Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([OH:14])=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[O:15]1[C:19]2([CH2:24][CH2:23][C:22]([CH2:25]O)=[CH:21][CH2:20]2)[O:18][CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)(=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:14][CH2:25][C:22]3[CH2:23][CH2:24][C:19]4([O:15][CH2:16][CH2:17][O:18]4)[CH2:20][CH:21]=3)=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: OCC1=CCC2(CC1)OCCO2
Reactant: CC(=O)N1CCc2cc(O)c(Br)cc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N1CCc2cc(OCC3=CCC4(CC3)OCCO4)c(Br)cc21
Reaction time: 1 h
Yield: 180.6 %

Procedure:
1-Acetyl-6-bromo-2,3-dihydro-1H-indol-5-ol (Tetrahedron 1973, 29, 1115) (1.10 g, 4.3 mmol), 1,4-dioxaspiro[4,5]dec-7-ene-8-methanol (D11, 0.88 g, 5.2 mmol) and triphenylphosphine (1.36 g, 5.2 mmol) were stirred under Ar in dry THF (50 ml) as diethyl azodicarboxylate (0.82 ml, 5.2 mmol) was added dropwise. The mixture was stirred for 1 h, diluted with ethyl acetate (100 ml), washed with brine, dried (Na2SO4) and evaporated to give a dark oil. Chromatography on silica gel, eluting with 0-5% methanol/dichloromethane, gave the title compound (3.17 g) contaminated by substantial amounts of triphenylphosphine and diethyl azodicarboxylate-derived residues (NMR).
Reaction SMILES: [Br:1][C:2]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.[B-](F)(F)(F)[F:33].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.O>C(#N)C>[Br:1][C:2]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:13]=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([O:18][CH3:19])[C:17]=3[F:33])[N:9]=[C:4]2[CH:3]=1
Reactant: F[B-](F)(F)F
Reactant: COc1cc(CCc2cnc3c(cc(Br)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O
Solvent: CC#N
Product: COc1cc(CCc2cnc3c(cc(Br)n3S(=O)(=O)c3ccccc3)n2)c(F)c(OC)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (25.0 mg, 0.0498 mmol) and 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (17.6 mg, 0.0498 mmol) in acetonitrile (0.3 mL)/water (0.06 mL) was stirred at 50° C. overnight. The solvent was removed and the residue was used in the next step w/o purification. LCMS calculated for C22H20BrFN3O4S (M+H)+: m/z=520.0. Found 520.0.
Reaction SMILES: Cl[C:2](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)[C:3](=[O:5])[CH3:4].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.C(N(CC)CC)C>C(O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:2](=[N:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)[C:3](=[O:5])[CH3:4])=[CH:18][CH:17]=1
Reactant: CC(=O)C(Cl)=NNc1ccc(Br)cc1
Reactant: Sc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)C(=NNc1ccc(Br)cc1)Sc1ccc(Cl)cc1

Procedure:
1-chloro-1-[(4-bromophenyl)hydrazono]-2-propanone is reacted with 4-chlorothiophenol and triethyl amine in ethanol as Example 11 to yield 1-[(4-chlorophenyl)thio]-1-[(4-bromophenyl)hydrazono]-2-propanone.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[N:23]=[C:22]([NH2:24])[C:21]([N+:25]([O-])=O)=[CH:20][C:6]=1[C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11]1)=[O:8].CO>[Ni].C1COCC1>[NH2:25][C:21]1[C:22]([NH2:24])=[N:23][C:5]([O:4][CH2:3][CH2:2][F:1])=[C:6]([CH:20]=1)[C:7]([NH:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]([F:18])([F:17])[F:19])[CH2:14][CH2:15]1)=[O:8]
Reactant: Nc1nc(OCCF)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(OCCF)nc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(2-fluoro-ethoxy)-6-amino-5-nitro-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (220 mg, 0.56 mmol), Ra—Ni (50 mg), MeOH (5 mL) and THF (15 mL) is stirred at rt for 2 h under a hydrogen atmosphere (3.0 bar). The catalyst is removed by filtration and the filtrate is concentrated.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]([CH2:24][N:25]4[CH2:28][CH:27]([C:29]([O:31]CC)=[O:30])[CH2:26]4)[S:22][CH:23]=3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]([CH2:24][N:25]4[CH2:26][CH:27]([C:29]([OH:31])=[O:30])[CH2:28]4)[S:22][CH:23]=3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CN(Cc2cc(-c3noc(-c4ccc(Cc5ccccc5)cc4)n3)cs2)C1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1CN(Cc2cc(-c3noc(-c4ccc(Cc5ccccc5)cc4)n3)cs2)C1
Yield: 86.3 %

Procedure:
The title compound (67 mg) was synthesized in a yield of 86% as a white crystalline solid by conducting the reaction similar to that mentioned in Example 3 (3e) using ethyl 1-({4-[5-(4-benzylphenyl)-1,2,4-oxadiazol-3-yl]-2-thienyl}methyl)azetidine-3-carboxylate (82 mg, 0.18 mmol) that was obtained in Example 6 (6b), and a 1N aqueous solution of sodium hydroxide (0.54 ml, 0.54 mmol).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[S:14][C:13]2[CH2:12][CH2:11][CH2:10][O:9][C:8]=2[CH:7]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[S:14]1[C:13]2[CH2:12][CH2:11][CH2:10][O:9][C:8]=2[CH:7]=[C:6]1[CH:2]=[O:1]
Reactant: c1c(C2OCCO2)sc2c1OCCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: O=Cc1cc2c(s1)CCCO2

Procedure:
2-(1,3-Dioxolan-2-yl)-6,7-dihydro-5H-thieno[3,2-b]pyran (0.48 g, 2.24 mmol) was dissolved in acetone (25 ml) and water (25 drops) and stirred with polystyrene-sulfonic acid resin (MP-TsOH, Argonaut Technologies inc, 1.35 mmol/g, 200 mg, 0.27 mmol) overnight. The reaction mixture was filtered, the filtrate evaporated and azeotroped with toluene. The title compound was obtained as a pale orange oil (0.44 g).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:3]=1.[Br:20][C:21]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:22]=1[CH:23]=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:20][C:21]1[CH:28]=[CH:27][C:26]([O:29][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][CH2:12][O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[N:3]=2)=[CH:25][C:22]=1[CH:23]=[O:24]
Reactant: N#Cc1ccc(Cl)nc1OCCOC1CCCCO1
Reactant: O=Cc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(Br)c(C=O)c2)nc1OCCOC1CCCCO1
Temperature: 80 °C
Yield: 71.2 %

Procedure:
To a mixture of 6-chloro-2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-nicotinonitrile (2.4 g, 8.48 mmol) and 2-bromo-5-hydroxy-benzaldehyde (1.87 g, 9.33 mmol) in DMF (25 mL) was added potassium carbonate (1.75 g, 12.69 mmol). The resulting mixture was heated at 80° C. overnight. DMF was removed under reduced pressure, the residue was diluted with EtOAc (200 mL), washed with water (20 mL) and brine (3×20 mL), dried over Na2SO4, filtered, and concentrated to give white solid. Purification was accomplished by flash chromatography on silica gel using 5-25% EtOAc/hexanes as gradient elution yielding the title compound (2.7 g, 71%) as white solid. 1H NMR (400 MHz, CDCl3) δ ppm 10.35 (s, 1H), 7.88 (d, J=8.2 Hz, 1H), 7.75 (d, J=2.7 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.28 (dd, J=8.6, 3.5 Hz, 1H), 6.60 (d, J=8.2 Hz, 1H), 4.64 (s, 1H), 4.28 (t, J=4.9 Hz, 2H), 3.97-3.80 (m, 2H), 3.72-3.60 (m, 1H), 3.55-3.42 (m, 1H), 1.84-1.64 (m, 2H), 1.61-1.49 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1([CH3:48])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([O:37]C(=O)N(C)C)[CH2:20][C@@H:21]3[O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[CH:16][C@H:15]4[O:43]C(OC)=O)[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1.CC1(C)COC(C([C@@H]2[C@]3(C)[C@H]([C@H]4[C@H](CC3)[C@]3(C)C(C[C@@H](OC(OC)=O)C[C@@H]3OC(OC)=O)=C[C@H]4OC(OC)=O)CC2)C)OC1>>[CH3:48][C:2]1([CH3:1])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([OH:37])[CH2:20][C@@H:21]3[O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[CH:16][C@H:15]4[OH:43])[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1
Reactant: COC(=O)O[C@@H]1C=C2C[C@@H](OC(=O)N(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12
Agent: COC(=O)O[C@@H]1CC2=C[C@@H](OC(=O)OC)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Product: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 71.2 %

Procedure:
The reaction and workup procedures of Example 140 were repeated except that 95 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α-(tert-butyldimethylsilyl)oxy-3β-(N,N-dimethylcarbamoyl)oxy-7α-(methoxycarbonyl)oxypregna-5-ene was used in lieu of 100 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,3β,7α-tris(methoxycarbonyloxy)pregn-5-ene to give 55 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α-(tert-butyldimethylsilyl)oxypregn-5-ene-3β,7α-diol showing the following physical properties.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][CH:6]([O:8][CH2:9][CH2:10][C:11]#[N:12])[CH3:7])#[N:2].C(#N)C=C.C(O)CO.[OH-].[Li+].COC(C)C#N.[C:29]([CH2:31][CH2:32][O:33][CH:34](O)C)#[N:30]>CO>[C:11]([CH2:10][CH2:9][O:8][CH:6]([O:5][CH2:4][CH2:3][C:1]#[N:2])[CH3:7])#[N:12].[CH3:34][O:33][CH2:32][CH2:31][C:29]#[N:30]
Reactant: CC(O)OCCC#N
Agent: CC(OCCC#N)OCCC#N
Agent: COC(C)C#N
Agent: [Li+]
Solvent: CO
Solvent: OCCO
Solvent: C=CC#N
Product: COCCC#N
Temperature: 50 °C
Reaction time: 2 h

Procedure:
As in Example 1, bis(2-cyanoethoxy)ethane was prepared by the addition of 623 g (11.73 moles) of acrylonitrile to 310 g (5.0 moles) of ethylene glycol containing 1.0 g of anhydrous lithium hydroxide at 55°-60° C. over a period of 90 min. The reaction was permitted to stir an additional 2 hr at 50° C. The reaction contents were cooled to 25° C. and 88.0 g (2.75 moles) of methanol was added over a period of 1 hr while maintaining the temperature between 25°-30° C. The mixture was allowed to stir an additional 12 hr at room temperature. Analysis by NMR revealed the crude product mixture to be 79.7 wt % of bis(2-cyanoethoxy)ethane, 17.4 wt % methoxypropionitrile, 1.78 wt % methanol, 0.72 wt % of 2-cyanoethoxyethanol, and 0.33 wt % acrylonitrile.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])[CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])[CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1cccc(COc2nn(Cc3ccccc3)cc2CO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccco2)nc1COc1cccc(COc2nn(Cc3ccccc3)cc2C=O)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 98.5 %

Procedure:
A mixture of {1-benzyl-3-[(3-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazol-4-yl}methanol (0.51 g), activated manganese dioxide (1.50 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 3 days. Manganese dioxide was removed by filtration and the filtrate was concentrated. The obtained crystals were collected by filtration to give 1-benzyl-3-[(3-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carbaldehyde (0.50 g, yield 96%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 135-136° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:21])([CH3:20])[CH2:10][NH:11][CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[NH2:19])=[CH:4][CH:3]=1.C1([O:28][C:29](=O)[NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]3[N:41]([CH3:42])[N:40]=[N:39][N:38]=3)[CH:32]=2)C=CC=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([CH3:21])([CH3:20])[CH2:10][NH:11][CH2:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[NH:19][C:29]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]3[N:41]([CH3:42])[N:40]=[N:39][N:38]=3)[CH:32]=2)=[O:28])=[CH:6][CH:7]=1
Reactant: Cn1nnnc1-c1cccc(NC(=O)Oc2ccccc2)c1
Reactant: CC(C)(CNCC1CCCCC1N)Cc1ccc(F)cc1
Product: Cn1nnnc1-c1cccc(NC(=O)N[C@@H]2CCCC[C@H]2CNCC(C)(C)Cc2ccc(F)cc2)c1

Procedure:
Using the amine from Step e and [3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-carbamic acid phenyl ester, the titled compound was prepared by the methods desribed in Step d of Example 2.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][CH:5]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=2[S:28]([CH3:31])(=[O:30])=[O:29])[C:4]=1[C:32](OCC)=[O:33].[C:37]1([NH:43][NH2:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCOCC1>[O:19]=[C:7]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=2)[C:3]2[CH2:2][N:43]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[NH:44][C:32](=[O:33])[C:4]=2[CH:5]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=2[S:28]([CH3:31])(=[O:29])=[O:30])[NH:6]1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)C1=C(CBr)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1S(C)(=O)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)NN(c1ccccc1)C2

Procedure:
Ethyl 6-(bromomethyl)-4-[4-cyano-2-(methylsulphonyl)phenyl]-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (150 mg, 0.256 mmol; Example 19A) was initially charged in dioxane (3.5 ml). Phenylhydrazine (83.0 mg, 0.767 mmol) was added dropwise to the reaction mixture, and the mixture was then stirred at boiling point for 3 h. The reaction mixture was then separated directly by preparative HPLC (Method 12). This gave 9 mg (6% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:30])[NH:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10]1.[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].S([O-])([O-])(=O)=O>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:30])[NH:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10]1.[C:31]([O-:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([O-:36])=[O:35]
Reactant: O=C(O)/C=C/C(=O)O
Agent: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Agent: O=S(=O)([O-])[O-]
Product: O=C([O-])/C=C/C(=O)[O-]

Procedure:
By using 1.0 g of 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydrocarbostyril and 290 mg of fumaric acid, and treated by procedures similar to those employed in the case of preparation of the sulfate as mentioned above, and recrystallized from ethanol to yield 0.97 g of 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydrocarbostyril·fumarate.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=O)[CH2:2][CH3:3].[CH3:14][O:15][S:16]([OH:19])(=[O:18])=[O:17].C(OC1C=CC=CC=1C(N)=[NH:26])C>>[CH3:14][O:15][S:16]([OH:19])(=[O:18])=[O:17].[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:26])=[NH:9])[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1C(N)=O
Reactant: CCOc1ccccc1C(=N)N
Agent: COS(=O)(=O)O
Product: CCCOc1ccccc1C(=N)N
Yield: 74 %

Procedure:
The title compound (74% yield) was prepared from 2-n-propoxybenzamide in a manner similar to that described for the preparation of 2-ethoxybenzamidine methyl sulfate in Preparation 6 above.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O[C:44]1[CH:45]=[CH:46][C:47]([CH:50]=[C:51]2[NH:56][C:55](=[O:57])[C:54](=[CH:58][CH2:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62]C=3)[NH:53][C:52]2=[O:66])=[N:48][CH:49]=1>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([O:12][C:44]1[CH:49]=[N:48][C:47](/[CH:50]=[C:51]2\[NH:56][C:55](=[O:57])/[C:54](=[CH:58]/[C:59]3[CH:60]=[CH:65][CH:64]=[CH:63][CH:62]=3)/[NH:53][C:52]\2=[O:66])=[CH:46][CH:45]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccccc1
Reactant: O=c1[nH]c(=Cc2ccc(O)cn2)c(=O)[nH]c1=CCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(C(=O)Oc1ccc(/C=c2\[nH]c(=O)/c(=C/c3ccccc3)[nH]c2=O)nc1)c1ccccc1

Procedure:
2-(Tert-butoxycarbonylamino)-2-phenylacetic acid was dissolved in DMF and treated with HBTU. Compound C were then added into the mixture and stirred. After the completion of reaction, the reaction mixture was partitioned by K2CO3(aq) and CH2Cl2. The organic layer was collected, dried over MgSO4(s), and dried by rotary evaporator. The solid residues were then purified by column chromatography to get Compound 8. mp 198° C.; 1H-NMR (400 MHz, CDCl3): δ 1.50 (s, 9H), 5.48 (s, 1H), 5.58-5.59 (m, 1H), 6.78 (s, 1H), 7.11 (s, 1H), 7.37-7.50 (m, 13H), 8.22 (s, 1H), 8.42 (s, 1H), 12.46 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Br:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[Br:25])[CH:21]([CH3:26])[NH:20][CH2:19][CH2:18]2>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH2:19][CH2:18][C:17]4[C:22](=[CH:23][C:24]([Br:25])=[C:15]([Br:14])[CH:16]=4)[CH:21]3[CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2cc(Br)c(Br)cc21
Product: CC1c2cc(Br)c(Br)cc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dibromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: CS(O[CH:6]1[CH2:10][O:9][CH:8]2[CH:11]([O:14][CH2:15][CH2:16][O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][O:13][CH:7]12)(=O)=O.[N:25]([Na])=[N+:26]=[N-:27]>CN(C=O)C>[N:25]([CH:6]1[CH2:10][O:9][CH:8]2[CH:11]([O:14][CH2:15][CH2:16][O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][O:13][CH:7]12)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=N[Na]
Reactant: CS(=O)(=O)OC1COC2C(OCCOCc3ccccc3)COC12
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1COC2C(OCCOCc3ccccc3)COC12
Temperature: 140 °C

Procedure:
To a suspension of 6-(2-(benzyloxy)ethoxy)hexahydrofuro[3,2-b]furan-3-yl methanesulfonate (1.40 g, 3.91 mmol) in DMF (15 mL) was added azidosodium (1.38 g, 21.15 mmol) and the mixture was heated at 140° C. for 48 h then the mixture was filtered. The filtrate was diluted with DCM (200 mL), then washed with water (100 mL×3), followed by brine (100 mL×2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product. The crude product was used in the next reaction without further treating.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([CH3:14])[CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1.C(O[CH:18](OCC)[N:19]([CH3:21])[CH3:20])C>>[CH3:18][N:19]([CH:21]=[C:9]1[CH2:8][CH:7]([CH3:14])[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]1=[O:13])[CH3:20]
Reactant: CCOC(OCC)N(C)C
Reactant: COc1ccc2c(c1)C(=O)CCC2C
Product: COc1ccc2c(c1)C(=O)C(=CN(C)C)CC2C
Yield: 75 %

Procedure:
The 3,4-dihydro-2-dimethylaminomethylene-7-methoxy-4-methyl-1(2H)-naphthalenone starting material was prepared from 3,4-dihydro-7-methoxy-4-methyl-1-(2H) naphthalenone (950 mg, 5.0 mmol) [Gupta, A S; et al Tetrahedron (1967), 23, 2481], and N,N-dimethylformamide diethyl acetal (2.6 ml, 15.0 mmol). The product was purified by chromatography on silica (70% ethyl acetate in hexane—ethyl acetate) to give 3,4-dihydro-2-dimethylaminomethylene-7-methoxy-4-methyl-1(2H) naphthalenone as a yellow oil (920 mg). δH (CDCl3) 7.77 (1H, s), 7.58 (1H, d, J 2.9 Hz), 7.12 (1H, d, J 8.4 Hz), 6.97 (1H, dd, J 2.9, 8.4 Hz), 3.85 (3H, s), 3.13 (6H, s), 3.01-2.90 (2H, m), 2.76-2.70 (1H, m) and 1.28 (3H, d, J 6.9 Hz). IR (liquid film) 1647 (s), 1547 (s) cm−1.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])(=[O:5])[CH3:4].Cl[CH:15]1[CH2:19][CH2:18][CH:17]=[CH:16]1>CN(C=O)C>[CH:19]1([O:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:3](=[O:5])[CH3:4])[CH2:18][CH2:17][CH:16]=[CH:15]1
Reactant: ClC1C=CCC1
Reactant: CC(=O)Nc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccccc1OC1C=CCC1
Reaction time: 8 h
Yield: 67.6 %

Procedure:
To a suspension of sodium hydride (60 proc. in paraffin; 297 mg, 7.43 mmol, 1.1 equiv.) in DMF (3 ml) a solution of 2-acetamido-phenol (1.02 g, 6.75 mmol, 1.0 equiv.) in DMF (12 ml) was added dropwise at 0° C. After 30 minutes chlorocyclopent-2-ene (R. Moffett, Organzic Synthesis, Wiley: New York 1963, Collect. Vol. IV, p.238-241) (762 mg, 0.76 ml, 7.43 mmol, 1.1 equiv.) was added by a syringe and stirring was continued overnight. Aqueous work-up followed by flash chromatography on silica gel (heptane/ethyl acetate, 2:1 continued to 1:1) afforded 992 mg (68%) of the subtitle compound as a dark, yellow oil.
Reaction SMILES: [CH:1]1[C:10]2[C@H:11]3[CH2:16][NH:15][CH2:14][CH2:13][C@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.Cl[CH2:18][CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)=[O:22].C([O-])([O-])=O.[K+].[K+]>>[CH:1]1[C:10]2[C@H:11]3[CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)=[O:22])[CH2:14][CH2:13][C@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1
Reactant: c1cc2c3c(c1)[C@H]1CNCC[C@H]1N3CCC2
Reactant: O=C(CCCCl)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(CCCN1CC[C@@H]2[C@H](C1)c1cccc3c1N2CCC3)c1ccncc1
Yield: 18.4 %

Procedure:
The title compound (0.080 g, 18%) was prepared by the general method of Example 402 from (±)-cis-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (0.25 g, 1.2 mmol), 4-chloro-1-(4-pyridinyl)-1-butanone (0.36 g, 2.0 mmol), KI (catalytic) and K2CO3 (0.28 g, 2.0 mmol) after chromatographic purification as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ1.68-2.18 (m, 7H), 2.20-2.65 (m, 5H), 2.69 (t, J=6.4 Hz, 2H), 2.72-2.82 (m, 1H), 2.92-3.08 (m, 3H), 3.15-3.28 (m, 2H), 6.62 (t, J=7.5 Hz, 1H), 6.86 (d, J=7.6 Hz, 1H), 6.89 (d, J=7.4 Hz, 1H), 7.70-7.80 (m, 2H), 8.75-8.82 (m, 2H) ppm.