Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]12[CH2:16][CH:12]3[CH2:13][CH:14]([CH2:15]1)[C:10](C(O)=O)([CH2:11]3)[CH2:9]2.OS(O)(=O)=O.[N-:26]=[N+]=[N-].[Na+]>C(Cl)(Cl)Cl.O>[O:1]=[S:2]1(=[O:20])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]12[CH2:16][CH:12]3[CH2:13][CH:14]([CH2:15]1)[C:10]([NH2:26])([CH2:11]3)[CH2:9]2
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)C12CC3CC1CC(CN1CCCS1(=O)=O)(C3)C2
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: NC12CC3CC1CC(CN1CCCS1(=O)=O)(C3)C2
Yield: 73.4 %

Procedure:
To a stirred solution of the acid obtained in step III (0.39 g, 1.31 mmol) in CHCl3 (7 mL) was added conc. H2SO4 (1.4 mL, 26 mmol). Solid NaN3 (0.26 g, 3.93 mmol) was added slowly in portions by keeping the reaction temperature below 40° C. The reaction mixture was stirred at r.t for 2, h then it was cooled to ice bath temperature, diluted with water, and extracted with EtOAc. The aqueous layer was basified by adding 50% NaOH solution and extracted with CHCl3. The combined organic layer was washed with brine, dried over Na2SO4, and the solvent was evaporated under reduced pressure to obtain 1-[(1,1-dioxidoisothiazolidin-2-yl) methyl]tricyclo[3.3.1.03,7]nonan-3-amine (0.26 g) as viscous liquid in 74% yield. m/z (M+1) 271; 1H NMR (CDCl3) 300 MHz δ 3.32 (t, J=6.8 Hz, 2H), 3.10 (t, J=7.4 Hz, 2H), 2.92 (s, 2H), 2.40-2.28 (m, 3H), 2.01-1.83 (m, 3H), 1.75-1.52 (m, 6H), 1.50-1.43 (m, 1H), 1.39-1.32 (m, 1H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14](=[O:22])/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[CH3:23][Si:24](Cl)([CH3:26])[CH3:25]>C1COCC1.CCCCCC>[CH3:23][Si:24]([CH3:26])([CH3:25])[O:22][C:14](/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH2:13]
Reactant: C[Si](C)(C)Cl
Reactant: CCCCC/C=C/C(C)=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=C(/C=C/CCCCC)O[Si](C)(C)C
Yield: 73.3 %

Procedure:
Pursuant to Dienylester Formation Protocol I, diisopropylamine (7.0 mL, 50.0 mmol, 1.4 eq) and n-butyllithium (32.4 mL, 46.5 mmol, 1.3 eq, 1.44 M in hexane) in THF (33 mL) were reacted with a solution of (E)-non-3-en-2-one (5.9 mL, 35.6 mmol, 1.0 eq) in THF (10 mL) and trimethylsilylchloride (8.0 mL, 62.6 mmol, 1.8 eq) in THF (30 mL). For the silylenolether, no aqueous workup was undertaken. n-Hexane (100 mL) was added to the reaction mixture, the residue filtered off and the solvent evaporated. The raw product was purified by distillation to yield 5.54 g (26.1 mmol, 74%) of (E)-trimethyl(nona-1,3-dien-2-yloxy)silane as a colorless oil.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([NH2:38])[CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:39](#[N:42])[CH:40]=[CH2:41].[OH-].[Na+].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH2:1]([O:17][CH2:18][CH:19]([NH:38][CH2:41][CH2:40][C:39]#[N:42])[CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=CC#N
Reactant: CCCCCCCCCCCCCCCCOCC(N)COCCCCCCCCCCCCCCCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCC)NCCC#N
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
A mixture of 1,3-di(n-hexadecyloxy)-2-aminopropane (500 mg., 0.93 mmoles), acrylonitrile (75 ml.) and 2 wt. % aqueous sodium hydroxide solution (75 ml.) was heated to 60° C. Tetrabutyl ammonium hydroxide (1 ml. of 40 wt. % aqueous solution) was then added and the resulting mixture stirred for 15 minutes at 90° C. The reaction mixture was then cooled, causing precipitation of solids, which were isolated by filtration and found (TLC) to contain a large quantity of unreacted starting material. Using fresh acrylonitrile and aqueous sodium hydroxide solution in each cycle, the solids were treated two more times by the above procedure The third cycle solid product was purified by silica gel chromatography (elution with toluene:ethyl acetate) [200 mg., 36% yield, m.p. 45°-46° C., ir (CHCl3) 2250 cm-1, n.m.r. (CDDl3) δ3.07 (t, 2, --NHCH2CH2CN) and 2.53 (t, 2, --NHCH2CH2CN)].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1[N+:21]([O-])=O)[O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1)([O-])=O.CC(O)=O>C1COCC1.[Zn]>[N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([O:7][C:6]2[CH:5]=[C:4]([NH2:1])[C:20]([NH2:21])=[CH:19][CH:18]=2)=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3ccccc23)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc3ccccc23)cc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(3,4-Dinitro-phenoxy)-quinoline (Step A, 400 mg, 1.2 mmol) was dissolved in THF at 0° C., and AcOH (1.5 mL) was added followed by zinc dust (2.5 g, 38 mmol). The mixture was stirred at RT for 1 h then filtered on a silica pad. The solvent was evaporated; the residue was dissolved in CH2Cl2 and washed with 1M NaOH. The organic phases were dried, filtered and evaporated to give the title compound, as a brown-orange oil.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[N:6]=[C:7]([F:29])[N:8]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=1)#[N:2].[OH-].[K+].OO.CC[O:36]CC>CC(C)=O>[C:1]([CH2:3][CH2:4][C:5]1[N:6]=[C:7]([F:29])[N:8]([C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=1)(=[O:36])[NH2:2]
Reactant: N#CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: CCOCC
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: NC(=O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
4-(2-Cyanoethyl)-2-fluoro-1-triphenylmethylimidazole was dissolved in acetone and treated with aqueous KOH. Hydrogen peroxide was added in portions over seven days at ambient temperature. Extractive work-up and trituration with ether gave 4-(2-carbamoylethyl)-2-fluoro-1-triphenylmethylimidazole, having the following n.m.r. spectrum in CDCl3 : 2.58 (m, 4H); 5.3 (br s, 1H; 6.0 (br s, 1H); 6.26 (s, 1H); 7.0-7.35 (m, 15H).
Reaction SMILES: [C:1](O)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]1([CH:19]=[CH:18][C:16]([OH:17])=[CH:15][CH:14]=1)[OH:13]>CCOCC>[OH:13][C:12]1[CH:19]=[C:18]2[C:16](=[CH:15][CH:14]=1)[O:17][C:1](=[O:10])[CH2:2][CH:3]2[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Oc1ccc(O)cc1
Reactant: O=C(O)C=Cc1ccccc1
Solvent: CCOCC
Product: O=C1CC(c2ccccc2)c2cc(O)ccc2O1
Yield: 97 %

Procedure:
6-Hydroxy-4-phenyl-3,4-dihydrocoumarin (II) was prepared in a similar way in 97% yield from cinnamic acid and hydroquinone. M.p. 138° (IPE-Ether).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14]C2CCCCO2)=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH:6]2.Cl.O.N>O1CCCC1>[OH:14][CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]2[C:7]=1[NH:6][C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:4]2
Reactant: CCOC(=O)c1cc2c(C)ccc(OCCOC3CCCCO3)c2[nH]1
Agent: Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(C)ccc(OCCO)c2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.6 %

Procedure:
Ethyl 4-methyl-7-[2-(2-tetrahydro-2H-pyranyl)oxyethoxy]-1H-indole-2-carboxylate (3.20 g, 9.21 mmol) was dissolved in tetrahydrofuran (70 ml), followed by adding thereto 2N hydrochloric acid (30 ml) at room temperature. The mixture was stirred at room temperature for 3 hours, after which water (200 ml) and then 28% aqueous ammonia were added thereto to neutralize (pH=7 to 8) the reaction mixture. Subsequently, the reaction mixture was extracted twice with ethyl acetate and the extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was crystallized from ethyl acetate to obtain ethyl 7-(2-hydroxyethoxy)-4-methyl-1H-indole-2-carboxylate (1.93 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([N:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)[OH:22])=[O:20])=[CH:14][CH:13]=1)[CH:7]=[CH:6]2.[CH3:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([N:21]([OH:22])[C:19](=[O:20])[NH:18][C:15]2[CH:14]=[CH:13][C:12]([N:8]3[C:9]4[C:5](=[CH:4][C:3]([NH:2][C:36](=[O:37])[N:35]([CH3:39])[CH3:34])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)=[CH:17][CH:16]=2)=[CH:24][C:25]=1[C:30]([F:33])([F:32])[F:31]
Reactant: Nc1ccc2c(ccn2-c2ccc(NC(=O)N(O)c3ccc(Cl)c(C(F)(F)F)c3)cc2)c1
Reactant: CN(C)C(=O)Cl
Agent: Cl
Product: CN(C)C(=O)Nc1ccc2c(ccn2-c2ccc(NC(=O)N(O)c3ccc(Cl)c(C(F)(F)F)c3)cc2)c1

Procedure:
The title compound can be synthesized from 1-[4-(5-aminoindol-1-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)-3-hydroxyurea hydrochloride and N,N-dimethyl-carbamic acid chloride by using the same techniques as in Example 41.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-])=O)[CH:27]=4)=[CH:14][N:15]3[C:18]3[N:23]=[CH:22][N:21]=[C:20]([NH:24][CH3:25])[CH:19]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>[Ni].CO.CN(C=O)C>[NH2:32][C:28]1[CH:27]=[C:26]([C:13]2[C:12]3[C:16](=[CH:17][C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[CH:10][CH:11]=3)[N:15]([C:18]3[N:23]=[CH:22][N:21]=[C:20]([NH:24][CH3:25])[CH:19]=3)[CH:14]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CNc1cc(-n2cc(-c3cccc([N+](=O)[O-])c3)c3ccc(-c4ccc(OC)cc4)cc32)ncn1
Agent: [Ni]
Solvent: CN(C)C=O
Solvent: CO
Product: CNc1cc(-n2cc(-c3cccc(N)c3)c3ccc(-c4ccc(OC)cc4)cc32)ncn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
Methanol/DMF (2:1, 20 mL) was added to 6-(6-(4-methoxyphenyl)-3-(3-nitrophenyl)-1H-indol-1-yl)-N-methylpyrimidin-4-amine (70 mg, 0.16 mmol) and Raney nickel (Raney Ni; about 50 mg). The mixture was stirred at room temperature for 12 hours under hydrogen gas (1 atm). The reaction solution was filtered using a diatomite pad and concentrated under reduced pressure. The target compound (60 mg) was obtained as brown solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)([OH:3])=[O:2].O[N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20].ClCCl.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[C:15]1(=[O:20])[N:14]([O:2][C:1]([C:4]2[CH:5]=[CH:6][C:7]([B:10]([OH:12])[OH:11])=[CH:8][CH:9]=2)=[O:3])[C:18](=[O:19])[CH2:17][CH2:16]1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(ON1C(=O)CCC1=O)c1ccc(B(O)O)cc1
Reaction time: 0.17 h

Procedure:
4-Carboxyphenyl-boronic acid (CPBA, Example 1, 0.25 g, 1.51 mmol) and N-hydroxysuccinimide (0.26 g, 2.26 mmol) were dissolved in 8.5 ml DMF using a magnetic stirrer. 20 ml of dichloromethane (CH2Cl2) was then added, and the solution was stirred for 10 minutes. N,N'-dicyclohexyl-carbodiimide (DCC, 0.93 g, 4.52 mmol) in 3 ml CH2Cl was then added. The solution was left to react under a nitrogen atmosphere overnight (approx. 12 hours) at ambient temperature, and then filtered to remove the insoluble urea byproduct (DCU). The title compound was used in subsequent reactions without further purification.
Reaction SMILES: [C:1]1([OH:9])[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8].NC1C=CC=CN=1.S(Cl)([Cl:19])=O.S(=O)(=O)(O)O.[N+:26]([O-:29])(O)=[O:27]>C1(C)C=CC=CC=1.C(O)(=O)C.O>[Cl:19][C:4]1[CH:5]=[C:6]([N+:26]([O-:29])=[O:27])[C:1]([OH:9])=[C:2]([CH3:8])[C:3]=1[CH3:7]
Reactant: Cc1cccc(O)c1C
Reactant: O=[N+]([O-])O
Reactant: O=S(Cl)Cl
Agent: Nc1ccccn1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(Cl)cc([N+](=O)[O-])c(O)c1C
Temperature: 25 °C

Procedure:
2,3-Xylenol (5 g, 40.9 mmol) was dissolved in toluene (100 ml), and the solution was added with 2-aminopyridine (0.3 g, 3.2 mmol). The mixture was added with thionyl chloride (3.3 ml) at room temperature with stirring, and then stirred at 7 C.° for 15 hours. The reaction mixture was cooled to room temperature, and then excessive reagents and solvent were evaporated under reduced pressure to obtain an oily substance. The substance was dissolved in acetic acid (12.5 ml), and the solution was added with concentrated sulfuric acid (50 ml), and then added dropwise with a mixed acid (2.5 ml of 70% nitric acid+10 ml of concentrated sulfuric acid) at room temperature over 30 minutes or more. The mixture was further stirred for 2 hours, and poured into iced water (500 ml). The precipitates were collected by filtration, and dried to obtain a crude product (3.8 g). The product was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1 v/v) to obtain the title compound (1.5 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[N:8]=[C:7]([C:12]3[C:13](C4C=CC(OCC)=CC=4)=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=3)[NH:6][C:5]=2[C:4]([CH2:31][CH2:32][CH3:33])=[N:3]1.[OH-].[Na+].[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.[CH3:43][C:44](C)=[O:45]>>[CH3:33][CH2:32][CH2:31][C:4]1[C:5]2[N:6]=[C:7]([C:12]3[CH:13]=[C:14]([S:18]([N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)(=[O:19])=[O:20])[CH:15]=[CH:16][C:17]=3[O:45][CH2:44][CH3:43])[NH:8][C:9](=[O:11])[C:10]=2[N:2]([CH3:1])[N:3]=1
Reactant: CCCc1nn(C)c2c(=O)nc(-c3cccc(S(=O)(=O)Cl)c3-c3ccc(OCC)cc3)[nH]c12
Reactant: CN1CCNCC1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3OCC)nc12
Temperature: 0 °C
Yield: 85 %

Procedure:
In a 3-necked flask, 3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo(4,3-d)pyrimidin-5-yl)-(4-ethoxyphenyl)benzene sulfonyl chloride (100 g, 0.24 mol) was mixed with acetone (1000 ml) at room temperature and NaOH (9.74 g, 47%). N-methyl piperazine (26.8 g, 0.27 mol) was added dropwise. The reaction mixture was stirred for 45 mm, cooled to 0° C., and filtered. The collected precipitate was washed with water twice and dried at 50° C. under 10 mm Hg to yield pure sildenafil in 85% yield.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@:13]1([CH3:37])[S:19][C@H:18]2[N:15]([C:16](=[O:20])[CH2:17]2)[C@H:14]1[C:21]([O:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].C(N(CC)CC)C>ClCCl>[CH:12]([C@:13]1([CH3:37])[S:19][C@H:18]2[N:15]([C:16](=[O:20])[CH2:17]2)[C@H:14]1[C:21]([O:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])=[O:11]
Reactant: C[C@@]1(CO)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@@]1(C=O)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: -60 °C
Reaction time: 3 h

Procedure:
100 ml of dichloromethane were treated with 0.84 ml (9.6 mmol) of oxalyl chloride under argon and cooled to -60° C. Thereto there were added dropwise 0.73 ml (10.25 mmol) of DMSO, followed by 2.5 g (6.52 mmol) of benzhydryl (2S,3R,5R)-3-hydroxymethyl-3-methyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylate dissolved in 100 ml of dichloromethane. The mixture was stirred at the same temperature for 3 hours and then 3.2 ml (23.0 mmol) of triethylamine were added. The cooling bath was removed and the mixture was left to warm to room temperature. The orange solution was poured into 1000 ml of 0.2N hydrochloric acid and the aqueous phase was extracted twice with dichloromethane. The organic phases were washed with water and saturated, aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The thus-obtained product (2.50 g, 100%) can be processed without further purification or can be recrystallized from diethyl ether.
Reaction SMILES: Cl.Cl.Cl.[CH2:4]([N:6]([CH2:32][CH3:33])[CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[C:22]([CH:23]=1)=[N:21][C:20]1[C:15](=[CH:16][CH:17]=[C:18]([O:24][CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH:19]=1)[CH:14]=2)[CH3:5].[CH2:34]=[O:35].CC[O:38][CH2:39]C>S(=O)(=O)(O)O>[CH2:28]([N:27]([CH2:30][CH3:31])[CH2:26][CH2:25][O:24][C:18]1[CH:17]=[CH:16][C:15]2[C:20]([C:19]=1[CH2:34][OH:35])=[N:21][C:22]1[C:23]([CH2:39][OH:38])=[C:10]([O:9][CH2:8][CH2:7][N:6]([CH2:4][CH3:5])[CH2:32][CH3:33])[CH:11]=[CH:12][C:13]=1[CH:14]=2)[CH3:29]
Reactant: C=O
Reactant: CCN(CC)CCOc1ccc2cc3ccc(OCCN(CC)CC)cc3nc2c1
Reactant: CCOCC
Agent: Cl
Agent: O=S(=O)(O)O
Product: CCN(CC)CCOc1ccc2cc3ccc(OCCN(CC)CC)c(CO)c3nc2c1CO
Reaction time: 0.75 h

Procedure:
To a solution of 23.43 g of 3,6-bis(2-diethylaminoethoxy)acridine trihydrochloride (U.S. Pat. No. 3,740,403) in 85 ml of concentrated sulfuric acid was added 2.94 g of paraformaldehyde. The mixture was stirred 45 minutes, then added to 1.5 liters of ether. The resulting solid was collected, dissolved in water, sodium bicarbonate was added and the mixture extracted with six 75 ml portions of chloroform. These extracts were placed on an alumina column which was then eluted with ether and then methylene chloride. The methylene chloride extract was concentrated, giving 4.0 g of the desired product as yellow crystals, mp 95°-96° C.
Reaction SMILES: [CH2:1]([N:6]=[C:7]=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].FC(F)(F)C(O)=O.[CH2:16]([O:23][C:24]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]=[CH:26][C:25]=1[CH:38]1[CH2:41][NH:40][CH2:39]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.C(N(CC)C(C)C)(C)C>[CH2:1]([NH:6][C:7]([N:40]1[CH2:41][CH:38]([C:25]2[CH:26]=[CH:27][C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:29][C:24]=2[O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:39]1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN=C=O
Reactant: c1ccc(COc2ccc(C3CNC3)c(OCc3ccccc3)c2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCCCCNC(=O)N1CC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67 %

Procedure:
In a 10 ml round-bottomed flask, 0.15 g of 3-(2,4-bis(benzyloxy)phenyl)azetidine trifluoroacetate is dissolved in 3 ml of tetrahydrofuran in the presence of 0.1 ml of N,N-diisopropylethylamine. 0.04 ml of pentyl isocyanate is added and the reaction mixture is then stirred for 20 minutes at ambient temperature. The reaction mixture is extracted with ethyl acetate and the organic phases are then combined and dried over magnesium sulphate. The residue is chromatographed on silica gel (9/1 heptane/ethyl acetate). 0.1 g of 3-(2,4-bis(benzyloxy)phenyl)azetidine-1-carboxylic acid pentylamide is obtained. Yield=67%.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([Cl:29])[CH:23]=4)[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][CH:65]=1>>[C:68]([C:67]1[CH:70]=[CH:71][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)=[O:31])=[CH:65][CH:66]=1)#[N:69]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cc(F)cc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: N#Cc1ccc(N)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cc(F)cc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 87 (0.4 g, 0.71 mmol), was reacted with diisopropylethylamine (0.82 g, 6.4 mmol), diphenylphosphinic chloride (0.67 g, 2.8 mmol), then reacted with 4-aminobenzonitrile (Aldrich) (0.34 g, 2.8 mmol) to give rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide as a white solid (Yield, 0.14 g, 55%).
Reaction SMILES: B.O1CCCC1.O1CCCC1.[CH2:12]([N:19]1[C:26](=O)[C:23]2([CH2:25][CH2:24]2)[NH:22][C:21](=O)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH2:12]([N:19]1[CH2:26][C:23]2([CH2:25][CH2:24]2)[NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CN(Cc2ccccc2)C(=O)C2(CC2)N1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc(CN2CCNC3(CC3)C2)cc1
Reaction time: 1 h
Yield: 59.2 %

Procedure:
A borane-tetrahydrofuran complex (0.93 M tetrahydrofuran solution) (375 ml, 0.35 mol) was added to a tetrahydrofuran (200 ml) solution of the compound (20 g, 86.8 mmol) obtained in Step 2 above with ice cooling and then the resulting mixture was heated to reflux for 19 hours. Methanol (130 ml) was added to the reaction mixture with ice cooling, the resulting mixture was stirred for 60 minutes, and the solvent was concentrated under reduced pressure. Ethanol (450 ml), water (150 ml), and triethylamine (150 ml) were added to the resulting residue, the resulting mixture was heated to reflux for 2 hours, and then the solvent was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to give the title compound (10.4 g, 59%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[C:11](=[O:20])[NH:12][C:13]([NH:16][N+]([O-])=[O:18])=[N:14][CH:15]=2)[CH:5]=[N:6][C:7]=1[CH3:8].[CH3:21][O:22][C:23]1[C:24]([CH2:29][CH2:30][CH2:31][CH2:32]N)=[N:25][CH:26]=[CH:27][CH:28]=1>C(O)C>[OH2:18].[OH2:22].[CH3:21][O:22][C:23]1[C:24]([CH2:29][CH2:30][CH2:31][CH2:32][NH:16][C:13]2[NH:12][C:11](=[O:20])[C:10]([CH2:9][C:4]3[CH:5]=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)=[CH:15][N:14]=2)=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cnc1C
Reactant: COc1cccnc1CCCCN
Solvent: CCO
Product: COc1cccnc1CCCCNc1ncc(Cc2cnc(C)c(C)c2)c(=O)[nH]1
Product: O

Procedure:
Equimolar amounts of 5-(5,6-dimethyl-3-pyridylmethyl)-2-nitroamino-4-pyrimidone and 4-(3-methoxy-2-pyridyl)butylamine were heated together under reflux in ethanol for 24 hours. An additional 0.1 molar equivalent of the amine was added and the mixture was heated under reflux for a further 24 hours, evaporated to dryness and purified to give 2-[4-(3-methoxy-2-pyridyl)butylamino]-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidone dihydrate, m.p. 93°-94°.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:3]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:6]1[N:7]=[C:2]([CH3:1])[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:5]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1

Procedure:
The title compound was prepared from 6-methyl-4-(4-trifluoromethyl-phenyl)-1H-pyrimidin-2-one (5.1 g, 20.0 mmol) and phosphoryl chloride (10 mL) according to step 3 of the general procedure I. Obtained as a light brown solid (4.1 g, 75%). MS (ISP) 273.1 [(M+H)+]; mp 82-83° C.