Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:35])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH2:30][C@H:31]5[CH2:33][O:32]5)[CH2:22][CH2:21]4)[C:14]3=[O:34])[CH:7]=2)[CH2:3][CH2:2]1.[CH3:36][NH2:37]>>[CH:1]1([NH:4][C:5](=[O:35])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH2:30][C@H:31]([OH:32])[CH2:33][NH:37][CH3:36])[CH2:22][CH2:21]4)[C:14]3=[O:34])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OC[C@H]3CO3)CC2)c1=O
Reactant: CN
Product: CNC[C@@H](O)COc1ccccc1C1(Nc2nccn(-c3cc(C(=O)NC4CC4)ccc3C)c2=O)CC1

Procedure:
The title compound was prepared using a similar method to that described for Example 299b from (R)-N-cyclopropyl-4-methyl-3-(3-(1-(2-(oxiran-2-ylmethoxy)phenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)benzamide (Example 299a) and methylamine.
Reaction SMILES: ClC1C=CC=C(C(OO)=O)C=1.[CH3:12][O:13][C:14](=[O:28])[C:15]1[CH:20]=[CH:19][C:18]([C:21]#[C:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:17][C:16]=1[Cl:27].C(OCC)C>ClCCl>[CH3:12][O:13][C:14](=[O:28])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]=[CH:23][N:24]([CH3:25])[CH3:26])=[CH:17][C:16]=1[Cl:27]
Reactant: COC(=O)c1ccc(C#CCN(C)C)cc1Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)c1ccc(CC=CN(C)C)cc1Cl
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
Under an atmosphere of nitrogen, purified meta-chloroperbenzoic acid (16.0 g, 93 mmol) was added portionwise to a stirred solution of 2-chloro-4-(3-dimethylaminopropyn-1-yl)-benzoic acid methyl ester of Step A (23.5 g, 93.4 mmol) in 200 mL of dichloromethane at −10° C. After the addition was complete, the solution was stirred at reduced temperature for 30 minutes and then filtered through a column of basic alumina (400 g, Brockman activity I) packed with dichloromethanemethanol (9:1, v/v). The intermediate N-oxide was eluted with the above solvent system. The dichloromethane was then carefully replaced with methanol by evaporation at or below room temperature, taking care that the mixture is never allowed to evaporate to dryness. The methanolic solution was heated at 60° C. overnight, and then was concentrated in vacuo. The residue was purified by flash chromatography (on Merck-60 silica gel, hexane-ethyl acetate 1:1) to give 12.1 g of a slightly impure product. Trituration with diethyl ether provided the pure title compound (6.15 g) as an orange solid.
Reaction SMILES: Cl.[Cl:2][C:3]1([CH:15]([Cl:17])[Cl:16])[O:7]C(C(F)(F)F)=[N:5][C:4]1([CH2:13][CH3:14])[CH3:12].O.Cl>CO>[ClH:2].[NH2:5][C:4]([CH3:12])([CH2:13][CH3:14])[C:3](=[O:7])[CH:15]([Cl:17])[Cl:16]
Reactant: CCC1(C)N=C(C(F)(F)F)OC1(Cl)C(Cl)Cl
Agent: Cl
Solvent: O
Solvent: CO
Product: CCC(C)(N)C(=O)C(Cl)Cl
Reaction time: 8 h

Procedure:
The 5-chloro-5-(dichloromethyl)-4-ethyl-4-methyl-2-trifluoromethyloxazoline hydrochloride prepared in the preceding step was dissolved in 1800 mL of methanol, 72 mL of water, and 190 mL of concentrated hydrochloric acid, warmed to 50° C., and stirred at that temperature overnight. The crude reaction mixture was cooled and poured into an ice/water/ethyl ether mixture. The phases were separated and the ether layer was extracted once with water. The ether was saved (organic I). The combined aqueous layers were washed once with ethyl ether, and the organic layer was combined with organic I (organic II). The aqueous layer was neutralized with saturated aqueous sodium bicarbonate and extracted twice with ethyl ether. The combined ether layers were washed with water, brine, dried over anhydrous magnesium sulfate, treated with activated charcoal, and filtered through Celite™. To the resulting colorless solution was bubbled in anhydrous hydrogen chloride keeping the temperature below 20° C. The resulting white solid was filtered and dried yielding 124.8 g of the expected 3-amino-1,1-dichloro-3-methyl-2-pentanone hydrochloride as a white solid. The ethyl ether filtrate was combined with organic II and concentrated in vacuo; the resulting residue (150 g) was taken in a mixture of methanol/water/concentrated hydrochloric acid and heated at 50° C. over the weekend. The previously described workup yielded another 51 g of 3-amino-1,1-dichloro-3-methyl-2-pentanone hydrochloride. The total amount obtained was 175.8 g (61% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:10])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1.[NH3:11]>>[CH3:10][C:4]1[C:3]([CH2:2][NH2:11])=[CH:8][CH:7]=[C:6]([CH3:9])[N:5]=1
Reactant: Cc1ccc(CCl)c(C)n1
Reactant: N
Product: Cc1ccc(CN)c(C)n1

Procedure:
The solution of 3-(chloromethyl)-2,6-dimethylpyridine (850 mg, 5.5 mmol) in ammonia solution (10 mL) was stirred at 90° C. for 2 hours and then concentrated to give the crude product which was used for next step directly without further purification. LCMS (ESI) m/z=137.1 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:14])=O.CN(C)C=O>C(Cl)Cl>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:14])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(I)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 4-iodobenzoic acid (20.0 g, 80.6 mL) in CH2Cl2 (350 mL) at 0° C. was treated with oxalyl chloride (42.3 mL of a 2.0 M solution in CH2Cl2, 81.7 mmol). Dimethylformamide was added (0.5 mL) until a homogeneous solution was achieved and then the cooling bath was removed. The reaction mixture was stirred at ambient temperature for 3 hours and then concentrated to provide crude 4iodobenzoyl chloride as a waxy oil that was used without further purification.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].[C:12]([O:16][C:17]([NH:19][C@H:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:21][OH:22])=[O:18])([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl>[C:12]([O:16][C:17]([NH:19][C@H:20]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:21][O:22][S:8]([CH3:7])(=[O:10])=[O:9])=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H](COS(C)(=O)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
11 ml of pyridine and then 6.6 ml of methanesulfonyl chloride were added dropwise, at room temperature, to a solution containing 9.9 g of 2(R)-t-butoxycarbonylamino-2-phenylethanol [prepared as described in step (a) above] dissolved in 120 ml of methylene chloride. This mixture was stirred for 15 hours at room temperature, after which the solvent was removed by distillation. The residue was dissolved in ethyl acetate and water and the ethyl acetate layer was separated. This layer was washed with an aqueous solution of potassium hydrogen sulfate and an aqueous solution of sodium bicarbonate and then dried over anhydrous magnesium sulfate, after which the solvent was distilled off. The crystalline residue was collected by filtration and washed with a small amount of diisopropyl ether and cyclohexane to give 12.2 g of the title compound, melting at 108°-109° C.
Reaction SMILES: [CH:1]1([O:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH2:5][CH:4]=[CH:3][CH2:2]1.ClC1C=C(C(OO)=[O:24])C=CC=1>C(Cl)Cl>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][O:6][CH:1]2[CH2:5][CH:4]3[CH:3]([O:24]3)[CH2:2]2)=[CH:13][CH:12]=1
Reactant: COc1ccc(COC2CC=CC2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(COC2CC3OC3C2)cc1
Temperature: 25 °C

Procedure:
To a solution of 1-[(cyclopent-3-en-1-yloxy)methyl]-4-methoxybenzene (9.64 g, 47.2 mmol) in dry DCM (52 ml) at 0° C. under an atmosphere of nitrogen was added 3-chlorobenzene-1-carboperoxoic acid (CAS number 937-14-4; 16.29 g, 94 mmol). The reaction mixture was warmed to room temperature for 17 hours then filtered. The filtrate was washed with a saturated solution of sodium thiosulfate and then with a saturated solution of sodium bicarbonate. The organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (silica, 0-50% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)[C@@H:12]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:13])=CC=1)([O-])=O.C(=O)([O-])[O-].[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[C:18]([O:17][C:15](=[O:16])[NH:14][C@H:12]([C:11](=[O:10])[NH:34][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:13])([CH3:19])([CH3:20])[CH3:21]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of (S)-2-tert-butoxycarbonylamino-propionic acid 4-nitro-phenyl ester (200 mg, 0.645 mmol) and MP-carbonate (664 mg, 1.93 mmol, Biotage, Part #:800268) in CH2Cl2 (1.5 mL) was added benzylamine (70 mg, 0.645 mmol). The reaction mixture was stirred for 1 h. The reaction mixture was then filtered and concentrated in vacuo to afford ((S)-1-benzylcarbamoyl-ethyl)-carbamic acid tert-butyl ester, m/z 279.4 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].O.S(OC)(O[CH3:20])(=O)=O>C(OCC)C>[CH3:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1ccc(OC)cc1
Temperature: 25 °C

Procedure:
Ethyl 4-hydroxybenzoate (15.0 g, 0.09 mol) is stirred into an initial mixture of KOH (6.3 g, 0.11 mol) in dist. water (60 ml) under protective gas. Dimethyl sulfate (8.8 ml, 0.09 mol) is added dropwise to the clear solution with stirring and ice-cooling such that the temperature does not exceed 15° C. After addition is complete, the cooling is removed, and to complete the reaction the reaction mixture is stirred at RT for 45 min and under reflux for 2 h, then cooled to RT. The deposited oil is taken up in diethyl ether (50 ml). The aqueous phase separated off is extracted with diethyl ether (150 ml), and the ethereal extracts obtained are combined, washed with sodium hydroxide solution (10% strength, 50 ml) and with saturated NaCl solution, dried over Na2SO4 sicc. and concentrated in vacuo: colorless oil, yield: 15.7 g (97%).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>CCCCCC.C(OCC)(=O)C>[CH:17]([C:14]1[CH:13]=[CH:12][C:11]([CH:7]2[C:6]3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[C:3]([CH3:29])=[C:2]([C:35]4[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=4)[C:10]=3[O:9][CH2:8]2)=[CH:16][CH:15]=1)([CH3:19])[CH3:18]
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: COc1ccc(B(O)O)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(-c2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OCC3c2ccc(C(C)C)cc2)cc1
Yield: 40 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and (4-methoxyphenyl)boronic acid, the title compound was synthesized in the same manner as in Example 101. Yield: 40%. Melting point: 129-131° C. (hexane-ethyl acetate).
Reaction SMILES: [OH:1][CH:2]([C:4]1[S:8][C:7]([C:9](=O)[CH2:10][CH2:11][C:12](=O)[CH:13]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[N:6][CH:5]=1)[CH3:3].C([O-])(=O)C.[NH4+:37].[OH-].[Na+]>C(O)(=O)C>[CH3:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH:13]([C:12]2[NH:37][C:9]([C:7]3[S:8][C:4]([CH:2]([OH:1])[CH3:3])=[CH:5][N:6]=3)=[CH:10][CH:11]=2)[CH2:14][CH:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[CH:22][CH:23]=1)(=[O:28])=[O:29]
Reactant: [NH4+]
Reactant: CC(O)c1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(C)(=O)=O)cc2)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(O)c1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(C)(=O)=O)cc3)[nH]2)s1
Temperature: 90 °C
Reaction time: 3 h
Yield: 34.7 %

Procedure:
A mixture of 1-[5-(1-hydroxyethyl)-1,3-thiazol-2-yl]-5-[4-(methylsulfonyl)phenyl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (0.57 g), ammonium acetate (0.46 g) and acetic acid (5 mL) was stirred at 90° C. for 3 hr. The reaction mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was concentrated, 2M aqueous sodium hydroxide solution (1 mL), tetrahydrofuran (4 mL) and methanol (4 mL) were added to the residue, and the mixture was stirred with heating under reflux for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography, and the title compound (0.19 g, yield 34%) was obtained as a yellow amorphous solid from a fraction eluted with tetrahydrofuran-hexane (3:1, volume ratio). MS: 461 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Br[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[C:5]([C:4]1[CH:3]=[C:2]([C:11]2[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: Cc1cccc(Br)c1
Reactant: N#Cc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1cccc(-c2cccc(C#N)c2)c1
Temperature: 105 °C
Reaction time: 15 h
Yield: 66.2 %

Procedure:
A mixture of 3-bromobenzonitrile (910 mg), Pd(Ph3P)4 (290 mg), (Me3Sn)2 (1.64 g) and dioxane (20 mL) was sealed under argon in a pressure tube. The tube was then heated at 100-110° C. for 3 hours with stirring and another 15 hours at 80° C. To the reaction mixture was added 1-bromo-3-methylbenzene (940 mg), Pd(PPh3)4 (290 mg) and dioxane (5 mL) under argon. The sealed tube was heated at 135-140° C. with stirring for two days. The catalyst was filtered off and the filtrate was poured into water and extracted with ethyl acetate (3×). The organic layer was washed with brine, dried over Mg2SO4, concentrated and purified on silica gel column (ethyl acetate/hexane, 1:3) to afford 0.64 g of 3-(3-cyanophenyl)-1-methylbenzene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH:12]1[CH2:27][N:16]2[CH2:17][CH2:18][N:19]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:20][CH:15]2[CH2:14][CH2:13]1.[H-].[Na+].[CH3:30]I>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:30])[CH:6]=[C:5]2[CH2:11][CH:12]1[CH2:27][N:16]2[CH2:17][CH2:18][N:19]([C:21]3[N:22]=[CH:23][CH:24]=[CH:25][N:26]=3)[CH2:20][CH:15]2[CH2:14][CH2:13]1
Reactant: Fc1ccc2[nH]cc(CC3CCC4CN(c5ncccn5)CCN4C3)c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(CC2CCC3CN(c4ncccn4)CCN3C2)c2cc(F)ccc21
Temperature: 50 °C
Yield: 47.1 %

Procedure:
A flame-dried flask was charged with 0.103 g (0.28 mmol) of (7RS,9aSR)-7-(5-fluoro-1H-indol-3-yl)methyl-2-(pyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Example 50), anhydrous DMF (1 mL) and 12 mg (0.30 mmol) of sodium hydride (60% oil dispersion). The suspension was treated with 0.019 mL (0.31 mmol) of methyl iodide and the mixture was heated at 50° C. for 16 h. The mixture was cooled to room temperature, concentrated in vacuo, and diluted with methylene chloride (25 mL) and water (25 mL), and the layers were separated. The organic phase was dried (sodium sulfate), filtered and evaporated to a solid residue. The solid was washed with ethyl acetate (2×), the ethyl acetate was evaporated to give 50 mg of the title compound. 1H NMR (CDCl3): δ1.00-1.31 (m, 3H), 1.64-2.23 (m, 6H), 2.54-3.1 (m, 5H), 3.69 (s, 3H), 4.51-4.56 (m, 2H), 6.43 (dd, J=1 Hz, 1H), 6.83 (s, 1H), 6.93 (m, 1H), 7.15 (m, 2H), 8.27 (d, J=1 Hz, 2H). TLC Rf: 0.81 (90:10:1 methylene chloride:methanol:ammonium hydroxide).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)(=[O:3])[CH3:2].[N:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:24]=[O:25].CO>C(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[C:18]([NH:22][C:24]([NH:23][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:25])[CH:19]=[CH:20][CH:21]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CN=C=O
Reactant: CC(=O)OCCCCCCOCCCCc1cccc(N)c1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)Nc1cccc(CCCCOCCCCCCOC(C)=O)c1
Reaction time: 0.5 h

Procedure:
6-[4-(3-Aminophenyl)butoxy]hexyl acetate (2.84 g) in CH2Cl2 (30 ml) was treated with ethyl isocyanatoacetate (1.2 ml). After 0.75 h the mixture was treated with MeOH (2 ml) and stirred for 0.5 h. The mixture was concentrated, purified on a 10 g silica Bond Elut cartridge eluting with Et2O-petroleum ether(1:1) and then with Et2O to give the title compound (3.33 g) ES+ve 437 (MH)+.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3](=[O:11])[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[ClH:13].[CH3:14][O:15][C:16]1[C:24]2[O:23][C:22](C)(C)C[C:20]=2[C:19]([C:27]2[C@@H:36]3[C@@H:31]([CH2:32][CH:33]=[CH:34][CH2:35]3)[C:30](=[O:37])[N:29]([C:38]3[CH:43]=[CH:42][C:41]([C:44](N4CCN(C/C=C/C5C=CC=CC=5)CC4)=[O:45])=[CH:40][CH:39]=3)[N:28]=2)=[CH:18][CH:17]=1>>[ClH:13].[CH3:22][O:23][C:24]1[CH:20]=[C:19]([C:27]2[C@@H:36]3[C@@H:31]([CH2:32][CH:33]=[CH:34][CH2:35]3)[C:30](=[O:37])[N:29]([C:38]3[CH:39]=[CH:40][C:41]([C:44]([N:8]4[CH2:7][CH2:6][N:5]([CH2:4][C:3]([N:2]([CH3:12])[CH3:1])=[O:11])[CH2:10][CH2:9]4)=[O:45])=[CH:42][CH:43]=3)[N:28]=2)[CH:18]=[CH:17][C:16]=1[O:15][CH3:14]
Reactant: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(C/C=C/c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2
Reactant: CN(C)C(=O)CN1CCNCC1
Agent: Cl
Product: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(CC(=O)N(C)C)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from intermediate product A6 and N,N-dimethyl-2-piperazin-1-yl-acetamide as described for compound 8. M.p. 93–94° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][N:24]=3)=[CH:18][CH:17]=2)[CH2:4][O:3]1.C1C=C(Cl)C=C(C(OO)=[O:40])C=1>ClCCl.[O-]S([O-])=O.[Na+].[Na+]>[CH3:1][C:2]1([CH3:31])[N:6]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@@H:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:24]=[CH:25][C:26]([S:29]([CH3:30])=[O:40])=[CH:27][N:28]=3)=[CH:18][CH:17]=2)[CH2:4][O:3]1
Reactant: CSc1cnc(Nc2ccc(CC[C@H]3COC(C)(C)N3C(=O)OC(C)(C)C)cc2)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1cnc(Nc2ccc(CC[C@H]3COC(C)(C)N3C(=O)OC(C)(C)C)cc2)nc1
Reaction time: 0.67 h
Yield: 111.5 %

Procedure:
To a stirred solution of (5)-tert-butyl 2,2-dimethyl-4-(4-(5-(methylthio)pyrimidin-2-ylamino)phenethyl)oxazolidine-3-carboxylate (393 mg) in dichloromethane (5 ml) was added m-CPBA (218 mg) and stirring was continued at RT for 40 min. The reaction mixture was then diluted with aq. Na2SO3 solution and extracted with dichloromethane. The organic layers were dried over MgSO4 and concentrated in vacuo to give (4S)-tert-butyl 2,2-dimethyl-4-(4-(5-(methylsulfinyl)pyrimidin-2-ylamino)phenethyl)oxazolidine-3-carboxylate (454 mg, 85% purity, 95% yield) as a yellow oil. MS (ISP): 461.4 ([M+H]+), 405.3 ([M+H—C4H8—CO2]+).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[C:15]([CH:20]([O:22][CH2:23][CH3:24])[CH3:21])[CH:14]=[CH:13][CH:12]=3)=[O:5])C.[OH-].[Na+].C(O)C>C(O)(=O)C>[CH2:23]([O:22][CH:20]([C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[C:17]1[C:18]([CH3:19])=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[CH:8][C:9]=1[NH:10]2)[CH3:21])[CH3:24]
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(C(C)OCC)c3c2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(C)c1cccc2[nH]c3cnc(C(=O)O)c(C)c3c12
Yield: 87.5 %

Procedure:
500 mg of 5-(1-ethoxyethyl)-4-methyl-beta-carboline-3-carboxylic acid ethyl ester was refluxed with 5 ml of 1N sodium hydroxide solution and 20 ml of ethanol for 3 hours. Then it was acidified with glacial acetic acid, suctioned off and washed with water. 400 mg of 5-(1-ethoxyethyl)-4-methyl-beta-carboline-3-carboxylic acid was obtained, which after good drying over phosphorus pentoxide in a vacuum was further reacted.
Reaction SMILES: C(O)C.[Na].[CH2:5]([OH:17])[C@H:6]([OH:16])[C@@H:7](O)[C@H:8]([OH:14])[C:9]([C:11]([OH:13])=[O:12])=[O:10]>CC(C)=O>[O:12]=[C:11]1[O:13][C@H:7]([C@H:6]([CH2:5][OH:17])[OH:16])[C:8]([OH:14])=[C:9]1[OH:10]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: [Na]
Solvent: CC(C)=O
Solvent: CCO
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O

Procedure:
JP-AS 58-177986 describes a process which comprises the addition of ethanol and acetone to the sodium salt of 2-keto-L-gulonic acid, neutralization with hydrochloric acid, separation of the precipitated sodium chloride by filtration and subsequently the keeping of the reaction mixture at temperatures in the range from 25° C. to 75° C., whereby L-ascorbic acid is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[S:11]([NH:14][C@H:15]([CH2:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(=[O:13])=[O:12].[CH2:35](O)[C:36]1[CH:44]=[CH:43][C:42]2[O:41][CH2:40][O:39][C:38]=2[CH:37]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[CH2:40]1[O:41][C:42]2[CH:43]=[CH:44][C:36]([CH2:35][N:14]([S:11]([C:3]3[C:2]([CH3:1])=[CH:7][C:6]([O:8][CH3:9])=[CH:5][C:4]=3[CH3:10])(=[O:12])=[O:13])[C@H:15]([CH2:23][N:24]3[C:25](=[O:34])[C:26]4=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]4[C:28]3=[O:29])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:37][C:38]=2[O:39]1
Reactant: OCc1ccc2c(c1)OCO2
Reactant: COc1cc(C)c(S(=O)(=O)N[C@H](CN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)c(C)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
To a cooled (ice bath) solution of tert-butyl 2(R)-(2,6-dimethyl-4-methoxybenzene sulfonylamino)-3-phthalimido-propionate (6.9 g, 14.12 mmol) in dry benzene (150 ml) with piperonyl alcohol (3.22 g, 21.2 mmol) and tributyl phosphine (5.3 ml, 21.2 mmol) was added 1,1′-(azodicarbonyl)-dipiperidine (5.35 g,, 21.2 mmol). The mixture was allowed to warm to ambient temperature overnight. The material was loaded onto a flash silica gel column using ethyl acetate-hexanes (30%) as eluant, providing tert-butyl 2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-phthalimido-propionate as a white solid (8.59 g).