Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([C:9]#[N:10])[C:7]([NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[NH2:10][C:9]1[C:8]2[C:7]([N:12]=[C:13]3[C:14]=1[CH2:15][CH2:16][CH2:17][CH2:18]3)=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=2
Reactant: O=C1CCCCC1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Nc1c2c(nc3ccc([N+](=O)[O-])cc13)CCCC2
Temperature: 25 °C
Yield: 33.3 %

Procedure:
To a mixture of 5-nitroanthranilonitrile (1.63 g, 10 mmol) and cyclohexanone (10.3 ml, 100 mmol) was added zinc chloride (1.36 g, 10 mmol) and the mixture was refluxed under heating for 20 min. The reaction mixture was cooled to room temperature and diluted with ethyl acetate, and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure and chloroform was added to the obtained brown oil. The resulting yellow precipitate was collected by filtration and dried under reduced pressure at 80° C. This solid (1.56 g) was diluted with ethyl acetate and 1N aqueous sodium hydroxide solution, and ether was added. The insoluble matter was collected by filtration and dried under reduced pressure at 80° C. to give 9-amino-7-nitro-1,2,3,4-tetrahydroacridine (810 mg, 33%) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[C:4](F)=[CH:5][C:6](F)=[C:7]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH:17]3[CH2:19][CH2:18]3)[C:13]3=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:12]3[N:11]=2)[CH:8]=1)#[N:2].[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][OH:35])[CH2:29][CH2:28]1>>[C:1]([C:3]1[C:4]([O:35][CH2:34][CH2:33][N:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)=[CH:5][C:6]([O:35][CH2:34][CH2:33][N:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)=[C:7]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH:17]3[CH2:19][CH2:18]3)[C:13]3=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:12]3[N:11]=2)[CH:8]=1)#[N:2]
Reactant: OCCN1CCOCC1
Reactant: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(F)cc1F
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(OCCN2CCOCC2)cc1OCCN1CCOCC1

Procedure:
The title compound was obtained as the minor product (33% yield) from the reaction between 2-((5-cyano-2,4-difluorophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 414) and 2-morpholinoethanol according to the procedure described in Example 419.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([OH:16])=[O:15].[OH-].[Na+].[CH2:19](Br)[CH2:20][CH2:21][CH3:22].Cl>O.CS(C)=O>[CH2:19]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=2)[C:2](=[O:1])[C:3]([C:14]([OH:16])=[O:15])=[CH:4]1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCBr
Reactant: COc1ccc2c(O)c(C(=O)O)cnc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCn1cc(C(=O)O)c(=O)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
11.0 g. (50 millimoles) of 4-hydroxy-7-methoxyquinoline-3-carboxylic acid is introduced into a suspension of 14.0 g. (351 millimoles) of pulverized sodium hydroxide in 200 ml. of dimethyl sulfoxide. The mixture is stirred for 10 minutes at room temperature, and then 16.1 ml. (150 mmol) of butyl bromide is added dropwise thereto so that the temperature does not exceed 25° C. Thereafter, the mixture is stirred for 2 hours at room temperature, poured into water, and acidified with hydrochloric acid. The thus-precipitated product is filtered off, washed with water, dried, and recrystallized from dimethylformamide.
Reaction SMILES: [CH2:1]([O:7][C:8]1[C:9](=[O:20])[O:10][C:11]2[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:21]([O:24][CH2:25][CH2:26][CH2:27]Br)(=[O:23])[CH3:22]>>[CH2:1]([O:7][C:8]1[C:9](=[O:20])[O:10][C:11]2[C:18]([O:19][CH2:27][CH2:26][CH2:25][O:24][C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(=O)OCCCBr
Reactant: CCCCCCOc1c(O)c2cccc(O)c2oc1=O
Product: CCCCCCOc1c(O)c2cccc(OCCCOC(C)=O)c2oc1=O

Procedure:
In the same manner as in Reference Example 1, except that an equimolar amount of 3-hexyloxy-4,8-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-ethoxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and 3-bromopropyl acetate was used in place of 2-bromoethyl acetate in Reference Example 1, 3-hexyloxy-4-hydroxy-8-(3-acetoxypropyloxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([CH2:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[S:23][C:17]=2[N:16]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:15]1=[O:39].CC1C=C[C:44]([S:47](OCCCO[Si](C)(C)C(C)(C)C)(=O)=S)=[CH:43][CH:42]=1.[OH2:62].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[OH:62][CH2:42][CH2:43][CH2:44][S:47][C:21]1[C:18]2[C:19](=[O:20])[N:14]([CH3:13])[C:15](=[O:39])[N:16]([CH2:35][CH:36]([CH3:37])[CH3:38])[C:17]=2[S:23][C:22]=1[CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2cc(Cc3cccc4ccccc34)sc21
Reactant: Cc1ccc(S(=O)(=S)OCCCO[Si](C)(C)C(C)(C)C)cc1
Reactant: O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCO)c(Cc3cccc4ccccc34)sc21
Reaction time: 16 h
Yield: 39.7 %

Procedure:
Prepared according to the procedure described in Example 5 from n-butyllithium (2.0M solution in hexanes, 0.32 ml) and diisopropylamine (0.093 ml) in anhydrous tetrahydrofuran (5 ml), 3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.20 g) in anhydrous tetrahydrofuran (5 ml) and 3-{[dimethyl(1,1-dimethylethyl)silyl]oxy}propyl 4-methylphenylthiosulfonate (0.19 g, J. Med. Chem. 1995, 38, 2557) in anhydrous tetrahydrofuran (2 ml). The crude adduct was dissolved in tetrahydrofuran (6 ml) and treated with tetrabutylammonium fluoride hydrate (0.20 g). After 16 hours, the solution was diluted with water (30 ml) and extracted with ether (2×30 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica, eluting with ether and was then recrystallised from ethyl acetate/hexane to give the title compound (0.098 g).
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].C(O)(C)(C)C.C(N(CC)CC)C.Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][C:33]([S:36]([C:39]3[CH:40]=[C:41]([NH2:45])[CH:42]=[CH:43][CH:44]=3)(=[O:38])=[O:37])=[CH:32][CH:31]=2)=[CH:24][CH:23]=1>ClCCl>[F:21][C:22]1[CH:23]=[CH:24][C:25](/[CH:28]=[CH:29]/[C:30]2[CH:31]=[CH:32][C:33]([S:36]([C:39]3[CH:40]=[C:41]([NH:45][S:2]([NH2:5])(=[O:4])=[O:3])[CH:42]=[CH:43][CH:44]=3)(=[O:38])=[O:37])=[CH:34][CH:35]=2)=[CH:26][CH:27]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Nc1cccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3)cc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: NS(=O)(=O)Nc1cccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To dichloromethane (1 mL) at 0° C. was added chlorosulfonyl isocyanate (0.03 mL, 0.26 mmol) and tert-butanol (0.03 mL, 0.26 mmol). The mixture was stirred for 10 minutes then triethylamine (0.054 mL, 0.39 mmol) was added followed by [3-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)phenyl]amine hydrochloride (Example 212, 100 mg, 0.26 mmol). The reaction was allowed to warm to room temperature and stirred for 2 hours. The mixture was partitioned between ethyl acetate and water.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl>O>[C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:14][C@H:16]2[O:18][CH2:17]2)=[CH:7][CH:6]=1)(=[O:10])[NH2:11]
Reactant: ClCC1CO1
Reactant: NC(=O)Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)Cc1ccc(OC[C@@H]2CO2)cc1
Temperature: 5 °C
Yield: 96.7 %

Procedure:
p-Hydroxyphenyl acetamide (30.02 g) was dissolved in 106.5 g of water containing sodium hydroxide (9.6 g) and the solution was cooled to 5° C. Epichlorohydrin (18.5 g, 98.9% e.e.) was dropped in the solution over a period of 10 minutes under stirring at the same temperature and the solution was stirred for 24 hours. Sodium hydroxide (2.4 g) was added thereto and the mixture was stirred for 5 hours. Resulting crystals were filtrated by suction, washed with water and dried in vacuo to give crude (S)-1-[p-(carbamoylmethyl)phenoxy]-2,3-epoxypropane (39.8 g). The optical purity of it was 91.2% e.e. by measurement of Chiral column OD (Daisel Chemical Industries Ltd.).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([C:14]#[N:15])[S:12][CH:13]=2)[C:4]1=[O:16].[C:17]([NH:27][C:28]1[CH:37]=[C:36]2[C:31]([CH:32]=[CH:33][C:34]([S:38](Cl)(=[O:40])=[O:39])=[CH:35]2)=[CH:30][CH:29]=1)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>>[C:14]([C:11]1[S:12][CH:13]=[C:9]([CH2:8][N:5]2[CH2:6][CH2:7][C@H:3]([NH:2][S:38]([C:34]3[CH:33]=[CH:32][C:31]4[C:36](=[CH:37][C:28]([NH:27][C:17]([O:19][CH2:20][C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)=[O:18])=[CH:29][CH:30]=4)[CH:35]=3)(=[O:40])=[O:39])[C:4]2=[O:16])[CH:10]=1)#[N:15]
Reactant: N#Cc1cc(CN2CC[C@H](N)C2=O)cs1
Reactant: O=C(Nc1ccc2ccc(S(=O)(=O)Cl)cc2c1)OCc1ccccc1
Agent: Cl
Product: N#Cc1cc(CN2CC[C@H](NS(=O)(=O)c3ccc4ccc(NC(=O)OCc5ccccc5)cc4c3)C2=O)cs1

Procedure:
The title compound is prepared from 4-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)thiophene-2-carbonitrile hydrochloride as described in EXAMPLE 125, Part C using N-Cbz-7-aminonaphthalene-2-sulfonyl chloride in place of 7-methoxynaphthalene-2-sulfonyl chloride. The crude product is purified by column chromatography eluting with a gradient of 10% EtOAc/CH2Cl2 to 25% EtOAc/CH2Cl2 to provide the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[C:9]2[CH3:23])=[CH:4][CH:3]=1.ClS([N:28]=[C:29]=O)(=O)=O>CN(C=O)C.C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:29]#[N:28])=[C:9]2[CH3:23])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1c(C#N)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Temperature: 20 °C
Yield: 76.7 %

Procedure:
To a cold solution of 1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole (Example 1) (750 mg, 2.28 mmol) in DMF (8 ml) and acetonitrile (8 ml) at -78° C., chlorosulfonyl isocyanate (200 μl, 2.28 mmol) was added. The reaction mixture was warmed to 20° C. over 4 hours, quenched by adding excess of water, and extracted with ethyl acetate. The organic fractions were washed with brine, dried (MgSO4), filtered and concentrated. The crude colorless liquid (0.77 g) was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give 1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole-3-carbonitrile (620 mg, 77%) as a white solid: mp (DSC) 205° C. Anal Calc'd. for C19H15N2SFO2 : C, 64.39; H, 4.27; N, 7.90. Found: C, 64.11; H, 4.45; N, 7.60.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:14]([N:21]=[C:22]=[S:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C.CN(C)C1C=CN=CC=1>[CH:8]1([N:7]([C:22]([NH:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[S:23])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: S=C=NCc1ccccc1
Reactant: c1ccc(NC2CCCCC2)cc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: S=C(NCc1ccccc1)N(c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N-cyclohexylaniline (0.1 ml, 0.57 mmol) in acetonitrile (4 ml) was added a catalytic amount of 4-(dimethylamino)pyridine (5 mg, 0.04 mmol). To this mixture was added benzyl isothiocyanate (0.11 ml, 0.83 mmol) dropwise, and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, and the residue purified on preparative silica gel plates, developing with 20% ethyl acetate/hexanes, to furnish (N-cyclohexyl-N-phenylamino)-N-benzylthiocarboxamide as a white solid, (M+1)=324.8.
Reaction SMILES: Cl.[NH:2]([C:4]1[C:5](=[O:10])[NH:6][CH:7]=[CH:8][N:9]=1)[NH2:3].C(N(CC)CC)C.C[O:19][C:20](=O)[N:21]=[C:22](SC)[C:23]([C:37]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[C:39]([O:45][CH2:46][CH2:47][O:48][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])[C:38]=1[F:56])=[N:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:35]=[C:34]([CH3:36])[O:33][N:32]=2)=[CH:27][CH:26]=1>CN(C=O)C>[Si:49]([O:48][CH2:47][CH2:46][O:45][C:39]1[C:38]([F:56])=[C:37]([CH:23]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[N:35]=[C:34]([CH3:36])[O:33][N:32]=3)=[CH:29][CH:30]=2)[C:22]2[NH:21][C:20](=[O:19])[N:2]([C:4]3[C:5](=[O:10])[NH:6][CH:7]=[CH:8][N:9]=3)[N:3]=2)[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=1)([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OCCO[Si](C)(C)C(C)(C)C)c1F
Reactant: NNc1ncc[nH]c1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(OCCO[Si](C)(C)C(C)(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncc[nH]c3=O)c(=O)[nH]2)c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 45.1 %

Procedure:
3-Hydrazino-1H-pyrazin-2-one hydrochloride (24 mg) and triethylamine (0.033 ml) were added to 3 ml of a DMF solution containing 70 mg of (2-{3-[2-(t-butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene)carbamic acid methyl ester (Example (200a)). The resulting mixture was stirred at 85° C. for 16 hours and then concentrated under reduced pressure. The residue was dissolved in 5 ml of methanol, and 58 mg of sodium cyanotrihydroborate and 0.056 ml of acetic acid were further added thereto. The mixture was stirred at room temperature for 15 hours. To this reaction mixture, 40 ml of ethyl acetate and 20 ml of water were added. The organic layer was washed with 20 ml of water and then with 20 ml of saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (34 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[C@@H:20]3[CH2:24][C@H:23]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[C@@H:22]([OH:30])[C@H:21]3[OH:31])=[C:13]([NH:32]C(C3C=CC(OC)=CC=3)C3C=CC(OC)=CC=3)[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[C@@H:20]3[CH2:24][C@H:23]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[C@@H:22]([OH:30])[C@H:21]3[OH:31])=[C:13]([NH2:32])[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc(NC(c3ccc(OC)cc3)c3ccc(OC)cc3)c3ncn([C@@H]4C[C@H](NC(=O)CC)[C@@H](O)[C@H]4O)c3n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4C[C@H](NC(=O)CC)[C@@H](O)[C@H]4O)c3n2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A cooled (0° C.) solution of 1-[6-{[Bis-(4-methoxy-phenyl)-methyl]-amino}-9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-9H-purin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.1 g, 0.149 mmol) in dry dichloromethane (4 ml) is treated dropwise with TFA (2 ml). The mixture is stirred at room temperature for 12 h and then concentrated in vacuo. The residue is co-evaporated with chloroform three times to remove excess trifluoro acetic acid and purification of the residued by preparative HPLC affords the title compound. LC-MS (0.1% formic acid, acetonitrile): (MH+ 445.3).
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[CH3:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=1[N:15]=[C:16]=[O:17].O>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=1[NH:15][C:16]([N:8]=[C:7]1[NH:6][C:4](=[O:5])[CH2:3][N:2]1[CH3:1])=[O:17]
Reactant: CN1CC(=O)N=C1N
Reactant: Cc1ccsc1N=C=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccsc1NC(=O)N=C1NC(=O)CN1C
Temperature: 90 °C
Reaction time: 6 h
Yield: 17.9 %

Procedure:
To a stirred suspension of 3.0 g (26.0 mM) of creatinine in 50 ml of anhydrous DMF was added dropwise a solution of 3.7 g (26 mM) of 3-methyl-2-thienyl isocyanate in 35 ml of toluene. After stirring at 90° C. for 6 hrs., the reaction mixture was cooled and poured into 100 ml of water. The separated solid was collected, washed with water and recrystallized from ethyl acetate to give 1.2 g of the above urea as a grey-white solid, m.p. 201°-202° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:22]([O:24][CH2:25][CH3:26])=[O:23].CI.[C:29](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]([CH3:29])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2n1COC
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cccc(N(C)S(=O)(=O)c3cccs3)c2n1COC
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
A mixture of ethyl 1-(methoxymethyl)-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (1.03 g), methyl iodide (0.24 ml), potassium carbonate (0.36 g) and N,N-dimethylformamide (10 ml) was stirred overnight at room temperature. Water was added to the reaction mixture, and the resulting crystals were collected by filtration, washed with water, and dried to give the title compound (1.06 g, yield 99%) as colorless crystals. melting point 143-145° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:23][CH3:24].COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(C)N=2)C=CC=1OC>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:23][CH3:24])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: CCBr
Agent: COc1ccc(C2=NN(C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: CCN1N=C(c2ccc(OC)c(OC)c2)[C@@H]2CCCC[C@@H]2C1=O

Procedure:
Prepared from compound 1 and bromoethane as described for compound 8. Crystallized from methanol. M.p. 105-106° C.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][NH2:27]>>[C:1]([NH:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22][OH:21])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: NCCNCCO
Product: CCCCCCCCCCCCCCCCCC(=O)NCCNCCO

Procedure:
The dehydration condensation reaction of stearic acid with N-hydroxyethyl ethylene diamine was carried out, and the reaction product was hydrolyzed and distilled to give N-stearoyl-N′-hydroxyethyl ethylene diamine. It was dissolved in ethanol, and 1.1-fold equivalents (based on the amine) of formalin was added dropwise thereto under reflux, then 1.1-fold equivalents (based on the amine) of formic acid was added dropwise thereto, and the mixture was aged for 5 hours. The reaction product was further quaternarized with methyl chloride to give N-stearoylaminoethyl-N-hydroxyethyl-N,N-dimethyl ammonium chloride.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:18])=[N:6][C:5]=2[N:19]=1.Cl[C@@H:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=1)[CH3:22]>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:12][OH:13])=[N:8][C:7]([S:18][C@H:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=3)[CH3:22])=[N:6][C:5]=2[N:19]=1
Reactant: C[C@@H](Cl)c1ccc(F)cn1
Reactant: CC(C)C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Product: CC(C)C[C@H](CO)Nc1nc(S[C@@H](C)c2ccc(F)cn2)nc2nc(N)sc12
Yield: 17.7 %

Procedure:
The title compound was prepared by General method A starting from (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (550 mg, 1.8 mmol) and 2-[(1R)-1-chloroethyl]-5-fluoropyridine (0.46 g, 2.9 mmol). The product was purified by flash column chromatography followed by preparative HPLC (Column: Reprosil, eluent isopropanol:heptane 20:80, flow: 16 mL/min) collecting the first eluting isomer, to yield 135 mg (18% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH:10]([C:11]([O:13][CH3:14])=[O:12])[C:5]2=[CH:4][CH:3]=1.[N-:15]=[N+:16]=[N-:17].[Na+].[CH:19](OCC)(OCC)OCC>CC(O)=O>[N:1]1([C:2]2[N:7]=[C:6]3[CH2:8][CH2:9][CH:10]([C:11]([O:13][CH3:14])=[O:12])[C:5]3=[CH:4][CH:3]=2)[CH:19]=[N:17][N:16]=[N:15]1
Reactant: COC(=O)C1CCc2nc(N)ccc21
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(OCC)OCC
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)C1CCc2nc(-n3cnnn3)ccc21
Temperature: 100 °C

Procedure:
To a flask charged with methyl 2-amino-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxylate (500 mg, 2.6 mmol) and a stir bar was added sodium azide (340 mg, 5.2 mmol), triethyl orthoformate (2.2 mL, 13 mmol), and HOAc (10 mL). The mixture was heated to 100° C. for 2 hours. The solvent was removed on a rotavapor, and the residue was taken into aq. Sodium carbonate, extracted with EtOAc (50 Mk×3), dried over sodium sulfate, and purified by MPLC (DCM-MeOH). After removal of solvent, an off-white solid was collected as the desired methyl 2-(1H-tetrazol-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxylate. LC-MS (IE, m/z): 248 [M+1]+;
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:8]=[C:9]([CH2:17][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:10]=[CH:11][C:12]=1[CH:13]=[C:14](Br)Br.[OH2:23]>>[Cl:6][C:7]1[CH:8]=[C:9]([CH2:17][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:10]=[CH:11][C:12]=1[CH2:13][C:14]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:23]
Reactant: Clc1cc(CN2CCCC2)ccc1C=C(Br)Br
Reactant: C1CCNC1
Reactant: O
Product: O=C(Cc1ccc(CN2CCCC2)cc1Cl)N1CCCC1
Temperature: 25 °C

Procedure:
A mixture of pyrrolidine (150 ml) and water (15 ml) was stirred at r.t. 1-[[3-chloro-4-(2,2-dibromoethenyl)phenyl]methyl]-pyrrolidine (crude, max. 44.70 mmol) was added to the mixture and subsequently, the mixture was stirred overnight at r.t. The solvent was evaporated, yielding 1-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-pyrrolidine as a crude that was used as such in the next reaction step.