Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7](=[N:14][O:15][CH2:16][C:17]1[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1.[C:30](Cl)(=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>ClCCl>[CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7](=[N:14][O:15][CH2:16][C:17]1[N:22]=[C:21]([NH:23][C:30](=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:20]=[CH:19][CH:18]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1ncoc1C(=NOCc1cccc(N)n1)c1ccccc1
Reactant: CCCCCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCC(=O)Nc1cccc(CON=C(c2ccccc2)c2ocnc2C)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 6-[({[(4-methyl-1,3-oxazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine (90 mg, 0.29 mmol) in dichloromethane (2 mL) were added pyridine (35 mg, 0.44 mmol) and after 15 min stirring n-hexanoyl chloride (43 mg, 0.32 mmol). After stirring at room temperature for 4 h the mixture was passed through a cartridge filled with basic alumina and 1 g silica. After rinsing with dichloromethane the final compound was eluted with heptane/ethylacetate (1/1) to afford after evaporation N-{6-[({[(4-methyl-1,3-oxazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}hexanamide (95 mg, 72%).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:29]=[CH:28][S:27][CH:26]=1>>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:25]5[CH:29]=[CH:28][S:27][CH:26]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Brc1ccsc1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Product: OC1(c2ccsc2)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Yield: 81 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 3-bromothiophene, the title compound was formed in 81% yield as an off-white solid, mp 273°-277° C. (dec). free base: 1H NMR (CDCl3, 250 MHz) 7.17 (m, 7H), 6.94 (m, 4H), 4.26 (s, 1H), 3.46 (s, 1H), 2.84 (m, 2H), 2.71 (m, 2H), 2.60 (d, J=1.4 Hz, 2H), 2.12 (m, 2H), 1.83 (m, 2H) MS (CI, CH4) m/z 388 (M+1,100), 416 (M+29,20), 370 (51), 304 (10), 196 (12) hydrochloride salt:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH:20]1([N:26]=[C:27]=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(N(CC)CC)C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH:18][C:27]([NH:26][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:28])[CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C=NC1CCCCC1
Reactant: CCOC(=O)c1ccc(-c2cc(N)ccc2Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2cc(NC(=O)NC3CCCCC3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
A mixture of 5′-amino-2′-chloro-biphenyl-4-carboxylic acid ethyl ester (350 mg) and cyclohexyl isocyanate (0.32 ml) in dry THF (15 ml) containing triethylamine (0.62 ml) was stirred at room temp for 48 h. The mixture was then evaporated and the residue partitioned between water and DCM. The dried extracts were evaporated giving the crude title compound as a white solid (616 mg, >100%, contaminated with dicyclohexyl-urea)
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:22][C:23]1[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]#[N:30])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccccc1CBr
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1ccccc1C#N
Yield: 90.6 %

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.602 g, 2.25 mmol), α-bromo-o-tolunitrile (0.668 g, 3.41 mmol), KI (100 mg, 0.60 mmol), and DIPEA (0.80 mL, 4.59 mmol) in DMF (11 mL) was heated at 60° C. for 23 hours. Purification of the crude material by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.78 g (91%) of 2-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzonitrile as a tan solid. 1H NMR (CDCl3) δ 1.63-1.73 (m, 3H), 2.02-2.07 (m, 1H), 2.26-2.38 (m, 2H), 2.48 (s, 6H), 3.69 (s, 2H), 4.12 (d, 2H, J=10.8 Hz), 6.83-6.89 (m, 3H), 6.99 (d, 1H, J=7.2 Hz), 7.19-7.26 (m, 3H), 7.64 (d, 1H, J=7.8 Hz), 8.27 (d, 2H, J=3.9 Hz). 13C NMR (CDCl3) δ 19.44, 25.53, 29.42, 52.72, 67.05, 109.86, 118.06, 122.19, 125.90, 130.68, 131.41, 131.54, 132.02, 138.18, 145.77, 147.23, 159.61; ES-MS m/z 383 (M+H). Anal. Calcd. For C25H26N4C, 78.50; H, 6.852; N, 14.65. Found: C, 78.28; H, 6.93; N, 14.57.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9](=[O:20])[CH:8]=1)(=O)=O.[C:23]1([C:29]#[CH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:23]1([C:29]#[C:30][C:7]2[CH:12]=[C:11]([CH3:13])[N:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9](=[O:20])[CH:8]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C#Cc1ccccc1
Reactant: CCOC(=O)Cn1c(C)cc(OS(=O)(=O)C(F)(F)F)cc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1c(C)cc(C#Cc2ccccc2)cc1=O

Procedure:
A solution of 4-trifluoromethylsulfonyloxy-6-methyl-1-ethoxycarbonylmethyl-2-pyridinone from step 2 above (2.0 g, 5.4 mmol), phenylacetylene (1.1 g, 11 mmol), triethylamine (3.6 mL, 25 mmol), and PdCl2(PPh3)2 (0.42 g, 0.6 mmol) in DMF (20 mL) was heated to 90° C. under inert atmosphere for 1 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc and aqueous NaHCO3. The organic phase was separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using 1:1 EtOAc:hexanes as eluant to give the title compound as an amorphous solid (1.5 g; TLC Rf=0.35, 1:1 EtOAc:hexanes; HPLC RT=8.64 min, method A).
Reaction SMILES: [C:1]([OH:6])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:7]([CH2:9][NH2:10])[OH:8]>N1C=CC=CC=1>[OH:8][CH2:7][CH2:9][NH:10][CH:2]([CH2:3][CH3:4])[C:1]([OH:6])=[O:5]
Reactant: NCCO
Reactant: C/C=C/C(=O)O
Solvent: c1ccncc1
Product: CCC(NCCO)C(=O)O

Procedure:
A solution of 86 g of crotonic acid (1 mole) and ethanolamine (1 mole) in pyridine (200 ml) is refluxed for 2-3 hours and subsequently cooled. The resulting product is filtered and recrystallized to yield the title compound having m.p. 178-180° C. (Compound 1.1, Table 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.[CH2:10]([N:17]1[CH2:22][CH:21]=[C:20]([CH2:23]O)[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:10]([N:17]1[CH2:18][CH:19]=[C:20]([CH2:23][O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[I:9])[CH2:21][CH2:22]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccc(Cl)cc1I
Reactant: OCC1=CCN(Cc2ccccc2)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(OCC2=CCN(Cc3ccccc3)CC2)c(I)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-2-iodo-phenol 4ii (20.32 g, 0.08 mol), (1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-methanol (20.5 g, 0.08 mol) and triphenylphosphine (23.58 g, 0.09 mol) in dry THF (150 mL) was added DEAD (17.4 g, 0.09 mol) at 0° C. under nitrogen atmosphere. After addition, the mixture was stirred at room temperature overnight. The mixture was concentrated to dryness and the residue was basified by Na2CO3 solution (10% 100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water (2×100 mL) and brine (200 mL), dried over Na2SO4, concentrated to dryness. The residue was purified by column on silica gel to afford 1-benzyl-4-(4-chloro-2-iodo-phenoxymethyl)-1,2,3,6-tetrahydro-pyridine 4iii (30 g). 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J=2.4 Hz, 1H), 7.22-7.38 (m, 6H), 6.70 (d, J=8.8 Hz, 1H), 5.82 (s, 1H), 4.43 (s, 2H), 3.63 (s, 2H), 3.05 (s, 2H), 2.67 (t, J=5.6 Hz, 2H), 2.28 (s, 2H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][OH:29])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br/[CH:39]=[CH:40]/[CH2:41][C:42]([O:45][Si:46]([CH2:51][CH3:52])([CH2:49][CH3:50])[CH2:47][CH3:48])([CH3:44])[CH3:43].[H-].[Na+].C1OCCOCCOCCOCCOC1>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29]/[CH:39]=[CH:40]/[CH2:41][C:42]([O:45][Si:46]([CH2:47][CH3:48])([CH2:49][CH3:50])[CH2:51][CH3:52])([CH3:43])[CH3:44])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC[Si](CC)(CC)OC(C)(C)C/C=C/Br
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@H](CC[C@]4(C)C(CO)=CC[C@@H]34)[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)C/C=C/OCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 100 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene (400 mg, 0.734 mmol), 1-bromo-4-triethylsilyloxy-4-methyl-(2E)-pentene (431 mg, 1.47 mmol), sodium hydride (60% in oil, 88 mg, 2.20 mmol), 15-crown-5 (162 mg, 0.735 mmol) and tetrahydrofuran (1 ml) were subjected to reaction using a procedure similar to that of Example 5(1) (at room temperature for 2 hours), worked up and purified by column chromatography (hexane:toluene=3:2) to give the titled compound (556 mg, 100%) as a colorless oil.
Reaction SMILES: [Cl: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][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27](O)=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.[N:37]1([CH2:43][CH2:44][NH2:45])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(P(=O)(OCC)OCC)#N>>[Cl: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][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([NH:45][CH2:44][CH2:43][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1
Reactant: NCCN1CCOCC1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21
Agent: CCOP(=O)(C#N)OCC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)NCCN4CCOCC4)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 5-{2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and 2-morpholin-4-ylethanamine using diethyl cyanophosphonate as a coupling reagent. Mass: 621.20 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[CH:6]=[C:5]2[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.P(Cl)(Cl)([Cl:22])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:22])[CH:6]=[C:5]2[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(-c2cccc(Cl)c2)c2cc(Br)ccc2[nH]1
Product: Clc1cccc(-c2cc(Cl)nc3ccc(Br)cc23)c1
Yield: 100 %

Procedure:
A mixture of intermediate 4 (0.16 mol) in phosphoryl chloride (500ml) was stirred and refluxed for one night. The mixture was evaporated till dryness, the residue was taken up in ice and water, alkalized with NH4OH and extracted with DCM. The organic layer was decanted, dried (MgSO4), filtered off and evaporated, yielding 56 g (100%) of 6-bromo-2-chloro-4-(3-chlorophenyl)quinoline, mp.125° C. (intermediate 5).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1([Br:12])[CH2:10][CH2:9][CH2:8][CH2:7][NH:6][C:5]1=[O:11].I[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>C1COCC1>[C:18]([O:17][C:15]([CH2:14][N:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C:4]([Br:12])([Br:3])[C:5]1=[O:11])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)CI
Reactant: O=C1NCCCCC1(Br)Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1CCCCC(Br)(Br)C1=O

Procedure:
To a suspension of 300 mg of sodium hydride in 25 ml THF add a solution of 2.71 g of 3,3-dibromoperhydroazepin-2-one [R. Wineman et al., J. Am. Chem. Soc., 80, 6233 (1958)] and 2.50 g of t-butyl iodoacetate in 25 ml THF, carrying out the operation under N2. Stir the reaction at room temperature for several hours, quench with aqueous NaHSO3, isolate the organic phase, dry and concentrate in vacuo to obtain 1-t-butoxycarbonylmethyl-3,3-dibromoperhydroazepin-2-one.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:17])=[C:7]([CH3:16])[C:8]([OH:15])=[C:9]([C:12](=O)[CH3:13])[C:10]=1[CH3:11])(=[O:3])[CH3:2].Cl.[NH2:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:37]=[CH:36][C:27]([CH2:28][CH:29]2[S:33][C:32](=[O:34])[NH:31][C:30]2=[O:35])=[CH:26][CH:25]=1>>[C:1]([O:4][C:5]1[C:6]([CH3:17])=[C:7]([CH3:16])[C:8]([OH:15])=[C:9]([C:12](=[N:19][O:20][CH2:21][CH2:22][O:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:28][CH:29]3[S:33][C:32](=[O:34])[NH:31][C:30]3=[O:35])=[CH:36][CH:37]=2)[CH3:13])[C:10]=1[CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)c(C)c(O)c(C(C)=O)c1C
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Product: CC(=O)Oc1c(C)c(C)c(O)c(C(C)=NOCCOc2ccc(CC3SC(=O)NC3=O)cc2)c1C
Yield: 44.6 %

Procedure:
Following a procedure similar to that described in Example 46, but using 0.32 g of 5'-acetoxy-2'-hydroxy-3',4',6'-trimethylacetophenone and 0.40 g of 5-[4-(2-aminooxyethoxy)benzyl]thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)], 0.28 g of the title compound was obtained as an amorphous powder, melting at 60°-75° C. (softening point).
Reaction SMILES: [CH3:1][N:2]1C2C(=CC=CC=2)C=C1CNC.[CH3:14][N:15]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[C:17]([CH:24]=O)=[CH:16]1.CN1C2C(=CC=CC=2)C(C)=C1C=O>>[CH3:14][N:15]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[C:17]([CH2:24][NH:2][CH3:1])=[CH:16]1
Reactant: CNCc1cc2ccccc2n1C
Reactant: Cn1cc(C=O)c2cccnc21
Agent: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1cn(C)c2ncccc12
Yield: 45 %

Procedure:
According to the procedure of Preparation 40 (c), except substituting 1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.4 g, 2.5 mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.2 g, 45%) was prepared as a yellow oil: MS (ES) m/e 176 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[C:11](=[O:20])[NH:12][C:13]([NH:16][N+]([O-])=O)=[N:14][CH:15]=2)[CH:5]=[N:6][C:7]=1[CH3:8].[Br:21][C:22]1[C:23]([CH2:28][S:29][CH2:30][CH2:31]N)=[N:24][CH:25]=[CH:26][CH:27]=1>C(O)C>[Br:21][C:22]1[C:23]([CH2:28][S:29][CH2:30][CH2:31][NH:16][C:13]2[NH:12][C:11](=[O:20])[C:10]([CH2:9][C:4]3[CH:5]=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)=[CH:15][N:14]=2)=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cnc1C
Reactant: NCCSCc1ncccc1Br
Solvent: CCO
Product: Cc1cc(Cc2cnc(NCCSCc3ncccc3Br)[nH]c2=O)cnc1C

Procedure:
A mixture of 5-(5,6-dimethyl-3-pyridylmethyl)-2-nitroamino-4-pyrimidone and 1.2 molar equivalents of 2-(3-bromo-2-pyridylmethylthio)ethylamine was heated under reflux in ethanol for 48 hours, evaporated to dryness and the product isolated as 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidone, m.p. 105°-7°.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:3]([NH:5][O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:4].[CH3:28][N:29]([CH3:34])[S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl.N1C=CC=CC=1>[C:7]([O:6][NH:5][C:3](=[O:4])[C@@H:2]([NH:1][S:30]([N:29]([CH3:34])[CH3:28])(=[O:32])=[O:31])[CH2:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][CH:20]=1)(=[O:13])=[O:14])([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)ONC(=O)[C@@H](N)CS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)N[C@@H](CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)C(=O)NOC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-2-amino-N-tert-butoxy-3-(4-phenoxyphenylsulfonyl)-propionamide (1.5 g) in methylene chloride (20 ml) and pyridine (1.2 ml) was added dimethylsulfamoyl chloride (1 ml), and the mixture stirred overnight at room temperature. The mixture was partitioned between methylene chloride and water, and after the organic layer was dried over magnesium sulfate, solvent was removed under reduced pressure. The residue was chromatographed on silica gel, eluting with 0-45% ethyl acetate/hexane, to give (R)-N-tert-butoxy-2-dimethylaminosulfonamido-3-(4-phenoxyphenylsulfonyl)-propionamide (1.6 g).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].CN1CCCC1=O.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][SH:30])=[CH:27][CH:26]=1.[H-].[Na+]>O>[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][S:30][C:2]2[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])=[CH:27][CH:26]=1
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: COc1ccc(CS)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)Cc1ccc([N+](=O)[O-])c(SCc2ccc(OC)cc2)c1

Procedure:
A mixture of methyl 3-fluoro4-nitrophenylacetate(1.05 g), N-methylpyrrolidinone(10 mL) and 4-methoxybenzyl mercaptan was stirred under argon and treated with sodium hydride(0.22 g of a 60% dispersion in mineral oil) and the resulting mixture was stirred at ambient temperature for 0.5 h. Water was added and the mixture was extracted with ether, and the extract was washed with brine, dried and evaporated to dryness. The residue was purified by flash chromatography eluting with increasingly polar mixtures of ethyl acetate and hexane to give the product (1.35 g), [m/e365, (M+NH4)+].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([C:12]2[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][C:13]=2[CH3:21])[N:7]=1)=[O:5])[CH3:2].[NH2:22][C:23]1[C:24]([O:38][CH3:39])=[C:25]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:26]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:28]=1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([C:12]2[CH:17]=[C:16]([C:18](=[O:20])[NH:22][C:23]3[CH:28]=[C:27]([C:29]([CH3:31])([CH3:32])[CH3:30])[CH:26]=[C:25]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:24]=3[O:38][CH3:39])[CH:15]=[CH:14][C:13]=2[CH3:21])[N:7]=1)=[O:5])[CH3:2]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: CCOC(=O)c1cc(N)n(-c2cc(C(=O)O)ccc2C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(N)n(-c2cc(C(=O)Nc3cc(C(C)(C)C)cc(NS(C)(=O)=O)c3OC)ccc2C)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.4 %

Procedure:
5-Amino-1-(5-carboxy-2-methyl-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (46 mg, 0.159 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU) (67 mg, 0.175 mmol) were combined in DMF (500 μL) and stirred for 5 min at room temperature N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (48 mg, 0.175 mmol) was added to the reaction mixture followed by i-Pr2NEt (83 μL, 0.477 mmol). The solution was stirred at room temperature for 48 h then poured onto saturated NaHCO3. The aqueous layer was extracted with CH2Cl2 and the combined extracts were dried over Na2SO4, filtered, and concentrated. Purification by semi-prep HPLC provided the title compound (41 mg, 48%) as a yellow solid (TFA salt): mp 104-111° C. (dec.); ESI MS m/z 544 [C26H33N5O6S+H]+; HPLC>98%, tR=20.79 min.
Reaction SMILES: [CH3:1][C:2](=[N:7][OH:8])[C:3](=[O:6])[CH2:4][CH3:5].[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.C(O)(=O)C.Cl>C(OCC)C>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]2[O:6][C:3]([CH2:4][CH3:5])=[C:2]([CH3:1])[N+:7]=2[O-:8])=[CH:12][CH:11]=1
Reactant: CCC(=O)C(C)=NO
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCc1oc(-c2ccc(Cl)cc2)[n+]([O-])c1C

Procedure:
1.00 g (8.69 mmol) of 2,3-pentanedione 2-oxime and 1.34 g (9.55 mmol) of 4-chlorobenzaldehyde are initially charged in 2 ml (34.94 mmol) of glacial acetic acid. With ice-cooling of the reaction mixture, hydrogen chloride gas is then introduced for 30 min. 10 ml of diethyl ether are then added to the reaction mixture. A precipitate is formed, which is filtered off with suction and washed twice with in each case 2 ml of diethyl ether. The precipitate is resuspended in about 5 ml of water, and the suspension is made basic using ammonia. The suspension is then extracted four times with in each case 10 ml of dichloromethane. The combined organic phases are dried over magnesium sulfate and the solvent is removed on a rotary evaporator. The residue is used without further purification in the subsequent reaction.
Reaction SMILES: Cl.[CH2:2]([S:4]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[S:18][C:17]([NH:19][C:20](=[O:35])[N:21]([CH:28]3[CH2:33][CH2:32][CH:31]([CH3:34])[CH2:30][CH2:29]3)[CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:16][CH:15]=2)[CH2:9][CH2:8]1)(=[O:6])=[O:5])[CH3:3].[F:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1>>[CH2:2]([S:4]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[S:18][C:17]([NH:19][C:20](=[O:35])[N:21]([CH:22]3[CH2:27][CH2:26][N:25]([C:41](=[O:42])[C:40]4[CH:44]=[CH:45][C:37]([F:36])=[CH:38][CH:39]=4)[CH2:24][CH2:23]3)[CH:28]3[CH2:29][CH2:30][CH:31]([CH3:34])[CH2:32][CH2:33]3)=[N:16][CH:15]=2)[CH2:9][CH2:8]1)(=[O:5])=[O:6])[CH3:3]
Reactant: CCS(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCNCC3)C3CCC(C)CC3)s2)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Product: CCS(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCC(C)CC3)C3CCN(C(=O)c4ccc(F)cc4)CC3)s2)CC1
Yield: 86.1 %

Procedure:
Prepared as described in general procedure (N) using 3-[5-(4-ethanesulfonyl-piperazin-1-ylmethyl)-thiazol-2-yl]-1-(4-methyl-cyclohexyl)-1-piperidin-4-yl-urea hydrochloride (46 mg, 0.075 mmol), TEA (26 μL, 0.19 mmol) and 4-fluorobenzoyl chloride (10 μL, 0.083 mmol) and to afford 41 mg (86%) of the desired product after purification.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[CH:14][N:13]=1>O1CCCC1.C(OCC)(=O)C>[Cl:11][C:12]1[N:17]=[C:16]([S:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:3])=[CH:5][CH:6]=2)[CH:15]=[CH:14][N:13]=1
Reactant: Nc1ccc(S)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(Sc2ccnc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
To a suspension of sodium hydride (60% dispensed in mineral oil, 0.97 g, 24 mmol) in anhydrous tetrahydrofuran (80 mL), was added 4-aminobenzenethiol (2.77 g, 22 mmol) dissolved in tetrahydrofuran (20 mL) over 5 minutes. The mixture was stirred at room temperature for 30 minutes, to this was added a solution of 2,4-dichloropyrimidine (3.00 g, 20 mmol) dissolved in tetrahydrofuran (20 mL) over 5 minutes. The resulting mixture was stirred at room temperature for 64 hours, diluted with ethyl acetate (100 mL), washed with water and brine. After being dried (Na2SO4), the organic solution was concentrated in vacuo. The residue was flash chromatographed on silica gel using 5% of acetone in dichloromethane as eluant to give the product (3.60 g, 75%).