Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[C:3]12([C:13]3[CH:14]=[C:15]([C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[CH:29]=[C:28]([C:33]([OH:35])=[O:34])[CH:27]=[CH:26]5)[CH:16]=[CH:17][C:18]=3[C:19]([O:21]C)=[O:20])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2>C(O)CCC>[C:3]12([C:13]3[CH:14]=[C:15]([C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[CH:29]=[C:28]([C:33]([OH:35])=[O:34])[CH:27]=[CH:26]5)[CH:16]=[CH:17][C:18]=3[C:19]([OH:21])=[O:20])[CH2:12][CH:7]3[CH2:6][CH:5]([CH2:11][CH:9]([CH2:8]3)[CH2:10]1)[CH2:4]2
Reactant: COC(=O)c1ccc(-c2ccc3cc(C(=O)O)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: O=C(O)c1ccc2cc(-c3ccc(C(=O)O)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1
Temperature: 110 °C

Procedure:
2 g of potassium hydroxide are added to a solution of 1.20 g (2.72 mmol) of the diester obtained in Example 15 in 50 ml of n-butanol and the mixture is heated at 110° C. for 24 hours. After the same treatment as in Example 8, and recrystallization from the ethyl acetate-THF mixture, 605 mg (52%) of the expected derivative are isolated, which derivative melts at 333°-335° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[C:26]([O:30][C:31](=[O:36])[NH:32][CH2:33][CH2:34][NH2:35])([CH3:29])([CH3:28])[CH3:27]>>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][NH:35][CH2:34][CH2:33][NH:32][C:31](=[O:36])[O:30][C:26]([CH3:28])([CH3:27])[CH3:29])=[CH:18][C:3]=1[C:4](=[O:5])[NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][CH:12]([CH2:13]3)[CH2:17]1)[CH2:9]2
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCCl)ccc1Cl
Product: CC(C)(C)OC(=O)NCCNCCNc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Yield: 94.4 %

Procedure:
Prepared according to the method of Example 4 using 2-chloro-5-(2-chloroethyl)amino-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (WO 99/29661) (0.2 g) and (2-amino-ethyl)-carbamic acid tert butyl ester (0.25 g) to deliver the sub-title compound as a brown oil (0.25 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[CH3:25][C@@H:26]1[O:30][C:29](=[O:31])[NH:28][CH2:27]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:28]4[CH2:27][C@H:26]([CH3:25])[O:30][C:29]4=[O:31])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: C[C@H]1CNC(=O)O1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4C[C@H](C)OC4=O)cc3)CC2)c(C)c1
Yield: 80.8 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (435 mg) described in Preparation Example 177 and (S)-5-methyloxazolidin-2-one (121 mg) described in Preparation Example 42, the title compound (330 mg) was obtained.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([NH2:19])[CH:16]([CH3:18])[CH3:17].[C:20]([O:24][C:25]([N:27]1[CH2:33][CH2:32][CH2:31][C@H:28]1[CH:29]=O)=[O:26])([CH3:23])([CH3:22])[CH3:21].[OH-].[Na+]>ClCCCl.O>[CH2:15]([NH:19][CH2:29][C@@H:28]1[CH2:31][CH2:32][CH2:33][N:27]1[C:25]([O:24][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:26])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)CN
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCCl
Product: CC(C)CNC[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 76.1 %

Procedure:
Sodium triacetoxyborohydride (2.9 g, 14 mmol, 1.4 eq) is added to a solution of isobutylamine (0.77 g, 10 mmol, 1.05 eq) and N-(tert-butoxycarbonyl)-L-prolinal (2 g, 10 mmol, 1 eq) in 1,2-dichloroethane (35 ml). After 1 hr water (25 ml) followed by 2N aqueous sodium hydroxide (25 ml) is added. The aqueous layer is separated and extracted with dichloromethane (3×50 ml). The organic layers are combined and dried over magnesium sulphate, filtered, and concentrated in vacuo giving a residue. The residue is purified by flash chromatography, eluting with 20-70% methanol in ethyl acetate to give the tert-butyl (2S)-2-[(isobutylamino)methyl]pyrrolidine-1-carboxylate (1.95 g, 76%): 1H NMR (300 MHz, CDCl3) δH: 3.69-4.07 (1H, m), 3.19-3.50 (2H, m), 2.67-2.87 (1H, m), 2.48-2.65 (1H, m), 2.35-2.47 (2H, m), 1.62-2.01 (5H, m), 1.34-1.53 (9H, m) and 0.88 (6H, d); LCMS: Rt=2.74 (6 min method) [M+H]=257.5.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].[Cl:7][C:8]1[C:9]([CH3:36])=[C:10]([C:29]2[CH:30]=[N:31][C:32](F)=[CH:33][CH:34]=2)[C:11]([O:27][CH3:28])=[C:12]([CH:14]([N:16]2[C:20]3=[N:21][CH:22]=[N:23][C:24]([NH2:25])=[C:19]3[C:18]([CH3:26])=[N:17]2)[CH3:15])[CH:13]=1>>[NH2:25][C:24]1[N:23]=[CH:22][N:21]=[C:20]2[N:16]([CH:14]([C:12]3[C:11]([O:27][CH3:28])=[C:10]([C:29]4[CH:34]=[CH:33][C:32]([O:5][CH2:4][CH2:3][OH:6])=[N:31][CH:30]=4)[C:9]([CH3:36])=[C:8]([Cl:7])[CH:13]=3)[CH3:15])[N:17]=[C:18]([CH3:26])[C:19]=12
Reactant: OCCO
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccc(F)nc1
Agent: [H-]
Agent: [Na+]
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccc(OCCO)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.7 %

Procedure:
Sodium hydride (20 mg, 0.5 mmol) was added to 1,2-ethanediol (0.5 mL, 9 mmol) and the mixture was stirred at room temperature for 10 min. At this time 1-{1-[5-chloro-3-(6-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (10 mg, 0.023 mmol) was added and then the reaction was stirred at 110° C. overnight. The crude was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (1.8 mg, 17%). The product was isolated as a single enantiomer. LCMS calculated for C23H26ClN6O3 (M+H)+: m/z=469.2; Found: 469.1.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:20]=[CH:19][C:14]([O:15][CH2:16][C:17]#[N:18])=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:3]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[N-:32]=[N+:33]=[N-:34].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:20]=[CH:19][C:14]([O:15][CH2:16][C:17]4[NH:34][N:33]=[N:32][N:18]=4)=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:3]1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCc1c(-c2ccccc2)n(C)c2ccc(-c3ccc(OCC#N)cc3)cc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCc1c(-c2ccccc2)n(C)c2ccc(-c3ccc(OCc4nnn[nH]4)cc3)cc12

Procedure:
The desired product was prepared using a procedure similar to step 6 of example 3. Thus, [4-(1-methyl-3-pentyl-2-phenyl-1H-indol-5-yl)-phenoxy]-acetonitrile (0.152 g, 0.372 mmol) was reacted with NaN3 (0.121 g, 1.860 mmol) and NH4Cl (0.099 g, 1.860 mmol) in DMF (5 ml) to give the product (0.117 g, 0.259 mmol, 70%) as a white solid, dec. 181-185° C. 1H NMR (DMSO-d6) δ 0.76 (t, J=7.0 Hz, 3H), 1.13-1.22 (m, 4H), 1.51-1.57 (m, 2H), 2.66 (t, J=7.5 Hz, 2H), 3.56 (s, 3H), 5.53 (s, 2H), 7.15 (d, J=8.7 Hz, 2H), 7.42-7.45 (m, 3H), 7.48 (t, J=8.6 Hz, 2H), 7.54 (t, J=7.2 Hz, 2H), 7.65 (d, J=8.7 Hz, 2H), 7.74 (d, J=1.2 Hz, 1H), 16.80 (broad s, 1H); IR (solid) 3030, 2930, 2860, 1605, 1520, 1480, 1370 and 1240 cm−1; [ESI(−)], m/z 450 (M−H)−; Anal. Calcd. for C28H29N5O: C, 74.48; H, 6.47; N, 15.51 Found: C, 74.49; H, 6.26; N, 15.30.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[NH2:21][C@@H:22]([CH:28]([CH3:30])[CH3:29])[C:23]([N:25]([CH3:27])[CH3:26])=[O:24]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:21][C@@H:22]([CH:28]([CH3:30])[CH3:29])[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: CC(C)[C@H](N)C(=O)N(C)C
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccccc1C1(N[C@H](C(=O)N(C)C)C(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.92 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and 0.99 g of the compound obtained in Step 82-2 as starting materials, respectively 1.07 g (Isomer A, pale yellow solid) and 1.73 g (Isomer B, colorless solid) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:24][CH2:23][C:18]2(OCC[O:19]2)[CH2:17][CH2:16]1.Cl.C(=O)(O)[O-].[Na+]>CO>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:24][CH2:23][C:18](=[O:19])[CH2:17][CH2:16]1
Reactant: COCOc1ccc(C2CCC3(CC2)OCCO3)c(OCOC)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COCOc1ccc(C2CCC(=O)CC2)c(OCOC)c1
Reaction time: 1.5 h
Yield: 79 %

Procedure:
A round bottomed flask was charged with 8-[2,4-bis(methoxymethoxy)phenyl]-1,4-dioxaspiro[4.5]decane (3.20 g) and methanol (50 ml). Over a 20 min period, aqueous hydrochloric acid (50 ml, 1M) was added to the stirred solution, at room temperature and the reaction mixture stirred for 1.5 hr. Solid sodium bicarbonate was added until the reaction mixture was neutralised and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (30 ml) and water (10 ml), and the aqueous layer was extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified via flash column chromatography (SiO2, ethyl acetate/petroleum ether, 1:4, v/v), affording the title compound (2.20 g, 60%) as a white powder. δH (CDCl3) 1.85-1.96 (2H, m), 2.14-2.22 (2H, m), 2.46-2.59 (4H, m), 3.39 (1H, tt), 3.49 (3H, s), 3.52 (3H, s), 5.16 (2H, s), 5.23 (2H, s), 6.67-6.71 (1H, m), 6.85 (1H, m), 7.08 (1H, d).
Reaction SMILES: [CH2:1]([C:7]([OH:9])=[O:8])[C@H:2]([OH:6])[C:3]([OH:5])=[O:4].Cl.[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([NH2:27])[CH2:20]C2C=CC=CC=2)=[CH:15][CH:14]=1)=[CH2:12].C(C1C=CC([C@@H](N)C)=CC=1)=C>CO>[C:3]([OH:5])(=[O:4])[C@H:2]([CH2:1][C:7]([OH:9])=[O:8])[OH:6].[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([C@H:19]([NH2:27])[CH3:20])=[CH:15][CH:14]=1)=[CH2:12]
Reactant: C=Cc1ccc([C@@H](N)Cc2ccccc2)cc1
Agent: C=Cc1ccc([C@H](C)N)cc1
Agent: Cl
Agent: O=C(O)C[C@H](O)C(=O)O
Solvent: CO
Product: C=Cc1ccc([C@@H](C)N)cc1
Reaction time: 15 h
Yield: 19.1 %

Procedure:
37.4 g (0.279 mol) of L-(-)-malic acid are added to a solution of 41.06 g (0.279 mol) of (R), (S)-1-(4-vinylphenyl)-ethylamine in 250 ml of methanol at 0° C. After 15 hours, the precipitated crystals (31.0 g) are filtered off under suction, and the mother liquor is evaporated down in vacuo until crystallization begins again. A further 15 g of product are obtained. The crystal fractions are combined and recrystallized twice, in each case from 250 ml of methanol, with the addition of about 50 mg of di-tert-butyl-p-cresol. Yield: 15.2 g of white crystalline powder, [α]D20 =+2.10° (H2O, c=0.95).
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[CH:11][C:12]3[C:13]([Br:19])=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[C:30](Cl)=[O:31]>>[Br:19][C:13]1[C:12]2[C:11]([C:30]([C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:20]=3)=[O:31])=[C:10]3[CH:6]([CH2:2][C:3]([OH:5])=[O:4])[CH2:7][CH2:8][N:9]3[C:17]=2[CH:16]=[C:15]([F:18])[CH:14]=1
Reactant: CC(C(=O)[O-])C1CCn2c1cc1c(Br)cc(F)cc12
Reactant: O=C(Cl)c1ccc2ccccc2n1
Product: O=C(O)CC1CCn2c1c(C(=O)c1ccc3ccccc3n1)c1c(Br)cc(F)cc12

Procedure:
Starting from (+/−)-methyl(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (Example 7, Step 8) and quinoline-2-carbonyl chloride, the title compound was synthesized following the procedures described in Step 1 of Example 61 and Step 10 of Example 7.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([F:8])[C:5]2[O:9][C:10]3[C:15]([C@@:16]4([CH2:21][CH2:20][O:19]/[C:18](=[N:22]\C(=O)C5C=CC=CC=5)/[NH:17]4)[C:4]=2[CH:3]=1)=[CH:14][C:13]([NH:31][C:32]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][N:33]=1)=[CH:12][CH:11]=3.N.CO>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([F:8])[C:5]2[O:9][C:10]3[C:15]([C@@:16]4([CH2:21][CH2:20][O:19][C:18]([NH2:22])=[N:17]4)[C:4]=2[CH:3]=1)=[CH:14][C:13]([NH:31][C:32]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][N:33]=1)=[CH:12][CH:11]=3
Reactant: Cc1cccnc1Nc1ccc2c(c1)[C@@]1(CCO/C(=N\C(=O)c3ccccc3)N1)c1cc(Cl)nc(F)c1O2
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccnc1Nc1ccc2c(c1)[C@@]1(CCOC(N)=N1)c1cc(Cl)nc(F)c1O2
Temperature: 50 °C

Procedure:
To a solution of (S,Z)—N-(3-chloro-1-fluoro-7-((3-methylpyridin-2-yl)amino)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazinan]-2′-ylidene)benzamide (0.069 g, 0.130 mmol) in THF (2 mL) was added ammonia, 2.0M solution in methanol (10 ml, 20.00 mmol) and heated in a sealed tube at 50° C. for 15 h. The reaction was concentrated and purified by HPLC to afford (S)-3-chloro-1-fluoro-N7-(3-methylpyridin-2-yl)-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine as a white solid. MS m/z=426.1 [M+H]+.
Reaction SMILES: O=[C:2]=[N:3]S(Cl)(=O)=O.[C:8]12([CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)[N:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11][N:10]1[CH:19]=[CH:20][CH:21]=[C:9]21.CN(C)C=O>C1COCC1>[C:2]([C:19]1[N:10]2[CH2:11][CH2:12][N:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]3([CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH2:23][CH2:22]3)[C:9]2=[CH:21][CH:20]=1)#[N:3]
Reactant: CCOC(=O)N1CCn2cccc2C12CCN(C(=O)OC(C)(C)C)CC2
Reactant: O=C=NS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCn2c(C#N)ccc2C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of N-(oxomethylene)sulfamoyl chloride (23.9 μL, 0.27 mmol) in THF (200.0 μL) was slowly added to a solution of 1-tert-butyl 2′-ethyl 3′,4′-dihydro-2′H-spiro[piperidine-4,1′-pyrrolo[1,2-a]pyrazine]-1,2′-dicarboxylate (100 mg, 0.27 mmol) in THF (1.0 mL) at −78° C. under nitrogen. The reaction mixture was stirred for 1 hour at −78° C. N,N-dimethylformamide (39.9 μL, 0.51 mmol) was then slowly added to the cold reaction mixture. The reaction mixture was then allowed to slowly warm to room temperature. The reaction was filtered and purified by reverse phase preparatory-LC-MS (10-99% CH3CN/H2O) using HCl modifier to give 1-tert-butyl 2′-ethyl 6′-cyano-3′,4′-dihydro-2′H-spiro[piperidine-4,1′-pyrrolo[1,2-a]pyrazine]-1,2′-dicarboxylate. ESI-MS m/z calc. 388.2, found 389.3 (M+1)+; Retention time: 1.82 minutes (3 minute run).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:47])[CH2:15][N:16]1[C:25](=[O:26])[C:24]2[N:23]([CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[C:22]([N:32]3[CH2:37][CH2:36][CH2:35][CH:34]([NH:38]C(OC(C)(C)C)=O)[CH2:33]3)=[N:21][C:20]=2[N:19]([CH3:46])[C:17]1=[O:18])=[O:5])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:47])[CH2:15][N:16]1[C:25](=[O:26])[C:24]2[N:23]([CH2:27][CH:28]=[C:29]([CH3:30])[CH3:31])[C:22]([N:32]3[CH2:37][CH2:36][CH2:35][CH:34]([NH2:38])[CH2:33]3)=[N:21][C:20]=2[N:19]([CH3:46])[C:17]1=[O:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)COc1ccccc1C(=O)Cn1c(=O)c2c(nc(N3CCCC(NC(=O)OC(C)(C)C)C3)n2CC=C(C)C)n(C)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)COc1ccccc1C(=O)Cn1c(=O)c2c(nc(N3CCCC(N)C3)n2CC=C(C)C)n(C)c1=O
Temperature: 25 °C

Procedure:
A solution of 209 mg of 1-(2-{2-[(ethoxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine in 4 ml methylene chloride is combined with 1 ml of trifluoroacetic acid and stirred for half an hour at ambient temperature. For working up the reaction mixture is diluted with methylene chloride and washed with saturated potassium carbonate solution. The organic phase is dried, evaporated down and chromatographed through a silica gel column with methylene chloride/methanol (1:0 to 4:1) as eluant.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=O)=[N:2]1.CN1CCOCC1.[NH2:28][CH2:29][C:30]1[S:31][CH:32]=[CH:33][CH:34]=1.C(Cl)CCl>C1COCC1.C(OCC)(=O)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([NH:28][CH2:29][C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[O:16])=[N:2]1
Reactant: O=C(O)c1ccccc1/C=C/c1n[nH]c2ccccc12
Reactant: NCc1cccs1
Solvent: ClCCCl
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCc1cccs1)c1ccccc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.5 %

Procedure:
A solution of (E)-2-[2-(1H-indazol-3-yl)vinyl]benzoic acid (35 mg, 0.13 mmol) obtained in Step 1 of Example 47 in THF (1.0 mL) was sequentially added with 4-methylmorpholine (29 μL, 0.27 mmol), 2-(aminomethyl)thiophene (23 mg, 0.28 mmol) and EDC (36 mg, 0.19 mmol) and stirred at room temperature for 1.0 hour. The reaction mixture was added with water and ethyl acetate to separate the mixture into organic layer and aqueous layer and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform/methanol=100/0 to 90/10) and the obtained compound was crystallized from a mixed solvent of hexane/ethyl acetate (9/1, 1.0 mL) to obtain Compound 141 (11 mg, 17%).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:7]([C:12]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:15][NH:14][CH2:13]1)[CH2:8][CH2:9][CH2:10][CH3:11]>O.C1COCC1.[Rh]>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH:16]1([C:12]2([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:13][NH:14][CH2:15]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCCCCC1(c2ccccc2)CNC1
Agent: [Rh]
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC1(C2CCCCC2)CNC1
Temperature: 80 °C
Reaction time: 23 h
Yield: 54.8 %

Procedure:
254 mg of rhodium-on-alumina at 5% are added to 652 mg (2.62 mmol) of 3-pentyl-3-phenylazetidine oxalate (cf.) in 13 ml of water and 6.5 ml of THF. The medium is placed under a hydrogen atmosphere at 6 bar of pressure and heated at 80° C. After 23 hours, the reaction medium is filtered through celite and the solvents are evaporated off. 0.43 g of 3-cyclohexyl-3-pentylazetidine oxalate is obtained with a yield of 64%.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)([O-:14])=[O:13]>C(O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:18][C:17]2[CH:20]=[CH:21][CH:22]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(N=Cc2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A mixture of 4-methanesulfonyl-phenylamine (5.6 g, 33 mmol) and 3-nitro-benzaldehyde (5.45 g, 36 mmol) in ethanol (100 mL) was prepared. The reaction mixture was heated to reflux for 16 h. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford (4-methanesulfonyl-phenyl)-(3-nitro-benzylidene)-amine (10 g, 99%) as a white solid: LC/MS m/e calcd for C14H12N2O4S (M+H)+: 305.33, observed: 305.1.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[CH2:27][NH:28][NH2:29]>C(O)C>[NH2:10][C:6]1[NH:29][N:28]([CH2:27][C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([Br:23])[CH:25]=2)[C:4](=[O:3])[CH:5]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NNCc1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2cccc(Br)c2)[nH]1
Reaction time: 2 h

Procedure:
20.5 g of β-amino-β-ethoxyacrylic acid ethyl ester together with 1.5 g of p-toluenesulphonic acid were dissolved in 200 ml of ethanol. 26 g of m-bromobenzylhydrazine were added dropwise to this solution, under nitrogen. After stirring for 2 hours, the mixture was left to stand overnight and the compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting Point: 160°, 12 g (35%).
Reaction SMILES: [CH:1]1(/[CH:6]=[CH:7]/[C@H:8]([C@@H:10]2[O:14][C:13](=[O:15])[C@H:12]([O:16][CH2:17][CH3:18])[C@@H:11]2[OH:19])[OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:21][C@@H:22]1[C:28](=[O:29])[NH:27][C:26]2[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=2[O:24][CH2:23]1.C(C(CCCC)C([O-])=O)C.[Na+]>C1COCC1>[CH:1]1(/[CH:6]=[CH:7]/[C@@H:8]([OH:9])[C@H:10]([OH:14])[C@@H:11]([OH:19])[C@@H:12]([O:16][CH2:17][CH3:18])[C:13]([NH:21][C@@H:22]2[C:28](=[O:29])[NH:27][C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[O:24][CH2:23]2)=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCO[C@H]1C(=O)O[C@@H]([C@H](O)/C=C/C2CCCC2)[C@H]1O
Reactant: N[C@H]1COc2ccccc2NC1=O
Agent: CCCCC(CC)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CCO[C@@H](C(=O)N[C@H]1COc2ccccc2NC1=O)[C@H](O)[C@@H](O)[C@H](O)/C=C/C1CCCC1
Temperature: 25 °C

Procedure:
110 mg of 52 (407 μmol), 87 mg of 4 (407 μmol) and 169 mg of sodium 2-ethylhexanoate (1.02 mmol) in 2 mL of THF are successively introduced into a Wheaton tube, with stirring and under an argon atmosphere. The stirring is maintained at RT for 24 h. The reaction medium is concentrated to dryness. The residues are chromatographed on a silica cartridge (8 g, eluent AcOEt). 75 mg of expected product Ex20 are recovered.
Reaction SMILES: [I:1]Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:6][C:5]=1[CH3:15].C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:3][C:4]1[C:5]([CH3:15])=[CH:6][C:7]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:8][C:9]=1[I:1]
Reactant: Cc1cc(-n2cncn2)ccc1N
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(-n2cncn2)cc(I)c1N

Procedure:
Iodine monochloride (5.103 g) was added dropwise to a stirred solution of 1-(4-amino-3-methylphenyl)-1,2,4-triazole (5.22 g) and sodium acetate (2.583 g) in acetic acid (100 cm3). After 16 hours volatile material was removed in vacuo and the residue was partitioned between dichloromethane (100 cm3) and sodium carbonate solution (50 cm3). The organic phase was washed with sodium thiosulphate solution (10 g in 50 cm3 water), dried (MgSO4) and evaporated to give a solid which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with ethyl acetate. Combination and evaporaton of the appropriate fractions gave a solid which was recrystallised from ethyl acetate-ether to afford the title compound, m.p. 151°-154° (3.1 g).