Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1(CCN2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)CCCCCC1.Cl.Cl.[N:35]1([CH2:42][CH2:43][C:44]2C=CC(N)=CC=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[N:35]1([CH2:42][CH2:43][C:44]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][CH:30]([CH3:31])[CH3:32])[CH:24]=[CH:23][CH:22]=4)=[O:18])=[CH:14][CH:15]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12
Reactant: Nc1ccc(CCN2CCCCCC2)cc1
Agent: Cl
Product: CC(C)COc1cccc2[nH]c(C(=O)Nc3ccc(CCN4CCCCCC4)cc3)cc12

Procedure:
This compound is synthesized analogously to Example 1 from 4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see Example 8) and amine 70.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]([C:5]1[C:17]([CH2:18][CH2:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:16]([OH:28])[C:8]2[N:9]=[C:10]([CH:13]3[CH2:15][CH2:14]3)[N:11]([CH3:12])[C:7]=2[CH:6]=1)=[O:4].[BH4-].[Na+].[Cl-].[NH4+].O>C(O)C>[CH3:29][N:2]([CH3:1])[C:3]([C:5]1[C:17]([CH2:18][CH2:19][CH:20]([OH:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:16]([OH:28])[C:8]2[N:9]=[C:10]([CH:13]3[CH2:15][CH2:14]3)[N:11]([CH3:12])[C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2c(nc(C3CC3)n2C)c(O)c1CCC(=O)c1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CN(C)C(=O)c1cc2c(nc(C3CC3)n2C)c(O)c1CCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
A solution of 1.5 g (4.0 mmol) 2-cyclopropyl-7-hydroxy-3-methyl-6-(3-oxo-3-phenyl-propyl)-3H-benzoimidazole-5-carboxylic acid dimethylamide in ethanol (22 ml) was treated with 283 mg (6.3 mmol) sodium borohydride and the reaction was stirred at room temperature for 3 h. A saturated ammonium chloride solution was added, the reaction was poured into water and extracted with dichloromethane (3×100 ml). The organic layers were dried over magnesium sulphate and concentrated in vacuo to afford 1.5 g (100%) of the title compound as a orange-brown solid. m.p. 92+-94° C.
Reaction SMILES: CC1C(N2CCN(C(C3C=CC(I)=CC=3)=O)CC2)=NC=C(C)C=1.C(C1CN(CC2C=CC(OC)=CC=2)C(=O)N1)(C)C.[CH3:42][C:43]1[C:44]([N:50]2[CH2:55][CH2:54][N:53]([C:56]([C:58]3[CH:63]=[CH:62][C:61]([N:64]4[CH:68]([CH:69]([CH3:71])[CH3:70])[CH2:67][N:66](CC5C=CC(OC)=CC=5)[C:65]4=[O:81])=[CH:60][CH:59]=3)=[O:57])[CH2:52][CH2:51]2)=[N:45][CH:46]=[C:47]([CH3:49])[CH:48]=1>>[CH3:42][C:43]1[C:44]([N:50]2[CH2:51][CH2:52][N:53]([C:56]([C:58]3[CH:59]=[CH:60][C:61]([N:64]4[CH:68]([CH:69]([CH3:70])[CH3:71])[CH2:67][NH:66][C:65]4=[O:81])=[CH:62][CH:63]=3)=[O:57])[CH2:54][CH2:55]2)=[N:45][CH:46]=[C:47]([CH3:49])[CH:48]=1
Reactant: COc1ccc(CN2CC(C(C)C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)cc3)C2=O)cc1
Agent: COc1ccc(CN2CC(C(C)C)NC2=O)cc1
Agent: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NCC4C(C)C)cc3)CC2)c(C)c1

Procedure:
Using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (253 mg) described in Preparation Example 113 and 4-isopropyl-1-(4-methoxybenzyl)imidazolidin-2-one (149 mg) described in Preparation Example 210 and by the reaction and treatment in the same manner as in Example 506, the title compound (145 mg) was obtained via 3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-4-isopropyl-1-(4-methoxybenzyl)imidazolidin-2-one.
Reaction SMILES: [CH:1]([N:3]([CH2:22][CH:23]1[NH:34][C:33]2[C:31](=[O:32])[NH:30][C:28]([NH2:29])=[N:27][C:26]=2[NH:25][CH2:24]1)[C:4]1[CH:21]=[CH:20][C:7]([C:8](=[O:19])[NH:9][C@H:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][C:13]([O-:15])=[O:14])=[CH:6][CH:5]=1)=[O:2].C([O-])=O.C1COCC1.P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.N(CCO)(CCO)CCO.C([O-])=O.[NH4+].[Mg+2].[Cl-].[Cl-].[Cl-].[K+].P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O>O.C1COCC1>[CH2:24]1[NH:25][C:26]2[NH:27][C:28]([NH2:29])=[N:30][C:31](=[O:32])[C:33]=2[NH:34][CH:23]1[CH2:22][N:3]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:9][C@H:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:19])=[CH:20][CH:21]=1)[CH:1]=[O:2]
Reactant: Nc1nc2c(c(=O)[nH]1)NC(CN(C=O)c1ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)O)cc1)CN2
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: O=C[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: OCCN(CCO)CCO
Solvent: O
Product: Nc1nc(=O)c2c([nH]1)NCC(CN(C=O)c1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)N2
Reaction time: 0.03 h

Procedure:
10-formyltetrahydrofolate-synthetase catalyzes the reaction, formate+THF+ATP→10-formyl-THF+ADP+Pi. A test tube containing 100 μL 1 M triethanolamine buffer (pH 7.5), 100 μL 1 M ammonium formate (pH 7.5), 100 μL 25 mM MgCl2, 100 μL 2 M KCl, 100 μL 10 mM THF, freshly made 100 μL 20 mM ATP, and 390 μL water was pre-incubated for 2 min at 30° C. A 10 μL aliquot of the extracted sample containing enzyme was added and incubated 15 min at 30° C. The reaction was terminated by adding 2 mL 0.36 N HCl. The 10-formyl-THF formed during the incubation period was converted to 5,10-methenyl-THF by the acid. The absorbency was measured at 350 nm against a water blank and the 5,10-methenyl-THF formed was determined by using an extinction coefficient of 24,900 M-1 cm-1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([CH:19]1[O:21][CH2:20]1)Cl>CC(C)=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:17][CH:19]2[CH2:20][O:21]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(O)cc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(OCC2CO2)cc1
Temperature: 25 °C
Yield: 83.1 %

Procedure:
4-Ethoxyphenol (0.25 g, 1.81 mmol), anhydrous potassium carbonate (0.50 g, 3.62 mmol) and epichlorohydrin (0.57 ml, 7.24 mmol) were added to acetone (4.52 ml) and the resulting heterogeneous solution was refluxed for 16 hrs. The mixture was cooled to room temperature, filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The resulting oil was dissolved in toluene (20 mL), washed sequentially with water (15 mL), 5% aqueous NaOH (20 mL) and water again (20 mL). The organic layer was dried with MgSO4 and concentrated under reduced pressure to yield 0.292 g (83%) of 2-((4-ethoxyphenoxy)methyl)oxirane as a white solid (mp=41° C.). 1H NMR (400 MHz, CDCl3) δ 6.91-6.77 (m, 4H), 4.17 (dd, J=11.0, 3.2, 1H), 3.98 (q, J=7.0, 2H), 3.91 (dd, J=11.0, 5.6, 1H), 3.34 (m, 1H), 2.90 (dd, J=4.9, 4.1, 1H), 2.75 (dd, J=5.0, 2.7, 1H), 1.39 (t, J=6.98, 3H). 13C NMR (75 MHz, CDCl3) δ 153.72, 152.78, 115.90, 115.90, 115.59, 115.59, 69.71, 64.18, 50.49, 44.98, 15.15. HRMS (m/z): [MNa]+ calc. for C11H14O3Na+, 217.08. found 217.0826.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]([O:14][CH3:15])=[O:13])([O-])=O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O.[Pd]>[NH2:1][C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cccn1Cc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccn1Cc1ccccc1N
Reaction time: 2 h

Procedure:
A mixture of 1117 g methyl 1-(2-nitrobenzyl)-pyrrole-2-carboxylate in 1117 mL of tetrahydrofuran, 458 g of potassium carbonate in 840 mL of water and 19 g of 5% palladium on carbon is stirred and heated to a temperature of 60°. The heat is removed and a solution of 1876 g of sodium hypophosphite hydrate in 3725 mL of water is added slowly over a period of one hour. The refluxing is controlled by the rate of the addition. When the addition is complete the mixture is refluxed, with stirring, for 2 hours. After stirring at room temperature for 5 hours, the reaction mixture is allowed to stand overnight. Methylene chloride (4 L) is added, the mixture is stirred for 3 hours and then filtered through filter-cel. The methylene chloride layer is separated and dried over magnesium sulfate. The magnesium sulfate is filtered off and the filtrate is concentrated to dryness to give a residue which is dried at 40°-50° and high vacuum to yield methyl 1-(2-aminobenzyl)-pyrrole-2-carboxylate, m.p. 95°-97°.
Reaction SMILES: [CH3:1][CH:2]([OH:9])[CH2:3][NH:4][CH2:5][CH:6]([OH:8])[CH3:7].[C:10](O)(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17]>>[CH3:1][CH:2]1[O:9][C:10]2([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[O:8][CH:6]([CH3:7])[CH2:5][N:4]2[CH2:3]1
Reactant: CC(C)CCCCCC(=O)O
Reactant: CC(O)CNCC(C)O
Product: CC(C)CCCCCC12OC(C)CN1CC(C)O2
Temperature: 180 °C
Reaction time: 3.5 h

Procedure:
To a 1 liter stirred reactor, equipped with a distillation column, condenser, and graduated receiver, the following constituents were added: 331.2 g of diisopropanol amine (DIPA) and 390.5 g (98%) of isononanoic acid. The contents were heated to 180° C. under a nitrogen blanket. After 3.5 hours, 43.4 g of water was collected overhead. The pressure was then slowly lowered to strip out unreacted DIPA. At a batch temperature of 183° C. and a pressure of 60 Pa, a cut consisting of 188 g of DIPA was removed. The batch temperature was then raised to 200° C. and the pressure dropped 333 Pa. During this period, a cut of 220 g of the amide acetal was recovered. The water of reaction passed through the condenser and was not captured with the amide acetal. This represents a 35% conversion of the isononanoic acid to amide acetal.
Reaction SMILES: [CH2:1]([Si:3]([C:8]#[CH:9])([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].C([Li])CCC.CN(C)P(=O)(N(C)C)N(C)C.Br[CH2:27][C@@H:28]([CH3:37])[CH2:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH2:8]([Si:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[C:1]#[C:2][CH2:27][C@@H:28]([CH3:37])[CH2:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1)[CH3:9]
Reactant: C[C@H](CBr)COC1CCCCO1
Reactant: C#C[Si](CC)(CC)CC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC[Si](C#CC[C@@H](C)COC1CCCCO1)(CC)CC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of triethylsilyl acetylene (6.25 g, 8 mL, 44.7 mmol) in anhydrous tetrahydrofuran (150 mL) was mixed with a 2.5 M solution of n-butyl lithium (19.6 mL, 49.2 mmol) in hexane at −70° C. in argon. After stirring for 15 min at this temperature hexamethyl phosphoric triamide (19.4 g, 18.8 mL, 108 mmol) was added and the mixture stirred a further 15 min. A solution of 2-((S)-3-bromo-2-methylpropoxy)tetrahydropyrane (10.6 g, 44.7 mmol) in anhydrous tetrahydrofuran (40 mL) was added in drops to this solution and this was the slowly heated to room temperature. After adding saturated ammonium chloride solution (40 mL), the mixture was concentrated to low volume in a vacuum, the residue taken up in water (150 mL) and extracted with cyclohexane/diethyl ether (1:1.3×100 mL). The combined organic phases were dried with sodium sulphate and concentrated to low volume in a vacuum. The raw product (11 g) was purified by flash chromatography (400 g, 20×7.5 cm) with ethyl acetate/cyclohexane (1:30).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>ClCCl.C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][O:14]1
Reactant: OCCCCCCCCCCCBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: BrCCCCCCCCCCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
50 g (0.199 mol) of 11-bromo-1-undecanol (Aldrich) was dissolved in 500 ml of dichloromethane, and the mixture was cooled to 0° C. 22.15 ml (0.242 mol) of dihydropyran were added dropwise over a period of two hours; the reaction was started by addition of a few crystals of p-toluenesulphonic acid at the beginning of the addition. After the addition was complete, the reaction mixture was stirred for 15 min and stopped by addition of 0.5 g of NaHCO3. After evaporation of the dichloromethane, the pale yellow syrup obtained was dissolved in ethyl acetate and purified by filtration through silica gel. Yield=65.3 g (98%).
Reaction SMILES: [CH3:1][C:2]([C:4]([CH3:6])=[CH2:5])=[CH2:3].[C:7]([O:15][CH3:16])(=[O:14])/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11]>C1(C)C=CC=CC=1>[CH3:3][C:2]1[CH2:1][C@@H:9]([C:10]([O:12][CH3:13])=[O:11])[C@H:8]([C:7]([O:15][CH3:16])=[O:14])[CH2:5][C:4]=1[CH3:6]
Reactant: COC(=O)/C=C/C(=O)OC
Reactant: C=C(C)C(=C)C
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CC(C)=C(C)C[C@H]1C(=O)OC

Procedure:
2,3-dimethylbutadiene (9.84 g, 0.12 mol) and dimethyl fumarate (14.4 g, 0.1 mol) were stirred together in toluene (40 ml) at 50° C. for 24 hr. The solvent was removed in vacuo and the solid residue recrystallised from diethyl ether, to give the title compound in 85%, yield. N.m.r: δH (90 MHz, CD3OD) 3.71 (s,6H), 2.55 (m,2H), 2.10 (m,4H), 1.74 ppm (s,6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:15]1[C:16]([F:27])=[C:17]2[C:21](=[CH:22][C:23]=1[F:24])[NH:20][CH:19]=[C:18]2[CH:25]=[O:26]>>[F:27][C:16]1[C:15]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=2)=[C:23]([F:24])[CH:22]=[C:21]2[C:17]=1[C:18]([CH:25]=[O:26])=[CH:19][NH:20]2
Reactant: O=Cc1c[nH]c2cc(F)c(Br)c(F)c12
Reactant: OCC1(c2ccc(Br)cc2)CCC1
Product: O=Cc1c[nH]c2cc(F)c(-c3ccc(C4(CO)CCC4)cc3)c(F)c12

Procedure:
[1-(4-bromophenyl)cyclobutyl]methanol, prepared as described in Example 72 (steps 1 and 2), is treated with 5-bromo-4,6-difluoro-1H-indole-3-carbaldehyde, prepared as described in Example 6 (steps 1-4), in a manner similar as described in Example 6 step 5 to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=O)=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C>[C:28]([O:27][C:25](=[O:26])[NH:24][C:20]1([C:17]2[CH:18]=[CH:19][C:14]([C:5]3[C:6]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)=[CH:7][C:2]4[NH:1][C:35](=[O:37])[CH2:34][CH2:33][NH:32][C:3]=4[N:4]=3)=[CH:15][CH:16]=2)[CH2:21][CH2:22][CH2:23]1)([CH3:30])([CH3:31])[CH3:29]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(NCCC(=O)O)c(N)cc3-c3ccccc3)cc2)CCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CCN4)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a solution of 3-((3-amino-6-(4-(1-((tert-butoxycarbonyl)amino)cyclobutyl)phenyl)-5-phenylpyridin-2-yl)amino)propanoic acid (100 mg, 0.20 mmol) in dry DMF (1 ml) was added EDC (153 mg, 0.80 mmol) and HOBT (122 mg, 0.796 mmol) under nitrogen. The resulting mixture was stirred overnight at room temperature. Water was added and the mixture was extracted with EtOAc (3×10 ml). The combined organic phases were dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 55% EtOAc in cyclohexane) to give the title compound (68 mg, 71%). 1H NMR (500 MHz, CDCl3): 8.38 (1H, br s), 7.94 (1H, br s), 7.72-7.12 (8H, m), 7.01-6.99 (2H, m), 5.00 (1H, s), 3.68-3.66 (2H, m), 2.82-2.80 (2H, m), 2.52-2.20 (4H, m), 2.00-1.95 (1H, m), 1.79-1.65 (1H, m), 1.40-1.10 (9H, br)
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[NH:13][CH:14]=[C:15]2[C:20](=[O:21])OC(C)(C)OC2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:29][O:28][C:27]1[CH:26]=[C:25]2[C:12](=[CH:11][C:10]=1[O:9][CH2:8][CH2:7][CH2:6][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[NH:13][CH:14]=[CH:15][C:20]2=[O:21]
Reactant: COc1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1OCCCN1CCCC1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cc2c(=O)cc[nH]c2cc1OCCCN1CCCC1
Yield: 27.6 %

Procedure:
After refluxing a solution of 5-((3-(3-pyrrolidin-1-ylpropoxy)-4-methoxyanilino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (4.9 g, 12 mmol) in phenyl ether (50 ml) for 1 minute, the mixture was poured into petroleum ether (500 ml). The solid was collected by filtration and purified by reverse phase chromatography on a Diaion (trade mark of Mitsubishi) HP20SS resin column eluting with water/methanol (100/0 increasing to 20/80). After removal of the solvent by evaporation, the purified product was azeotroped with a mixture of ethanol and toluene to give 6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)-1,4-dihydroquinolin-4-one (1 g, 27%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1.C(O)CCO.O[N:17]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]1=[O:23].C1(N(C2CCCCC2)C(N)=O)CCCCC1>O1CCOCC1>[C:18]([OH:23])(=[O:9])[CH2:19][CH2:20][C:21]([NH2:17])=[O:22].[NH2:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1O
Agent: NC(=O)N(C1CCCCC1)C1CCCCC1
Agent: Nc1cccc(B(O)O)c1
Solvent: OCCCO
Solvent: C1COCCO1
Product: NC(=O)CCC(=O)O

Procedure:
PBA-XX-CO2H(6.3 g, 0.018 moles) was suspended in dry dioxane (60 mL). 1,3-Propanediol (1.4 g, 0.018 moles) was added, and the mixture was gently heated until all solid dissolves (about 10 minutes). The solvent was removed by rotary evaporation to leave a pale yellow syrup, which was co-evaporated twice with dioxane (30 mL each). The residue was then dissolved in dioxane (225 mL) and N-hydroxysuccinimide (2.3 g, 0.20 moles) was added, followed by N,N-dicyclohexylcarbodiimide (4.1 g, 0.020 moles). The solution was stirred under an atmosphere of dry nitrogen for 6 hours at room temperature, during which time the white precipitate of N,N-dicyclohexylurea formed. The precipitate was filtered and washed with dioxane (50 mL). The combined filtrates were concentrated to about 30 mL. Dry diethyl ether (200 mL) was slowly added to the stirred concentrate, causing precipitation of a white solid. The mixture was chilled in an ice/water bath for 1 hour, then filtered. The solid was washed with dry ether (50 mL), and dried in vacuo. Yield: 8.0 g (91%); M.P. 111°-117° C. (open capillary, uncorrected). 1H NMR (300 MHz, DMSO-d6) δ 9.85 (singlet, 1H, ArNHCOR), 7.85 (singlet, 1H, ArH), 7.82 (triplet, J=5.7 Hz, 1H, CONHCH2), 7.64 (doublet, J=7.9 Hz, 1H, ArH), 7.29 (doublet, J=7.3 Hz, 1H, ArH), 7.22 (doublet of doublets, J=7.6 Hz, 1H, ArH), 4.07 (triplet, J=5.4 Hz, 4H, BOCH2CH2), 3.05-2.95 (multiplet, 2H, CONHCH2), 2.79 (singlet, 4H succinimidyl COCH2), 2.62 (triplet, J=7.3 Hz, 2H, CH2CO2.R), 2.50 (triplet, J=6.7 Hz, 2H, NHCOCH2), 2.36 (triplet, J=6.7 Hz, 2H, NHCOCH2, 1.50-1.41 (multiplet, 2H, NHCH2CH2), 1.97 (quintet, J=5.4 Hz 2H, BOCH2CH2), 1.61-1.51 (multiplet, 2H, CH2), 1.41-1.30 (multiplet, 4H, CH2). 13C NMR (75.5 MHz, DMSO-d6) δ 171.3, 170.6, 170.5, 169.2, 138.9, 128.1, 128.0, 124.3, 121.4, 61.5, 38.2, 31.7, 30.4, 30.1, 28.6, 26.8, 25.4, 23.9, 15.1. HPLC: Retention time of product, 18.2±0.1 minutes under the conditions described above.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH2:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)[CH2:14][CH3:15]>>[CH2:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1)[CH2:14][CH3:15]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Product: CCCc1ccc(S(=O)(=O)Nc2nc(CC(=O)OCC)cs2)cc1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-n-propylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (16.0 mg) with purity >90%. LCMS (pos) m/z 369.0.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1[CH:30]=[CH:29][C:6]([CH:7]([C:17]2[CH:25]=[CH:24][C:23]([N:26]([CH3:28])[CH3:27])=[CH:22][C:18]=2[C:19]([OH:21])=[O:20])[C:8]2[CH:13]=[CH:12][C:11]([N:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>O>[CH3:16][N:14]([CH3:15])[C:11]1[CH:10]=[CH:9][C:8]([C:7]2([C:6]3[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:31])=[CH:30][CH:29]=3)[C:17]3[C:18](=[CH:22][C:23]([N:26]([CH3:28])[CH3:27])=[CH:24][CH:25]=3)[C:19](=[O:21])[O:20]2)=[CH:13][CH:12]=1
Reactant: CN(C)c1ccc(C(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3)OC(=O)c3cc(N(C)C)ccc32)cc1
Temperature: 92.5 °C
Reaction time: 9 h
Yield: 93.9 %

Procedure:
To a 500 ml reaction vessel, 21.5 g of 2-[4,4'-bis(dimethylamino) benzhydryl]-5-dimethylaminobenzoic acid having a purity of 97.0% was charged and 250 g of water was added. To the dispersion thus obtained, 21.5 g of activated carbon; SHIRASAGI-C (manufactured by Takeda Chemical Ind. Co.) and 2.0 g of a 49% aqueous NaOH solution were added and stirred at 90 to 95° C. Through the reaction system thus obtained air was blown for 9 hours at a rate of 400 ml/min. After finishing the reaction, the reaction mass was filtered and the obtained cake was slurried in water, and completely dissolved by adding 19.5 g of a 36% aqueous HCl solution. Thereafter, the activated carbon was filtered. The filtrate was neutralized to pH7.0 with a 49% aqueous NaOH solution. The precipitated crystals were filtered, washed and dried to obtain 20.1 g of 3,3-bis(4-dimethylaminophenyl)-6-dimethylaminophthalide. The yield was 95.4%. Formation of by-product in the reaction was 1.5%. Selectivity of reaction was 98.4%.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8]([Cl:12])[N:9]=[C:10](Cl)[C:5]=2[S:4][CH:3]=1.[C:13]1([C@H:19]([NH2:21])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Br:1][C:2]1[C:6]2[N:7]=[C:8]([Cl:12])[N:9]=[C:10]([NH:21][C@@H:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:20])[C:5]=2[S:4][CH:3]=1
Reactant: Clc1nc(Cl)c2scc(Br)c2n1
Reactant: C[C@@H](N)c1ccccc1
Product: C[C@@H](Nc1nc(Cl)nc2c(Br)csc12)c1ccccc1
Yield: 82.8 %

Procedure:
The target compound (540 mg, 83% yield) was prepared in the same manner as Step 1 of Example 44 using 7-bromo-2,4-dichlorothieno[3,2-d]pyrimidine (500 mg, 1.77 mmol) and (R)-1-phenylethanamine (0.68 mL, 5.31 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[N:9](CC2C=CC=CC=2)[C:10](=[O:24])[CH2:11][C@@:12]([CH3:23])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=2)[N:13]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC1N(CC2C=CC=CC=2)C(=O)C[C@](C2C=CC=C(N)C=2)(C)N=1)(C)(C)C>C(OCC)(=O)C.CO>[C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[NH:9][C:10](=[O:24])[CH2:11][C@:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=2)([CH3:23])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cccc([N+](=O)[O-])c2)CC(=O)N1Cc1ccccc1
Agent: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cccc(N)c2)CC(=O)N1Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cccc(N)c2)CC(=O)N1
Yield: 15.7 %

Procedure:
Starting from [(S)-1-benzyl-4-methyl-4-(3-nitro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (0.98 mmole), the crude material was chromatographed on silica using n-heptane/ethyl acetate (5:2) to give a first fraction containing [(S)-4-(3-amino-phenyl)-1-benzyl-4-methyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (224 mg) as a colourless foam. MS (ESI): m/z=409.4 [ M+H]+ The second fraction was obtained using ethyl acetate/MeOH (9:1) to give [(S)-4-(3-amino-phenyl)-4-methyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (49 mg) as a colourless oil. MS (ESI): m/z=319.3 [ M+H]+.