Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:26])[N:12]([C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][CH:25]=4)[NH:22][CH:21]=[CH:20]5)[CH2:13][CH2:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:26])[N:12]([C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][CH:25]=4)[N:22]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH:21]=[CH:20]5)[CH2:13][CH2:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: BrCc1ccccn1
Reactant: O=C1c2sc(-c3ccc(Cl)cc3)nc2CCN1c1ccc2[nH]ccc2c1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1c2sc(-c3ccc(Cl)cc3)nc2CCN1c1ccc2c(ccn2Cc2ccccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
Dissolve 2-(4-chloro-phenyl)-5-(1H-indol-5-yl)-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (49 mg, 0.13 mmol) in DMF (1 mL) and add sodium hydride (17 mg, 0.42 mmol). Stir the mixture at room temperature for 30 min then add 2-bromomethyl-pyridine hydrobromide (35 mg, 0.14 mmol). Stir the mixture at room temperature for 5 h, then dilute with EtOAc (30 mL) and wash with saturated NaHCO3 (10 mL). Dry, filter and concentrate the organic solution. Purify the crude material by flash chromatography, using a linear gradient of 20% to 80% EtOAc/hexanes as eluent, to give the title compound (32 mg, 52%). MS (ES+) 471.0 (M+1)+. 1H NMR (400 MHz, CDCl3) δ: 8.55-8.53 (m, 1H), 8.05 (d, 2H, J=8.4 Hz), 7.73 (dt, 1H, J=7.7, 1.8 Hz), 7.62 (d, 2H, J=8.8 Hz), 7.57-7.55 (m, 2H), 7.45 (d, 1H, J=8.8 Hz), 7.30-7.26 (m, 1H), 7.10 (dd, 1H, J=8.6, 2.0 Hz), 7.03 (d, 1H, J=7.9 Hz), 6.52 (d, 1H, J=3.5 Hz), 5.53 (s, 2H), 4.10 (t, 2H, J=7.0 Hz), 3.27 (t, 2H, J=7.0 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:31])=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)=[CH:15][C:14]([C:28]([NH2:30])=[NH:29])=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl[Sn]Cl>Cl>[NH2:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:28]([NH2:30])=[NH:29])[CH:15]=3)[NH:10][C:9]=2[C:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([Br:1])[C:3]=2[OH:31])=[CH:24][CH:23]=1
Reactant: Cc1cc(Br)c(O)c(-c2[nH]c3ccc(C(=N)N)cc3c2Cc2ccc([N+](=O)[O-])cc2)c1
Agent: Cl
Agent: Cl[Sn]Cl
Product: Cc1cc(Br)c(O)c(-c2[nH]c3ccc(C(=N)N)cc3c2Cc2ccc(N)cc2)c1
Reaction time: 15 h
Yield: 40 %

Procedure:
A mixture of 2-(3-bromo-2-hydroxy-5-methyl-phenyl)-3-(4-nitro-benzyl)-1H-indole-5-carboxamidine 203 (100 mgs, 0.2 mmol), SnCl2 (100 mgs) and 6N HCl is heated at reflux for 1 hr. The reaction is cooled, let stand for 12-18 h, and the residue is isolated. The residue is taken up in 0.1N HCl and purified by reverse phase HPLC (0.01%HCl/acetonitrile) with a 2-90% gradient to yield 42% of 3-(4-amino-benzyl)-2-(3-bromo-2-hydroxy-5-methyl-phenyl)-1H-indole-5-carboxamidine as a white solid (38 mgs, 0.08 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:23])[CH:14]=[C:15]2[C:19](=[O:20])OC(C)(C)[O:16]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C=O.[CH3:26][NH2:27].[CH3:28]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12][C:13]([C:14]2[CH2:26][N:27]([CH3:28])[C:19](=[O:20])[C:15]=2[OH:16])=[O:23])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CO
Reactant: CC1(C)OC(=O)C(=CC(=O)NCCCc2ccc(Cl)c(Cl)c2)O1
Reactant: CN
Agent: C=O
Product: CN1CC(C(=O)NCCCc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Yield: 56 %

Procedure:
Reaction of N-[3-(3,4-dichlorophenyl)-propyl]-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-acetamide (0.432 g, 1.20 mmol) with the paraformaldehyde-methylamine adduct in methanol using a procedure similar to the one described in the preparation of compound 44 (method 44B) gave 0.232 g (56% yield) of the title compound as white crystals; mp 157–158° C. (dec) (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm); 1.81 (2H, m, CH2), 2.57 (2H, t, J=7.5 Hz, CH2), 3.05 (3H, s, NCH3), 3.33 (2H, m, NCH2), 3.98 (2H, s, NCH2), 6.95 (1H, broad t, NH), 7.05 (1H, broad dd, aromatic), 7.21 (1H, d, J=2 Hz, aromatic), 7.26 (1H, d, J=8.1 Hz, aromatic), 10.13 (1H, broad, OH). Anal. Calcd for C5H16Cl2N2O3: C, 52.49; H, 4.70; N, 8.16. Found: C, 52.39; H, 4.80; N, 7.89.
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]([Cl:13])([Cl:12])[C:6]1[N:10]=[C:9](Cl)[S:8][N:7]=1.[CH3:14][N:15]([C:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=1)[C:16](=[O:19])[CH2:17][OH:18].O>C(C(C)=O)C(C)C>[CH3:14][N:15]([C:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=1)[C:16](=[O:19])[CH2:17][O:18][C:9]1[S:8][N:7]=[C:6]([C:5]([Cl:13])([Cl:12])[Cl:4])[N:10]=1
Reactant: Clc1nc(C(Cl)(Cl)Cl)ns1
Reactant: CN(C(=O)CO)C1=CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CN(C(=O)COc1nc(C(Cl)(Cl)Cl)ns1)C1=CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
3.1 g (0.07 mol) of lithium hydroxide hydrate are added in portions, at 0° C., to 16.7 g (0.07 mol) of 3-trichloromethyl-5-chloro-1,2,4-thiadiazole and 11.8 g (0.07 mol) of hydroxyacetic acid N-methyl-N-cyclohex-1-enylamide in 100 ml of methyl isobutyl ketone, and the mixture is stirred for 30 minutes at 0° C. and then overnight at 25° C. After water has been added, the reaction product which separates out as a solid is filtered off under suction, washed and dried. 22.0 g (84.8% of theory) of 3-trichloromethyl-1,2,4-thiadiazol-5-yl-oxyacetic acid N-methyl-N-cyclohexen-1-yl-amide are obtained in the form of beige-colored crystals of melting point 78° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:8][CH:7]=2.[Cl:18][C:19]1[CH:35]=[CH:34][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27](O)=[C:26]([CH2:31][CH2:32][CH3:33])[CH:25]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:35]=[CH:34][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([O:1][CH2:2][CH2:3][C:4]3[NH:5][C:6]4[C:11]([CH:12]=3)=[CH:10][C:9]([CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=4)=[C:26]([CH2:31][CH2:32][CH3:33])[CH:25]=2)=[CH:21][CH:20]=1
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1O
Reactant: COC(=O)Cc1ccc2[nH]c(CCO)cc2c1
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1OCCc1cc2cc(CC(=O)O)ccc2[nH]1

Procedure:
Using the procedures in Example 15, steps F and G, the title compound was prepared from methyl 2-(2-hydroxyethyl)indole-5-acetate and 4-(4-chlorophenoxy)-2-propylphenol.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([C:13]#[N:14])[C:4](=[O:15])[CH:3]=1.Cl.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23]Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([O:15][CH2:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: N#Cc1c(-c2ccco2)[nH]c(N)cc1=O
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1c(OCc2ccccn2)cc(N)nc1-c1ccco1

Procedure:
From 6-amino-2-furan-2-yl-4-oxo-1,4-dihydro-pyridine-3-carbonitrile, 2-picolyl chloride hydrochloride and cesium carbonate in DMF. ES-MS m/e (%): 293 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[CH2:14]([N:18]=[C:19]=[S:20])[CH2:15][CH2:16][CH3:17]>ClCCl>[CH2:14]([NH:18][C:19]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[S:20])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCN=C=S
Reactant: Nc1ccccc1N1CCOCC1
Solvent: ClCCl
Product: CCCCNC(=S)Nc1ccccc1N1CCOCC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of 4-(2-aminophenyl)morpholine (5.8 g) in dichloromethane (60 ml) was treated with n-butyl isothiocyanate (5 g) and mixture stirred at room temperature for 4 days to yield 1-(n-butyl)-3-(2-morpholinophenyl)thiourea as a pale yellow solid (m.p. 105° C.).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=[C:8]([Cl:15])[C:9]=1[O:10][CH2:11][CH:12]1[CH2:14][CH2:13]1.Cl>CN(C=O)C.O>[Br:3][C:4]1[CH:5]=[C:6]([CH:16]([CH2:4][CH2:9][O:10][CH3:11])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=[C:8]([Cl:15])[C:9]=1[O:10][CH2:11][CH:12]1[CH2:13][CH2:14]1
Reactant: CCOC(=O)Cc1cc(Cl)c(OCC2CC2)c(Br)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CCOC)c1cc(Cl)c(OCC2CC2)c(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.4 %

Procedure:
To a stirred solution of NaH (0.3 g, 12.5 mmol) in DMF (10 mL) was added ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate (2.0 g, 5.70 mmol) at 0° C. The reaction mixture was stirred at 0° C. over a period of 30 min. To the reaction mixture was added 2-bromo ethyl methyl ether (0.87 g, 6.25 mmol) and stirred at 0 oC for 30 min. After completion of starting material (by TLC), the reaction mixture was diluted with water (20 mL), acidified with 1N HCl (pH=5) and extracted with EtOAc (3×50 mL). Combined organic layers were washed with water (3×25 mL), brine and dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the crude material was purified by column chromatography to afford ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)-phenyl)-4-methoxybutanoate (560 mg) as an off white solid.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:12]O)[C:5]([CH3:14])=[CH:4][CH2:3]1.S(Cl)([Cl:17])=O>ClCCl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:12][Cl:17])[C:5]([CH3:14])=[CH:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: CC1=CCN(C)c2c(CO)cccc21
Solvent: ClCCl
Product: CC1=CCN(C)c2c(CCl)cccc21
Yield: 81 %

Procedure:
1,4-Dimethyl-8-hydroxymethyl-1,2-dihydroquinoline (0.9 g) was dissolved in dichloromethane (30 ml). To this solution was added dropwise thionylchloride (0.6 g) with stirring under ice-cooling, and the mixture was stirred for 30 minutes. After completion of the reaction, dichloromethane was distilled off under reduced pressure, and n-hexane was added to the residue. The mixture was concentrated under reduced pressure to give 1,4-dimethyl-8-chloromethyl-1,2-dihydroquinoline (0.8 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][CH2:16]Br)/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][CH2:16][N:18]=[N+:19]=[N-:20])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)/C(=N\OCCBr)c1csc(N)n1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=N\OCCN=[N+]=[N-])c1csc(N)n1
Yield: 96.3 %

Procedure:
1 g of ethyl 2-(2-amino-4-thiazolyl)-2-[(Z)-(2-bromoethoxy)imino]-acetate in 20 ml of dimethylformamide is warmed to 50° C. for 12 hours with 9.5 g of sodium azide. The mixture is diluted with ethyl acetate, washed three times with water, dried over magnesium sulphate and evaporated. After recrystallization from acetone/isopropanol, there is obtained 0.85 g of ethyl 2-(2-amino-4-thiazolyl)-2-[(Z)-(2-azidoethoxy)imino]-acetate of melting point 123°-124° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[F:31][C:32]1[C:33]([C:38]([NH:40][NH2:41])=O)=[N:34][CH:35]=[CH:36][CH:37]=1>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:38]([C:33]3[C:32]([F:31])=[CH:37][CH:36]=[CH:35][N:34]=3)=[N:40][N:41]=[C:14]2[CH2:13]1)=[O:11]
Reactant: NNC(=O)c1ncccc1F
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(Cl)c(F)c1Cl)N1CCn2c(nnc2-c2ncccc2F)C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
4-[(2,4-Dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37)(0.3 g, 1.031 mmol) was dissolved in Dichloromethane (DCM) (2.58 ml). triethyloxonium tetrafluoroborate (0.235 g, 1.237 mmol) was added and the solution was left to stir, under an argon atmosphere for 30 minutes. 3-Fluoro-2-pyridinecarbohydrazide (I31) (0.192 g, 1.237 mmol) was added and the solution was left to stir for a further 40 minutes. The solvent was removed under reduced pressure and 1-butanol (2.58 ml) was added. The reaction mixture was left to reflux at 120° C., under an argon atmosphere for 3.5 hours. The solvent was removed under reduced pressure to afford crude product in 0.887 g. The crude material was purified by flash chromatography (Biotage Isolera 4, 50 g cartridge) with a gradient of MeOH 0-10% in DCM. The solvent was removed under reduced pressure to afford 0.254 g of the desired compound. The isolated material was purified using MDAP to afford the purified product in 0.110 g.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=[C:10]3[CH:9]=[C:8]2/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:4][CH:3]=1>CCO.CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=[C:10]3[CH:9]=[C:8]2[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=1
Reactant: CCOC(=O)/C=C/c1cc2cc(OC)cnc2n1Cc1ccc(Cl)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CCc1cc2cc(OC)cnc2n1Cc1ccc(Cl)cc1

Procedure:
To a solution of Ethyl (E)-3-[1-(4-chloro-benzyl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl]-acrylate (100 mg, 0.270 mmol) in a mixture of EtOH (2 mL) and EtOAc (2 mL) was added Pd/C (˜15 mg) and maintained under an atmosphere of H2 for 36 hrs. The resulting slurry was filtered through celite eluting with EtOAc, and the solvent evaporated to afford the title acid as a green oil used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13](=[N:15]O)[CH3:14])[CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:15][CH:13]([CH:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12]1)[CH3:14]
Reactant: CC(=NO)C1CC(=O)N(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(N)C1CCN(Cc2ccccc2)C1
Yield: 102.7 %

Procedure:
30 ml of anhydrous tetrahydrofuran (THF) was added to 650 mg of 1-benzyl-4-(1-hydroxyiminoethyl)-2-pyrrolidone and 500 mg of lithium aluminum hydride and the obtained mixture was refluxed for 20 h. After the decomposition of lithium aluminum hydride, the precipitate was filtered and washed thoroughly with THF. The wash solution was added to the filtrate. The solvent was distilled off under reduced pressure to obtain 587 mg of the desired compound in the form of a light yellow oil.
Reaction SMILES: O.[ClH:2].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[NH:17])=[CH:8][CH:7]=1)([O-])=O>CO>[ClH:2].[NH2:3][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[NH:17])=[CH:8][CH:7]=1
Reactant: N=C1CCCN1c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: N=C1CCCN1c1ccc(N)cc1
Reaction time: 17 h

Procedure:
2.5 g of water-moist palladium on activated carbon (5% of Pd) are added to a solution of 25.0 g (103 mmol) of 1-(4-nitrophenyl)pyrrolidin-2-ylideneamine, hydrochloride, in 500 ml of methanol, and the mixture is hydrogenated at room temperature for 17 hours. The catalyst is filtered off, and the filtrate is evaporated, giving 1-(4-aminophenyl)pyrrolidin-2-ylideneamine, hydrochloride, as a brownish solid; ESI 176.
Reaction SMILES: C(OC(=O)[N:10]([CH2:21][CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:32]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[O:33])[CH:30]=2)[NH:25][C:24]=1[C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[C:42]([CH3:47])[CH:41]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)C1C=CC=CC=1.[H][H].[NH4+].[OH-]>[OH-].[OH-].[Pd+2].COCCO>[CH3:47][C:42]1[CH:41]=[C:40]([C:24]2[NH:25][C:26]3[C:31]([C:23]=2[CH2:22][CH2:21][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:30][C:29]([C:32]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:33])=[CH:28][CH:27]=3)[CH:45]=[C:44]([CH3:46])[CH:43]=1
Reactant: [H][H]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N4CCOCC4)cc3c2CCN(CCCCc2ccncc2)C(=O)OCc2ccccc2)c1
Agent: [Pd+2]
Agent: [NH4+]
Agent: [OH-]
Solvent: COCCO
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N4CCOCC4)cc3c2CCNCCCCc2ccncc2)c1

Procedure:
A mixture of 113 mg (0.175 mmol) of [2-[2-(3,5-dimethylphenyl)-5-(morpholine-4-carbonyl)-1H-indol-3-yl]ethyl]-(4-pyridin-4-ylbutyl)carbamic acid benzyl ester, 50 mg of 20% palladium hydroxide on carbon, and 10 mL of 2-methoxyethanol was shaken with hydrogen (approx. 50 psig) in a pressure vessel for 2.5 hours. The catalyst was removed by filtration through Celite, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient elution from 99:1:0.1 to 94:6:0.6 CH2Cl2-MeOH-concd. NH4OH) yielded 53.2 mg (60%) of a white, stiff foam; homogeneous by TLC in 95:5:0.5 CH2Cl2-MeOH-concd. NH4OH. 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (ESI): m/e=511.5 (M+H).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20](Br)[CH:21]=1>>[Br:15][C:16]1[CH:21]=[C:20]([N:5]2[CH2:6][C@@H:1]3[CH2:7][C@H:4]2[CH2:3][N:2]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:19]=[N:18][CH:17]=1
Reactant: Brc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cncc(Br)c1

Procedure:
tert-Butyl (1S,4S)-2,5-diazabicyclo [2.2.1]heptane-2-carboxylate, prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), and 3,5-dibromopyridine (purchased from Avocado Research Chemicals, Ltd.) were coupled according to the procedure described in Example 1A to provide the title compound. MS (DCI/NH3) m/z 354 (M+H)+.
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[CH3:7]/[C:8](/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:9]\[CH:10]=[O:11].Cl>>[OH:11][C@@H:10]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])/[CH:9]=[C:8](\[CH3:7])/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COP([O-])OC
Reactant: C/C(=C\C=O)c1ccccc1
Agent: Cl
Product: COP(=O)(OC)[C@H](O)/C=C(\C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
The solution of ALB in tetrahydrofuran (0.1 M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 μl, 0.40 mmol) at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes, then (E)-β-methylcinnamaldehyde (0.40 mmol) was added thereto. After reacting for 81 hours, 1N hydrochloric acid was added thereto to stop the reaction. The mixture was extracted with ethyl acetate (10 ml×three times), and the combined extracts were washed with brine and dried over Na2SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain dimethyl (S,E)-1-hydroxy-3-methyl-3-phenyl-2-propenylphosphonate as a final product in a yield of 93%. The chemical reaction in this Example is shown in chemical formula 35. ##STR29##
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH2:30][CH2:31][NH:32][CH2:33][CH:34]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21]>>[CH3:19][S:20]([C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH2:34][CH2:33][N:32]([C:9]([C:8]3[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:7]=3[N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[O:11])[CH2:31][CH:30]=2)=[CH:27][CH:28]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)c1ccc(C2=CCNCC2)cc1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Product: CS(=O)(=O)c1ccc(C2=CCN(C(=O)c3cc([N+](=O)[O-])ccc3N3CCOCC3)CC2)cc1

Procedure:
According to the procedure described for the synthesis of example 4, step f, the title compound has been synthesized from 2-Morpholin-4-yl-5-nitro-benzoic acid and 4-(4-Methanesulfonyl-phenyl)-1,2,3,6-tetrahydro-pyridine. MS (m/e): 470.1 (M−H, 100%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[C:3]=1[CH2:16][C:17]([OH:19])=O>O>[F:15][C:11]1[CH:12]=[CH:13][C:14]2[C:17](=[O:19])[CH2:16][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[S:8][C:9]=2[CH:10]=1
Reactant: O=C(O)Cc1c(Cl)cccc1Sc1cccc(F)c1
Solvent: O
Product: O=C1Cc2c(Cl)cccc2Sc2cc(F)ccc21
Reaction time: 3 h
Yield: 82.5 %

Procedure:
The mixture of 8.0 g of 2-chloro-6-(m-fluoro-phenylthio)-phenylacetic acid and 80 g at polyphosphoric acid was stirred at 120°-125° C. for 3 hours. After cooling, to the mixture was added water and the mixture was extracted with chloroform. The extract was washed with 100 ml of 1% sodium hydroxide solution, then water, dried over anhydrous sodium sulfate and freed of the solvent to afford 6.2 g (83%) of 3-fluoro-9-chloro-10,11-dihydrodibenzo[b,f]thiepin-11-one having a melting point of 109°-111° C.
Reaction SMILES: CS(O[C@@H:6]1[C@@H:11]([CH3:12])[CH2:10][N:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:8][C@H:7]1[NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])(=O)=O.[N-:42]=[N+:43]=[N-:44].[Na+]>CN(C=O)C>[N:42]([C@H:6]1[C@@H:11]([CH3:12])[CH2:10][N:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N:19]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:8][C@H:7]1[NH:34][C:35]([O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:36])=[N+:43]=[N-:44]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1OS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N=[N+]=[N-]
Temperature: 90 °C
Yield: 98.9 %

Procedure:
To a solution of (3R,4R,5S)-1-{3-[bis(tert-butoxycarbonyl)amino]pyridin-4-yl}-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-4-yl methanesulfonate (0.57 g, 0.96 mmol) in DMF (5.0 mL), sodium azide (0.31 g, 4.8 mmol) was added. The reaction mixture was heated at 90° C. for 5 h then allowed to cool. The solution was then partitioned between EtOAc and water. The layers were separated organic layer was washed with aq. Na2CO3 and brine, then dried, filtered and concentrated under reduced pressure to give the sub-title compound (0.52 g, 99%). LCMS calc. for C26H42N7O6 (M+H)+: m/z=548.3. Found: 548.4.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH:24]([CH3:26])[CH3:25])=[N:7][C:8]([CH:21]([CH3:23])[CH3:22])=[C:9]([CH2:18][CH:19]=O)[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O.[Br-].[CH3:28][C:29]1[CH:54]=[CH:53][CH:52]=[CH:51][C:30]=1[CH2:31][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[CH:24]([C:6]1[C:5]([CH2:3][OH:2])=[C:10]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[C:9]([CH2:18][CH2:19][CH2:28][C:29]2[CH:54]=[CH:53][CH:52]=[CH:51][C:30]=2[CH3:31])=[C:8]([CH:21]([CH3:23])[CH3:22])[N:7]=1)([CH3:26])[CH3:25]
Reactant: Cc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1c(C(C)C)nc(C(C)C)c(CC=O)c1-c1ccc(F)cc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccccc1CCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from methyl-2,6-diisopropyl-4(4-fluorophenyl)-5-(2-oxoethyl)-3-pyridinecarboxylate (Example 82, Step A) and 2-methylbenzyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps F-H. 1H NMR (300 MHz, CDCl3): δ 7.07 (m, 7 H), 6.90 (m, 1 H), 4.31 (s, 2 H), 3.39 (sept, J=6.6 Hz, 1 H), 3.15 (sept, J=6.6 Hz, 1 H), 2.43 (t, J=7.5 Hz, 2 H), 2.34 (m, 2 H), 2.17 (s, 3 H), 1.6 (m, 2 H), 1.31 (d, J=6.6 Hz, 6 H), 1.27 (d, J=6.6 Hz, 6 H), 1.15 (m, 1 H). FAB-MS: calcd for (C28H34FNO) 419, found 420 (M+H). Anal. Calcd for C28H34FNO: C, 80.15; H, 8.17; N, 3.34. Found: C, 80.12; H, 8.01; N, 3.25. mp 65-70° C. Rf=0.4 (20% ethyl acetate/hexane).