Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([CH2:11]O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:13]([C:15]1[NH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)#[N:14].CC1C(B2OC(C)(C)C(C)(C)[O:28]2)=C(C)NN=1>>[CH3:20][C:17]1[N:16]([CH2:11][C:1]23[CH2:8][CH:7]4[CH2:6][CH:5]([CH2:4][C:3]([CH3:2])([CH2:9]4)[O:28]2)[CH2:10]3)[C:15]([C:13]#[N:14])=[CH:19][CH:18]=1
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(C#N)[nH]1
Product: Cc1ccc(C#N)n1CC12CC3CC(CC(C)(C3)O1)C2

Procedure:
The title compound was prepared by substituting 1-hydroxymethyl-3-methyl-2-oxadamantane for 1-adamantanemethanol and 2-cyano-5-methylpyrrole for 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE 2A.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[C:14]([C:26]3[N:27]([CH3:31])[N:28]=[CH:29][CH:30]=3)[CH:13]=2)=[O:10])=[CH:4][CH:3]=1.[Cl:32]N1C(=O)CCC1=O>CO>[Cl:32][C:30]1[CH:29]=[N:28][N:27]([CH3:31])[C:26]=1[C:14]1[CH:13]=[C:12]([NH:11][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:10])[CH:17]=[CH:16][C:15]=1[O:18][CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1nccc1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1OCCN1CCCC1
Solvent: CO
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1OCCN1CCCC1
Reaction time: 1 h
Yield: 38 %

Procedure:
To a solution of 1-(4-chloro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-urea in cold methanol was added a solution of N-chloro succinimide (0.044 g, 0.3215 mmol) in methanol. The reaction mixture was stirred for 60 minutes. Then the methanol was evaporated and the residue was purified using silica flash chromatography with 15% methanol in DCM as eluant. The fractions containing the product were evaporated and dried in vacuo to afford 1-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(4-chloro-phenyl)-urea (Compound 17) (0.05 g, 38%) as an off-white solid. LCMS m/z (%)=474 (M+H35Cl35Cl, 100), 476 (M+H35Cl37Cl, 81.7), 478 (M+H37Cl37Cl, 11.2). 1H NMR (400 MHz, DMSO-d6) δ: 8.83 (bs, 1H), 8.73 (bs, 1H), 7.61 (s, 1H), 7.54 (dd, J=2.65, 2.69 Hz, 1H), 7.46 (dd, J=2.06, 2.11 Hz, 2H), 7.37 (d, J=2.7 Hz, 1H), 7.31 (dd, J=2.09, 2.04 Hz, 2H), 7.16 (d, J=9.03 Hz, 1H), 4.2-4.0 (bm, 2H), 3.65 (s, 3H), 2.7-2.5 (bm, 2H), 2.4-2.3 (bm, 4H), 1.7-1.5 (bm, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([I:10])[CH:9]=1)=[O:4].C(N(CC)CC)C.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](O)(=[O:26])=[O:25])=[CH:20][CH:19]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]([S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[CH:7]=[C:8]([I:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(I)c[nH]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(I)cn1S(=O)(=O)c1ccc(C)cc1
Yield: 80.2 %

Procedure:
4-Iodo-1H-pyrrole-2-carboxylic acid methyl ester 57d (25.1 g, 100 mmol) was dissolved in 150 mL of dichloromethane followed by addition of triethylamine (30.6 mL, 220 mmol), 4-dimethylaminopyridine (1.22 g, 10 mmol) and p-toluenesulfonic acid (21 g, 110 mmol). The reaction mixture was reacted at 20° C. overnight. The reaction was monitored by TLC until the disappearance of the starting materials and quenched by addition of 30 mL of hydrochloric acid (1 N). The mixture was extracted with dichloromethane (50 mL×3). The combined organic extracts were washed with saturated aqueous sodium carbonate and saturated brine successively, dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 4-iodo-1-(toluene-4-sulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester 57e (32.5 g, yield 80.2%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12])[C:8]([O:10][N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22])=[O:9]
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1Cl
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)ON2C(=O)CCC2=O)cc1Cl
Temperature: 10 °C
Reaction time: 8 h
Yield: 112.3 %

Procedure:
A 3-neck 1 L round-bottom flask equipped with a magnetic stirrer, ice cooling bath, thermometer and an argon inlet tube was set up and charged with 2-chloro-1,4-benzenedicarboxylic acid, 1-methyl ester (Example 1; 21.5 g, 0.1 mol) in tetrahydrofuran (250 mL). The solution was cooled to 10° C. under argon and was treated in succession with N-hydroxysuccinimide (12.66 g, 0.11 mol) and 1,3-dicyclohexylcarbodiimide (21.66 g, 0.105 mol). These reagents were washed in with additional tetrahydrofuran (100 mL). A precipitate started to form immediately. The cooling bath was removed and the reaction mixture was stirred at ambient temperature overnight, and then diluted with diethyl ether (400 mL) and stirred for another 30 min. The precipitate was collected by filtration, and the filter cake was washed with diethyl ether (3×50 mL). The dried solids (DCU) weighed 22.2 g (>99% of theory). The combined filtrates were diluted with hexane (100 mL) then were transferred to a 2 L separatory funnel and were washed in turn with cold saturated sodium bicarbonate solution (150 mL) and brine (150 mL). Each aqueous layer was back-extracted in turn with diethyl ether (200 mL), then the combined organic extracts were dried (MgSO4), and evaporated to give crude 1-[[3-chloro-4-(methoxycarbonyl)benzoyl]oxy]-2,5-pyrrolidinedione (˜35 g) as a colorless solid. This material was used directly in the next step without purification.
Reaction SMILES: [CH3:1][P:2]([CH3:23])([CH2:4][CH2:5][N:6]([CH2:11][C:12]([S:15]CC1C=CC=CC=1)([CH3:14])[CH3:13])[CH2:7][CH2:8][O:9][CH3:10])=S.[Na].[Cl-].[NH4+]>O1CCCC1.C(Cl)(Cl)Cl>[CH3:23][P:2]([CH3:1])[CH2:4][CH2:5][N:6]([CH2:7][CH2:8][O:9][CH3:10])[CH2:11][C:12]([CH3:14])([CH3:13])[SH:15]
Reactant: COCCN(CCP(C)(C)=S)CC(C)(C)SCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COCCN(CCP(C)C)CC(C)(C)S
Temperature: -50 °C

Procedure:
A solution of N-(2-dimethylphosphinothioylethyl)-N-(2-methoxyethyl)-2-benzylthio-2-methylpropylamine (500 mg) in dry tetrahydrofuran (10 cm3) was placed in a flask fitted with a low temperature condenser (-50° C.), drying tube and gas inlet. The flask was flushed with nitrogen, the solution cooled to -50° C., and then dry ammonia (40 cm3) was condensed into the flask. Small pieces of sodium were then added to this mixture until the blue colouration persisted for at least 1 hour. The blue colouration was then discharged by the addition of ammonium chloride, and the mixture allowed to warm to room temperature. As the ammonia evaporated steps were taken to ensure that no air entered the apparatus. [The flask and its contents were then transfered to a glove box containing a nitrogen atmosphere for subsequent operations.] The reaction mixture was then filtered and the solvent removed under reduced pressure to give a yellow oil containing some solid material. The oil was dissolved in chloroform, the solid removed by filtration, and the solvent removed under reduced pressure to give 2-[N-(2-dimethylphosphinoethyl)-2-methoxyethylamino]-1,1-dimethylethanethiol as an oil.
Reaction SMILES: CO[C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.[NH:27]([CH2:31][CH2:32][OH:33])[CH2:28][CH2:29][OH:30]>CO.O1CCCC1>[OH:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][OH:33])[C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Reactant: OCCNCCO
Solvent: CO
Solvent: C1CCOC1
Product: O=C(C(=O)N(CCO)CCO)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Yield: 30.6 %

Procedure:
A solution of 4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.5 g) in methanol (40 mL) and tetrahydrofuran (10 mL) was treated with diethanolamine (0. 162 g) and the mixture was refluxed for 18 hours. The solvents were removed by evaporation and the residue was crystallized from acetone to give 0.185 g of N,N-bis(2-hydroxyethyl)-4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetamide as a colorless solid, mp 128°-133° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH:7]2[CH2:8][CH:3]1[CH:4]=[CH:5][C:6]2=[O:9].[O-][Mn](=O)(=O)=O.[K+].O.CC1(C)[C@H]2C[C@@H]1CCC2=C.[O-][Mn](=O)(=O)=O.[K+]>C(Cl)Cl>[CH3:1][C:2]1([CH3:10])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][C:6]2=[O:9]
Reactant: CC1(C)C2C=CC(=O)C1C2
Agent: O=[Mn](=O)(=O)[O-]
Agent: C=C1CC[C@H]2C[C@@H]1C2(C)C
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC1(C)C2CCC(=O)C1C2

Procedure:
6,6-Dimethylbicyclo[3.1.1]hept-3-en-2-one—KMnO4 (5.71 g) was ground into a fine powder and combined with acidic alumina (22.55 g) and water (5.6 mL) for 5 minutes in order to form a homogenous mixture. (−)-β-Pinene (1.16 mL), and methylene chloride (200 mL) were placed in a 250 mL round bottom flask; the moistened KMnO4/acidic alumina was added in small portions slowly to the solution. As the KMnO4/acidic alumina was added, the reaction turned into a dark purple color solution. The reaction was allowed to continue to stir until TLC indicated all starting material had reacted. The solution was filtered through fritted glass, and the residue was washed twice with 50 mL of methylene chloride. The filtrate was concentrated and yielded 6,6-dimethyl-bicyclo[3.1.1]heptan-2-one as a light yellow oil. The oil was purified via column chromatography (85:15, Hex: EtOAc) and like fractions were combined. 1H NMR (300 MHz, CDCl3): (ppm) 0.96(s, 3H), 1.34 (s, 3H), 1.59(d, 1H), 1.86-2.13 (m, 2H), 2.20-2.30 (m, 1H), 2.31-2.43 (m, 1H), 2.45-2.68 (m, 3H). (ESI, Pos) m/z 161.0 (M+23).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:31]([OH:33])=O)[C:18]3[C:23]([CH3:24])=[N:22][N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:19]=3[N:20]=2)=[C:11]([F:34])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:44]([O:48][C:49]([N:51]1[CH2:56][CH2:55][NH:54][CH:53]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH2:52]1)=[O:50])([CH3:47])([CH3:46])[CH3:45]>C(Cl)Cl.O>[C:44]([O:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:31]([C:17]2[C:18]3[C:23]([CH3:24])=[N:22][N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:19]=3[N:20]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][C:11]=3[F:34])[CH:16]=2)=[O:33])[CH:53]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH2:52]1)=[O:50])([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)N1CCNC(c2ccccc2)C1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(=O)O)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3c3ccccc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.1 %

Procedure:
To a suspension of 571 mg of 6-(4-benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid in 14 ml of DCM were added 0.64 ml of Hünig's base, 408 mg of BEP and 390 mg of 3-phenyl-piperazine-1-carboxylic acid tert-butyl ester. The reaction was stirred overnight at r.t. For workup it was diluted with water and DCM and the layers were separated. The organic layer was washed with water twice, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, heptane/EtOAc gradient) to obtain 900 mg (100%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][CH2:8][C:9]1[C:14]([OH:15])=[CH:13][CH:12]=[C:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1>>[C:1]([O:5][C:6](=[O:23])[CH2:7][CH2:8][C:9]1[C:14]([O:15][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]/[C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)=[CH:13][CH:12]=[C:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(/C=C/CCCCBr)cc1
Reactant: CC(C)(C)OC(=O)CCc1nc(C(=O)OC(C)(C)C)ccc1O
Product: COc1ccc(/C=C/CCCCOc2ccc(C(=O)OC(C)(C)C)nc2CCC(=O)OC(C)(C)C)cc1
Yield: 50.3 %

Procedure:
Under the conditions of example 1 D, 440 mg of 3-(6-tert-butoxycarbonyl-3-hydroxy-2-pyridyl)-propionic acid-tert-butyl ester is reacted with 367 mg of (1E)-6-bromo-1-(4-methoxyphenyl)-1-hexene, worked up, and the crude product is chromatographed on silica gel with hexane/0-8% ethyl acetate. 350 mg of 3-{6-tert-butoxycarbonyl-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid-tert-butyl ester is obtained as oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.[CH2:13]([O:15][C:16](=[O:21])[CH2:17][C:18](=[NH:20])[NH2:19])[CH3:14]>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[CH:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)[C:17]([C:16]([O:15][CH2:13][CH3:14])=[O:21])=[C:18]([NH2:19])[NH:20][C:18]=1[NH2:19])=[O:21])[CH3:14]
Reactant: O=Cc1ccnc2ccccc12
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1ccnc2ccccc12
Yield: 58 %

Procedure:
Upon heating a solution of 7.8 g quinoline-4-aldehyde and 13.0 g amidinoacetic acid ethyl ester in 200 ml ethanol for two hours, 2,6-diamino-4-(quinol-4-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 145° (ethanol) is obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[C:21]([OH:22])=[C:20]([O:23][CH3:24])[C:19]([O:25][CH3:26])=[CH:18][C:17]=1[CH3:27])(=[O:3])[CH3:2].N(S([O-])(=O)=O)(S([O-])(=O)=[O:31])[O].[K+].[K+].O.P(O)(O)([O-])=O.[K+]>CN(C)C=O.CO>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[C:21](=[O:22])[C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[C:18](=[O:31])[C:17]=1[CH3:27])(=[O:3])[CH3:2]
Reactant: COc1cc(C)c(CCCCCCCCCCCOC(C)=O)c(O)c1OC
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCCOC(C)=O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 672 h
Yield: 77.2 %

Procedure:
To a solution of 6-(11-acetoxyundecyl)-2,3-dimethoxy-5-methylphenol (8 g) in dimethylformamide (400 ml) are added potassium nitrosodisulfonate (24 g), water (400 ml), methanol (30 ml) and monopotassium phosphate (1.0 g). The mixture is stirred at room temperature for 28 days. The reaction product is extracted with dichloromethane and the dichloromethane layer is washed with water and dried over magnesium sulfate. The solvent is distilled off to thereby leave crude crystals. The crude crystals are recrystallized from hexane to yield 6.4 g of 6-(11-acetoxyundecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone as orange-yellow needles, m.p.: 41° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C(N(CC)C(C)C)(C)C>CC(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ncccn1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncccn2)C1

Procedure:
A mixture of 3-aminomethyl-pyrrolidine-1-carboxylic acid benzyl ester (0.15 g), 2-bromopyrimidine (0.25 g), 2-propanol (10 mL), and of N,N-diisopropylethylamine (0.1 mL) was heated to reflux overnight. Purification of the residue obtained after concentration under reduced pressure by preparative chromatography, and eluting with ethyl acetate, gave 3-(pyrimidin-2-ylaminomethyl)-pyrrolidine-1-carboxylic acid benzyl ester as a solid:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][C@@H:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[O:7][C:6]1=[O:22].[N:23]1[S:27][N:26]=[C:25]2[CH:28]=[C:29]([CH:32]=O)[CH:30]=[CH:31][C:24]=12.CO.[BH4-].[Na+]>C(OCC)(=O)C.C(Cl)Cl>[N:23]1[S:27][N:26]=[C:25]2[CH:28]=[C:29]([CH2:32][NH:1][CH2:2][CH2:3][CH2:4][N:5]3[CH2:9][C@@H:8]([C:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=5)[N:13]=[CH:12][CH:11]=4)[O:7][C:6]3=[O:22])[CH:30]=[CH:31][C:24]=12
Reactant: COc1ccc2nccc([C@@H]3CN(CCCN)C(=O)O3)c2c1
Reactant: O=Cc1ccc2nsnc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2nccc([C@@H]3CN(CCCNCc4ccc5nsnc5c4)C(=O)O3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.7 %

Procedure:
A mixture of (R)-3-(3-amino-propyl)-5-(6-methoxy-quinolin-4-yl)-oxazolidin-2-one (0.15 g, 0.5 mmol), benzo[1,2,5]thiadiazole-5-carbaldehyde (92 mg, 0.56 mmol), methanol (0.5 ml), methylene chloride (1.8 ml), 3 Å dry molecular sieve (1 g) was stirred at room temperature for 16 hours. Sodium borohydride (28 mg, 0.76 mmol) was added and the mixture was stirred for 3 hours. After concentration of the solvent the residue was dissolved in ethyl acetate and the organic phase was washed with water, dried over magnesium sulfate and concentrated. The residue was chromatographed on silicagel eluting with methylene chloride-methanol (99-1 first, then 90-10) to give (R)-3-{3-[(benzo[1,2,5]thiadiazol-5-ylmethyl)-amino]-propyl}-5-(6-methoxyquinolin-4-yl)-oxazolidin-2-one (150 mg, 59%).
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2]C.[CH2:8]([O:15][C@H:16]1[CH2:20][CH2:19][CH2:18][C@@H:17]1[NH2:21])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:22]1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH3:22][CH:1]([S:4]([NH:21][CH:17]1[CH2:18][CH2:19][CH2:20][CH:16]1[O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:5])=[O:6])[CH3:2]
Reactant: C1CCC2=NCCCN2CC1
Reactant: N[C@H]1CCC[C@@H]1OCc1ccccc1
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC1CCCC1OCc1ccccc1
Temperature: 0 °C
Yield: 269 %

Procedure:
Scheme IA, step A: In a 250 mL 3 neck flask fitted with a stirrer and thermometer, propanesulfonyl chloride (4.47 g, 1.2 eq) was added dropwise to (1S,2S)-2-benzyloxycyclopentylamine (5.00 g, 10 mmol) and DBU (5.98 g, 1.5 eq) in CH2Cl2 (100 mL) while stirring at 0° C. under a nitrogen atmosphere. The reaction was allowed to warm to room temperature and stirred overnight at this temperature. In the morning, the reaction was diluted with CH2Cl2 (100 mL) and the organic layer was washed two times with H2O, dried over Na2SO4, filtered, and concentrated under reduced vacuum to yield 10.13 g as a viscous oil. This material was purified via silica gel chromatography employing the Water's Prep. 2000 and eluting with a solvent of hexane/ethyl acetate 4:1 to yield the intermediate title compound (8.0 g, 95%) as a white solid. Ion spray M.S. 296 (M*−1). Analysis calculated for C15H23NO3S: Theory: C, 60.58; H, 7.80; N, 4.71. Found: C, 60.39; H, 7.79; N, 4.73.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:21][C:22]2[CH:23]=[C:24]([C:28]3[C:33]([CH3:34])=[CH:32][C:31]([OH:35])=[CH:30][C:29]=3[CH3:36])[CH:25]=[CH:26][CH:27]=2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:37][CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].[CH2:46]([NH:48][CH2:49][CH2:50]O)[CH3:47].[C:52](OC(=O)C)(=[O:54])[CH3:53]>>[C:52]([N:48]([CH2:46][CH3:47])[CH2:49][CH2:50][O:35][C:31]1[CH:32]=[C:33]([CH3:34])[C:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][N:8]([S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[C:6]3[CH:5]=[CH:4][C:3]([CH2:37][CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[C:2]([F:1])[CH:7]=3)[CH:23]=2)=[C:29]([CH3:36])[CH:30]=1)(=[O:54])[CH3:53]
Reactant: CCNCCO
Reactant: Cc1cc(O)cc(C)c1-c1cccc(CN(c2ccc(CCC(=O)OC(C)(C)C)c(F)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Product: CCN(CCOc1cc(C)c(-c2cccc(CN(c3ccc(CCC(=O)OC(C)(C)C)c(F)c3)S(=O)(=O)c3ccccc3[N+](=O)[O-])c2)c(C)c1)C(C)=O

Procedure:
In the same manner as in Example 196, the title compound (0.19 g) was obtained as a colorless amorphous powder from tert-butyl 3-(2-fluoro-4-{[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methyl][(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate, 2-(ethylamino)ethanol and acetic anhydride
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9]O)[C:5]([CH2:11][OH:12])=[C:4]([CH:13]=[CH2:14])[N:3]=1.[OH-].[Na+].C(=S)=[S:18]>>[CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][SH:18])[C:5]([CH2:11][OH:12])=[C:4]([CH:13]=[CH2:14])[N:3]=1
Reactant: S=C=S
Reactant: C=Cc1nc(C)c(O)c(CO)c1CO
Agent: [Na+]
Agent: [OH-]
Product: C=Cc1nc(C)c(O)c(CS)c1CO

Procedure:
Treatment of the product of Step D with sodium hydroxide and carbon disulfide by the procedure described in Example 1, Step C, yields 2-methyl-3-hydroxy-4-mercaptomethyl-5-hydroxymethyl-6-vinylpyridine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([N:24]2[C:28](=[O:29])[CH2:27][CH:26]([NH:30][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:25]2)[CH:20]=[CH:21][C:22]=1[OH:23]>CN(C1C=CN=CC=1)C.O1CCOCC1.CCOC(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:23][C:22]1[CH:21]=[CH:20][C:19]([N:24]2[C:28](=[O:29])[CH2:27][CH:26]([NH:30][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:25]2)=[CH:18][C:17]=1[F:16]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(NC1CC(=O)N(c2ccc(O)c(F)c2)C1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc2nccc(Oc3ccc(N4CC(NC(=O)c5ccccc5)CC4=O)cc3F)c2cc1OC
Temperature: 160 °C

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinoline (0.14 g, 0.6 mmol), N-(1-(3-fluoro-4-hydroxyphenyl)-5-oxopyrrolidin-3-yl)benzamide (Step 4, 0.20 g, 0.6 mmol) and DMAP (78 mg, 0.6 mmol) in 2 mL of dioxane (in a microwave tube) was heated in a microwave (Personal Chemistry, Emrys Optimizer) at 160° C. for 1 h. The mixture was cooled to RT and diluted with 50 mL of EtOAc. The solution was washed with 20 mL of satd. NaHCO3 followed by 20 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (50% to 100% EtOAc in hexanes then to 5% MeOH/EtOAc) to provide a white solid. MS (ESI pos. ion) m/z: 502.3 (M+H). Calc'd Exact Mass for C28H24FN3O5: 501.51.