Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:18])[CH:10]=[CH:11][C:12]=3[OH:17])[C:7](=[O:19])[C:6]=2[C:5]([OH:20])=[CH:4][CH:3]=1.[NH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][OH:27].CN(C)CCN(C)C>>[OH:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22][NH:21][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:18])[CH:10]=[CH:11][C:12]=3[OH:17])[C:7](=[O:19])[C:6]=2[C:5]([OH:20])=[CH:4][CH:3]=1
Reactant: NCCNCCO
Reactant: O=C1c2c(O)ccc(O)c2C(=O)c2c(O)ccc(O)c21
Agent: CN(C)CCN(C)C
Product: O=C1c2c(O)ccc(O)c2C(=O)c2c(NCCNCCO)ccc(O)c21
Reaction time: 60 h

Procedure:
A suspension of 5.44 g. of 1,4,5,8-tetrahydroxy-9,10-anthracenedione [P. G. Marshall, J.C.S., 254 (1937)] in a solution of 2.08 g. of 2-(2-aminoethylamino)ethanol in 50 ml. of N,N,N',N'-tetramethylethylenediamine is stirred and heated under reflux for 17 hours, then allowed to cool. The solid is collected by filtration and washed 3 times with N,N,N',N'-tetramethylethylenediamine, then twice with hexane. The first filtrate and the diamine washings are combined and the solution is allowed to stand for 60 hours as a solid separates. This solid is collected and washed as above to give 0.524 g. of a dark blue solid. This solid is purified by dry column chromatography on deactivated (i.e., air-equilibrated) silica gel by the procedure of B. Loev and M. M. Goodman [Chem. and Ind., 2026 (1967)], eluting with chloroform-methanol (3:1) and monitoring the eluate fractions by thin layer chromatography on silica gel with the same solvent mixture. The cuts which showed only the slower of two purple spots were pooled and evaporated to give 0.42 g. of the product of the Example as a dark blue solid, mp. 196°-198° C.
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[SH:10].[C:11]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:11][S:10][C:2]1[NH:3][C:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:1]=1
Reactant: O=C([O-])[O-]
Reactant: Sc1nc2c([nH]1)CCCC2
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CSc1nc2c([nH]1)CCCC2
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 4,5,6,7-tetrahydro-1H-benzimidazole-2-thiol (500 mg) in acetone (5 mL) were added K2CO3 (1344 mg) and MeI (0.223 mL) at room temperature. After stirring for 1 h, the mixture was quenched with water, and extracted with ethyl acetate, and the extract was washed with brine and dried over magnesium sulfate. The residue was purified by column chromatography (silica gel, eluted with 40%-90% EtOAc in hexane) to give 2-(methylsulfanyl)-4,5,6,7-tetrahydro-1H-benzimidazole (545 mg) as a white solid.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[C:6]12(C(=O)C3C[CH:11]1[CH2:12][CH2:13]3)[CH2:10][CH2:9][CH2:8][CH2:7]2>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:4]=[C:3]1[C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[CH:11]2[CH2:1][CH:2]1[CH2:13][CH2:12]2
Reactant: [Li]CCCC
Reactant: O=C1C2CCC(C2)C12CCCC2
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1C2CCC(C2)C12CCCC2
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
To a suspension of (methyl)triphenylphosphonium bromide (17.6 g, 48.4 mmol) in THF (100 mL) at −78° C. was added n-butyllithium (18.1 mL of 2.5 M solution in THF, 45 mmol) and the mixture was stirred 30 min. To this mixture was added spiro[bicyclo[2.2.1]heptane-2,1′-cyclopentan]-3-one (5.30 g, 32.3 mmol), and the reaction was stirred at ambient temperature for 18 h. Hexanes (200 mL) were added, and the mixture was filtered. The filtrate was concentrated, and the residue was purified on an 80 g silica gel column, eluting with hexanes, to obtain 3-methylenespiro[bicyclo[2.2.1]heptane-2,1′-cyclopentane] (4.80 g, 91.7%) as oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21]OS(CC3C=CC(C)=CC=3)(=O)=O)[CH2:16]2)[CH2:11][CH2:10]1)#[N:2].[N-:34]=[N+:35]=[N-:36].[Na+]>>[N:34]([CH2:21][CH:17]1[CH2:18][CH2:19][CH2:20][N:15]([CH:12]2[CH2:11][CH2:10][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])[CH2:14][CH2:13]2)[CH2:16]1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(CS(=O)(=O)OCC2CCCN(C3CCN(c4ccccc4C#N)CC3)C2)cc1
Agent: [Na+]
Product: N#Cc1ccccc1N1CCC(N2CCCC(CN=[N+]=[N-])C2)CC1

Procedure:
The title compound was prepared from 23 (1.37 g, 3.0 mmol) and sodium azide (0.4 g, 6.0 mmol) according to the procedure described in 12 to give the title compound.
Reaction SMILES: NC1SC=C(C(=O)C(N[C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15](CSC2C(C4C=CC(O)=C(O)C=4)=CN=C(C4C=CC=CC=4)N=2)=[C:16]3[C:20]([OH:22])=[O:21])=O)N=1.Cl.FC1C2OC(C3C=CC=CC=3)(C3C=CC=CC=3)OC=2C=CC=1CON>CC(N(C)C)=O>[O:19]=[C:18]1[N:17]2[CH:12]([S:13][CH2:14][CH:15]=[C:16]2[C:20]([OH:22])=[O:21])[CH2:11]1
Reactant: Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4nc(-c5ccccc5)ncc4-c4ccc(O)c(O)c4)CS[C@H]23)cs1
Agent: Cl
Agent: NOCc1ccc2c(c1F)OC(c1ccccc1)(c1ccccc1)O2
Solvent: CC(=O)N(C)C
Product: O=C(O)C1=CCSC2CC(=O)N12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[(5-(3,4-dihydroxyphenyl)-2-phenyl-4-pyrimidinyl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (66 mg) (0.1 mmol) and 47 mg (0.13 mmol) of O-[(4-fluoro-2,2-diphenyl-1,3-benzodioxol-5-yl)methyl]hydroxylamine hydrochloride are dissolved in 1 ml of absolute of dimethylacetamide. After stirring at room temperature for 20 hours the mixture is concentrated in a high vacuum at room temperature and the residue is treated with 0.45 ml of ethanol and 3 ml of water. The precipitated product is filtered off and washed with water. After drying in a high vacuum at room temperature there are obtained 98 mg of (6R,7R)-7-[(Z)-2(2-amino-4-thiazolyl)-2-[[(4-fluoro-2,2-diphenyl-1,3-benzodioxol-5-yl)methoxy]imino]acetamido]-3-[[5-(3,4-dihydroxyphenyl)-2-phenyl-4-pyrimidinyl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C@@:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:8][CH:7]=1)([OH:5])[CH3:4].FC(F)(F)[C@](C1C=CC(N2CCN(S(C3SC=CC=3)(=O)=O)C[C@H]2CC2C=CC(F)=CC=2)=CC=1)(O)C.FC(F)(F)[C@](C1C=CC(N2CCN(S(C3SC=CC=3)(=O)=O)C[C@@H]2CC2C=CC(F)=CC=2)=CC=1)(O)C.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[F:35][C:2]([F:1])([F:34])[C@@:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@H:13]2[CH2:26][C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)=[CH:8][CH:7]=1)([OH:5])[CH3:4]
Reactant: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2Cc2ccc(F)cc2)cc1)C(F)(F)F
Agent: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2Cc2ccc(F)cc2)cc1)C(F)(F)F
Agent: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@H]2Cc2ccc(F)cc2)cc1)C(F)(F)F
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@H]2Cc2ccc(F)cc2)cc1)C(F)(F)F

Procedure:
(2R)-1,1,1-trifluoro-2-(4-((2S)-2-(4-fluorobenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2R)-2-(4-fluorobenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-(4-fluorobenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1H NMR (400 MHz, CD3OD) δ 7.93-7.81 (m, 1H), 7.61 (d, J=2.5 Hz, 1H), 7.56-7.43 (m, 2H), 7.30-7.15 (m, 3H), 7.08-6.91 (m, 4H), 4.11 (br. s., 1H), 3.84 (d, J=11.0 Hz, 1H), 3.60 (d, J=11.3 Hz, 1H), 3.55-3.46 (m, 1H), 3.40-3.35 (m, 1H), 3.21-2.96 (m, 1H), 2.72-2.47 (m, 3H), 1.70 (s, 3H). m/z (ESI, +ve ion) 529.0 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=0.895 μM; GK-GKRP EC50 (LC MS/MS)=1.25 μM.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:47]1[C:42](=[CH:43][C:44]([Cl:57])=[C:45]([CH2:48][C:49]3[CH:54]=[CH:53][C:52]([CH2:55][CH3:56])=[CH:51][CH:50]=3)[CH:46]=1)[CH:41]([OH:58])[CH2:40]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:61]I>C1COCC1>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:47]1[C:42](=[CH:43][C:44]([Cl:57])=[C:45]([CH2:48][C:49]3[CH:54]=[CH:53][C:52]([CH2:55][CH3:56])=[CH:51][CH:50]=3)[CH:46]=1)[CH:41]([O:58][CH3:61])[CH2:40]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)C(O)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc3c(cc2Cl)C(OC)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Reaction time: 3 h
Yield: 84.9 %

Procedure:
To a solution of (1S,3′R,4′S,5′R,6′R)-3′,4′,5′-tris(benzyloxy)-6′-(benzyloxymethyl)-5-chloro-6-(4-ethylbenzyl)-2,3,3′,4′,5′,6′-hexahydrospiro[indene-1,2′-pyran]-3-ol (26 mg, 0.032 mmol) in dry THF (0.8 mL) was added NaH (1.5 mg, 0.036 mmol, 60%) and CH3I (3.1 μL, 0.049 mmol) at room temperature. The reaction mixture was stirred for 3 h and quenched by addition of 5 mL of water when TLC showed the reaction was complete. Ethyl acetate (10 mL) was added to the mixture and the organic layer was separated. The aqueous layer was extracted 2× with ethyl acetate (10 mL). The combined organic layers were washed 1× with 10% HCl (10 mL), 2× with water (10 mL), 2× with brine (10 mL) prior to drying over anhydrous Na2SO4. Concentration under reduced pressure and purification of the crude product by prepared TLC provided 22 mg of the pure product.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:35][N:36]=[C:37]=[O:38]>ClCCl>[C:1]1([N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:37](=[O:38])[NH:36][CH3:35])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)OCCCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Reaction time: 15 h

Procedure:
100 mg of 4-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]butan-1-ol was dissolved in 4 ml of dichloromethane, mixed with 0.1 ml of triethylamine and 20 mg of methyl isocyanate and stirred for 15 hours. Another 0.1 ml of triethylamine and 20 mg of methyl isocyanate were added, allowed to stir for 20 hours, and then concentrated by evaporation in a vacuum. The residue was purified using chromatography on silica gel.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24]CC)=[O:23])=[CH:16][CH:15]=1)=[C:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:7]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:6]2.[OH-].[Na+]>C1COCC1.CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:18][CH:19]=1)=[C:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:7]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:6]2
Reactant: CCCCCc1cc2cc(OC)ccc2c(Oc2ccc(/C=C/C(=O)OCC)cc2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCc1cc2cc(OC)ccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccccc1
Yield: 92.8 %

Procedure:
Ethyl ester (115) (0.48 g, 0.97 mmol) was saponified with 1 N NaOH in THF and EtOH to give 0.42 g (93%) of the title compound (116) as a white solid. 1H NMR (400 MHz, CDCl3): δ 0.78 (t, J=6.8 Hz, 3H), 1.10-1.25 (m, 4H), 1.40-1.55 (m, 2H), 2.53 (t, J=7.8 Hz, 2H), 3.93 (s, 3H), 6.22 (d, J=16.0 Hz, 1H), 6.58 (d, J=8.8 Hz, 2H), 7.04 (dd, J1=9.1 Hz, J2=2.4 Hz, 1H), 7.08-7.14 (m, 2H), 7.16 (d, J=2.4 Hz, 1H), 7.19-7.30 (m, 5H), 7.58 (s, 1H), 7.62 (d, J=15.9 Hz, 1H), 7.69 (d, J=9.2 Hz, 1H). LCMS (ESI): m/z 467 (M+H)+, m/z 465 (M−H)−.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7].[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1>CO.[Pd]>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]2[NH:13][C:12]3[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([NH2:8])=[O:7])[C:4]=3[N:3]=2)=[CH:17][CH:16]=1
Reactant: NC(=O)c1cccc(N)c1N
Reactant: O=Cc1ccc(Br)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NC(=O)c1cccc2[nH]c(-c3ccc(Br)cc3)nc12
Yield: 17 %

Procedure:
To a mixture of 2,3-diaminobenzamide dihydrochloride (synthesized as described in U.S. Pat. No. 6,737,421, column 11, EXAMPLE 2, step (e), 5 g, 22.3 mmol) and 4-bromobenzaldehyde (4.13 g, 22.3 mmol) in methanol (200 mL) was added 10% Pd/C (1.3 g). The mixture was refluxed overnight, then cooled and filtered though a pad of celite. The filtrate was concentrated under vacuum and purified by chromatography on a silica gel column with 0-10% methanol/dichloromethane to provide the title compound (1.2 g, 17%). MS (ESI) m/e 317 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[C:12]([OH:14])=O.ClC(N(C)C)=C(C)C.FC(F)(F)C(O)=O.[NH2:30][CH2:31][C:32]([N:34]1[CH2:38][CH2:37][CH2:36][C@H:35]1[C:39]#[N:40])=[O:33].C(N(CC)CC)C>C(Cl)Cl.C1COCC1>[C:39]([C@@H:35]1[CH2:36][CH2:37][CH2:38][N:34]1[C:32](=[O:33])[CH2:31][NH:30][C:12]([C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[CH:7][CH:6]=1)=[O:14])#[N:40]
Reactant: N#C[C@@H]1CCCN1C(=O)CN
Reactant: O=C(O)c1ccnc2ccc(F)cc12
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: N#C[C@@H]1CCCN1C(=O)CNC(=O)c1ccnc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-Fluoroquinoline-4-carboxylic acid (17) (0.054 g, 0.282 mmol) was dissolved in a 1:1 mixture of dry DCM and THF (5 mL). 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.052 mL, 0.395 mmol) was added to this solution, and the mixture was stirred for 30 minutes at rt. Then, a solution of (S)-1-(2-aminoacetyl)pyrrolidine-2-carbonitrile 2,2,2-trifluoroacetate (0.075 g, 0.282 mmol) prepared as described in general procedure B and triethylamine (80 μL, 0.571 mmol) in 3 mL dry THF was added, and the mixture was stirred for 2 h. After evaporation of volatiles, the residue was dissolved in DCM (15 mL), washed with saturated sodium bicarbonate and brine. The organic layer was dried over sodium sulfate, filtrated and purified using flash chromatography (95-5 ethyl acetate-methanol) to yield white crystals
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([CH2:22][N:23]3[CH2:33][CH2:32][C:26]4([O:31][CH2:30][CH2:29][CH2:28][O:27]4)[CH2:25][CH2:24]3)[N:18]2[CH3:21])=[C:14]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[N:13]=1>>[CH3:21][N:18]1[C:17]([CH2:22][N:23]2[CH2:24][CH2:25][C:26]3([O:27][CH2:28][CH2:29][CH2:30][O:31]3)[CH2:32][CH2:33]2)=[N:16][C:15]2[C:19]1=[N:20][C:12]([N:3]1[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=[C:2]1[CH3:1])=[N:13][C:14]=2[N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CCC3(CC2)OCCCO3)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC4(CC3)OCCCO4)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-methylbenzimidazole and 9-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)-1,5-dioxa-9-azaspiro[5.5]undecane were reacted to give 400. LCMS m/z: 519.2 (MH+)
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[N:5]=[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:28][Cl:29].CCCCCC.C([Li])CCC.[Cl-].[NH4+]>O1CCCC1>[Cl:29][CH2:28][C:3](=[O:2])[C@@H:4]([N:5]=[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: ClCBr
Reactant: COC(=O)[C@H](Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(CCl)[C@H](Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 99.7 %

Procedure:
N-(diphenylmethylene)-L-phenylalanine methyl ester (3.35 g) and bromochloromethane (0.83 ml) were added to dehydrated tetrahydrofuran (97 ml), and the mixture was cooled to −78° C. Then, a 1.53 M n-butyllithium hexane solution (8.3 ml) was added thereto. The mixture was stirred for 35 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction solution to terminate the reaction. The resulting reaction solution was extracted twice with ethyl acetate at room temperature. The ethyl acetate layer was then washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. After magnesium sulfate was removed, the ethyl acetate solution was concentrated to obtain desired (3S)-1-chloro-3-(diphenylmethylene)amino-4-phenyl-2-butanone (3.52 g) in a yield of 99.7%.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][N:19]1[CH:23]=[C:22]([C:2]2[N:7]=[N:6][C:5]([N:8]3[CH2:17][CH2:16][C:11]4([O:15][CH2:14][CH2:13][O:12]4)[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH:21]=[N:20]1
Reactant: Clc1ccc(N2CCC3(CC2)OCCO3)nn1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1cc(-c2ccc(N3CCC4(CC3)OCCO4)nn2)cn1
Temperature: 100 °C

Procedure:
In a two-neck flask was placed 8-(6-chloropyridazin-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane, prepared as in STEP 1 above (3.07 g, 12 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (3.24 g, 15.6 mmol), K2CO3 (6.62 g, 48 mmol), and Pd(PPh3)4 (693 mg, 0.6 mmol). The resulting mixture was degassed and refilled with N2 (3 times). 1,4-Dioxane/H2O (15 mL/5 mL) was added and the resulting mixture was heated at 100° C. for 4 h. The resulting mixture was then poured into EtOAc/H2O (100 mL/100 mL). The organic layer was washed with brine (100 mL), dried (Na2SO4), and filtered. The solvent was removed by roto-evaporator and the resulting residue purified by column using EtOAc as the eluent to yield 8-(6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane.
Reaction SMILES: C(OCC([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)C(=C)C.[CH2:16]([O:20]C1C=CC(N)=CC=1)[C:17](=[CH2:19])[CH3:18]>>[CH2:16]([O:20][C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:9])[C:17](=[CH2:18])[CH3:19]
Reactant: C=C(C)COc1ccc(N)cc1
Reactant: C=C(C)COCC(=O)Nc1ccccc1
Product: C=C(C)COc1ccccc1N

Procedure:
The starting material was ortho-methallyloxyacetamidobenzene, which was obtained under the same conditions as those described in Example 4, paragraph (4.1), for paramethallyloxyacetamidobenzene.
Reaction SMILES: Br[C:2]1[C:3]([CH3:17])=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([NH:8][C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])=[N:6][CH:7]=1.C(N(CC)CC)C.C(O)=O>[Pd].C1(C)C=CC=CC=1>[CH:11]1([C:9]([NH:8][C:5]2[C:4]([N+:14]([O-:16])=[O:15])=[C:3]([CH3:17])[CH:2]=[CH:7][N:6]=2)=[O:10])[CH2:12][CH2:13]1
Reactant: Cc1c(Br)cnc(NC(=O)C2CC2)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: O=CO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccnc(NC(=O)C2CC2)c1[N+](=O)[O-]
Yield: 72.3 %

Procedure:
Toluene (60 ml) was added to 3.0 g (10.0 mmol) of 5-bromo-2-cyclopropanecarboxamido-4-methyl-3-nitropyridine, 10% Pd-C (100 mg) and 2.9 g (28.6 mmol) of triethylamine, followed by stirring and heating under reflux. 1.9 g (41.3 mmol) of formic acid was dropwise added to this solution, followed by stirring for 5 hours. The reaction liquid was brought to room temperature and filtered to remove the catalyst. The filtrate was subjected to vacuum concentration. Chloroform (100 ml) and water (100 ml) were added to the residue and the obtained mixture was caused liquid--liquid separation. The aqueous phase was further extracted with chloroform (50 ml) once. The organic phases were combined, dried over anhydrous magnesium sulfate and subjected to vacuum concentration. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 1.6 g of the title compound (yield 72%).
Reaction SMILES: II.[Br-].[C:4]1([CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[O:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(O)=O.[Na+]>C(OCC)C.BrCCC=C>[C:13]1([CH:10]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:11]([OH:12])[CH2:6][CH2:5][CH:4]=[CH2:9])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=CC(c1ccccc1)c1ccccc1
Agent: C=CCCBr
Agent: II
Agent: O=C([O-])O
Solvent: CCOCC
Product: C=CCCC(O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 165.3 %

Procedure:
A dry three-neck, round-bottom flask fitted with a reflux condensor, air-balance drop funnel and nitrogen inlet was charged with Mg (0.11 g, 4.44 mmol) and a crystal of I2. The flask was warmed (heat gun) to volatilize the I2 under vacuum, and then was allowed to cool. Dry ethyl ether (10 ml) was added next followed by introduction of catalytic neat 4-bromo-1-butene (0.02 g). The reaction was initiated by brief warming and then the rest of total amount of bromide (0.4 g, 2.96 mmol) in dry ethyl ether (5 ml) was added dropwise over 5 minutes. The mixture was refluxed for 30 minutes and then was allowed to reach 0° C. Into the stirred Grignard reagent solution was added dropwise a solution of diphenylacetaldehyde 1 (0.64 g, 3.26 mmol) in dry ethyl ether (5 ml), and the reaction mixture was stirred for an additional 3.5 hr at room temperature. Saturated aqueous NaHCO3 was added to the reaction mixture at 0° C., the organic phase was separated and the aqueous phase was extracted with ethyl ether (3×20 ml). The combined organic phases were washed with brine and water, then dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and flash chromatography of the crude residue (SiO2, hexane/Ethyl Acetate 9:1) gave 1,1-diphenyl-hex-5-en-2-ol 8 (0.68 g, 91%) as a liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14])=[CH:4][CH:3]=1.[C:23]1([N:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1.C(OCC)(=O)C>[C:23]1([N:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:30](=[O:31])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:4][CH:3]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: COC(=O)CCCC=C(c1ccc(N)cc1)c1cccnc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(O)CCCC=C(c1ccc(NC(=O)N(c2ccccc2)c2ccccc2)cc1)c1cccnc1

Procedure:
A mixture of 2.4 g of methyl 6-(4-aminophenyl)-6-(3-pyridyl)-hex-5-enoate and 2.1 g of N,N-diphenyl-carbamoylchloride is stirred in 25 ml of pyridine for 18 hours at ambient temperature. The solvent is eliminated and the residue is taken up in ethyl acetate. The organic phase is washed with water, dried and evaporated down. The residue is saponified in a mixture of 20 ml of ethanol and 6 ml of 4N sodium hydroxide solution for 30 minutes at 50° C. The reaction solution is diluted with water and extracted with ethyl acetate. Then the aqueous phase is neutralised by the addition of citric acid, the precipitate formed is suction filtered and recrystallised from ethyl acetate/isopropanol.