Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)=[O:4].[N:34]1([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][C@H:35]1[C:44](O)=[O:45].CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][C@@H:2]([NH:1][C:44]([C@@H:35]2[CH2:36][C:37]3[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:43][N:34]2[C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[O:45])[C:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]([CH2:22][CH:23]3[CH2:24][CH2:25]3)[S:18]([CH3:21])(=[O:19])=[O:20])[CH2:9][CH2:10]2)=[O:4])=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)N(CC1CC1)c1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2N(CC2CC2)S(C)(=O)=O)CC1

Procedure:
tert-Butyl 3-{N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(cyclopropylmethyl)(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]carbamoyl}(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate was prepared from (2R)-2-amino-3-(4-chlorophenyl)-1-(4-{2-[(cyclopropylmethyl)(methylsulfonyl)amino]phenyl}-piperazinyl) propan-1-one (Example 58, Step 3) (224 mg, 0.457 mmol), according to the procedure for Preparation XIX using Boc-L-Tic-OH (135 mg, 0.487 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (285 mg, 0.959 mmol), HOAT (68 mg, 0.50 mmol), and DMF (7 mL). The compound was isolated (339 mg). MS (ESI, pos. ion) m/z: 750 (M+H), (ESI, neg. ion) m/z: 748 (M−H). Calc'd for C39H48ClN5O6S: 750.35.
Reaction SMILES: [CH3:1][N:2]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)[CH2:3][C:4](OCC)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:17][C:16]([F:18])([F:19])[C:15]([C:12]1[CH:13]=[CH:14][C:9]([N:2]([CH2:3][CH2:4][OH:5])[CH3:1])=[CH:10][CH:11]=1)([OH:24])[C:20]([F:21])([F:23])[F:22]
Reactant: CCOC(=O)CN(C)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(CCO)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
Ethyl N-methyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-glycinate (272 mg, 0.76 mmol) was dissolved in anhydrous THF(5 mL) under argon and 1M lithium aluminum hydride solution in THF (1.1 mL, 1.1 mmol) was added. The resulting solution was stirred at ambient temperature over 18 h. The reaction was quenched slowly with ethyl acetate then diluted with H2O. The layers were separated and the organic phase was washed with water followed by brine. The organics were dried over MgSO4, filtered and concentrated in vacuo. The resultant oil was purified by flash chromatography (4:1 hexanes/EtOAc) to afford the title compound as a yellow oil (176 mg, 73%). 1H NMR (CDCl3) δ 7.56 (d, 2H), 6.86 (d, 2H), 3.86 (t, 2H), 3.55 (t, 2H), 3.06 (s, 3H). Anal. Calc. for C12H13NO2F6+0.1H2O: C, 45.18; H, 4.17; N, 4.39. Found: C, 45.01; H, 4.05; N, 4.28. HRMS (MH+) Calc.: 318.0918. Found: 318.0929.
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH:9]=O)([CH3:4])([CH3:3])[CH3:2].[CH3:15]OP(C(=[N+]=[N-])C(=O)C)(=O)OC.C([O-])([O-])=O.[K+].[K+]>CO>[C:1]([Si:5]([O:6][CH2:7][C:8]([CH3:12])([CH3:11])[C:9]#[CH:15])([CH3:14])[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C=O)CO[Si](C)(C)C(C)(C)C
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC(C)(C)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.5 %

Procedure:
To a solution of 3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propionaldehyde (0.84 g, 3.9 mmol) in methanol (20 mL) was added (1-diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (0.9 g, 4.7 mmol) and K2CO3 (1.1 g, 7.8 mmol). The solution was stirred overnight at room temperature and then the reaction mixture was washed with water. The crude residue was purified by flash chromatography (eluted with: petroleum ether:EtOAc=100:2) to afford the title compound (0.17 g, 21%): 1H NMR (CDCl3, 400 MHz) delta 0.05 (s, 6H), 0.90 (s, 9H), 1.19 (s, 6H), 2.06 (s, 1H), 3.45 (s, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]([C@H:41]2[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[N:44]([C:51](=[O:59])[C:52]3[CH:57]=[CH:56][C:55](O)=[CH:54][CH:53]=3)[C@@H:43]([CH3:60])[CH2:42]2)[C:38](=[O:40])[CH3:39])=[CH:33][CH:32]=1.CCOC(/N=N/C(OCC)=O)=O>C1C=CC=CC=1>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([N:37]([C@H:41]2[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[N:44]([C:51](=[O:59])[C:52]3[CH:57]=[CH:56][C:55]([O:1][CH2:2][CH2:3][CH2:4][N:5]4[CH2:9][CH2:8][CH2:7][C:6]4=[O:10])=[CH:54][CH:53]=3)[C@@H:43]([CH3:60])[CH2:42]2)[C:38](=[O:40])[CH3:39])=[CH:35][CH:36]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: O=C1CCCN1CCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCN3CCCC3=O)cc2)c2ccccc21
Reaction time: 0.08 h
Yield: 45 %

Procedure:
N-(3-hydroxypropyl)-2-pyrrolidone was dissolved in benzene at room temperature with PPh3 (0.044 g, 0.16 mmol) added (2S,4R)-N-(4-chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (0.100 g, 0.22 mmol) and stirred for 5 min. DEAD (0.029 g, 0.16 mmol) was added and the reaction was stirred for 18 h at room temperature. The reaction was concentrated and purified by silica gel chromatography (4% MeOH/96% CH2Cl2 to 5% MeOH/95% CH2Cl2 to 6% MeOH/94% CH2Cl2) to afford the product in 45% yield.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[O:8][C:7]([CH2:9][OH:10])=[CH:6][CH:5]=1.[CH3:11]I>CN(C=O)C>[Br:3][C:4]1[O:8][C:7]([CH2:9][O:10][CH3:11])=[CH:6][CH:5]=1
Reactant: CI
Reactant: OCc1ccc(Br)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1ccc(Br)o1
Reaction time: 0.08 h
Yield: 20.9 %

Procedure:
Sodium hydride (95%, 28 mg, 1.12 mmol) was diluted in dry DMF (1 mL) and cooled to 0° C. (5-bromo-2-furanyl)methanol (177 mg, 1 mmol) in DMF (2 mL) was added, and the mixture was stirred for 5 minutes. Methyl iodide (0.07 mL, 1.12 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was quenched by the careful addition of water, then extracted with ethyl acetate (20 mL), followed by dichloromethane (20 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography, eluting with EtOAc/hexanes. The desired fractions were combined and concentrated, giving 40 mg (21%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:18]([F:28])[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:29])#[N:2].[CH3:33]I>>[C:1]([C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH3:33])[S:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:18]([F:28])[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:29])#[N:2]
Reactant: CI
Reactant: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3ccc(-c4ccccc4)c(F)c3)C2=O)c1
Product: CN([C@H]1CCN(Cc2cccc(C#N)c2)C1=O)S(=O)(=O)c1ccc(-c2ccccc2)c(F)c1

Procedure:
The title compound is prepared as described in EXAMPLE 26, Part A using 2-fluorobiphenyl-4-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide and methyl iodide. The crude product is purified by column chromatography eluting with gradient of 10% EtOAc/CH2Cl2 to 20% EtOAc/CH2Cl2 to afford the title compound as a white foam.
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:13])(=[NH:12])[CH2:8][CH2:9][CH2:10][CH3:11].[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[O:25])([O-:16])=[O:15]>C1C=CC=CC=1>[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24]([NH:12][C:7](=[NH:13])[CH2:8][CH2:9][CH2:10][CH3:11])=[O:25])([O-:16])=[O:15]
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Reactant: CCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: c1ccccc1
Solvent: CC(C)=O
Product: CCCCC(=N)NC(=O)Nc1ccccc1[N+](=O)[O-]

Procedure:
Following a procedure similar to that described in Example 1 but using 2.3 g. sodium in 150 ml. dry acetone, 13.6 g. valeramidine hydrochloride, and 16.4 g. 2-nitrophenyl isocyanate in 300 ml. benzene, there was obtained after recrystallization from ethyl alcohol 9.1 g. of the hydrochloride of 1-(2-nitrophenyl)-3-(pentanimidoyl)urea; m.p. 130°-132°C.
Reaction SMILES: [C@@H:1]1([N:10]2[C:14]3[N:15]=[CH:16][NH:17][C:18](=[O:19])[C:13]=3[CH:12]=[CH:11]2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].C(O[C:24](=[O:26])[CH3:25])(=O)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:2]([O:3][C@H:2]1[C@H:4]([O:5][C:4](=[O:5])[CH3:6])[C@@H:6]([CH2:8][O:9][C:24](=[O:26])[CH3:25])[O:7][C@H:1]1[N:10]1[C:14]2[N:15]=[CH:16][NH:17][C:18](=[O:19])[C:13]=2[CH:12]=[CH:11]1)(=[O:3])[CH3:1]
Reactant: O=c1[nH]cnc2c1ccn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(=O)[nH]cnc32)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
A solution of 3.0 g of 7-β-D-arabinofuranosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidine-4-one, eight ml of acetic anhydride, 150 ml of pyridine, and 50 mg of p-dimethylaminopyridine is stirred at room temperature for 24 hours, evaporated in vacuo, co-evaporated with xylenes, and distributed between ethyl acetate and water. The ethyl acetate layer is washed with saturated NaHCO3 and dried with MgSO4. Removal of the ethyl acetate provides 7-(2,3,5-tri-O-acetyl-β-D-arabinofuranosyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one. This is dissolved in 150 ml of dry pyridine, treated with 8.8 g of phosphorus pentasulfide, and heated under reflux for 5 hours. The pyridine is removed in vacuo and the residue is treated with water. The precipitate is filtered, washed with water, and recrystallized from ethanol to afford 7-(2,3,5-tri-O-acetyl-β-D-arabinofuranosyl)-3,7-dihydro-4H-pyrrolo-[2,3-d]pyrimidine-4-thione. A solution of 5.0 g of 7-(2,3,5-tri-O-acetyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine-4-thione, 200 ml of methanol, and 54 mg of sodium methalate is heated under reflux for 2 hours and treated with IRC-50 ion exchange resin. The filtrate is evaporated in vacuo and the resulting residue is recrystallized from ethanol-water to provide 7-β-D-arabinofuranosyl-3,7-dihydro-4H-pyrrolo[2,3-d]-pyrimidine-4-thione.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([OH:14])=O)[C:6]3[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18][C:5]=3[C:4]=2[CH:3]=1.CCN=C=NCCCN(C)C.Cl.[C:32]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([N:42]3[CH2:41][CH2:40][N:39]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:44][CH2:43]3)=[O:14])[C:6]3[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)N2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28 %

Procedure:
2-(8-chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid (0.2 g, 0.719 mmol) in 10 mL of DCM was taken, EDCI.HCl (137 mg, 0.719 mmol) was added and stirred for 10 min at RT, N-Boc piperazine (133 mg, 0.719 mmol) was added to the reaction mixture and stirred for 24 h at RT. Reaction was monitored by TLC & LCMS. After completion of the reaction, reaction mixture was concentrated and purified by column chromatography (neutral alumina; 2% Methanol-DCM) then purified by reverse phase chromatography to afford 90 mg of tert-butyl 4-(2-(8-chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetyl)piperazine-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[C:7]([C@@H:8]([OH:10])[CH3:9])=[C:6]([F:11])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[F:14].[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C.Cl>CCOCC>[CH3:15][S:16]([O:10][C@H:8]([C:7]1[C:2]([F:1])=[C:3]([F:14])[C:4]([F:13])=[C:5]([F:12])[C:6]=1[F:11])[CH3:9])(=[O:18])=[O:17]
Reactant: C[C@H](O)c1c(F)c(F)c(F)c(F)c1F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[C@H](OS(C)(=O)=O)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
To an ice-cooled solution of 0.21 g (1 mmol) of (S)-(-)-1-(pentafluorophenyl)ethanol and 0.17 g (1.5 mmol) of methanesulfonyl chloride in 2 m(of ether, was added dropwise 0.22 m((1.6 mmol) of triethylamine. After it was stirring for two hours at room temperature, 1N hydrochloric acid was added to the reaction mixture and was extracted with ether. This ether solution was washed with 1N hydrochloric acid and an aqueous solution of 5 wt% potassium carbonate , and the solvent was distilled off under reduced pressure. The subsequent distillation gave 0.24 g (yield: 83%) of (S)-(-)-1-(pentafluorophenyl)ethyl methanesulfonate having the aforementioned physical properties.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:46]=[C:45]([O:47][CH3:48])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]=1[O:49][CH3:50]>>[CH3:50][O:49][C:38]1[C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:45]([O:47][CH3:48])=[CH:46][C:37]=1[CH2:36][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COc1cc(CCl)c(OC)c2ccccc12
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cc(OC)c3ccccc3c2OC)cc1

Procedure:
(ff) In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylate with 2-chloromethyl-1,4-dimethoxy-naphthalene there was obtained tert-butyl (3RS,4RS)-3-(1,4-dimethoxy-naphthalen-2-ylmethoxy)-4-{4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl}-piperidine-1-carboxylate as a pale yellow syrup; MS: 689 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]=[C:10]([C:18](=O)[CH3:19])[C:11]([O:13][CH:14]1[CH2:17][CH2:16][CH2:15]1)=[O:12].[NH2:21][C:22]([CH2:28][F:29])=[CH:23][C:24]([O:26][CH3:27])=[O:25]>C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:11]([O:13][CH:14]2[CH2:17][CH2:16][CH2:15]2)=[O:12])=[C:18]([CH3:19])[NH:21][C:22]([CH2:28][F:29])=[C:23]1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)C=C(N)CF
Reactant: CC(=O)C(=Cc1cccc(Cl)c1Cl)C(=O)OC1CCC1
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(CF)NC(C)=C(C(=O)OC2CCC2)C1c1cccc(Cl)c1Cl
Temperature: 25 °C

Procedure:
The product of step (a) (1.7 g, 5.4 mmoles) and methyl 3-amino-4-fluoro-2-butenoate (0.72 g, 5.4 mmoles) were mixed and heated to 95° (oil bath temperature) under an atmosphere of nitrogen for 6 hours. The oil was allowed to cool to room temperature. Chromatography on silica eluting with petroleum ether (60°-80° )/ethyl acetate mixtures, afforded the title compound as a yellow solid, which was recrystallised from petroleum ether (60°-80° ) to afford the title compound 0.37 g, mp 148°-9°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH:21]2[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=O)[CH2:23][CH2:22]2)[C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[OH:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1C=O.[BH4-].C(OC(=O)C)(=O)C>C(O)C>[OH:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:27][N:24]1[CH2:25][CH2:26][CH:21]([N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:22][CH2:23]1
Reactant: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=Cc1ccccc1O
Agent: [BH4-]
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(Cc3ccccc3O)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The product from example 13 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). 2-Hydroxybenzaldehyde (0.122 ml, 1.1 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 16 mg; HRMS (FAB+, NBA) (M+H)+ 459.2633, C29H35N2O3 requires 459.2648; LC-MS: (M+H)+ 459.2, tr 5.81 min.
Reaction SMILES: [C:1]12[C:18](=[O:19])[O:17][C:15](=O)[C:13]3=[C:14]1[C:5](=[CH:6][C:7]1[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:4]=[CH:3][CH:2]=2.[NH2:20][CH2:21][CH2:22][NH:23][CH2:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][NH2:30]>C1(C)C=CC=CC=1>[O:17]=[C:15]1[C:13]2[C:14]3[C:5](=[CH:4][CH:3]=[CH:2][C:1]=3[C:18](=[O:19])[N:30]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21][N:20]1[C:18](=[O:19])[C:1]3[CH:2]=[CH:3][CH:4]=[C:5]4[C:14]=3[C:13](=[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]3=[CH:6]4)[C:15]1=[O:17])[CH:6]=[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]1=2
Reactant: NCCNCCCNCCN
Reactant: O=C1OC(=O)c2c3ccccc3cc3cccc1c23
Solvent: Cc1ccccc1
Product: O=C1c2cccc3cc4ccccc4c(c23)C(=O)N1CCNCCCNCCN1C(=O)c2cccc3cc4ccccc4c(c23)C1=O
Yield: 49.9 %

Procedure:
A mixture of 1.6 g (6 mmol) of anthracene-1,9-dicarboxylic anhydride in 40 ml of toluene was treated with 0.5 g (3 mmol) of N,N'-bis(2-aminoethyl)-1,3-propanediamine dissolved in 10 ml of toluene. The mixture was refluxed for 4 h and then filtered. The solution was allowed to cool and the solid formed was filtered, washed, dried and recrystallized from toluene. 0.93 g (50%) of N,N'-bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquinolin-2-yl)ethyl]-1,3-propanediamine were obtained. M.p. 191° C. (toluene). 1 H-NMR (CDCl3) δ=1.84 (q, 2H, J=6 Hz, --CH2 --); 2.74 (broad, s, 2H, NH); 2.89 (t, 4H, J=6 Hz, CH2); 3.02 (t, 4H, J=6 Hz, CH2); 4.31 (t,4H, J=6 Hz, CH2); 7.54 (m, 4H, H-5 and H-9); 7.73 (m, 2H,H-10); 7.89 (d, 2H, J=8 Hz, H-8); 8.22 (d, 1H, J=8 Hz, H-4); 8.51 (s,2H, H-7); 8.57 (d, 2H, J=8 Hz, H-6); 9.78 (d,2H, J=8 Hz, H-11) p.p.m.. Anal. Calculated for C39H32N4O4 : C 75.46; H 5.19; N 9.02. Found: C 75.14; H 5.37; N 8.78. Acetate m.p. 155° C. Methanesulfonate m.p. 243° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][N:12]([CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:22]([OH:24])=[O:23])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:38][O:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44]Cl)=[CH:42][CH:41]=1>CN(C=O)C.CCOCC>[Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][N:12]([CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:22]([O:24][CH2:44][C:43]2[CH:46]=[CH:47][C:40]([O:39][CH3:38])=[CH:41][CH:42]=2)=[O:23])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CN(C(C(=O)O)c2ccccc2Cl)C[C@@H]1c1ccccc1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)C(c2ccccc2Cl)N2C[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of crude 2-(R/S)-(3-(R)-(t-butyldimethylsilyloxymethyl)-4-(S)-phenylpyrrolidin-1-yl)-(2-chlorophenyl)acetic acid (from EXAMPLE 10, Step A), 338 mg (1.0 mmol) of cesium carbonate and 0.14 mL (1.0 mmol) of 4-(methoxy)benzyl chloride in 3 mL of DMF was stirred at rt for 22 h. The reaction mixture was diluted with 100 mL of ether and washed with 100 mL of 1.0 N NaHCO3. The layers were separated and the aqueous phase was extracted with 100 mL of ether. The combined organic phases were dried over MgSO4 and concentrated. Flash chromatography using 9:1 v/v hexanes/EtOAc as the eluant afforded 377 mg (63%, two steps) of the title compound: RF: 0.68 (4:1 v/v hexanes/EtOAc). For the pair of diastereomers: 1H NMR (300 MHz) δ 0.0, 0.01, 0.02,0.04 (4s, 6H), 0.86,0.88 (2s, 9H), 2.42 (m, 1H), 2.67 (m, 1H), 2.84-3.10 (m, 4H), 3.57-3.62 (m, 2H), 3.83 (s, 31), 4.80, 4.81 (2s, 1H), 5.10 (ABq, J=12.1, 2H), 6.83-6.87 (m, 2H), 7.20-7.41 (m, 10H), 7.73 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][C:18]([CH3:20])([CH3:19])[C:12]2=[N:11][C:10]=1[C:21]([O:23]CC)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>CO.O>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][C:18]([CH3:20])([CH3:19])[C:12]2=[N:11][C:10]=1[C:21]([OH:23])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCC2(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)CCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
Intermediate 4, ethyl 3-(benzyloxy)-8,8-dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-2-carboxylate (342 mg, 1 mmol) was suspended in 5 mL of methanol, treated with a solution of LiOH (48 mg, 2 mmol) in 5 ml H2O then stirred at room temperature for 1 h. The reaction was quenched with 2 mL of 1N HCl. The resulting precipitate was collected by filtration and dried to give 260 mg of the title compound as a crystalline solid (Yield=83%). 1H NMR (300 MHz, CDCl3) δ ppm: 7.46–7.59 (2 H, m) 7.25–7.40 (3 H, m) 5.44 (2 H, s) 3.98–4.15 (2 H, m) 2.04–2.19 (2 H, m) 1.34 (6 H, s); LC/MS m/z 315 (M+H).
Reaction SMILES: [CH3:1][O:2][C@H:3]([C@@H:6]([C@@H:9]([CH2:11][O:12][CH3:13])[OH:10])[O:7][CH3:8])[CH:4]=[O:5].O.[NH2:15][NH2:16]>CO>[NH:15]([C:4]([C@@H:3]([C@@H:6]([C@@H:9]([CH2:11][O:12][CH3:13])[OH:10])[O:7][CH3:8])[O:2][CH3:1])=[O:5])[NH2:16]
Reactant: NN
Reactant: COC[C@@H](O)[C@@H](OC)[C@H](C=O)OC
Solvent: CO
Solvent: O
Product: COC[C@@H](O)[C@@H](OC)[C@@H](OC)C(=O)NN
Reaction time: 48 h

Procedure:
1.7 g (8.5 mmoles) of 2,3,5-tri-O-methyl-D-ribose are dissolved in 5 ml of absolute methanol. While stirring, 4.25 g (85 mmoles) of 100% hydrazine hydrate (dissolved in 5 ml of absolute methanol) are added. As a result slight heating occurs. Stirring is carried out for 2 days of room temperature. Following this methanol and superfluous hydrazine hydrate are removed in a rotary evaporator at room temperature (oil pump vacuum). Following this drying is carried out for one day under oil pump vacuum. A colorless oil is obtained. Yield: 1.6 g (92 %).