Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH:5]=[CH:6][CH:7]([NH:23][C:24](=[O:37])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:8][C:9]1[N:10]=[CH:11][N:12]([CH2:14][CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:38])[CH2:5][CH2:6][CH:7]([NH:23][C:24](=[O:37])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:8][C:9]1[N:10]=[CH:11][N:12]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C=CC(Cc1cn(CC=Cc2ccccc2)cn1)NC(=O)CCCCCCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC(Cc1cn(CCCc2ccccc2)cn1)NC(=O)CCCCCCc1ccccc1

Procedure:
A solution of 5-[1-(3-phenyl-allyl)-1H-imidazol-4-yl]-4-(7-phenyl-heptanoylamino)-pent-2-enoic acid ethyl ester (110 mg, 0.21 mmol) and Pd/C (50 mg) in ethanol (100 mL) was subject to hydrogenation (42 psi) for 2 hr. The solution was filtered and the solvent removed. The residue, ESMS 518 (M+H+) was hydrolysed directly without characterisation.
Reaction SMILES: [CH3:1][P:2]([O-:9])[O:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH3:10][C:11]([O:13][CH:14]([C:17]#[N:18])[CH:15]=[CH2:16])=[O:12]>>[C:11]([O:13][CH:14]([C:17]#[N:18])[CH2:15][CH2:16][P:2]([CH3:1])(=[O:9])[O:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7])(=[O:12])[CH3:10]
Reactant: CC(C)CCOP(C)[O-]
Reactant: C=CC(C#N)OC(C)=O
Product: CC(=O)OC(C#N)CCP(C)(=O)OCCC(C)C
Temperature: 80 °C
Reaction time: 3 h
Yield: 100.9 %

Procedure:
235.0 g of isopentyl methanephosphonite are heated to 80° C. under nitrogen, and 0.5 g of tert.-butyl perpivalate is added. 63.9 g of acrolein cyanohydrin acetate and 2.5 g of tert.-butyl perpivalate are added drop-wise, with vigorous stirring at 80° C., within 3 hours. After reaction is complete, 155.2 g of 97.5% pure isopentyl methanephosphonite are distilled out under high vacuum. (Recovery: 95%). 141.8 g of isopentyl (3-acetoxy-3-cyanopropyl)methylphosphinate (yield=96.5%; purity=93.6%) are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C@@:7]2([CH3:27])[N:11]3[C:12]([C:15](O)=[O:16])=[CH:13][N:14]=[C:10]3[N:9]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)[C:8]2=[O:26])=[CH:4][CH:3]=1.Cl.[CH2:31]([O:34][C:35]([C:37]1([NH2:40])[CH2:39][CH2:38]1)=[O:36])[CH:32]=[CH2:33].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:31]([O:34][C:35]([C:37]1([NH:40][C:15]([C:12]2[N:11]3[C@@:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([Br:1])=[CH:29][CH:28]=4)([CH3:27])[C:8](=[O:26])[N:9]([C:18]4[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=4)[C:10]3=[N:14][CH:13]=2)=[O:16])[CH2:39][CH2:38]1)=[O:36])[CH:32]=[CH2:33]
Reactant: C=CCOC(=O)C1(N)CC1
Reactant: C[C@@]1(Cc2ccc(Br)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)O)n21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)C1(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(Br)cc2)C(=O)N3c2cc(Cl)cc(Cl)c2)CC1
Reaction time: 0.17 h
Yield: 92.9 %

Procedure:
To a suspension of (R)-5-(4-bromo-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid (1.00 g, 2.02 mmol) and 1-amino-cyclopropanecarboxylic acid allyl ester hydrochloride (430 mg, 2.42 mmol) in 6 mL of DMF at room temperature was added diisopropylethylamine (1.05 mL, 6.06 mmol), and the reaction mixture was stirred for 10 min. HATU (845 mg, 2.22 mmol) was then added, and the clear yellow reaction mixture was stirred at room temperature for 21 h. The reaction mixture was partitioned between 150 mL of ethyl acetate and 50 mL of 1M HCl. The organic phase was washed with satd. NaHCO3 solution, water (2×), and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (10-30% EtOAc in hexanes), to furnish 1.16 g of 1-{[(R)-5-(4-bromo-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid allyl ester (93%) as a colorless foam.
Reaction SMILES: N[C:2]1[S:3][C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH2:7][CH3:8])[N:6]=1.[ClH:14].N([O-])=O.[Na+]>O>[Cl:14][C:2]1[S:3][C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH2:7][CH3:8])[N:6]=1
Reactant: Cl
Reactant: CCOC(=O)c1sc(N)nc1CC
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1sc(Cl)nc1CC
Reaction time: 0.5 h

Procedure:
Ethyl 2-chloro-3-oxo-pentanoate is prepared from ethyl 3-oxo-pentanoate and sulfuryl chloride utilizing the procedure of Bankowski et al, Rocz. Chem., Volume 49, Page 1899 (1971). A mixture of 9.2 g (0.0515 mole) of ethyl 2-chloro-3-oxo-pentanoate, 3.92 g (0.0515 mole) of thiourea and 30 ml. of ethanol was held at reflux for 17 hours. Ethanol was removed under reduced pressure and the residue was treated with 300 ml. of saturated sodium bicarbonate solution. The solid precipitate was collected to give 11.2 g of white solid, m.p. 165°-170° C. which was recrystallized from ethanol to give 7.7 g (75%) of ethyl 2-amino-4-ethyl-5-thiazolecarboxylate as colorless prisms, m.p. 177°-179° C. To a solution of 7.0 g (0.0349 mole) of ethyl 2-amino-4-ethyl-5-thiazolecarboxylate and 0.2 g of CaSO4 in 60 ml. of concentrated HCl was added dropwise a solution of NaNO2 in 20 ml. of water in such a way that the reaction temperature did not exceed 30° C. The reaction mixture was stirred for 30 minutes and poured into a solution of 3.5 g (0.035 mole) of cuprous chloride in 30 ml. of 6N HCl. The resulting dark blue solution was stirred for 30 minutes and extracted with ether. The ether solution was dried and concentrated under reduced pressure. The residue was Kugelrohr distilled at 2 mm. to give 4.35 g of yellow liquid which was chromatographed on silica gel to give 4.0 g (52%) of the desired product as colorless liquid, nD25 =1.5189.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:16][NH2:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:19][CH2:20][O:21][CH3:22]>C1COCC1.CCOC(C)=O>[CH3:22][O:21][CH2:20][CH2:19][NH:17][CH2:16][C:10]1([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: NCC1(c2ccc([N+](=O)[O-])cc2)CCOCC1
Reactant: COCCBr
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCNCC1(c2ccc([N+](=O)[O-])cc2)CCOCC1

Procedure:
A solution of C-[4-(4-nitro-phenyl)-tetrahydro-pyran-4-yl]-methylamine (as prepared in Example 73, step (b)) in THF is treated with 1-bromo-2-methoxy-ethane and TEA. The mixture is diluted with EtOAc and washed with water. The organic layer is dried (MgSO4) and concentrated in vacuo. The residue is purified by silica gel chromatography with the appropriate solvent to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10]I)[N:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:6]=1)=[O:4].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CO>[CH3:1][O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10][N:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)[N:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:6]=1)=[O:4]
Reactant: CN1CCNCC1
Reactant: COC(=O)c1nc(CI)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Solvent: CO
Product: COC(=O)c1nc(CN2CCN(C)CC2)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Reaction time: 16 h

Procedure:
A mixture of 8.0 g (0.015 mole) of 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(iodomethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester [see Example 13(b)] and 3.3 ml of 1-methyl-piperazine in 160 ml of methanol is stirred for 16 hours at 40°. The reaction solution is then concentrated in vacuo; water is added to the residue and extraction is performed twice with methylene chloride. The organic phase is washed twice with ice water, and extraction is then performed twice with 2 N hydrochloric acid solution. To the aqueous acidified extracts there are added ice and sufficient 5 N sodium hydroxide solution to bring the pH-value to 10. The base that has precipitated is taken up in ether. The organic phase is washed twice with saturated sodium chloride solution; it is afterwards dried over sodium sulphate and concentrated in vacuo to dryness. There is obtained 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-[(4-methyl-1-piperazinyl)-methyl]-1H-1,2,4-triazole-3-carboxylic acid methyl ester as solidified foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](O)[CH:5]=[CH:6][C:7]=1[C:8](=[O:18])[CH:9]([CH3:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:24]([OH:26])=[O:25].FC1C=C(C=CC=1OCCCCCCC)C(O)=O>>[F:1][C:2]1[CH:3]=[C:4]([C:22]2[C:21]([F:20])=[C:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:28]=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])[CH:5]=[CH:6][C:7]=1[C:8](=[O:18])[CH:9]([CH3:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCC(C)C(=O)c1ccc(O)cc1F
Reactant: CCCCCCCCCOc1ccc(C(=O)O)cc1F
Agent: CCCCCCCOc1ccc(C(=O)O)cc1F
Product: CCCCCCCCCOc1ccc(C(=O)O)c(-c2ccc(C(=O)C(C)CCCCCCC)c(F)c2)c1F

Procedure:
The same procedure as in Example 20 was repeated, except that (+)-3-fluoro-4-(2-methylnonanoyl) phenol was used instead of (+)-3-fluoro-4-(2-methyloctanoyl) phenol in Example 20 and 3-fluoro-4-nonyloxy benzoic acid was instead of 3-fluoro-4-heptyloxy benzoic acid in Example 20, to obtain an objective compound having the aforementioned physical and chemical properties.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.Br[CH2:14][CH3:15]>CN(C)C=O>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:14][CH3:15])=[CH:6][CH:5]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccc2ccc(Br)cc21
Yield: 101.9 %

Procedure:
Sodium hydride (480 mg of a 60% dispersion in mineral oil) was added to a stirred solution of 6-bromoindole (1.8 g, 9.2 mmol) in dimethylformamide (20 ml) at 0° C. under a nitrogen atmosphere. After 1 hour bromoethane (1.1 ml, 14.7 mmol) was added and the cooling bath removed. After 12 hours the dimethylformamide was removed in vacuo. The residue was purified directly by flash column chromatoraphy (using 95% hexane, 5% ethyl acetate as eluant) to give 2.1 g of the subtitle compound as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[F:11].C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)OC1>O1CCOCC1.O.C1C=CC([P]([Pd]([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)=CC=1>[F:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[C:25]1[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nccc1-c1ccc(C(=O)O)cc1F
Temperature: 80 °C

Procedure:
To a solution of 4-bromo-3-fluorobenzoic acid (220 mg, 1.0 mmol) in dioxane/H2O (5:1, 12 mL) was added K2CO3 (414 mg, 3.0 mmol), tetrakistriphenylphosphine Pd(0) (58 mg, 0.05 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (214 mg, 1.1 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 12 h and was then partitioned between 6N NaOH and DCM. The pH of the aqueous phase was adjusted to ˜3 with 3M HCl and washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (196 mg, 89%): LC-MS (ES) m/z=221 (M+H)+.
Reaction SMILES: C([N:4]=[C:5]([NH2:23])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH:16][C:17]([NH:21][CH3:22])=[N:18][C:19]#[N:20])[N:11]=1)(=O)C.[OH-].[Na+]>CO>[NH:6]([C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH:16][C:17]([NH:21][CH3:22])=[N:18][C:19]#[N:20])[N:11]=1)[C:5]([NH2:23])=[NH:4]
Reactant: CNC(=NC#N)NCCSCc1csc(NC(N)=NC(C)=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNC(=NC#N)NCCSCc1csc(NC(=N)N)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2-(2-acetylguanidino)-4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazole (13.6 mg.), methanol (1 ml.) and 0.2 N aqueous sodium hydroxide solution (2 ml.) was stirred at room temperature for 20 minutes. This resulted in complete conversion to 2-guanidino-4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazole, identical with the free base of the product obtained in Example 3. The free base had a m.p. 159°-161° C. on recrystallization from aqueous dimethylformamide.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]4[CH:17]([C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:15][CH2:14]4.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.Br[CH:35]=[C:36]([C:38]1[CH:39]=[CH:40][C:41]([CH3:44])=[N:42][CH:43]=1)[CH3:37]>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH:35]=[C:36]([C:38]3[CH:43]=[N:42][C:41]([CH3:44])=[CH:40][CH:39]=3)[CH3:37])[C:6]3[CH2:11][CH2:12][N:13]4[CH:17]([C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:15][CH2:14]4
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCN1CC3
Reactant: CC(=CBr)c1ccc(C)nc1
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=Cn1c2c(c3cc(C)ccc31)C1CCCN1CC2)c1ccc(C)nc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
To a degassed solution of 10-methyl-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (50 mg, 0.22 mmol), potassium phosphate (93 mg, 0.44 mmol), L-proline (2 mg, 0.01 mmol) and Cu(I)iodide (8 mg, 0.04 mmol) in DMF (1 mL) was added 5-(1-bromoprop-1-en-2-yl)-2-methylpyridine (93 mg, 0.44 mmol). The reaction mixture was stirred at 120° C. for 18 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was filtered through Celite and the filtrate was diluted with water (50 mL), extracted with EtOAc (2×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to yield 10-methyl-7-(2-(6-methylpyridin-3-yl)prop-1-enyl)-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole. 1H NMR, (CD3OD, formate salt) δ (ppm): 8.65 (s, 1H), 8.0 (d, 1H), 7.4 (d, 1H), 7.35 (s, 1H), 7.15 (d, 1H), 7.08 (d, 2H), 5.0 (t, 1H), 3.6 (m, 3H), 3.4 (m, 1H), 3.09 (q, 2H), 2.85 (m, 1H), 2.6 (s, 3H), 2.42 (s, 3H), 2.2 (m, 3H), 2.0 (s, 3H). Chiral HPLC provided the enantiomers 193a and 193b.
Reaction SMILES: [OH:1][C@H:2]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][N:4]([CH2:16][C@H:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:5][CH2:6][CH2:7][C:8]1[S:12][C:11]([C:13]([NH2:15])=O)=[CH:10][CH:9]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[OH:24][C@H:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:16][N:4]([CH2:3][C@H:2]([OH:1])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:5][CH2:6][CH2:7][C:8]1[S:12][C:11]([CH2:13][NH2:15])=[CH:10][CH:9]=1
Reactant: NC(=O)c1ccc(CCCN(C[C@H](O)c2ccccc2)C[C@H](O)c2ccccc2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(CCCN(C[C@H](O)c2ccccc2)C[C@H](O)c2ccccc2)s1
Yield: 79.1 %

Procedure:
850 mg of 5-[3-[bis-[(R)-β-hydroxyphenethyl]amino]propyl]-2-thiophenecarboxamide and 300 mg of lithium aluminum hydride were boiled at reflux for 1.5 hours in 60 ml of tetrahydrofuran. The mixture was treated cautiously with 2N sodium hydroxide solution and extracted three times with ether. The ether solutions were washed neutral with water, dried and evaporated. Chromatography of the residue on silica gel with methanol gave 650 mg of 5-[3-[bis-[(R)-β-hydroxyphenethyl]amino]propyl]-2-aminomethyl-thiophene.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[Cl:26][C:27]1[C:28]([CH3:35])=[C:29]([NH:33]N)[CH:30]=[CH:31][CH:32]=1>>[Cl:26][C:27]1[C:28]([CH3:35])=[C:29]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:30]=[CH:31][CH:32]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: Cc1c(Cl)cccc1NN
Product: Cc1c(Cl)cccc1-n1nccc1-c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (3-chloro-2-methyl-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=447.3 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.O.[C:12]1(=[O:17])[CH2:16][CH2:15][CH:14]=[CH:13]1>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:14]2[CH2:15][CH2:16][C:12](=[O:17])[CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C1C=CCC1
Reactant: OB(O)c1ccc(Br)cc1
Solvent: O
Solvent: C1COCCO1
Product: O=C1CC[C@H](c2ccc(Br)cc2)C1
Temperature: 35 °C
Yield: 88.7 %

Procedure:
Alternatively, a 3 L three-necked round-bottomed flask equipped with a temperature probe and a nitrogen bubbler was charged with 4-bromophenylboronic acid (100 g, 498 mmol) and hydroxy[(S)-BINAP]rhodium(I) dimer (6.20 g, 4.17 mmol) in dioxane (1667 mL) and water (167 mL) at room temperature. The resulting suspension was degassed with nitrogen and 2-cyclopenten-1-one (27.8 mL, 332 mmol) was added in one portion. The mixture was further degassed for 5 minutes and heated at 35° C. for about 16 hours. The reaction mixture was cooled to room temperature and concentrated. The brown residue was treated with EtOAc (500 mL) and filtered. The filtrate was washed with a saturated solution of NaHCO3 (500 mL) and brine (500 mL), dried over MgSO4, filtered, and concentrated to afford a dark brown solid. The crude reaction product was purified by silica gel chromatography (1:9 EtOAc:heptane as eluant). Fractions containing product were combined and concentrated to afford (S)-3-(4-bromo-phenyl)-cyclopentanone (70.4 g, 89%, 95% ee as determined by chiral HPLC) as an ivory solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[CH:11]=[C:10]([CH:12]=O)[S:9][C:5]=2[N:6]=[CH:7][N:8]=1.[CH3:14][NH2:15].[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH3:1][S:2][C:3]1[C:4]2[CH:11]=[C:10]([CH:12]=[N:15][CH3:14])[S:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CSc1ncnc2sc(C=O)cc12
Reactant: CN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CN=Cc1cc2c(SC)ncnc2s1
Yield: 100 %

Procedure:
4-(Methylthio)thieno[2,3-d]pyrimidine-6-carbaldehyde (13 g), methylamine (33% in EtOH, 20.6 mL) and anhydrous MgSO4 (20 g) was stirred in DCM (465 ml) for 2 days at ambient temperature under an inert atmosphere. The reaction mixture was filtered then concentrated in vacuo to afford the title compound as a brown solid (13.8 g, 100%);
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[N+:28]([C:31]1[C:32]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[N:33][CH:34]=[CH:35][CH:36]=1)([O-:30])=[O:29]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:6]=[CH:7][C:8]([C:11]([N:40]2[CH2:41][CH2:42][N:37]([C:32]3[C:31]([N+:28]([O-:30])=[O:29])=[CH:36][CH:35]=[CH:34][N:33]=3)[CH2:38][CH2:39]2)=[O:13])=[N:9][CH:10]=1
Reactant: O=[N+]([O-])c1cccnc1N1CCNCC1
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3[N+](=O)[O-])CC2)nc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
5-(Methoxycarbonyl)-2-pyridinecarboxylic acid (20 g) was added in methylene chloride (200 ml), and then, dissolved with the addition of triethylamine (17 ml). The mixture was cooled, pivaloyl chloride (14.5 ml) was added at 0° C.˜5° C. and stirred at 5° C. for 2 hours. 1-(3-Nitro-2-pyridyl)piperazine (23 g) and triethylamine (18 ml) were added to the solution in order and the mixture was reacted at 5° C.˜10° C. for 2 hours. The reaction mixture was washed with aqueous sodium bicarbonate and water each twice and then, the separated organic layer was concentrated under reduced pressure. The concentrated residue was treated with ethanol for crystallization and water was added, then the precipitate was filtered. The crude product was recrystallized with ethanol and ether, filtered and dried to give a desired compound of 35.3 g (yield: 86%).
Reaction SMILES: [N:1]1([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:20][CH:21]([F:25])[C:22](F)=[O:23]>C1(C)C=CC=CC=1>[F:20][CH:21]([F:25])[C:22](=[O:23])[C:8](=[CH:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C(F)C(F)F
Reactant: COC(=O)C=CN1CCOCC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C(=CN1CCOCC1)C(=O)C(F)F
Temperature: -30 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
Methyl 3-morpholin-4-ylacrylate (96.3%, 8.5 g, 50 mmol) and triethylamine (5.2 g, 50 mmol) were initially charged in toluene (250 ml) and cooled to −30° C. At this temperature, difluoroacetyl fluoride (5.0 g, 50 mmol) was introduced. The reaction mixture was stirred at −30° C. for 3 h and then, over a period of 1 hour, warmed to room temperature. Under reduced pressure, the reaction mixture was freed from the solvent. The residue obtained was 15.5 g of an orange solid which, according to quant. 1H-NMR, consisted to 66.4% of methyl 4,4-difluoro-3-oxo-2-(morpholin-4-ylmethylidene)butyrate (yield: 82%). 1H-NMR (CDCl3): δ=3.4 (m, 2H), 3.7 (m, 2H), 3.75 (s, 3H), 3.85 (m, 2H), 6.6 (t, 1H), 7.85 ppm (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[O:11][N:10]=[C:9]([C:12]([O:14]CC)=O)[N:8]=2)=[CH:4][C:3]=1[F:19].Cl.[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CO.[OH-].[Na+].O.CN(C=O)C>[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][CH2:32][NH:33][C:12]([C:9]1[N:8]=[C:7]([CH2:6][C:5]2[CH:17]=[CH:18][C:2]([Cl:1])=[C:3]([F:19])[CH:4]=2)[O:11][N:10]=1)=[O:14]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: CCOC(=O)c1noc(Cc2ccc(Cl)c(F)c2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1noc(Cc2ccc(Cl)c(F)c2)n1
Yield: 28.3 %

Procedure:
This compound was prepared according to method F with ethyl 5-(4-chloro-3-fluorobenzyl)-1,2,4-oxadiazole-3-carboxylate (0.123 g; 0.433 mmol) in methanol (2 mL) and sodium hydroxide in water (2M, 2 mL); and 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), HATU (0.164 g; 0.432 mmol), N,N diisopropylethylamine (0.075 mL; 0.432 mmol) in DMF (4 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.053 g (28%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(4-chloro-3-fluorobenzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.