Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[Li]CCCC.[Cl:14][C:15]1[CH:26]=[CH:25][C:18]([C:19](N(OC)C)=[O:20])=[CH:17][N:16]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]([C:18]2[CH:17]=[N:16][C:15]([Cl:14])=[CH:26][CH:25]=2)=[O:20])=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Reactant: Clc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1)c1ccc(Cl)nc1
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a solution of 4-chlorobromobenzene (33.88 g, 177 mmol) in THF (200 mL), a solution of BuLi (118 mL, 142 mmol, 1.2 M solution in hexane) was added at −78° C. The mixture was stirred for 1 h and a solution of compound A (23.6 g, 118 mmol) in THF (100 mL) was added to it dropwise. The mixture was stirred for additional 1 h, quenched with saturated NH4Cl solution and extracted with ethyl acetate (300 mL). The organic layer was dried (Na2SO4), filtered and evaporated. The crude product was purified using column chromatography to obtain 23.4 g (79%) of compound B as light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])/[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].[CH3:10][N:11]([CH3:15])[CH2:12][CH2:13][NH2:14]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:9])[CH2:4][C@@H:5]([C:6]([OH:8])=[O:7])[NH:14][CH2:13][CH2:12][N:11]([CH3:15])[CH3:10]
Reactant: COC(=O)/C=C\C(=O)O
Reactant: CN(C)CCN
Solvent: CCN(CC)CC
Product: COC(=O)C[C@H](NCCN(C)C)C(=O)O
Yield: 33.2 %

Procedure:
28.6 g (0.22 mol) of maleic acid-monomethyl ester, 40 ml of triethylamine and 17.6 g (0.20 mol) of 2-dimethylaminoethylamine are reacted in a manner analogous to that described in Example 1. Further processing according to Example 1 yields 14.5 g (33.2% of theory) of a crystalline aspartic acid derivative, which melts at 164° to 166°.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([C:7](=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][N:6]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][NH2:25])=[CH:18][CH:17]=1>O.C(O)(C)(C)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH2:24][NH:25][C:2]2[N:1]=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:4]([OH:3])=[CH:5][N:6]=2)=[CH:20][CH:21]=1
Reactant: Nc1ncc(C(=O)c2ccccc2)o1
Reactant: NCCCc1ccc(Cl)cc1
Solvent: O
Solvent: CC(C)(C)O
Product: Oc1cnc(NCCCc2ccc(Cl)cc2)nc1-c1ccccc1
Yield: 0 %

Procedure:
2-Amino-5-benzoyloxazole (3.0 g, 16 mmol) was combined with p-chlorophenylpropylamine (2.7 g, 16 mmol) in 15 ml of water and t-butanol (2:1) and heated under reflux in nitrogen for 16 hours. The solvents were removed in a vacuum, and the residue was treated with hot acetonitrile and filtered. After concentration in vacuum, the filtrate was chromatographed on silica gel using hexane and ethyl acetate (1:1) as eluent to give 0.24 mg (4.4%) of the title compound as an oil. NMR (CDCl3): 1.8-2.0 (m, 2H), 2.4-2.7 (m, 2H), 3.1-3.4 (m, 2H), 5.0 (b s, 1H), 7.0-7.5 (m, 7H), 7.8 (s, 1H), 7.9-8.0 (m, 2H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37]O)[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][CH2:37][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[CH2:29][CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Reactant: CCc1ccccc1CO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1ccccc1COc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(=O)OC

Procedure:
In a similar manner as described for example B31, 845.5 mg of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate, 412 mg of (2-ethylphenyl)methanol, 1.06 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 928 mg of di-tert-butyl azodicarboxylate in 25 ml anhydrous dichloromethane yield the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]2([CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:15]([OH:17])=[O:16])[CH:12]=3)[CH2:7]2)[C:5](=[O:18])[NH:4][C:3]1=[O:19].OS(O)(=O)=O.[CH3:25]O>>[CH3:1][N:2]1[C@@:6]2([CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:15]([O:17][CH3:25])=[O:16])[CH:12]=3)[CH2:7]2)[C:5](=[O:18])[NH:4][C:3]1=[O:19]
Reactant: CO
Reactant: CN1C(=O)NC(=O)C12Cc1ccc(C(=O)O)cc1C2
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2c(c1)C[C@@]1(C2)C(=O)NC(=O)N1C

Procedure:
To a stirred solution of 3-methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidine-4,2′-indene]-5′-carboxylic acid (4.50 g, 17.3 mmol) in MeOH (500 mL) was added conc. H2SO4 (1 mL, 18 mmol) and the resulting mixture was heated at reflux for 24 h. The reaction mixture was concentrated in vacuo to a volume of about 150 mL and then partitioned between saturated aqueous sodium bicarbonate (200 mL) and CHCl3 (500 mL). The aqueous layer was extracted further with CHCl3 (250 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to dryness in vacuo to give the racemic product. Separation of the enantiomers was achieved by SFC on a ChiralPak AD-H column, eluting with CO2:i-PrOH-70:30, to give methyl (4S)-3-methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidine-4,2′-indene]-5′-carboxylate, the title compound, as the first major peak, and methyl (4R)-3-methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidine-4,2′-indene]-5′-carboxylate as the second major peak. MS: m/z=274.9 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[N:12]=[C:11]([CH3:13])[C:10]([C:14]([OH:16])=O)=[CH:9][N:8]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([NH2:28])[CH:23]=[CH:22]2.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C>[O:18]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([NH:28][C:14]([C:10]1[C:11]([CH3:13])=[N:12][C:7]([C:2]3[N:1]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:8][CH:9]=1)=[O:16])[CH:23]=[CH:22]2)[CH3:17]
Reactant: Cc1nc(-c2ncccn2)ncc1C(=O)O
Reactant: COc1ccc2c(ccn2N)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2NC(=O)c2cnc(-c3ncccn3)nc2C)c1
Temperature: 50 °C
Yield: 116.1 %

Procedure:
A solution of 2-pyrimidin-2-yl-4-methyl-pyrimidine-5-carboxylic acid (496 mg, 2.30 mmol) and 5-methoxy-indol-1-ylamine (0.98 mmol) in anhydrous DMF (10 mL) is stirred at 50° C. for 30 min. DMTMM (555 mg, 2.01 mmol) is added and stirred at 50° C. for an hour. DMF is evaporated off. The residue is mixed with water (40 mL) and stirred at rt for 20 minutes. The solid is collected by filtration, washed with water (3×5 mL) and dried in vacuum to afford 2-pyrimidin-2-yl-4-methyl-pyrimidine-5-carboxylic acid (5-methoxyl-indol-1-yl)-amide (410 mg) as a solid. MS: 361 (M+H); 1H NMR (300 MHz, CD3OD): δ 2.93(s, 3H), 4.84(s, 3H), 7.04(t, H), 6.50(d, H), 6.92(d, H), 7.14(s, H), 7.26-7.37(m, 2H), 7.72 (t, H), 9.09 (d, 2H), 9.27(s, H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:4][C:5]([CH3:15])=[C:6]([CH3:14])[C:7]=1[NH:8][CH2:9][C:10]([CH3:13])([OH:12])[CH3:11].[CH2:23]([O:25][CH2:26][C:27](Cl)=O)[CH3:24]>N1C=CC=CC=1>[CH2:23]([O:25][CH2:26][C:27]1[N:8]([CH2:9][C:10]([CH3:11])([OH:12])[CH3:13])[C:7]2[C:6]([CH3:14])=[C:5]([CH3:15])[N:4]=[C:3]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:2]=2[N:1]=1)[CH3:24]
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCC(C)(C)O)c1C
Reactant: CCOCC(=O)Cl
Solvent: c1ccncc1
Product: CCOCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CC(C)(C)O
Temperature: 5 °C

Procedure:
To the product from Part F (1-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-ylamino]-2-methylpropan-2-ol was added 10 ml of pyridine. Ethoxyacetyl chloride (3.014 g) was added dropwise to the resulting mixture. The resulting solution was brought to reflux for about 3 days with an intervening day of cooling at about 5° C. The solvent was removed under reduced pressure, and the resulting product dissolved in ethyl acetate containing sodium bicarbonate. The resulting mixture was extracted with water. The resulting organic layer was dried with magnesium sulfate, the solvent was removed under reduced pressure, and the product was cooled to about 5° C. The resulting solid was recrystallized from ethyl acetate. The supernatant was concentrated under reduced pressure to the point of crystallization. This was repeated, resulting in a total of three fractions of crystals in the amounts of 1.500 g, 2.370 g, and 1.527 g, respectively.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH:10](O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:13](=[O:26])[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1.[NH:27]1[C:36]2[C:31](=[CH:32][C:33]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:34][CH:35]=2)[CH2:30][CH2:29][CH2:28]1>>[CH3:1][CH:2]1[CH2:11][CH:10]([N:27]2[C:36]3[C:31](=[CH:32][C:33]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:34][CH:35]=3)[CH2:30][CH2:29][CH2:28]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:13](=[O:26])[C:14]1[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=1
Reactant: CCOC(=O)CCCCOc1ccc2c(c1)CCCN2
Reactant: COc1cc(C(=O)N2c3ccccc3C(O)CC2C)cc(OC)c1OC
Product: CCOC(=O)CCCCOc1ccc2c(c1)CCCN2C1CC(C)N(C(=O)c2cc(OC)c(OC)c(OC)c2)c2ccccc21
Yield: 36.3 %

Procedure:
Starting with 2-methyl-1-(3,4,5-trimethoxybenzoyl)-1,2,3,4-tetrahydro-4-quinolinol (1.3 g, 3.6 mmol) prepared in Reference Example 22 and ethyl 5-[(1,2,3,4-tetrahydro-6-quinolinyl)oxy]pentanoate (2.30 g, 8.28 mmol), the same procedure as shown in Example 1 was repeated to give the titled compound (806 mg, yield: 40%) as a colorless oil. (cis:trans=1:1.3)
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[Cl:34][CH2:35][CH2:36][O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=O)=[CH:40][CH:39]=1>>[Cl:34][CH2:35][CH2:36][O:37][C:38]1[CH:46]=[CH:45][C:41]([CH2:42][C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])[N:6]([C@@H:11]3[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]3[OH:13])[CH:5]=2)=[CH:40][CH:39]=1
Reactant: O=C(Cl)c1ccc(OCCCl)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(F)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: OC[C@H]1O[C@@H](n2cc(Cc3ccc(OCCCl)cc3)c3c(F)cccc32)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
4-Fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 2-(3) and 4-(2-chloroethyloxy)benzoyl chloride were treated in a manner similar to Example 3 to give the titled compound as a colorless powder. APCI-Mass m/Z 483/485 (M+NH4). 1H-NMR (DMSO-d6) δ 3.20-3.50 (m, 4H), 3.63-3.70 (m, 2H), 3.91 (t, J=5.1 Hz, 2H), 4.02 (s, 2H), 4.20 (t, J=5.0 Hz, 2H), 4.53 (t, J=5.5 Hz, 1H), 5.09 (d, J=5.3 Hz, 1H), 5.16 (d, J=5.0 Hz, 1H), 5.20 (d, J=5.8 Hz, 1H), 5.37 (d, J=9.2 Hz, 1H), 6.74 (dd, J=11.2, 7.9 Hz, 1H), 6.86 (d, J=8.7 Hz, 2H), 7.07 (m, 1H), 7.18 (d, J=8.5 Hz, 2H), 7.21 (s, 1H), 7.36 (d, J=8.3 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[C:3]#[N:4].C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[CH3:5][C:2]([NH:1][S:15]([CH3:14])(=[O:17])=[O:16])([CH3:6])[C:3]#[N:4]
Reactant: CC(C)(N)C#N
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C#N)NS(C)(=O)=O
Reaction time: 0.25 h
Yield: 54.9 %

Procedure:
To a stirred mixture of 8.4 g (0.1 mole) 2-amino-2-methylpropionitrile (the product of Example 1), and 10.1 g (0.1 mole) triethylamine in 125 ml methylene chloride, 11.5 g (0.1 mole) methanesulfonyl chloride in 25 ml methylene chloride were added dropwise over about 20 minutes in an exothermic addition reaction. The reaction mixture was stirred 15 minutes, then washed once with 100 ml water, washed twice with 50 ml water, dried over magnesium sulfate, and stripped to give 8.9 g of a brown oil.
Reaction SMILES: [CH:1]([C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=O.[C:37]([NH:40][NH2:41])(=[O:39])[CH3:38].Cl>O1CCCC1.O>[C:37]([NH:40][N:41]=[CH:1][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])(=[O:39])[CH3:38]
Reactant: CC(=O)NN
Reactant: O=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)NN=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Yield: 87.6 %

Procedure:
In a procedure similar to that described in Example I-3, diphenylmethyl 3-formyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate (104 mg) and acetylhydrazine (30 mg) are left to react in a mixture of tetrahydrofuran (8 ml) and water (1.51 ml) in the presence of hydrochloric acid (2 equivalents) at room temperature overnight to give diphenylmethyl 3-(2-acetylhydrazono)methyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate (101 mg). m.p. 130-138° C. Yield: 88%. IR: νmaxNujol 3250, 1782, 1715, 1670, 1597, 1535 cm-1. UV: λmaxEtOH 327nm(ε=24000). NMR: δCDCl 3 (60MHz) 220s3H, 3.72ABq(39;18Hz)2H, 3.82s2H, 5.00d(5Hz)1H, 5.87dd (9;5Hz)1H, 6.77-7.58ml5H, 8.05s1H, 9.65s1H. [α]D23 -258° (c= 0.493,CHCl3).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:12].[CH:29]1(Br)[CH2:31][CH2:30]1>>[CH2:31]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:12])[CH:29]=[CH2:30]
Reactant: BrC1CC1
Reactant: O=C(c1cc([N+](=O)[O-])ccc1O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Product: C=CCOc1ccc([N+](=O)[O-])cc1C(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1

Procedure:
The title compound was prepared in analogy to example 62 from (2-Hydroxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (compound 2.1) and cyclopropyl bromide. MS (m/e): 436.5 (MH+, 100%)
Reaction SMILES: CO.[ClH:3].Cl.Cl.[CH3:6][O:7][C:8]1[CH:32]=[CH:31][C:11]([CH2:12][CH2:13][NH:14][C:15]([NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[NH:19])=[NH:16])=[CH:10][CH:9]=1.[CH3:33][C:34]([CH3:36])=O>>[ClH:3].[CH3:33][C:34]1([CH3:36])[N:16]=[C:15]([NH:14][CH2:13][CH2:12][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:32][CH:31]=2)[NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[N:19]1
Reactant: CCCCCCCCCCNC(=N)NC(=N)NCCc1ccc(OC)cc1
Reactant: CC(C)=O
Agent: Cl
Solvent: CO
Product: CCCCCCCCCCNC1=NC(C)(C)N=C(NCCc2ccc(OC)cc2)N1

Procedure:
125 ml of methanol, 80 ml of acetone and 0.2 ml of concentrated hydrochloric acid were added to 2.0 g (4.5 mmol) of N1-(4-methoxyphenethyl)-N5-decyl-biguanide dihydrochloride. The mixture was refluxed for 24 hours, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution with a mixture of chloroform/methanol/acetic acid (8:0.6:0.6)), and dissolved in 70% aqueous acetonitrile. The solvent was distilled off under reduced pressure, followed by sufficient drying under reduced pressure to obtain 2.1 g of a colorless resinous solid.
Reaction SMILES: [CH:1]1([C:5](=O)[CH2:6][C:7]([O:9]C)=O)[CH2:4][CH2:3][CH2:2]1.[CH3:12][C:13]([CH3:18])([CH3:17])[C:14]([NH2:16])=[NH:15].C[O-].[Na+]>CO>[C:13]([C:14]1[N:16]=[C:7]([OH:9])[CH:6]=[C:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)[N:15]=1)([CH3:18])([CH3:17])[CH3:12]
Reactant: COC(=O)CC(=O)C1CCC1
Reactant: CC(C)(C)C(=N)N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1nc(O)cc(C2CCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
A mixture of methyl 3-cyclobutyl-3-oxo-propanoate (4.3 g, 27.53 mmol) and 2,2-dimethylpropanamidine (2.3 g, 22.10 mmol) was stirred in dry MeOH (50 mL) and NaOMe (5.0 g, 92 mmol) was added in portions at 10° C. The suspension was stirred at room temperature overnight. The reaction mixture was concentrated to roughly half of the volume and filtered. The filtrate was extracted with water and DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was stirred with acetone and the precipitate collected, dried under vacuum to give the title compound (3.15 g, 15.27 mmol, 66%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[F:22]>>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[F:22])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Cc1ccc(Br)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Yield: 40 %

Procedure:
Title compound was prepared according to the procedure described in example G from N-Boc-piperazine and 4-bromo-3-fluorotoluene (40% yield, yellow oil, MS (m/e): 295.2 (M+H+, 100%).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].[O:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[Li])[CH3:18]>O1CCCC1>[NH2:15][C:7]1[C:6]([C:4]([C:24]2[CH:23]=[C:22]([F:25])[CH:21]=[CH:20][C:19]=2[O:17][CH3:18])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: [Li]c1cc(F)ccc1OC
Solvent: C1CCOC1
Product: CCSc1ncc(C(=O)c2cc(F)ccc2OC)c(N)n1
Temperature: -78 °C

Procedure:
A solution of 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methylamide (400 mg, 1.65 mmol, Example 1) was dissolved in anhydrous tetrahydrofuran (6 mL) and cooled to −78° C. A solution of the freshly prepared 2-methoxyl-5-fluorophenyl lithium (˜5 equiv, prepared following the same procedure as described in Step A of Example 2) was added over 10–30 minutes and the orange colored reaction mixture was stirred at −78 to 0° C. for 1–3 hours until the complete consumption of the starting material. The resulting mixture was quenched with aqueous ammonium chloride solution, extracted with ethyl acetate (3×20 mL), washed with brine (2×10 mL), dried over sodium sulfate and evaporated in vacuo. The residue was purified on silica gel with 80/20→60/40 of hexane/ethyl acetate to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone as a white solid (277 mg). MS (M+H)+, 308.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.S(Cl)(Cl)=O.C(Cl)(Cl)(Cl)Cl.[CH2:17]([OH:19])[CH3:18]>>[C:4]([O:19][CH2:17][CH3:18])(=[O:5])/[CH:3]=[CH:2]/[C:1]([OH:6])=[O:7]
Reactant: O=C1C=CC(=O)O1
Reactant: CCO
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C/C(=O)O

Procedure:
Maleic anhydride (100.0 g, 1.02 mole) was dissolved in anhydrous ethanol (60 ml, excess) by heating the mixture in an erlenmeyer flask on a steam bath. Thionyl chloride (1.0 ml) was added using a syringe and the mixture heated with stirring for ten minutes. To the turbid mixture was added carbon tetrachloride (100 ml) and the liquid quickly filtered through a Buchner funnel having a coarse glass frit. The solid was discarded. The filtrate was allowed to cool during which the time the ethyl hydrogen fumarate product (92 g, 63%) crystallized.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:40])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=[O:24])[CH:21]=2)=[C:12]([CH2:26][N:27]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:28][CH3:29])[CH:11]=1)[C:2]1C=CC=CC=1.S(=O)(=O)(O)O.[CH3:46][CH2:47]O>>[CH2:1]([O:8][C:9](=[O:40])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][CH:19]=[C:20]([CH2:22][C:23]([O:25][CH2:46][CH3:47])=[O:24])[CH:21]=2)=[C:12]([CH2:26][N:27]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:28][CH3:29])[CH:11]=1)[CH3:2]
Reactant: CCN(Cc1cc(C(=O)OCc2ccccc2)ccc1-c1cncc(CC(=O)O)c1)C(=O)OCc1ccccc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cncc(-c2ccc(C(=O)OCC)cc2CN(CC)C(=O)OCc2ccccc2)c1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
3-[(N-Benzyloxycarbonyl-N-ethyl-amino)-methyl]-4-(5-carboxymethyl-pyridin-3-yl)-benzoic acid benzyl ester (1.74 g, 3.2 mmol) in EtOH (200 mL) was treated with sulfuric acid (2 mL), and the reaction was stirred at 95° C. for 2 hours. The mixture was cooled to room temperature and concentrated, and the residue was partitioned between EtOAc and H2O. The solution was extracted with EtOAc, and the combined organic layers were washed with 1N aqueous HCl and concentrated. The crude material was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give 3-[(N-benzyloxycarbonyl-N-ethyl-amino)-methyl]-4-(5-ethoxycarbonylmethyl-pyridin-3-yl)-benzoic acid ethyl ester.
Reaction SMILES: O[CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1>C(O)C.[Pd].C(O)(=O)C>[CH3:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: OCc1ccc2cc[nH]c2c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc2cc[nH]c2c1
Reaction time: 20 h

Procedure:
6-hydroxymethyl indole (6.135 g, 41.69 mmol) was dissolved in ethanol (70 ml). 10% Palladium on charcoal (0.610 g) was suspended in acetic acid (70 ml) and added to the ethanol (70 ml) solution. The mixture was placed on the high pressure hydrogenator at 60 psi. After 20 hours, the mixture was filtered through Celite and the resulting solution concentrated in vacuo. The mixture was purified by flash chromatography using chloroform as solvent to yield a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1.[C@@H:17]1([NH2:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:27][C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)=[CH:11][CH:10]=1
Reactant: COc1ccccc1-c1ccc(C=O)cc1
Reactant: N[C@H]1CCCc2ccccc21
Product: COc1ccccc1-c1ccc(CN[C@H]2CCCc3ccccc32)cc1

Procedure:
2′-Methoxy[1,1′-biphenyl]-4-carbaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@H:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].I[CH2:29][CH3:30]>O1CCCC1>[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@:22]([CH2:29][CH3:30])([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)[C@H]1C=C[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@]1(C(=O)OC)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 8 h

Procedure:
To a 1.00 M soluition of lithium hexamethyldisilazide in tetrahydrofuran (61.5 mL, 61.5 mmol) was added a solution of methyl (1R,4S)-4-[(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylate (6.71 g, 27.8 mmol) in tetrahydrofuran (10.0 mL) at −78° C. over 10 min. The resulted light brown solution was stirred at −78° C. for 30 min before iodoethane (2.67 mL, 33.4 mmol) was added in one portion. The mixture was then kept at −25° C. overnight. The reaction was quenched with aqueous NH4Cl. The organic layer was separated and the aqueous layer was further extracted with ether three times. The combined organic layers were then washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash column chromatography to yield the desired product as a 7:1 cis/trans mixture (4.83 g, 65%). MS calculated for C14H23NO4: (M+H) 170.2; found 170.1 (M+H-Boc).