)(CC(=O)[O-])OC
Reactant: N#Cc1c(Cl)c(C(F)(F)F)n(CBr)c1-c1ccc(Cl)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COP(=O)(CC(=O)OCn1c(-c2ccc(Cl)cc2)c(C#N)c(Cl)c1C(F)(F)F)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.3 %

Procedure:
A solution of potassium (dimethylphosphono)acetate (0.69 g, 4 mmol) in N,N-dimethylformamide is treated with 1-(bromomethyl)-4-chloro-2-(p-chlorophenyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (0.79 g, 2 mmol), stirred at room temperature for one hour, diluted with water and extracted with ethyl acetate. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous MgSO4 and concentrated in vacuo to obtain a brown oil. The oil is chromatographed using silica gel and a 1:1 hexanes/ethyl acetate mixture to give the title product as a viscous yellow oil (0.41 g) which is identified by 13C and 19FNMR spectral analyses.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1([CH3:44])[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C:11](=[O:21])[CH2:10][N:9]1[CH2:22][C@H:23]([NH:31]S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[C@@H:24]1[CH2:28][C@@H:27]([CH3:29])[C:26](=[O:30])[O:25]1.C1(S)C=CC=CC=1.C(=O)(O)[O-].[Na+].[C:57](OC(OC(C)(C)C)=O)([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58].N[C@H]([C@@H]1C[C@@H](C)C(=O)O1)CN1C(C)(C)CN(C2C=CC=CC=2C)C(=O)C1>C(#N)C.[Cl-].[Na+].O.C(OCC)(=O)C.O>[C:60]([O:59][C:57](=[O:58])[NH:31][C@H:23]([C@@H:24]1[CH2:28][C@@H:27]([CH3:29])[C:26](=[O:30])[O:25]1)[CH2:22][N:9]1[CH2:10][C:11](=[O:21])[N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:13][C:8]1([CH3:7])[CH3:44])([CH3:63])([CH3:62])[CH3:61]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1ccccc1N1CC(C)(C)N(C[C@H](NS(=O)(=O)c2ccccc2[N+](=O)[O-])[C@@H]2C[C@@H](C)C(=O)O2)CC1=O
Agent: Cc1ccccc1N1CC(C)(C)N(C[C@H](N)[C@@H]2C[C@@H](C)C(=O)O2)CC1=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: Cc1ccccc1N1CC(C)(C)N(C[C@H](NC(=O)OC(C)(C)C)[C@@H]2C[C@@H](C)C(=O)O2)CC1=O
Reaction time: 2 h
Yield: 61.2 %

Procedure:
704 mg of cesium carbonate (2.16 mmol) was added to a solution of 980 mg of N-{(S)-2-[2,2-dimethyl-4-(2-methylphenyl)-5-oxopiperazin-1-yl]-1-[(2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide obtained in Example (85a) (1.8 mmol) and 0.55 ml of thiophenol (content: 95%) (5.4 mmol) in acetonitrile (18 ml) under a nitrogen atmosphere at room temperature, and the mixture was stirred at the same temperature for two hours. Brine was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=20/1-10/1). 160 mg of sodium bicarbonate (1.9 mmol) and 416 mg of di-t-butyl dicarbonate (1.9 mmol) were added to a solution of 4-{(S)-2-amino-2-[(2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl]ethyl}-5,5-dimethyl-1-(2-methylphenyl)piperazin-2-one obtained above in ethyl acetate (7 ml)-water (7 ml), and the mixture was stirred at room temperature for 2.5 hours. Brine was added to the reaction mixture, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/ethyl acetate=2/1) to obtain 506 mg of the title compound (yield: 62%).