Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:3]=1.C([Li])CCC.[CH3:33][C:34]([CH3:56])([CH2:39][CH:40]([CH2:53][CH:54]=O)[CH2:41][CH2:42][CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C:35]([O:37][CH3:38])=[O:36]>O1CCCC1.CCCCCC>[CH3:33][C:34]([CH3:56])([CH2:39][CH:40]([CH2:53][CH:54]=[CH:8][C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1)[CH2:41][CH2:42][CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C:35]([O:37][CH3:38])=[O:36]
Reactant: c1ccc([P+](Cc2cccnc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)C(C)(C)CC(CC=O)CCCCO[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)C(C)(C)CC(CC=Cc1cccnc1)CCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8.8 g (22.6 mmol) 3-pyridylmethyltriphenylphosphonium chloride in 40 ml dry tetrahydrofuran at 0° is added slowly 9.0 ml (22.5 mmol) of 2.5M n-butyllithium in hexane. After stirring the resulting deep red solution at room temperature for 0.5 h, a solution of 3.23 g (9 mmol) of methyl 2,2-dimethyl-4-formylmethyl-8-(t-butyldimethylsilyloxy)-octanoate in 10 ml dry tetrahydrofuran is added slowly and then stirred for 16 h. The reaction is quenched by addition of saturated ammonium chloride solution and then extracted thrice with ether. The combined organic extracts are washed with water and brine, dried, filtered and concentrated. The residue is taken up in ether and the resulting precipitate is removed by filtration. The filtrate is evaporated and the residue is purified by silica gel chromatography using 1:1 hexane/ether to give methyl 2,2-dimethyl-4-[3-(3-pyridyl)-2-propenyl]-8-(t-butyldimethylsilyloxy)-octanoate; NMR (CDCl3): delta 5.7-6.4 (m,2H), 3.63 and 3.60 (two s,3H), 1.2 and 1.15 (two s,6H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[N:11]2[C:12]=1[C:13]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)=[C:14]3[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].C(=O)([O-])O.[Na+]>O1CCCC1>[C:34]([O:27][C:24]1[CH:25]=[CH:26][C:21]([C:13]2[C:12]3=[C:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=[C:10]4[N:11]3[C:15](=[CH:16][CH:17]=[CH:18]4)[C:14]=2[CH2:19][CH3:20])=[CH:22][CH:23]=1)(=[O:36])[CH3:35]
Reactant: CCc1c(-c2ccc(O)cc2)c2c(Cc3ccccc3)cc3cccc1n32
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCc1c(-c2ccc(OC(C)=O)cc2)c2c(Cc3ccccc3)cc3cccc1n32
Temperature: 25 °C
Reaction time: 24 h
Yield: 35 %

Procedure:
3-Benzyl-1-ethyl-2-(4-hydroxyphenyl)pyrrolo[2,1,5-cd]indolizine (143 mg, 0.66 mmol) was dissolved in 10 ml of dry tetrahydrofuran and -.10 ml of dry pyridine and acetic anhydride (0.6 ml, 5.43 mmol) was added. The mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into 100 ml of saturated sodium hydrogen carbonate and stirred for 20 minutes. The organic material was extracted into dichloromethane (4×50 ml), and the combined organic layers were washed with brine, dried over magnesium sulfate and the solvent was evaporated. The crude product was purified by column chromatography over silica gel 60, using 5% of diethyl ether in petroleum ether as the eluent to afford 91 mg (35%) of 2-(4-acetoxyphenyl)-3-benzyl-1-ethylpyrrolo[2,1,5-cd]indolizine as a solid. MS(SP): m/z 393 (M+). 1H-NMR (CDCl3, 300 MHz) δ: 1.39 (t, 3H); 2.37 (s, 3H); 3.10 (q, 2H); 4.29 (s, 2H); 6.94 (s, 1H); 7.05-7.25 (m, 7H); 7.52 (d, 2H); 7.61 (dd, 1H); 7.80 (d, 1H), 7.89 (d, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.[NH:15]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21]2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:15]3[CH2:20][CH2:19][C:18]4([C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH2:22][CH2:21]4)[CH2:17][CH2:16]3)=[CH:7][CH:6]=2)[S:12][N:11]=1
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Reactant: c1ccc2c(c1)CCC21CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nsc(-c2ccc(N3CCC4(CCc5ccccc54)CC3)nn2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
3-Chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (51 mg), 2,3-dihydrospiro[indene-1,4′-piperidine] hydrochloride (78 mg) and potassium carbonate (70 mg) were suspended in N,N-dimethylformamide (3 mL), and the suspension was stirred at 80° C. overnight. The mixture was cooled to room temperature, diluted with ethyl acetate, and washed twice with aqueous sodium hydrogen carbonate solution. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (15% ethyl acetate/hexane to 50% ethyl acetate/hexane) and recrystallized from hexane/ethyl acetate to give the object product (53 mg, 60%).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH2:16]([O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:8])[N:4]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cc(O)nn1-c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)nn1-c1ccccc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A mixture of 3-hydroxy-1-phenyl-1H-pyrazole-5-carboxylic acid (29.55 g), benzyl bromide (35 ml), potassium carbonate (40.99 g) and N,N-dimethylformamide (300 ml) was stirred overnight at 90° C. The reaction mixture was poured into dilute hydrochloric acid and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and benzyl 3-benzyloxy-1-phenyl-1H-pyrazole-5-carboxylate (51.33 g, yield 92%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [S:1]([O-:5])([OH:4])(=[O:3])=[O:2].[CH3:6]/[C:7](/[CH:29]=[CH:30]/[C:31]1[C:36]([CH3:38])([CH3:37])[CH2:35][CH2:34][CH2:33][C:32]=1[CH3:39])=[CH:8]\[CH2:9][P+:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C[O-].[Na+]>CO>[CH3:6]/[C:7](/[CH:29]=[CH:30]/[C:31]1[C:36]([CH3:38])([CH3:37])[CH2:35][CH2:34][CH2:33][C:32]=1[CH3:39])=[CH:8]/[CH2:9][P+:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[S:1]([O-:5])([OH:4])(=[O:3])=[O:2]
Reactant: CC1=C(/C=C/C(C)=C/C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)C(C)(C)CCC1
Agent: C[O-]
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CO
Product: CC1=C(/C=C/C(C)=C\C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)C(C)(C)CCC1
Temperature: 145 °C
Yield: 20 %

Procedure:
A 4000 ml round-bottom flask is initially charged with 2535 g (1.67 mol) of a 37.2% by weight solution of [(2E,4E)-3-methyl-5-(2,6,6-trimethylcyclohexen-1-yl)penta-2,4-dienyl]triphenylphosphonium hydrogensulfate in methanol under nitrogen, which is alkalized by addition of 111.30 g (0.618 mol) of a 30% by weight sodium methoxide solution in methanol, and the precipitated sodium sulfate is filtered off. The filtrate is pumped through a flow reactor heated to 145° C. with an exactly fixed residence time of 25 min. Subsequently, the solvent is distilled off, the residue is taken up in isopropanol and acidified with sulfuric acid to a pH of 0.3, and the unisomerized [(2E,4E)-3-methyl-5-(2,6,6-trimethylcyclohexen-1-yl)penta-2,4-dienyl]triphenylphosphonium salt of the general formula 2 is crystallized by adding 823 g of heptane and cooling to −10° C. After the crystals have been filtered off, 1648 g of an 11.2% by weight solution of [(2Z,4E)-3-methyl-5-(2,6,6-trimethylcyclohexen-1-yl)penta-2,4-dienyl]triphenylphosphonium-hydrogensulfate (0.327 mol) are obtained in a purity of 95% and a yield of 20%.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]3[CH2:12][CH2:13][CH2:14][C:9]=3[C:8]=2C(O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC(P([N:32]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.O>C1(C)C=CC=CC=1.CN(C=O)C>[C:1]1([C:7]2[S:11][C:10]3[CH2:12][CH2:13][CH2:14][C:9]=3[C:8]=2[NH2:32])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1c(-c2ccccc2)sc2c1CCC2
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c(-c2ccccc2)sc2c1CCC2
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-phenyl-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylic acid and TEA in toluene was added a solution of DPPA in toluene, followed by stirring at room temperature for 40 minutes, and then stirring at 90° C. for 60 minutes. Furthermore, a solution of (3R)-quinuclidinole in DMF was added thereto, followed by heating under reflux for 15 hours. To the reaction liquid was added water, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The oily substance obtained was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane:EtOAc) to obtain 2-phenyl-5,6-dihydro-4H-cyclopenta[b]thiophene-3-amine as a pale brown oil, but not a desired (3R)-1-azabicyclo[2.2.2]oct-3-yl(2-phenyl-5,6-dihydro-4H-cyclopenta[b]thien-3-yl)carbamate.
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11]([CH2:13][CH2:14][C:15]([OH:17])=O)[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:30][NH2:31]>C1COCC1>[CH2:1]([C:8]1[N:12]=[C:11]([CH2:13][CH2:14][C:15]([NH:30][NH2:31])=[O:17])[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(O)CCc1nc(Cc2ccccc2)no1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: NNC(=O)CCc1nc(Cc2ccccc2)no1
Temperature: 25 °C

Procedure:
To a solution of 3-(3-benzyl-1,2,4-oxadiazol-5-yl)propanoic acid (1.0 g, 4.3 mmol) in THF (15 mL) was added N,N-carbonyldiimidazole (0.77 g, 4.7 mmol). After refluxing for 2 hours, hydrazine (0.6 g, 20 mmol) was added to the reaction mixture slowly with syringe at 0° C. The reaction mixture was allowed to warm to room temperature slowly and then concentrated to yield the desired product as white solid. LCMS calculated for C12H15N4O2 (M+H): 247.1. found: 247.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[CH:5]=[O:6].[Cl:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[CH:17][C:18]=1[F:19]>>[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:18]=1[F:19])[O:20][C:9]1[C:8]([F:11])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: Oc1ccc(F)c(Cl)c1
Product: O=Cc1cc(F)c(Oc2ccc(F)c(Cl)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4,5-trifluorobenzaldehyde and 3-chloro-4-fluorophenol.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][Mg]Cl)=[CH:4][CH:3]=1.FC1C=CC(CCl)=CC=1.[Mg].Cl[Si:22]([CH2:25][Cl:26])([CH3:24])[CH3:23].Cl>CCOCC.CCCCCC>[Cl:26][CH2:25][Si:22]([CH3:24])([CH3:23])[CH2:6][C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Fc1ccc(C[Mg]Cl)cc1
Reactant: C[Si](C)(Cl)CCl
Agent: Cl
Agent: Fc1ccc(CCl)cc1
Agent: [Mg]
Solvent: CCCCCC
Solvent: CCOCC
Product: C[Si](C)(CCl)Cc1ccc(F)cc1
Yield: 93 %

Procedure:
To the 4-fluorobenzylmagnesiumchloride, prepared from parafluorobenzylchloride (1.59 g, 11 mmol) and magnesium (0.25 g, 11 mmol) in ether (20 ml), was added dropwise, at 0° C., chloro-chloromethyl-dimethylsilane (1.43 g, 10 mmol )in ether (5 ml). Then the mixture was refluxed 6 hours, cooled to 0° C., hydrolyzed with 3N HCl (20 ml) and extracted with ether. The ether solution was washed with water, brine, dried and evaporated. Chromatography (silica gel, hexane) afforded chloromethyl-dimethyl-4-fluorobenzyl silane as an oil (2.01 g, 93% yield) 1H NMR, CDCl3, TMS) δ:0.20 (s,6H), 2.27 (s,2H), 2.63 (s,2H), 6.90-7.13 (m,4H).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[C:7]1[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[S:22][C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[N:25]=3)=[CH:16][CH:15]=2)=[N:9][CH:10]=[CH:11][CH:12]=1>[Pd].C(O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]1[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[S:22][C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[N:25]=3)=[CH:16][CH:15]=2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1=COC(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: c1cnc(Oc2ccc(Nc3nc4ccccc4s3)cc2)c(C2CCCCO2)c1
Temperature: 25 °C

Procedure:
A mixture of N-(4-(3-(3,4-dihydro-2H-pyran-2-yl)pyridin-2-yloxy)phenyl)benzo[d]thiazol-2-amine (357 mg, 0.889 mmol) and palladium on carbon, wet (95 mg, 0.089 mmol) in ethanol (0.15M) was placed under an atmosphere of hydrogen (g) and stirred at room temperature. After the starting material was completely consumed, the mixture was filtered through a cake of celite, washed with MeOH & THF and filtrate was concentrated to dryness. The residue was purified by silica gel chromatography to give the desired product as a racemic mixture. MS (ESI, pos. ion) m/z: 404.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=3[O:36][CH3:37])=[C:20]([C:38]([F:41])([F:40])[F:39])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:43]>C(O)C>[ClH:43].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[O:36][CH3:37])=[C:20]([C:38]([F:39])([F:40])[F:41])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: COc1ccc(CCCOc2ccc(CCC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2C(F)(F)F)c(OC)c1
Agent: Cl
Solvent: CCO
Product: COc1ccc(CCCOc2ccc(CCC(N)(CO)CO)cc2C(F)(F)F)c(OC)c1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
Compound 19-3 (930 mg) was dissolved in ethanol (20 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give a white powder. The white powder was purified by HPLC, and the obtained residue was converted to hydrochloride by adding hydrogen chloride containing ether (1 mol/l, 15 ml). The precipitate was collected by filtration and dried to give the object product (460 mg) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=O)[C:4]=2[CH:3]=1.O.[NH2:17][NH2:18].C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[N:17][NH2:18])[C:4]=2[CH:3]=1
Reactant: NN
Reactant: O=C1c2ccccc2-c2ccc(Cl)cc21
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: NN=C1c2ccccc2-c2ccc(Cl)cc21
Yield: 100 %

Procedure:
A mixture of 2-chloro 9-fluorenone (18) (5 g, 23.3 mmoL), hydrazine monohydrate (6 mL, 120 mmoL, 5.2 eq) and acetic acid (1 mL) in ethanol (150 mL ) was refluxed for 2.5 h. The mixture was then evaporated to dryness to provide 5.3 g (100%) of product which was used without further purification: mp 139°-143° C..
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1([C:23]2C=CC=CC=2)[CH2:8][CH2:7][N:6]([CH2:9][C@@H:10]([C:12]2[CH:21]=[CH:20][C:15]3[C:16](=[O:19])[O:17][CH2:18][C:14]=3[C:13]=2[CH3:22])[OH:11])[CH2:5]1.Cl[C:30]1[N:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=1>>[OH:11][C@H:10]([C:12]1[C:13]([CH3:22])=[C:14]2[C:15](=[CH:20][CH:21]=1)[C:16](=[O:19])[O:17][CH2:18]2)[CH2:9][N:6]1[CH2:7][CH2:8][C:4]([CH2:3][NH:2][C:30]2[CH:31]=[CH:32][C:33]([C:36]#[N:37])=[CH:34][N:35]=2)([CH3:23])[CH2:5]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1c([C@@H](O)CN2CCC(CN)(c3ccccc3)C2)ccc2c1COC2=O
Agent: Cl
Product: Cc1c([C@@H](O)CN2CCC(C)(CNc3ccc(C#N)cn3)C2)ccc2c1COC2=O

Procedure:
6-((1-((R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-methylpyrrolidin-3-yl)methylamino)nicotinonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLE 18 starting from 5-[(R)-2-[3-(Aminomethyl)-3-phenylpyrrolidin-1-yl]-1-hydroxyethyl}-4-methyl-2-benzofuran-1(3H)-one hydrochloride [INTERMEDIATE 15] and 6-chloropyridine-3-carbonitrile.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.[CH3:13][CH2:14][CH:15]([NH2:18])[CH2:16][CH3:17]>>[CH2:14]([CH:15]([NH:18][C:8](=[O:10])[CH:7]=[CH:6][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:12][CH:11]=1)[CH2:16][CH3:17])[CH3:13]
Reactant: O=C(O)C=Cc1ccc(O)cc1
Reactant: CCC(N)CC
Product: CCC(CC)NC(=O)C=Cc1ccc(O)cc1

Procedure:
N-(1-Ethyl-propyl)-3-(4-hydroxy-phenyl)-acrylamide was prepared in a similar manner as described in example 4 from 4-hydroxy-cinnamic acid and 3-pentylamine. MS (M+H, 234.10).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14](O)=[O:15])=[O:8])(=[O:3])[CH3:2].CN1CCOCC1.[OH:35][C@H:36]([CH3:50])[C@H:37]([NH:42][C:43]([C@@H:45]1[CH2:49][CH2:48][CH2:47][NH:46]1)=[O:44])[C:38]([O:40][CH3:41])=[O:39]>C(Cl)Cl.CN(C=O)C>[C:1]([O:4][CH2:5][C@@H:6]([NH:17][C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([N:46]1[CH2:47][CH2:48][CH2:49][C@H:45]1[C:43]([NH:42][C@@H:37]([C@H:36]([OH:35])[CH3:50])[C:38]([O:40][CH3:41])=[O:39])=[O:44])=[O:15])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)[C@@H](NC(=O)[C@@H]1CCCN1)[C@@H](C)O
Reactant: CC(=O)OC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@@H](COC(C)=O)NC(=O)OCc1ccccc1)[C@@H](C)O
Reaction time: 3 h
Yield: 18.6 %

Procedure:
Compound 3 (1.0 g, 2.64 mmol) was dissolved in CH2Cl2 (10 mL), NMM (0.32 g, 3.17 mmol) and IBCF (0.41 g, 3.04 mmol) were added to the reaction mixture at −15° C. and stirred for minutes under inert atmosphere. A mixture of (2S,3R)-methyl 3-hydroxy-2-((S)-pyrrolidine-2-carboxamido)-butanoate (4) (0.73 g, 3.17 mmol) and NMM (0.35 mL) in DMF (3 mL) were added drop wise to the reaction mixture at −15° C. and stirring was continued for another 3 h at RT. The reaction mixture was diluted with DCM (200 mL), washed with water (20 mL), citric acid solution (2×20 mL) and brine (2×50 mL). The separated organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue obtained was purified by silica gel column chromatography eluting with 5% CH3OH/EtOAc to afford compound (5) (0.29 g, 19%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[CH:4][N:3]=1.[NH3:17]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:17])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[CH:4][N:3]=1
Reactant: Nc1ncc(-c2cccc(Cl)c2Cl)c(Cl)n1
Reactant: N
Product: Nc1ncc(-c2cccc(Cl)c2Cl)c(N)n1
Temperature: 125 °C

Procedure:
To 2-amino-4-chloro-5-(2,3-dichlorophenyl)pyrimidine (6.73 gms) was added ethanolic ammonia (30 equiv. in 50 ml EtOH) and the mixture sealed in a Parr reaction vessel and heated to 125° C. for 38 hours. After cooling, the mixture was concentrated in: vacuo and the residue mixed with 1N NaOH (75 ml), filtered, washes with water and dried in vacuo, 6.14 gms, mp. 208°-211° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:17][CH2:18][CH2:19]OS(C)(=O)=O)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[CH2:25]([CH2:28][NH2:29])[CH:26]=C.[CH3:30]N(C=O)C>>[CH2:28]([N:29]([CH2:19][CH2:18][CH2:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:9]=[CH:10]2)[CH3:30])[CH:25]=[CH2:26]
Reactant: CN(C)C=O
Reactant: C=CCCN
Reactant: CS(=O)(=O)OCCCc1ccc2c(ccn2-c2ccc(F)cc2)c1
Product: C=CCN(C)CCCc1ccc2c(ccn2-c2ccc(F)cc2)c1
Yield: 76 %

Procedure:
150 mg (0.43 mmol) Methanesulfonic acid 3-[1-(4-fluoro-phenyl)-1H-indol-5-yl]-propyl ester and 0.5 ml N-allylmethylamine in 1 ml DMF were stirred at 60° C. for 1 h. The solution was concentrated and dissolved in water, ether and 0.5M NaOH was added. The inorganic phase was extracted with ether and the combined organic phases were washed with water and dried over Na2SO4. Column chromatography with CH2Cl2/MeOH 19:1 yielded 105 mg (76%) Allyl-{3-[1-(4-fluoro-phenyl)-1H-indol-5-yl]-propyl}-methyl-amine as light brown oil, MS: 323 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([F:11])[CH:5]=1)[CH3:2].C(NC(C)C)(C)C.[Li].CN(C)[CH:22]=[O:23].C(O)(=O)C>O1CCCC1>[CH2:1]([O:3][C:4]1[C:5]([CH:22]=[O:23])=[C:6]([F:11])[C:7]([F:10])=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(F)c(F)c1
Reactant: CN(C)C=O
Agent: [Li]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOc1ccc(F)c(F)c1C=O

Procedure:
In a manner similar to the method described in example 52a, 4-ethoxy-1,2-difluoro-benzene (10 g, 63 mmol) prepared in example 91a was reacted with lithium diisopropylamine (39 mL, 1.8 M in THF, 70 mmol), N,N-dimethylformamide (5.88 mL, 76 mmol) and quenched with acetic acid (15.2 g, 253 mmol) in tetrahydrofuran to give 6-ethoxy-2,3-difluoro-benzaldehyde as a off white solid (Yield: 8.9 g, 76%).
Reaction SMILES: C1(OC)C=CC=CC=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16](/[C:19](/[C:38]2[NH:43][C:42](=[O:44])[C:41]([CH2:45][CH2:46][C:47]([NH2:49])=[O:48])=[CH:40][CH:39]=2)=[CH:20]\[C@H:21]2[CH2:25][CH2:24][C:23](=[O:26])[N:22]2CC2C=CC(OC)=CC=2OC)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>FC(F)(F)C(O)=O>[C:9]([C:13]1[CH:18]=[CH:17][C:16](/[C:19](/[C:38]2[NH:43][C:42](=[O:44])[C:41]([CH2:45][CH2:46][C:47]([NH2:49])=[O:48])=[CH:40][CH:39]=2)=[CH:20]\[C@H:21]2[CH2:25][CH2:24][C:23](=[O:26])[NH:22]2)=[CH:15][CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(CCC(N)=O)c(=O)[nH]2)c(OC)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(/C(=C\[C@H]2CCC(=O)N2)c2ccc(CCC(N)=O)c(=O)[nH]2)cc1
Temperature: 80 °C
Reaction time: 19 h
Yield: 23.2 %

Procedure:
Anisole (0.3 mL) was added to a solution of 3-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-oxo-1,2-dihydropyridin-3-yl)propanamide (82.6 mg) in trifluoroacetic acid (0.6 mL), and the mixture was stirred at 80° C. for 19 hours. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give the title compound as a colorless oil (14 mg).
Reaction SMILES: [CH2:1]([O:3][CH:4]=[CH:5][C:6](=O)[C:7]([OH:9])=[O:8])[CH3:2].Cl.[NH2:12][OH:13].O.[CH2:15](O)[CH3:16]>>[CH2:1]([O:3][CH:4]1[O:13][N:12]=[C:6]([C:7]([O:9][CH2:15][CH3:16])=[O:8])[CH2:5]1)[CH3:2]
Reactant: CCO
Reactant: NO
Reactant: CCOC=CC(=O)C(=O)O
Agent: Cl
Solvent: O
Product: CCOC(=O)C1=NOC(OCC)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
17.22 g of 4-ethoxy-2-oxo-3-butenoic acid prepared according to the method of L. Tietze et al. (Lutz-F. Tietze, Heinrich Meier and Edgar Voss, Synthesis 1988, 274) are dissolved in 50 ml of anhydrous ethanol, and 7.34 g of hydroxylamine hydrochloride is added thereto, and the mixture is stirred at room temperature for 4 hours. The reaction mixture is added with water and extracted with methylene chloride. The organic layer is washed with water, dried, and evaporated. The resulting residue is distilled under reduced pressure to yield 14.3 g of ethyl 5-ethoxyisoxazoline-3carboxylate. (yield 76%)