Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:5]2[CH:6]=[C:7]([C:14]([F:17])([F:16])[F:15])[CH:8]=[C:9]([CH:12]=O)[C:10]=2[CH:11]=1.OCC1N(S(C2C=CC=CC=2)(=O)=O)C2C(C=1)=C(C(F)(F)F)C=C(C=O)C=2.C([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)(OC(C)(C)C)=O.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[C:21]1([S:18]([N:4]2[C:5]3[C:10](=[C:9]([CH2:12][N:60]4[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]4)[CH:8]=[C:7]([C:14]([F:17])([F:15])[F:16])[CH:6]=3)[CH:11]=[C:3]2[CH2:2][OH:1])(=[O:20])=[O:19])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1cc(C(F)(F)F)cc2c1cc(CO)n2S(=O)(=O)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=Cc1cc(C(F)(F)F)c2cc(CO)n(S(=O)(=O)c3ccccc3)c2c1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=S(=O)(c1ccccc1)n1c(CO)cc2c(CN3CCNCC3)cc(C(F)(F)F)cc21

Procedure:
2-(Hydroxymethyl)-1-(phenylsulfonyl)-6-(trifluoromethyl)-1H-indole-4-carbaldehyde and 2-(Hydroxymethyl)-1-(phenylsulfonyl)-4-(trifluoromethyl)-1H-indole-6-carbaldehyde (Intermediates 71) in dry THF (8 mL), was distributed into two micro wave vials (47 mg, 0.12 mmol, in each), where after 1-BOC-piperazine (46 mg, 0.25 mmol), acetic acid (70 μL, 1.23 mmol) and NaB(OAc)3H (78 mg, 0.37 mmol) were added to each vial. The mixtures were irradiated with microwaves for 720 s at 130° C., filtered and concentrated. The residues were dissolved in MeOH (1.5 mL) and conc. HCl (0.5 mL) and irradiated using microwaves at 100° C. for 300 s, filtered and purified using preparative HPLC/UV (System A, 20-50% MeCN, 0.1% TFA). Concentration of fractions from the compound with shortest retention time gave 38 mg of [1-(phenylsulfonyl)-4-(piperazin-1-ylmethyl)-6-(trifluoromethyl)-1H-indol-2-yl]methanol. Purification was performed by preparative HPLC/UV (System A, 20-50% MeCN, 0.1% NH4OAc). Concentration was followed by extraction using DCM (×2) and aq. Na2CO3/brine. The organic layers were combined, dried, filtered and concentrated to give 7 mg, 6% of a light yellow solid. HPLC purity 98% RT=1.59 min (System A, 10-97% MeCN over 3 minutes), 98% RT=1.35 min (System B, 10-97% MeCN over 3 minutes). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 2.37 (s, 4 H) 2.88 (t, J=4.71 Hz, 4 H) 3.60 (s, 2 H) 4.95 (s, 2 H) 6.82 (s, 1 H) 7.45 (t, J=7.85 Hz, 2 H) 7.49 (s, 1 H) 7.56 (t, J=7.54 Hz, 1 H) 7.85 (d, J=8.48 Hz, 2 H) 8.19 (s, 1H). 13C NMR (126 MHz, CHLOROFORM-D) δ ppm 45.97 (s, 2 C) 54.23 (s, 2 C) 58.43 (s, 1 C) 63.31 (s, 1 C) 109.04 (s, 1 C) 117.93 (s, 1 C) 121.88-127.09 (m, 1 C) 122.09 (s, 1 C) 124.91 (s, 2 C) 126.55 (s, 2 C) 129.49 (s, 2 C) 134.32 (s, 1 C) 135.61 (s, 1 C) 137.53 (s, 1 C) 138.15 (s, 1 C) 141.98 (s, 1 C). COSY, HSQC and HMBC were also run to confirm the structure. MS (ESI+) for C21H22F3N3O3S m/z 454 (M+H)+
Reaction SMILES: C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.CN(CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1)C.[CH3:41][S:42][C:43]1[CH:44]=[C:45]([N:49]=[C:50]=[O:51])[CH:46]=[CH:47][CH:48]=1.[C:52]([O:56][CH2:57][CH:58]([OH:60])[CH3:59])(=[O:55])[CH:53]=[CH2:54].[N-]=C=O>C(OCC)(=O)C>[C:52]([O:56][CH2:57][CH:58]([O:60][C:50](=[O:51])[NH:49][C:45]1[CH:46]=[CH:47][CH:48]=[C:43]([S:42][CH3:41])[CH:44]=1)[CH3:59])(=[O:55])[CH:53]=[CH2:54]
Reactant: CSc1cccc(N=C=O)c1
Reactant: C=CC(=O)OCC(C)O
Agent: CN(C)CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [N-]=C=O
Solvent: CCOC(C)=O
Product: C=CC(=O)OCC(C)OC(=O)Nc1cccc(SC)c1
Temperature: 60 °C

Procedure:
0.05 g of 2,6-di-tert-butyl-4-methylphenol, 0.02 g of Desmorapid Z, 26.8 g of 3-(methylthio)phenyl isocyanate in 50 g of ethyl acetate were initially introduced into a 250 ml round-bottomed flask and heated to 60° C. Thereafter 21.1 g of 2-hydroxypropyl acrylate were added dropwise and the mixture was kept further at 60° C. until the isocyanate content had fallen below 0.1%. Thereafter, the ethyl acetate was distilled off at 5 mbar and cooling was effected. The product was obtained as a light yellow liquid.
Reaction SMILES: N(CCO)(CCO)CCO.Cl.[CH:12]([NH2:15])([CH3:14])[CH3:13].CC1N=CC(COP(O)(O)=O)=C(C=O)C=1O.[CH2:32]([CH:39]1[CH2:43][O:42][C:41](=[O:44])[N:40]1[C:45]([C@@H:47]1[CH2:52]CC(=O)C[C@H:48]1[C:54]1[CH:59]=[CH:58][C:57]([Br:60])=[CH:56][CH:55]=1)=[O:46])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>CS(C)=O>[NH2:15][C@@H:12]1[CH2:14][CH2:52][C@@H:47]([C:45]([N:40]2[C@H:39]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:43][O:42][C:41]2=[O:44])=[O:46])[C@H:48]([C:54]2[CH:55]=[CH:56][C:57]([Br:60])=[CH:58][CH:59]=2)[CH2:13]1
Reactant: O=C1CC[C@@H](C(=O)N2C(=O)OCC2Cc2ccccc2)[C@H](c2ccc(Br)cc2)C1
Reactant: CC(C)N
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: Cl
Solvent: CS(C)=O
Solvent: OCCN(CCO)CCO
Product: N[C@@H]1CC[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)[C@H](c2ccc(Br)cc2)C1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
To a solution of aqueous triethanolamine (684 mL, 100 mM) was added isopropylamine hydrochloride (102.6 g), pyridoxal phosphate (Vitamin B6; 1.14 g), and the enzyme ATA24 (22.8 g) [ATA-024 is also known as CDX-010 and purchased from Codexis, Inc., Redwood City, Calif., USA.] The mixture was treated with DMSO (228 mL) and heated to 45° C. using a Multimax (Mettler Toledo). The pH was adjusted to 8.6 when 4-benzyl-3-{[(1R,2R)-2-(4-bromophenyl)-4-oxocyclohexyl]carbonyl}-1,3-oxazolidin-2-one (5.7 g, 12.49 mmol) was added as a solution in DMSO (228 mL) by syringe pump over 3 h. An additional amount of the enzyme ATA24 (2 g) was added in 10 mL of buffer and allowed to react for approximately 4 h. An additional amount of the enzyme ATA24 (3 g) was added in 30 mL of buffer and the reaction aged overnight. The reaction was treated with aq. 6 N HCl to lower the pH to 2, and then aged for about 30 min. The reaction was then filtered and the enzyme precipitate was rinsed with 250 mL of 10% DMSO/pH 2.5 H2O (3×). The filtrate was extracted with MTBE (1 L), and the aqueous layer was separated, brought to pH 9.5 and subsequently extracted with MTBE (1 L). The organic layer was separated, washed with pH 11 brine (2×250 mL), dried (MgSO4), filtered and concentrated to afford the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][C:31]3[CH:40]=[CH:39][C:34]([C:35]([O:37]C)=[O:36])=[CH:33][CH:32]=3)[CH2:26][CH2:25]2)[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH-].[Na+].Cl.ClCCl.CO>C(O)C>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][CH:27]([CH2:30][C:31]3[CH:40]=[CH:39][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=3)[CH2:28][CH2:29]2)[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(CC2CCN(CCCN(C(=O)C3CCN(C(C)=O)CC3)c3ccc(Cl)c(Cl)c3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1CCC(C(=O)N(CCCN2CCC(Cc3ccc(C(=O)O)cc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 56.8 %

Procedure:
To a solution of the compound obtained in Example 233 (200 mg, 0.37 mmol) in ethanol (2 mL) was added aqueous solution of 1N-sodium hydroxide (0.56 mL, 0.56 mmol), and the mixture was stirred at 80° C. for 3 hours. To the mixture was added, dropwise aqueous solution of 1N-hydrochloric acid (0.56 mL, 0.56 mmol) under ice cooling, and the mixture was concentrated under reduced pressure. The concentrate was subjected to flash column chromatography (silica gel 20 g, dichloromethane/methanol=20/1 to 2/1), and the desired fraction was concentrated under reduced pressure. To the concentrate was added diisoprpyl ether, and the resulting precipitates were collected by filtration to give the titled compound (120 mg, 0.21 mmol, Yield 56%) as white amorphous substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])([CH:6]1[CH2:11][CH2:10][CH2:9][C:8](=O)[CH2:7]1)[CH3:5].Cl.[Cl:24][C:25]1[N:30]=[CH:29][C:28]([NH:31]N)=[CH:27][CH:26]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]([S:13]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:14])=[O:15])([CH:6]1[CH2:7][C:8]2[NH:31][C:28]3[CH:27]=[CH:26][C:25]([Cl:24])=[N:30][C:29]=3[C:9]=2[CH2:10][CH2:11]1)[CH3:5]
Reactant: NNc1ccc(Cl)nc1
Reactant: COC(=O)C(C)(C1CCCC(=O)C1)S(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)C(C)(C1CCc2c([nH]c3ccc(Cl)nc23)C1)S(=O)(=O)c1ccccc1
Temperature: 115 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
In a sealed tube, 50 mg (0.15 mmol) of (RS,SR)-2-benzenesulfonyl-2-(3-oxo-cyclohexyl)-propionic acid methyl ester in 4 mL of glacial acetic acid were treated with 27 mg (0.18 mmol, 1.2 eq) of (6-chloro-pyridin-3-yl)-hydrazine hydrochloride and stirred at 115° C. for 3 hours. An aqueous solution of NaHCO3 was added until pH=7 was reached, and the mixture was extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. A column chromatography on silica gel with heptane/EtOAc 1:1 followed by trituration with Et2O yielded 52 mg (76%) of (RS,SR)-2-benzenesulfonyl-2-(2-chloro-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-7-yl)-propionic acid methyl ester as a white solid, MS: 433 (MH+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH2:37])[CH:29]=3.Cl.[CH3:40][N:41]1[C:45]([C:46](Cl)=[O:47])=[CH:44][N:43]=[CH:42]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH:37][C:46]([C:45]1[N:41]([CH3:40])[CH:42]=[N:43][CH:44]=1)=[O:47])[CH:29]=3
Reactant: Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Reactant: Cn1cncc1C(=O)Cl
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cncc1C(=O)Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Yield: 29 %

Procedure:
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-11-amine bis(trifluoroacetate) and 1-methyl-1H-imidazole-5-carbonyl chloride hydrochloride as the starting materials in 29% yield. LCMS for C23H21ClN7O (M+H)+: m/z=446.2.
Reaction SMILES: COC1C=CC2SCCNCC=2C=1.[N+:14]([C:17]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20])([O-])=O>[Pd]>[NH2:14][C:17]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: [Pd]
Agent: COc1ccc2c(c1)CNCCS2
Product: COc1ccc(N)c(C(=O)O)c1

Procedure:
By way of example, and as shown in Example 9 and Scheme 1 below, 7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine may be prepared from 2-nitro-5-methoxybenzoic acid as follows. The nitro group of 2-nitro-5-methoxybenzoic acid is reduced, using H2 with Pd/C as a catalyst, to give 2-amino-5-methoxybenzoic acid. 2-amino-5-methoxybenzoic acid may be diazotized with NaNO2, and then treated with Na2S2, to provide a stable disulfide compound. Without further purification, the stable disulfide compound may be treated with SOCl2, and then reacted with 2-chloroethylamine, in the presence of Et3N, to give an amide. The amide compound may then be converted to a cyclized compound via a one-pot procedure, as follows. A reducing reagent (such as trimethylphosphine or triphenylphosphine) and a base (such as triethylamine) may be added to a solution of the amide compound in THF (tetrahydrofuran). The resulting reaction mixture may then be refluxed for 3 h. The reducing agent (trimethylphosphine or triphenylphine) cleaves the disulfide (S—S) to its monosulfide (—S), which, in situ, undergoes intramolecular cyclization with the chloride to yield a cyclized amide. The cyclized amide may then be reduced with LiAlH4 to yield the 1,4-benzothiazepine intermediate, 7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine. JTV-519 may then be prepared from 7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine by reacting the 7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine with 3-bromopropionic chloride, and then reacting the resulting compound with 4-benzyl piperidine.
Reaction SMILES: [NH2:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.C(=O)([O-])O.[Na+:26].Br[CH2:28][C:29](=O)[C:30](=[N:34][O:35][CH3:36])[C:31](Cl)=[O:32].[NH2:38][C:39]([NH2:41])=[S:40].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O>[NH2:41][C:39]1[S:40][CH:28]=[C:29](/[C:30](=[N:34]/[O:35][CH3:36])/[C:31]([NH:1][C@@H:2]2[C:20](=[O:21])[N:4]3[C:5]([C:17]([O-:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]4[N:15]([CH3:16])[N:14]=[N:13][N:12]=4)[CH2:7][S:8][C@H:3]23)=[O:32])[N:38]=1.[Na+:26]
Reactant: CON=C(C(=O)Cl)C(=O)CBr
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CSc3nnnn3C)CS[C@H]12)c1csc(N)n1
Reaction time: 0.08 h
Yield: 88.2 %

Procedure:
In a solvent mixture of 50 ml water and 35 ml tetrahydrofuran were dissolved 1.64 g of 7β-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid and 1.68 g of sodium hydrogen carbonate. To this solution was added a solution of 2.1 g 4-bromo-2-methoxyimino-3-oxobutyryl chloride in 15 ml tetrahydrofuran and the mixture was stirred at 20°-25° C. for 5 minutes. Then, a solution of 1.52 g thiourea in 20 ml water was added thereto and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was adjusted to pH 7.0 with 20% aqueous sodium carbonate solution and concentrated under reduced pressure. The concentrate was subjected to column chromatography using Diaion HP-40 (Mitsubishi Chemical Industries, Ltd.) and elution was carried out with 400 ml of water-isopropyl alcohol (9:1, v/v). The eluate was lyophilized to give 2.35 g of sodium 7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate. Yield 88.2%. Analysis by high-performance liquid chromatography showed that the proportion of the (E)-isomer was not more than 1% of the (Z)-isomer.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[C:7](=[O:17])[NH:8][C:9]([CH2:15]Cl)=[N:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)=[O:4].[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[NH:24]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:6]2[C:7](=[O:17])[NH:8][C:9]([CH2:15][N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)=[O:4].[CH3:1][O:2][C:3]([C:5]1[C:6]2[C:7](=[O:17])[NH:8][C:9]([CH2:15][N:24]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)=[O:4]
Reactant: COC(=O)c1cccc2nc(CCl)[nH]c(=O)c12
Reactant: C1CNCCNC1
Reactant: C1CNCCN1
Solvent: CC#N
Product: COC(=O)c1cccc2nc(CN3CCCNCC3)[nH]c(=O)c12
Product: COC(=O)c1cccc2nc(CN3CCNCC3)[nH]c(=O)c12
Reaction time: 8 h

Procedure:
Displacement of the chloro group of compound 4 with piperazine or [1,4]diazepane using General procedure F provides the compound 47A or 47B. To a stirring solution of 4 (1 eq) in acetonitrile was added piperazine or [1,4]diazepane (large excess) under a blanket of nitrogen. The solution was allowed to stir overnight and then evaporated to dryness. The crude material was purified via silica plug with 9:1 dichloromethane:methanol to afford a white solid, 4-Oxo-2-piperazin-1-ylmethyl-3,4-dihydro-quinazoline-5-carboxylic acid methyl ester, 47A or 2-[1,4]diazepan-1-ylmethyl-4-oxo-3,4-dihydro-quinazoline-5-carboxylic acid methyl ester, 47B.
Reaction SMILES: N[C@@H](C)CNC1SC([C:11](OCC)=[O:12])=C(C)N=1.[NH2:17][CH2:18][C@H:19]([NH:21][C:22]1[S:23][C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:25]([CH3:27])[N:26]=1)[CH3:20]>>[CH3:27][C:25]1[N:26]=[C:22]([N:21]2[C@H:19]([CH3:20])[CH2:18][NH:17][C:11]2=[O:12])[S:23][C:24]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)c1sc(N[C@H](C)CN)nc1C
Reactant: CCOC(=O)c1sc(NC[C@H](C)N)nc1C
Product: CCOC(=O)c1sc(N2C(=O)NC[C@H]2C)nc1C

Procedure:
Following the procedure as described in Preparation 4, making variations as required to replace (S)-ethyl 2-(2-aminopropylamino)-4-methylthiazole-5-carboxylate with (R)-ethyl 2-(1-aminopropan-2-ylamino)-4-methylthiazole-5-carboxylate, the title compound was obtained as a colorless solid (86%): MS (ES+) m/z 269.7 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([O:12][CH3:13])[CH:7]=1.C(Cl)Cl>[Pd].CCO>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([O:12][CH3:13])[CH:7]=1
Reactant: COC(=O)C=Cc1ccnc(OC)c1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)CCc1ccnc(OC)c1
Yield: 93 %

Procedure:
A suspension of 3-(2-methoxy-pyridin-4-yl)-acrylic acid methyl ester (1.3 g, 6.72 mmol, 1 eq) and Pd/C, 10% (357 mg, 0.05 eq, 10%) was stirred in a DCM (15 ml)/absolute EtOH (15 ml) solvent mixture under hydrogen atmosphere for 1 hour at room temperature. Palladium was filtered off over a celite pad, the solvent was evaporated and obtained crude was purified by chromatography on BIOTAGE SP1 purification device using 25 g normal phase silica SNAP coloumn and cyclohexane/EtOAc solvent system (gradient 3-30% of EtOAc in 20 coloumn volumes). Solvent from the gathered fractions of appropriate composition was evaporated and obtained was 3-(2-methoxy-pyridin-4-yl)-propionic acid methyl ester (1.22 g, yield=88.2%, purity=95%) in form of transparent colourless oil. MS: [M+H]+=196.14 1H NMR (300 MHz; CDCl3) δ/ppm 2.63 (t, J=7.91 Hz, 2H), 2.90 (t, J=7.91 Hz, 2H), 3.68 (s, 3H), 3.92 (s, 3H), 6.57 (s, 1H), 6.72 (dd, J=5.33 Hz, J=1.29 Hz, 1H), 8.06 (d, J=5.33 Hz, 1H)
Reaction SMILES: [O:1]=[C:2]([CH3:12])[CH2:3][CH:4]1[CH:6]([C:7]([OH:9])=[O:8])[C:5]1([CH3:11])[CH3:10].[C:13](=O)(O)[O-].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[O:1]=[C:2]([CH3:12])[CH2:3][CH:4]1[CH:6]([C:7]([O:9][CH3:13])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: CC(=O)CC1C(C(=O)O)C1(C)C
Reactant: O=C([O-])O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)C1C(CC(C)=O)C1(C)C
Reaction time: 4 h
Yield: 96.4 %

Procedure:
10 g of 3-(2-oxopropyl)-2,2-dimethyl-cyclopropane carboxylic acid in 100 ml of acetone were heated to 30° C. to 34° C. in the presence of 7.35 g of potassium bicarbonate and 5 ml of dimethyl sulfate. After 4 hours of stirring, 0.85 ml of dimethyl sulfate were added and the reaction medium was held at 30° to 34° C. for 20 hours. After filtration, the product was taken up in ethyl ether and the solvent was evaporated. The residue was chromatographed on silica (eluant: hexane - ethyl acetate 8-2) to obtain 10.43 g of the expected product.
Reaction SMILES: [CH2:1]([N:11]1[C:20](=[O:21])[C:19]2[N:18]([CH3:22])[CH:17]=[N:16][C:15]=2[N:14]([CH3:23])[C:12]1=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]CC=C.C[N+]1([O-])CC[O:28]CC1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[C:40]([OH:44])(C)([CH3:42])[CH3:41]>[Os](=O)(=O)(=O)=O.CC(C)=O.O>[OH:44][CH:40]([CH2:42][OH:28])[CH2:41][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][N:11]1[C:20](=[O:21])[C:19]2[N:18]([CH3:22])[CH:17]=[N:16][C:15]=2[N:14]([CH3:23])[C:12]1=[O:13]
Reactant: CC(C)(C)O
Reactant: C=CCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cn1cnc2c1c(=O)n(CCCCCCCCC(O)CO)c(=O)n2C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
1-(9-Decenyl)-3,7-dimethylxanthine (3.2 g, 10.1 mmol), 4-methylmorpholine-N-oxide (1.41 g, 12 mmol), 3 drops of 2.5% osmium tetroxide solution in t-butanol, acetone (40 ml) and water (10 ml) were stirred for 24 hours. Following addition of 5 ml of a saturated solution of sodium dithionite and a further 15 minutes of stirring, the reaction mixture was extracted with four 50 ml aliquots of 25% ethanol/dichloromethane. The combined organic portions were dried over sodium sulfate. Evaporating the solvents left a white solid residue, which upon recrystallization in ethanol produced 3.3 g of 1-(9,10-dihydroxydecyl)-3,7-dimethylxanthine (93% yield).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C@@H:9]([CH2:31][CH2:32][CH3:33])[CH:10]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH3:34][S:35]([O:8][C@@H:9]([CH2:31][CH2:32][CH3:33])[CH:10]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])(=[O:37])=[O:36]
Reactant: CCC[C@H](O)C(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC[C@H](OS(C)(=O)=O)C(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
500 ml of triethylamine are added to a solution of 236.9 g of 1 in 1.2 l of dichloromethane. With ice cooling, a solution of 83.6 ml of methanesulfonyl chloride in 200 ml of dichloromethane is added. The mixture is stirred at 5-100 for 30 minutes, the precipitated triethylamine hydrochloride is removed, and the product is subjected to conventional work-up, giving 2 as oil.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Cl)[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:15]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH2:8])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCC=Cc1ccccc1
Reactant: Nc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccccc1NCC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
3.24 g of ortho-phenylenediamine was dissolved in 30 ml of dimethylformamide, to the solution were added 2.07 g of potassium carbonate and 1.52 g of cinnamyl chloride, and the mixture was stirred overnight at a room temperature. After adding 100 ml of water, the reaction mixture was extracted twice with 100 ml and 50 ml of chloroform, and the extract was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate and evaporated to remove the solvent under a reduced pressure. The resulting residue was applied to a silica gel column and eluted with chloroform, to obtain 2.0 g of the title compound as light brown crystals.
Reaction SMILES: C[C:2]12[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[C:6](=[O:12])[O:5][C:3]2=[O:4].[CH3:13]C1CCC2C(OC(=O)C2C1)=O>[Ni]>[CH3:13][CH:11]1[CH2:10][CH2:9][CH2:8][CH:7]2[C:6]([O:5][C:3](=[O:4])[CH:2]12)=[O:12]
Reactant: CC1CCC2C(=O)OC(=O)C2C1
Reactant: CC12CCCCC1C(=O)OC2=O
Agent: [Ni]
Product: CC1CCCC2C(=O)OC(=O)C12

Procedure:
The aforesaid methylhexahydrophthalic anhydride which was liquid at ordinary temperatures was a mixture of 70% by weight of 4-methylhexahydrophthalic anhydride which was liquid at ordinary temperatures and was obtained by hydrogenating 4-methyl-Δ4 -tetrahydrophthalic anhydride at 150° C. in the presence of Raney nickel catalyst and 30% by weight of 3-methylhexahydrophthalic anhydride which was liquid at ordinary temperatures and was obtained by hydrogenating 3-methyl-Δ4 -tetrahydrophthalic anhydride in the same manner as described above.