Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].C(Cl)CCl.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:40][C:41]1[CH:49]=[CH:48][C:47]([I:50])=[CH:46][C:42]=1[C:43](O)=[O:44]>ClCCl.C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:43](=[O:44])[C:42]2[CH:46]=[C:47]([I:50])[CH:48]=[CH:49][C:41]=2[NH2:40])=[CH:21][CH:22]=1)[NH:5][C:6](=[O:15])[C:7]1[C:8]([Cl:14])=[CH:9][CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2cc(I)ccc2N)cc1)NC(=O)c1c(Cl)cccc1Cl
Reaction time: 8 h

Procedure:
The mixture of N-(2,6-dichlorobenzoyl)-4-amino-L-phenylalanine methylester(2.22 g), EDC/HCl (960 mg), HOBT (675 mg), triethylamine (834 μL), 2-amino-5-iodobenzoic acid (1.3 g) and dichloromethane (100 mL) was stirred overnight. The mixture was extracted with ethyl acetate and treated in accordance with the ordinary method to obtain a crude material of the intended compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[CH:12][NH:11][C:8]2=[N:9][CH:10]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH:11]1[C:8]2=[N:9][CH:10]=[C:5]([CH2:3][OH:2])[CH:6]=[C:7]2[CH:13]=[CH:12]1
Reactant: COC(=O)c1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cnc2[nH]ccc2c1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
To 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester (75 mg, 0.394 mmol) in THF at 0 C was added lithium aluminum hydride (45 mg, 1.18 mmol) and the reaction mixture was slowly allowed to warm to ambient temperature. The reaction was refluxed for 12 hr, allowed to cool and quenched with water. Extraction with ethyl acetate, washed with brine, dried (Na2SO4) to afford (1H-Pyrrolo[2,3-b]pyridin-5-yl)-methanol (57 mg, 98% yield).
Reaction SMILES: C(OC([N:8]1[CH2:25][CH2:24][CH2:23][C@H:9]1[C:10]([N:12]([CH3:22])[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])=O)(C)(C)C.C(OCC)(=O)C.[ClH:32]>>[ClH:32].[CH3:22][N:12]([CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10](=[O:11])[C@@H:9]1[CH2:23][CH2:24][CH2:25][NH:8]1
Reactant: CN(CCCc1ccccc1)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(CCCc1ccccc1)C(=O)[C@@H]1CCCN1

Procedure:
A solution of 1-(tert-butyloxycarbonyl)-N-methyl-N-(3-phenylpropyl)-L-prolinamide in ethyl acetate-hydrogen chloride (3,9 N, 30 ml.) was stirred at room temperature for one hour, then concentrated, affording N-methyl-N-(3-phenylpropyl)-L-prolinamide hydrochloride as a syrup (2.4 g.).
Reaction SMILES: FC(F)(F)S(O[C@@H:7]([C:12]1[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:8]([F:11])([F:10])[F:9])(=O)=O.[C:21]([O:25][CH2:26][CH2:27][N:28]([C@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][CH2:26][CH2:27][N:28]([C@H:36]1[CH2:40][CH2:39][N:38]([C@H:7]([C:12]2[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[C:8]([F:11])([F:10])[F:9])[CH2:37]1)[C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:33])[CH3:34])([CH3:22])([CH3:23])[CH3:24]
Reactant: O=S(=O)(O[C@@H](c1ccc(Cl)nc1)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OCCN(C(=O)OC(C)(C)C)[C@H]1CCNC1
Product: CC(C)(C)OCCN(C(=O)OC(C)(C)C)[C@H]1CCN([C@H](c2ccc(Cl)nc2)C(F)(F)F)C1

Procedure:
Prepared as described in Example 9B, Step D, using (S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (1.50 g, 4.37 mmol) and (S)-tert-butyl 2-tert-butoxyethyl(pyrrolidin-3-yl)carbamate (2.0 g, 6.98 mmol) in place of (S)-tert-butyl pyrrolidin-3-ylcarbamate (1.69 g, 81%)
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([CH3:18])[C:11]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[O:12].Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(Cl)(Cl)Cl>[CH2:23]([O:22][C:20]([NH:9][CH:10]([CH3:18])[C:11]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[O:12])=[O:21])[CH3:24]
Reactant: CCOC(=O)Cl
Reactant: CC(N)C(=O)c1cccs1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)NC(C)C(=O)c1cccs1
Reaction time: 2 h
Yield: 89.8 %

Procedure:
A solution of triethylamine (5.455 g) in chloroform (5 ml) was added dropwise to a stirred solution of 2-amino-1-(2-thienyl)-1-propanone hydrochloride (2.585 g) in chloroform (26 ml) under ice cooling in 5 minutes. To the mixture was added dropwise a solution of ethyl chloroformate (2.929 g) in chloroform (7 ml), and the stirring was continued for 2 hours under the same conditions. The reaction mixture was evaporated, and the residue was dissolved in a mixture of ethyl acetate and water. The organic layer was separated, washed successively with a saturated aqueous solution of sodium bicarbonate, water, 5% hydrochloric acid and water, dried over magnesium sulfate and evaporated to give an oil of 2-(2-ethoxycarbonylaminopropionyl)thiophene (2.752 g).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([CH3:29])=[CH:8]2)=[O:4].[NH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:30])[C:5]([C:3]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([CH3:29])[C:10]1=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(C)c(=O)n2Cc2ccccc2)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: Cc1cc2c(O)c(C(=O)NCC(=O)O)nc(-c3cccnc3)c2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Yield: 66.6 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-3-methyl-2-oxo-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (95 mg, 0.24 mmol), glycine (2.85 g, 38 mmol) and NaOMe solution (57 mL, 28 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH 3 with 4 M HCl, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 71 mg of the title compound as a yellow solid. MS: (+) m/z 445.11 (M+1).
Reaction SMILES: [C:1]1([Se]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-].C1(S(Cl)=O)C=CC=CC=1.[OH:19][OH:20].C[CH2:22][O:23]CC>C(Cl)Cl>[C:22]([O:19][OH:20])(=[O:23])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl[Se]c1ccccc1
Reactant: CCOCC
Reactant: OO
Agent: O=S(Cl)c1ccccc1
Agent: [Br-]
Solvent: ClCCl
Product: O=C(OO)c1ccccc1
Temperature: 0 °C

Procedure:
The diene (2) is treated with a halogenating agent such as phenylselenyl chloride or bromide or phenylsulfinyl chloride, preferably phenylselenyl chloride, in an approximately equimolar ratio in an inert solvent at about -80° C, for approximately 20 minutes; illustrative of such inert solvents are methylene chloride, ether and the like. After a standard workup the product residue is dissolved in an ethereal solvent, chilled to about 0° C. and oxidized with an agent such as 30% hydrogen peroxide or a peroxy acid such as peroxybenzoic acid to yield a haloghydrin analog (3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][C:12]2([CH2:16]CC[CH2:13]2)[NH:11][CH2:10][C:9]1([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20]C(N)(CC)CN.CC(C)(O)C#N>>[C:1]([O:5][C:6]([N:8]1[CH2:17][C:12]([CH3:13])([CH3:16])[NH:11][CH2:10][C:9]1([CH2:18][CH3:20])[CH3:19])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(C)(N)CN
Reactant: CC(C)(C)OC(=O)N1CC2(CCCC2)NCC1(C)C
Agent: CC(C)(O)C#N
Product: CCC1(C)CNC(C)(C)CN1C(=O)OC(C)(C)C

Procedure:
2-Ethyl-2,5,5-trimethyl-piperazine-1-carboxylic acid tert-butyl ester was synthesized in analogy to 8,8-dimethyl-6,9-diaza-spiro[4.5]decane-9-carboxylic acid tert-butyl ester starting from 2-methylbutane 1,2-diamine and acetone cyanohydrin.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:11]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nccc2c1[nH]c1cc(O)ccc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1nccc2c1[nH]c1cc(OCc3ccccc3)ccc12
Yield: 70 %

Procedure:
The title compound was synthesized from 1-methyl-7-hydroxy-β-carboline (0.500 g, 1.59 mmol) in presence of cesium carbonate (1.410 g, 4.33 mmol) and 1-bromomethylbenzene (0.432 g, 2.53 mmol) as described here above.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH3:13][NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=1)(=[O:17])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH3:13][NH:14][S:15]([C:18]1[CH:19]=[CH:20][C:21]([N:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)=[CH:22][CH:23]=1)(=[O:16])=[O:17]
Reactant: CNS(=O)(=O)c1ccc(F)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CNS(=O)(=O)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 6.9 %

Procedure:
A mixture of 1-(4-pyridyl)piperazine (0.86 g), N-methyl-4-fluorobenzenesulphonamide (1.00 g) and potassium carbonate (2.00 g) in N-methylpyrrolidone was stirred at 100° C. for 24 hours and then evaporated. The residue was partitioned between dichloromethane and 2N hydrochloric acid. The acid layer was washed with dichloromethane, filtered and made basic with sodium bicarbonate solution. The mixture was extracted several times with chloroform, and the combined extracts were washed with water, dried over magnesium sulphate and evaporated. The residue was crystallised from ethanol/ethyl acetate to give the title compound (0.12 g), m.p. 204°-206° C. Found: C,57.55; H,6.13; N,16.62. C16H20N4O2S requires: C,57.81; H,6.06; N,16.85%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([O:17][CH3:18])=[CH:12][CH:11]=2)=[O:9])=[CH:6][N:5]=[C:4](S(CC)(=O)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:31][S:32]([N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)(=[O:34])=[O:33]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:17][CH3:18])=[C:14]([F:16])[CH:15]=2)=[O:9])=[CH:6][N:5]=[C:4]([NH:41][CH:38]2[CH2:39][CH2:40][N:35]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:36][CH2:37]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2ccc(OC)c(F)c2)c(N)n1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)c2cnc(NC3CCN(S(C)(=O)=O)CC3)nc2N)cc1F

Procedure:
The same procedure as described in Example 90 was used starting with material from Example 372 and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(3-fluoro-4-methoxy-phenyl)-methanone as a white solid. MS (M+H)+: 424.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[NH2:29][CH2:30][C:31]1([OH:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH3:28][N:4]1[C:3]([CH2:2][NH:29][CH2:30][C:31]2([OH:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: NCC1(O)CCCCC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNCC3(O)CCCCC3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 1-(aminomethyl)cyclohexanol via General Procedure E to give 22 mg of 273 following reverse phase purification. MS (Q1) 491.3 (M)+
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:3].[C:10](Cl)(Cl)=[O:11].Cl.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[C:26]([C:28]3[CH:37]=[C:36]4[C:31]([CH2:32][CH2:33][NH:34][CH2:35]4)=[CH:30][CH:29]=3)[N:25]=[C:24]([NH2:38])[N:23]=2)[CH2:18][CH2:17]1>>[NH2:38][C:24]1[N:25]=[C:26]([C:28]2[CH:37]=[C:36]3[C:31]([CH2:32][CH2:33][N:34]([C:10]([NH:3][CH:2]([C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH3:1])=[O:11])[CH2:35]3)=[CH:30][CH:29]=2)[CH:27]=[C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]2)[N:23]=1
Reactant: CC(N)c1ccccc1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C(Cl)Cl
Agent: Cl
Product: CC(NC(=O)N1CCc2ccc(-c3cc(N4CCN(C)CC4)nc(N)n3)cc2C1)c1ccccc1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 40 starting from a-methylbenzenemethanamine (Aldrich, Cat. #M31104), phosgene and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=472.3.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([O:10][CH2:11][CH3:12])[N:7]=[C:6]([CH:13]2[C:21]3[C:16](=[C:17]([F:22])[CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=[O:23])[N:5]=1)[CH3:2].CN1C=CN=C1.[F:30][CH:31]([F:36])[S:32](Cl)(=[O:34])=[O:33].Cl>ClCCl.O>[CH2:11]([O:10][C:8]1[N:9]=[C:4]([O:3][CH2:1][CH3:2])[N:5]=[C:6]([CH:13]2[C:21]3[C:16](=[C:17]([F:22])[CH:18]=[CH:19][CH:20]=3)[N:15]([S:32]([CH:31]([F:36])[F:30])(=[O:34])=[O:33])[C:14]2=[O:23])[N:7]=1)[CH3:12]
Reactant: O=S(=O)(Cl)C(F)F
Reactant: CCOc1nc(OCC)nc(C2C(=O)Nc3c(F)cccc32)n1
Agent: Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: O
Product: CCOc1nc(OCC)nc(C2C(=O)N(S(=O)(=O)C(F)F)c3c(F)cccc32)n1
Temperature: 0 °C

Procedure:
3-(4,6-Diethoxy-1,3,5-triazin-2-yl)-7-fluoro-1,3-dihydro-2H-indol-2-one (1.0 g) and 1-methyl-1H-imidazole (0.51 g) are introduced as initial charge in 10 ml of dichloromethane and cooled to 0° C. under nitrogen. With stirring, difluoromethanesulfonyl chloride (0.46 g) is added dropwise and the mixture is after-stirred for 2 hours at 0° C. to 6° C. After adding 1-methyl-1H-imidazole (0.25 g) and difluoromethanesulfonyl chloride (0.23 g), the mixture is stirred for 2 hours at 0° C. to 10° C. After adding 5 ml of water, the mixture is adjusted to pH 2 using 10% strength hydrochloric acid, the organic solvent is largely distilled off in vacuo, and the solid is filtered off, washed with water and heptane and dried. This gives the title compound as a solid in an HPLC purity of 93% (1.19 g, 83% of theory). The UV absorption (maximum at 360 nm) verifies the N-sulfonylation of the product.
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:21](OC1C=CC=CC=1)=[O:22].[OH:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[O:4]1[CH2:5][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:21]([N:34]4[CH2:35][CH2:36][CH:31]([OH:30])[CH2:32][CH2:33]4)=[O:22])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Reactant: O=C(Cl)Oc1ccccc1
Reactant: OC1CCNCC1
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)N3CCC(O)CC3)nc12

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine, phenyl chloroformate and 4-hydroxy-piperidine, the title compound was prepared as off-white powder. MS: m/e=408(M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([NH2:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[ClH:12].Cl.NC1C=C(CC(N)C)C=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(O)(=O)C>[ClH:12].[NH:1]([C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([NH2:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1)[C:25]([CH3:26])=[O:27]
Reactant: CC(N)Cc1cccc(N)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(CC(C)N)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
15 gm of 1-(3'-amino-phenyl)-2-amino-propane were dissolved in glacial acetic acid, and ethereal hydrochloric acid was added to the solution. The resulting solution of 1-(3'-amino-phenyl)-2-amino-propane monohydrochloride was admixed with 15 ml of acetic acid anhydride, and the mixture was stirred for 10 minutes at room temperature. Thereafter, the reaction mixture was evaporated in a water aspirator vacuum, whereupon 1-(3'-acetamino-phenyl)-2-amino-propane hydrochloride crystallized out. Recrystallized from ethanol, the product had a melting point of 181°-183° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][OH:11].N1C=CN=C1.[CH:17]([Si:20](Cl)([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])([CH3:19])[CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][O:11][Si:20]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:17]([CH3:19])[CH3:18]
Reactant: COc1ccc(Br)c(CO)c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(CO[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
(2-Bromo-5-methoxyphenyl)methanol (1 eq) was dissolved in anhydrous DMF (1.1M solution) and imidazole (1.05 eq) was added. To the stirred solution triisopropylsilyl chloride (1.1 eq) was added and the resulting mixture was stirred at RT for 8 h. All volatiles were evaporated in vacuo and the residual material was filtered with PE/EtOAc (9:1) over a pad of silica gel. After evaporation in vacuo the product was obtained as a colourless oil (94%), which was used without further characterization in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH:13][CH3:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(=O)(O)[O-].[Na+].[C:20](OC(=O)C)(=O)[CH3:21]>>[CH3:14][N:13]1[C:12]2[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=2[N:1]=[C:20]1[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1ccc(NC)c(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1ccc2c(c1)nc(C)n2C

Procedure:
Ethyl 3-amino-4-methylaminobenzoate (1.00 g, 5.15 mmol) prepared in the Step 1-1-3 was dissolved in acetic anhydride (4 ml), and the mixture was heated under reflux for 19 hours. After being allowed to cool, the mixture was neutralized with a saturated sodium bicarbonate solution and subjected to extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (chloroform:methanol=10:1) to give the title compound (1.15 g, quantitative) as a light-brown oily substance.
Reaction SMILES: [Na].[C:2]([O:8][CH3:9])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].[CH2:10]([C:15]1[C:16](=[O:20])[CH2:17][CH2:18][CH:19]=1)[CH2:11][CH2:12][CH2:13][CH3:14].[Cl-].[Na+]>C(O)(=O)C.CO>[CH2:10]([C:15]1([CH:3]([C:2]([O:8][CH3:9])=[O:7])[C:4](=[O:5])[CH3:6])[CH2:19][CH2:18][CH2:17][C:16]1=[O:20])[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCC1=CCCC1=O
Reactant: COC(=O)CC(C)=O
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCCC1(C(C(C)=O)C(=O)OC)CCCC1=O
Reaction time: 48 h
Yield: 70.5 %

Procedure:
750 ml of absolute methanol was introduced into a 2 liter flask. 17.3 g of sodium were added thereto. 580 g of methyl acetoacetate and 456 g of 2-pentyl-cyclopent-2-en-1-one were then added and the mixture was allowed to stand for 48 hours at the ambient temperature. The reaction product was neutralised with 45 g of acetic acid and then poured into 3 liters of a 10% aqueous sodium chloride solution. The product was then worked up as described in Example 1 (a). There were thus obtained 567 g (yield = 70%) of 2-n-pentyl-(1-carbomethoxy-2-oxopropyl)-1-cyclopentanone having: nD20 = 1.4702, d420 = 1.0545.
Reaction SMILES: [C:1]1([C@@:7]2([CH3:29])[C:11](=[O:12])[N:10]([C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([O-])=[O:15])[C:9](=[O:21])[N:8]2[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:30][C@H:31]([C:40]1[CH:45]=[CH:44][C:43]2[O:46][CH2:47][O:48][C:42]=2[CH:41]=1)[CH2:32][C:33]([O:35]C(C)(C)C)=[O:34]>>[C:1]1([C@@:7]2([CH3:29])[C:11](=[O:12])[N:10]([C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([NH:30][C@H:31]([C:40]3[CH:45]=[CH:44][C:43]4[O:46][CH2:47][O:48][C:42]=4[CH:41]=3)[CH2:32][C:33]([OH:35])=[O:34])=[O:15])[C:9](=[O:21])[N:8]2[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)C[C@H](N)c1ccc2c(c1)OCO2
Reactant: CC(C)C[C@@H](C(=O)[O-])N1C(=O)N(Cc2ccccc2)[C@@](C)(c2ccccc2)C1=O
Product: CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)O)c1ccc2c(c1)OCO2)N1C(=O)N(Cc2ccccc2)[C@@](C)(c2ccccc2)C1=O

Procedure:
The compound was prepared analogously to Example 1 by reaction of 169.5 with tert-butyl (S)-3-amino-3-(3,4-methylenedioxyphenyl)propionate (prepared analogously to S. G. Davis et al., Tetrahedron Asymmetry 1991, 2, 183), cleavage of the tert-butyl ester with trifluoroacetic acid as described in Example 1, and subsequent purification of the crude product by means of preparative HPLC (RP18: eluent: acetonitrile/water=50/120). ES(+)-MS: 586.4 (M+H)+
Reaction SMILES: [CH2:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:15][CH:16]([CH3:40])[CH:17]([N:22]([CH3:39])[C:23]([C:25]1[S:26][C:27]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[CH:32][CH:31]=2)=[CH:28][N:29]=1)=[O:24])[C:18]([O:20][CH3:21])=[O:19]>>[CH3:15][CH:16]([CH3:40])[CH:17]([N:22]([CH3:39])[C:23]([C:25]1[S:26][C:27]([C:30]2[CH:31]=[CH:32][C:33]([NH:36][C:10](=[O:11])[C:9]3[CH:13]=[CH:14][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:7][CH:8]=3)=[CH:34][CH:35]=2)=[CH:28][N:29]=1)=[O:24])[C:18]([O:20][CH3:21])=[O:19]
Reactant: CCCCCc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)C(C(C)C)N(C)C(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1
Product: CCCCCc1ccc(C(=O)Nc2ccc(-c3cnc(C(=O)N(C)C(C(=O)OC)C(C)C)s3)cc2)cc1
Yield: 59 %

Procedure:
The title compound was synthesized analogous to Example 27, using 4-pentylbenzoyl chloride and intermediate 4. Yield: 59%; 1H NMR (DMSO-d6, 300 MHz): δ 10.38 (s, 1H), 8.86 (d, 1H), 7.95 (m, 4H), 7.78 (d, 2H), 7.37 (d, 2H), 6.27-4.76 (d, 1H), 3.68 (s, 3H), 3.47-2.95 (s, 3H), 2.68 (t, 2H), 2.38 (m, 1H), 1.63 (m, 2H), 1.30 (m, 4H), 1.03 (m, 3H), 0.90 (dd, 6H); MS (ESI) m/z 522.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]2[CH2:23][CH2:22][C@H:21]([CH2:24][C:25]([O:27]C)=[O:26])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.CO>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([C@H:18]2[CH2:23][CH2:22][C@H:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:20][CH2:19]2)=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)OCc3ccccc3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl [trans-4-(4-{[(benzyloxy)carbonyl]amino}phenyl)cyclohexyl]acetate (3.34 g, 8.76 mmol) in THF (42 mL) and MeOH (42 mL) was added 0.6M aqueous lithium hydroxide (43.6 mL, 26.27 mmol) and the mixture stirred at ambient temperature for 18 hours. The mixture was partitioned between EtOAc (200 mL) and 1M HCl (100 mL). The organic phase was concentrated in vacuo and the residue partitioned between EtOAc (300 mL) and brine (20 mL). The organic phase was dried (MgSO4), filtered and evaporated to give the title compound (3.19 g, 99%) as a white solid; 1H NMR (CDCl3) δ 1.05-1.15 (2H, m), 1.36-1.46 (2H, m), 1.74-1.87 (5H, m), 2.22 (2H, d), 2.34-2.41 (1H, m), 5.13 (2H, s), 6.58 (1H, s), 7.07 (2H, d), 7.21 (3H, t), 7.28-7.35 (4H, m); MS m/e (MH)+ 368