Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C@H:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:5]=2[C@H:4]([CH3:24])[CH2:3]1.CCN(S(F)(F)[F:31])CC>C(Cl)Cl>[F:31][C@@H:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:5]=2[C@H:4]([CH3:24])[CH2:3]1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1C[C@H](F)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: -20 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
tert-Butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (1.190 g, 3.558 mmol) was dissolved in methylene chloride (55 mL) and cooled to −20° C. The solution was treated with DAST (1.410 mL, 10.68 mmol) and stirred at −20° C. for 1 hour. The reaction was quenched with ice and then warmed to ambient temperature. The mixture was diluted with saturated NH4Cl and separated. The aqueous phase was extracted with methylene chloride (2×), and the combined organics were dried over Na2SO4 and concentrated to an oil. This oil was subjected to chromatography on SiO2 (Biotage 40S, load with methylene chloride) then eluted with 2.5% MeOH/DCM then 3.5% MeOH/DCM. The mixed fractions were concentrated, and the material was re-chromatographed on SiO2 (Biotage 40S, load with DCM) and eluted with 2 hexane/EtOAc. The product was collected as an oil to give tert-butyl 4-((5R,7S)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.725 g, 61%). LCMS (APCI+) m/z 337.0 [M+H]+; Rf 3.13 min.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:28](OCCC)[CH2:27][C@@:26]2([CH3:33])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:34])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:21])[CH2:13][S:14]([CH2:17][CH2:18][CH2:19][OH:20])(=[O:16])=[O:15])[CH2:3]1.[CH3:35][CH2:36]CCCC.CC(C)=O>>[C:35]([C@@:2]1([OH:1])[CH2:28][CH2:27][C@@:26]2([CH3:33])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:34])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:21])[CH2:13][S:14]([CH2:17][CH2:18][CH2:19][OH:20])(=[O:16])=[O:15])[CH2:3]1)#[CH:36]
Reactant: CCCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(=O)CS(=O)(=O)CCCO)CC[C@@H]32)C[C@@H]1O
Reactant: CCCCCC
Solvent: CC(C)=O
Product: C#C[C@@]1(O)CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(=O)CS(=O)(=O)CCCO)CC[C@@H]32)C1

Procedure:
Similarly prepared was 3α-hydroxy-21-(3′-hydroxypropylsulfonyl)-2β-propoxy-5α-pregnan-20-one; TLC Rf (hexane:acetone 2:1)=0.26.
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][S:9][C:10]1[N:15]2[CH:16]=[CH:17][N:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1)=[O:5].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>O1CCCC1>[O:1]1[C:2]2[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=2[C:4](=[O:5])[N:6]([CH2:7][CH2:8][S:9][C:10]2[N:15]3[CH:16]=[CH:17][N:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)[C:23]1=[O:24]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(NCCSc1cccc2nccn12)c1ccccc1O
Solvent: C1CCOC1
Product: O=c1oc2ccccc2c(=O)n1CCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.8 %

Procedure:
To a solution of 5-[2-[2-(hydroxy)benzoylamino]ethylthio]imidazo[1,2-a]pyridine (627 mg, 2.00 mmoles) in dry tetrahydrofuran (30 ml) was added 1,1'-carbonyldiimidazole (649 mg, 4.00 mmoles) and the mixture was stirred at room temperature for 15 hours. After the solvent was distilled off, chloroform was added to the residue, which was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent:ethyl acetate) to obtain 528 mg of the desired product (77.8%, colorless crystals).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C1([Mg]Cl)C=CC=CC=1.[CH3:21][C:22]([CH3:26])([CH3:25])[CH:23]=[O:24]>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:23]([OH:24])[C:22]([CH3:26])([CH3:25])[CH3:21])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: CC(C)(C)C=O
Reactant: COc1ccc(I)c([N+](=O)[O-])c1
Agent: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C(O)C(C)(C)C)c([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a solution of 4-iodo-3-nitroanisole (2.38 g, 8.50 mmol) in anhydrous THF (10 mL) at minus 40° C. under a nitrogen atmosphere, phenylmagnesium chloride (2 M in THF, 4.7 mL, 9.4 mmol) was added dropwise at a rate such that the temperature would not exceed minus 35° C. Upon completion of the addition, the mixture was stirred at minus 40° C. for one hour, followed by addition of trimethylacetaldehyde (1.13 mL, 10.2 mmol). The mixture was stirred at minus 40° C. for two hours and then at room temperature for another one hour. The reaction was quenched with brine (100 mL), and the mixture was extracted with CH2Cl2 (40 mL) three times. The combined organic phase was dried over Na2SO4 and concentrated in vacuo, and the residue was purified by silica gel column chromatography to yield racemic (R/S)-1-(4-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propanol (1.52 g, 74%). 1H NMR (400 MHz, CDCl3): δ 7.67 (d, 1H, J=9.2 Hz, Ph-H), 7.22 (d, 1H, J=2.4 Hz, Ph-H), 7.12 (dd, 1H, J=8.8 and 2.8 Hz, Ph-H), 5.27 (d, 1H, J=4.0 Hz, Ph-CH), 3.86 (s, 3H, OCH3), 2.01 (d, 1H, J=4.0 Hz, OH), 0.86 (s, 9H, C(CH3)3).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Cl[C:8]1[N:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=2[CH3:24])[CH:9]=1.[CH:25]1[C:33]2[C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[O:30][C:29]=2[C:28](B(O)O)=[CH:27][CH:26]=1>>[CH:25]1[C:33]2[C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[O:30][C:29]=2[C:28]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=3[CH3:24])[CH:9]=2)=[CH:27][CH:26]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1cc(Cl)ncn1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccc([N+](=O)[O-])cc1Nc1cc(-c2cccc3c2oc2ccccc23)ncn1
Temperature: 80 °C

Procedure:
An aqueous Na2CO3-solution (11.0 g, 104 mmol carbonate in 104 mL of water) is stirred with (6-chloropyrimidin-4-yl)-(2-methyl-5-nitro-phenyl)-amine (compound C3) (2.80 g, 10.6 mmol), 4-dibenzofuranboronic acid (3.36 g, 15.9 mmol) and bistriphenylphosphinpalladiumdichloride (0.74 g, 1.1 mmol) in ethylenglycoledimethylether (168 mL). The mixture is heated to 80° C. After 1 h the mixture is cooled and filtered. The product is purified by flash silica gel chromatography.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].S(Cl)([Cl:12])(=O)=O.[CH:14](OC)(OC)OC>CO>[ClH:12].[CH3:14][O:4][C:3](=[O:5])[C@@H:2]1[CH2:6][CH2:7][CH2:8][NH:1]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(OC)OC
Solvent: CO
Product: COC(=O)[C@@H]1CCCN1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 225.1 %

Procedure:
To a solution of L-Proline (115 g,1 mol)in methanol (1.2 L) at 0° C. was added sulfuryl chloride (45 mL, 0.55 mol) slowly during ~15-20 min, then the reaction mixture stirred overnight at room temperature. After 16 hours at room temperature and another 4 hours at reflux, trimethyl orthoformate (120 mL, 1.1 mol) was added and heating at reflux continued for another 24 hr. The reaction mixture was then concentrated and the resultant oil was placed under high vacuum for several days to afford the product as a clear oil (205 g).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)C>[N+:14]([C:10]1[CH:11]=[CH:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][C:9]=1[OH:13])([O-:16])=[O:15]
Reactant: Oc1cccc(-c2ccccc2)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(-c2ccccc2)cc1O

Procedure:
A solution of 3-phenyl phenol (2 g, 11 mmol) in acetic acid was treated with concentrated nitric acid drop-wise until all starting material was consumed. The solution was partitioned between water and methylene chloride. The organic phase was separated and the aqueous phase was extracted once more with methylene chloride. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) to afford desired (1.2 g, 50%). 1H NMR (CDCl3): d 10.65(s, 1H), 8.18 (d, 1H, J=10.0 Hz), 7.65 (d, 2H, J=6.0 Hz), 7.49 (m, 3H), 7.34 (s, 1H), 7.10 (d, 1H, J=10.0 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-])=O)[CH:10]=1)[NH:7][C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[CH:5]2.[NH4+].[Cl-]>O1CCCC1.CO.O.[Fe]>[NH2:11][C:9]1[CH:10]=[C:2]([CH3:1])[CH:3]=[C:4]2[C:8]=1[NH:7][C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[CH:5]2
Reactant: Cc1cc([N+](=O)[O-])c2[nH]c(-c3ccccn3)cc2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(N)c2[nH]c(-c3ccccn3)cc2c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
5-Methyl-7-nitro-2-(pyridin-2-yl)-1H-indole (6.9 g, 27.3 mmol) prepared in Preparation 8 was dissolved in a solvent mixture of tetrahydrofuran (130 mL), methanol (1 mL) and water (130 mL), and NH4Cl (14.6 g, 27.3 mmol) was added thereto. The reaction mixture was warmed to 60° C., iron powder (15.2 g, 273 mmol) was added thereto, and the mixture was stirred for 30 min. After completion of the reaction, the reaction mixture was filtered through a cellite to remove the solid. Certain amount of the solvent was removed under reduced pressure from the resulting solution, which was then extracted with EtOAc. The extracted organic material was dried over MgSO4, and the solvent was removed under reduced pressure to give the title compound (5.0 g, Yield 40%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.Br.CS(C)=[O:17]>O>[O:17]=[CH:11][C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:13])=[CH:5][CH:6]=1)=[O:12]
Reactant: CS(C)=O
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Agent: Br
Solvent: O
Product: COC(=O)c1ccc(C(=O)C=O)cc1
Temperature: 25 °C
Yield: 79 %

Procedure:
To a solution of 4-acetylbenzoic acid methyl ester (25 g, 0.14 mol) in dimethyl sulfoxide (300 mL) was added slowly a solution of hydrogen bromide in water (48%, 48 mL) at RT with stirring. The mixture was stirred at 60° C. overnight. After cooling to RT, it was poured into ice-water. The precipitate was filtered and dried to afford the desired product (15.6 g, 79%).
Reaction SMILES: Cl[CH2:2][CH:3]1[CH:5]([C:6]([O:8]CC)=O)[C:4]1([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=1)[CH3:11].C(=O)([O-])O.[Na+].[C:25]1([CH2:31][CH2:32][CH2:33][NH2:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O>[CH3:11][C:4]1([C:12]2[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=2)[C:18]#[N:19])[CH:5]2[CH:3]1[CH2:2][N:34]([CH2:33][CH2:32][CH2:31][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:6]2=[O:8]
Reactant: CCOC(=O)C1C(CCl)C1(C)c1cccc(C#N)c1
Reactant: NCCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(c2cccc(C#N)c2)C2CN(CCCc3ccccc3)C(=O)C21
Temperature: 100 °C
Yield: 39.1 %

Procedure:
To a solution of ethyl 3-(chloromethyl)-2-(3-cyanophenyl)-2-methylcyclopropanecarboxylate (Preparation 35, 170 mg, 0.62 mmol) in N,N-dimethylformamide (6.0 ml) at room temperature was added sodium hydrogen carbonate (52 mg, 0.62 mmol) followed by 3-phenylpropylamine (0.35 ml, 2.47 mmol). The mixture was heated at 100° C. for 6 h and under reflux for 5 h. After the mixture had cooled to room temperature, water (4 ml) was added and the aqueous layer was extracted with diethyl ether (3×4 ml). The combined ethereal extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude oil was purified by silica column chromatography eluting with a gradient of hexane:ethyl acetate (50:50 to 0:100) to afford the title compound (80 mg, 40%) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.P(=O)(O)(O)O.[N+]([O-])(O)=O.[N:17]([O-])=O.[Na+].[CH3:21][O:22][CH2:23][C:24](=[O:30])[CH2:25][C:26]([O:28][CH3:29])=[O:27].C([O-])(=O)C.[Na+]>CO>[CH3:21][O:22][CH2:23][C:24](=[O:30])[C:25](=[N:17][NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[C:26]([O:28][CH3:29])=[O:27]
Reactant: Nc1ccncc1
Reactant: COCC(=O)CC(=O)OC
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: CO
Product: COCC(=O)C(=NNc1ccncc1)C(=O)OC
Temperature: -6 °C
Reaction time: 0.17 h
Yield: 18.9 %

Procedure:
4-Aminopyridine (3.6 g, 38 mmol) was added to a mixture of phosphoric acid (10 mL, 150 mmol) and nitric acid (5 mL, 78 mmol) at −6° C. Sodium nitrite (3.2 g, 46 mmol) was added portionwise to the mixture at −6° C., and then crushed ice (ca. 25 g) was added into the solution. After stirring at −6° C. for 10 min, the mixture was poured into a suspension of methyl 4-methoxyacetoacetate (5.0 mL, 38 mmol) and sodium acetate (44 g, 540 mmol) in MeOH (100 mL) at 0° C. The mixture was partitioned between AcOEt and water. The aqueous layer was extracted with AcOEt. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residual solid was washed with AcOEt/hexane (1/3) to give the title compound (1.8 g, 19% yield) as a yellow solid: 1H NMR (300 MHz, CDCl3): δ ppm 3.48-3.53 (3H, m), 3.89-3.95 (3H, m), 4.64-4.69 (2H, m), 7.17-7.34 (2H, m), 8.54-8.60 (2H, m), 12.65 (1H, brs).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:34][N:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH2:40][CH2:41]O.[C:43]([OH:51])(=[S:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1.C(OCC)(=O)C>[C:43]([S:50][CH2:41][CH2:40][C:36]1[N:35]([CH3:34])[CH:39]=[CH:38][N:37]=1)(=[O:51])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: Cn1ccnc1CCO
Reactant: OC(=S)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1ccnc1CCSC(=O)c1ccccc1
Reaction time: 0.25 h

Procedure:
Triphenylphosphine (10.48 g) was dissolved in tetrahydrofuran (120 ml). To the solution were added diisopropyl azodicarboxylate (8.07 g) at 0° C. The mixture was stirred for 15 minutes at the same temperature. To the mixture were added a solution of 2-(1-methyl-2-imidazolyl)ethanol (2.52 g) in tetrahydrofuran (10 ml) and thiobenzoic acid (4.7 ml) in the order mentioned. The mixture was stirred for 2.5 hours at 0° C. and then for 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate, then washed with saturated solution of sodium hydrogencarbonate in water and saturated solution of sodium chloride in water in the order mentioned. The residue was dried over anhydrous sodium sulfate and concentrated under reduced pressure, which was then subjected to column chloromatography on silica gel (developing solvent: ethyl acetate-methanol: 100:0→93:7) to give the title compound (3.52 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].C(O)C.O1CCOCC1.[C-:28]#[N:29].[K+]>O>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][C:28]#[N:29])[C:9]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Sc2ccccc2)c(CCl)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: N#CCc1cc([N+](=O)[O-])ccc1Sc1ccccc1

Procedure:
230 g of 3-nitro-6-(phenylthio)-benzyl chloride, 540 ml of ethanol and 320 ml of dioxane are treated with a solution of 70.5 g of potassium cyanide in 150 ml of water. The mixture is heated to reflux for 3 hours and subsequently concentrated under reduced pressure. The residue is diluted with water and extracted with benzene. The organic phase is washed with water and evaporated under reduced pressure. There is obtained 3-nitro-6-(phenylthio)-phenylacetonitrile as a brown oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1.[C-:10]#[N:11].[Na+].[I-].[Na+].O>CN(C=O)C>[O:6]1[CH2:7][CH2:8][O:9][CH:5]1[CH2:4][CH2:3][CH2:2][C:10]#[N:11]
Reactant: [C-]#N
Reactant: ClCCCC1OCCO1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCCC1OCCO1
Temperature: 80 °C
Yield: 75.8 %

Procedure:
A mixture of 2-(3-chloropropyl)-1,3-dioxolane (15.88 g; 0.1054 moles), sodium cyanide (6.46 g; 0.132 moles) and sodium iodide (1.57 g; 0.0105 moles) in DMF (100 mL) was heated at 80° C., with magnetic stirring, under a nitrogen atmosphere for 15 hours. The mixture was allowed to cool, added to water (300 mL) and extracted with ethyl acetate (3×200 mL). The combined extracts were washed with water (200 mL) and saturated aqueous sodium chloride solution (100 mL) and then dried over sodium sulfate. Filtration and evaporation of solvent gave a crude yellow oil which was purified by chromatography on silica gel, eluting with hexane/ethyl acetate (5:2). Removal of solvent under vacuum gave the product 4-(1,3-dioxolan-2-yl)-butanenitrile (11.28 g; 76%) as a colorless oil. 1H NMR (CDCl3) δ 4.89-4.91 (1H, m), 3.92-4.01 (2H, m), 3.82-3.90 (2H, m), 2.40-2.46 (2H, m), 1.77-1.85 (4H, m).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16]OS(C)(=O)=O)[CH2:10][C@H:9]1[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:7].[NH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.C(N(CC)CC)C.[ClH:55]>CO.C(OCC)(=O)C>[ClH:55].[ClH:55].[F:40][C:2]([F:1])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:37])([F:38])[F:36])[CH:34]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:41][N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[CH2:10][C@H:9]1[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:7]
Reactant: CS(=O)(=O)OCCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Reactant: NN1CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCCNN2CCOCC2)C[C@H]1Cc1c[nH]c2ccccc12

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine (150 mg), 4-aminomorpholine (36 mg) and triethylamine (52 mg) in dry methanol (5 ml) was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate solution. The organic layer was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and methanol (10:1) to afford an oily product, which was treated with 4N hydrogen chloride in ethyl acetate solution (0.5 ml) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[3-(morpholinoamino)propyl]piperazine dihydrochloride (58 mg).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH3:9][C@@:10]12[C:16](=O)[C:15]([CH3:19])([CH3:18])[C@@H:13]([CH2:14]1)[CH2:12][CH2:11]2>O.CO>[CH3:9][C@@:10]12[CH2:14][CH:13]([CH2:12][CH2:11]1)[C:15]([CH3:19])([CH3:18])[C:16]2=[N:2][OH:3]
Reactant: CC1(C)C(=O)[C@@]2(C)CC[C@@H]1C2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(C)C(=NO)[C@@]2(C)CCC1C2
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of 23 g of hydroxylamine hydrochloride and 41 g of sodium acetate in 200 ml of water is added at RT to a solution of 38.1 g of (1S)-(+)-fenchone in 120 ml of MeOH and the mixture is then refluxed for 48 hours. After cooling to RT, the precipitate formed is filtered off, washed with water and dried under vacuum to give 41 g of the expected product.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:40])[C@@H:15]([NH:25][C:26]([C:28]2[CH:37]=[C:36]([OH:38])[C:35]3[C:30](=[CH:31][C:32]([CH3:39])=[CH:33][CH:34]=3)[CH:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:47]([O:54][C:55](=[O:58])[CH2:56]Br)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C.O>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:40])[C@@H:15]([NH:25][C:26]([C:28]2[CH:37]=[C:36]([O:38][CH2:56][C:55]([O:54][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:58])[C:35]3[C:30](=[CH:31][C:32]([CH3:39])=[CH:33][CH:34]=3)[CH:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccc(C)cc3c2)CC1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)c3ccc(C)cc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.0 g 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-naphthalene-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester in 12 ml of DMF, 645 mg of cesium carbonate and 447 mg of Bromo-acetic acid benzyl ester were added and the reaction mixture was stirred for 2 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The isolated crude product was pure enough for the next reaction step. Yield: 710 mg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])(=[O:21])=[O:20])[O:13][C:14]=1[CH:15]=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S(C(N)C2OC(C(O)=O)=C(OCC3C=CC=CC=3)C(=O)C=2)(=O)=[O:37])C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[C:23]([CH3:28])=[CH:24][CH:25]=[CH:26][CH:27]=2)(=[O:21])=[O:20])[O:13][C:14]=1[C:15]([OH:37])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1S(=O)(=O)NCc1cc(=O)c(OCc2ccccc2)c(C=O)o1
Reactant: NC(c1cc(=O)c(OCc2ccccc2)c(C(=O)O)o1)S(=O)(=O)c1ccccc1
Product: Cc1ccccc1S(=O)(=O)NCc1cc(=O)c(OCc2ccccc2)c(C(=O)O)o1

Procedure:
3-Benzyloxy-4-oxo-6-[(toluene-2-sulfonylamino)-methyl]-4H-pyran-2-carboxylic acid (12-02) (2.0 g, crude) was synthesized as a white solid from N-(5-benzyloxy-6-formyl-4-oxo-4H-pyran-2-ylmethyl)-2-methyl-benzenesulfonamide (11-02) (2.8 g, 6.74 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid (12-01).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[N+](N[C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[CH:18][N:17]=1)([O-])=O>N1C=CC=CC=1>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[CH:18][N:17]=1
Reactant: NCCCNc1ccccn1
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cnc(NCCCNc3ccccn3)[nH]c2=O)cn1
Yield: 69.7 %

Procedure:
2-(3-Aminopropylamino)pyridine (1.74 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (2.0 g) were heated together under reflux in pyridine (8 ml) for 22 hr. The mixture was stripped, the residue triturated with ether and then water (the pH of which was adjusted to 6.5 with dilute acetic acid) to give a white solid. Recrystallisation from isopropanol gave 2-[3-(pyrid-2-ylamino)propylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone, (1.87 g; 70%), m.p. 163°-165° C.