Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[CH:6]([N:19]1[CH2:22][C:21](=[O:23])[CH2:20]1)([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.C([O-])(O)=O.[Na+]>C1COCC1>[CH:6]([N:19]1[CH2:22][C:21]([CH:1]2[CH2:3][CH2:2]2)([OH:23])[CH2:20]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Br[Mg]C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: OC1(C2CC2)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
To a 0.5 M cyclopropylmagnesium bromide in THF (4.72 mL, 2.36 mmol), 1-benzhydryl-azetidin-3-one (200 mg, 0.843 mmol) in THF (3 mL) was added dropwise at −78° C. The reaction mixture was stirred at −78° C. for 2 hr. Then it was added saturated NaHCO3 solution and extracted with ether (3×20 mL). The organic layers were combined, dried (MgSO4) and concentrated to give a light yellow oil. The crude product was purified by Prep. HPLC column using CH3CN—H2O-ammonium acetate solvent system. Fractions were collected and concentrated. Then it was extracted with ethyl acetate. The organic layers were combined, dried (MgSO4) and concentrated to give a colorless oil as Grignard reaction product. (63 mg, 27% yield).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[H-].[Na+].Cl[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=1>CN(C=O)C.O>[NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][O:4][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)(N)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(N)COc1ccc(C#N)cn1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-2-methyl-1-propanol (0.5 ml, 5.60 mmol), in DMF (20 mL) was added NaH 60% (0.67 g, 16.80 mmol) and then 6-chloronicotinonitrile (2.03 g, 11.22 mmol). The mixture heated to 70° C. for 2 hours and then stirred at room temperature overnight. The reaction mixture was taken up in H2O and extracted with EtOAc. The organic phase was washed with water (3×), dried over Na2SO4 and concentrated under reduced pressure to provide the titled compound as a pale yellow solid. MS (DCI) m/z 235 (M+H)+.
Reaction SMILES: [Mg].II.[Cl:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][C:6]=1[Cl:12].[O:13]=[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]([N:24]([CH3:28])[C:25](=[O:27])[CH3:26])[CH2:16][CH2:15]1.S(=O)(=O)(O)O>C(OCC)C.O1CCCC1>[Cl:12][C:6]1[CH:7]=[C:8]([C:14]2([OH:13])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]([N:24]([CH3:28])[C:25](=[O:27])[CH3:26])[CH2:16][CH2:15]2)[CH:9]=[CH:10][C:5]=1[Cl:4]
Reactant: CC(=O)N(C)C1CCC(=O)c2ccccc21
Reactant: Clc1ccc(I)cc1Cl
Agent: II
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)N(C)C1CCC(O)(c2ccc(Cl)c(Cl)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.5 %

Procedure:
Magnesium turnings (2.04 g) and a crystal of iodine were stirred in dry diethyl ether (24 ml) as a solution of 1,2-dichloro-4-iodobenzene (23.17 g) in dry diethyl ether (60 ml) was added over 15 minutes. The mixture was stirred for 15 minutes and refluxed for a further 15 minutes to complete formation of the Grignard reagent. The mixture was cooled to room temperature and a solution of N-(1,2,3,4-tetrahydro-4-keto-1-naphthyl)-N-methylacetamide (12.3 g) in dry tetrahydrofuran (134 ml ) was added over 5 mutes. The mixture was stirred for 4 hours at room temperature, heated under reflux for 30 minutes, cooled and treated with 4N aqueous sulphuric acid (30 ml). The lower aqueous phase was separated and discarded, dichloromethane was added, and the solution was washed with water (2×25 ml). The organic layer was evaporated under vacuum to give a mixture of racemic cis-(1R*, 4S*)- and trans-(1R*, 4R*)-isomers (ratio 87:13 respectively by nmr spectroscopy techniques) as a light brown gum (24.5 g) which was stirred with diethyl ether (150 ml) for 1 hour, then filtered, to give the title compound as cream crystals (10.2 g, 49.5%), m.p. 146°-148° C.; Rf 0.41 (silica; chloroform, methanol; 95:5). Found: C,62.96; H,5.24; N,4.00 C19H19Cl2NO2 requires C,62.65; H,5.26; N 3.85%. GLC assay on a 2.1 m×4 mm 3% OV-17 column, temperature programmed from 100° to 275° C. at 10° C./minute, showed the product to be 96% pure (retention time 41.5 minutes) containing 3% recovered ketone.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([N+:18]([O-])=O)=[C:12]([CH:17]=2)[C:13]([O:15][CH3:16])=[O:14])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl-].[NH4+]>[Fe].C(O)C.O>[NH2:18][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cc(CN2CCOCC2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(CN2CCOCC2)ccc1N

Procedure:
Methyl 5-(morpholin-4-ylmethyl)-2-nitrobenzoate was allowed to undergo a reaction with iron and ammonium chloride in an ethanol-water mixed solvent to obtain methyl 2-amino-5-(morpholin-4-ylmethyl)benzoate.
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43]([O:45]C)=O)[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:47][CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[CH:27]=1.CCN(C(C)C)C(C)C.CN>CN(C=O)C>[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43]([NH:2][CH3:1])=[O:45])[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:47][CH:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)[CH:27]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
HATU (0.052 g, 0.138 mmol) was added into a mixture of methyl 4-(4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (0.050 g, 0.125 mmol) and Hünig's base (22 μL, 0.125 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. Methylamine (2M in THF, 1.0 mL, 2.0 mmol) was added and the coolant removed. The reaction mixture was stirred at ambient temperature overnight. The product was triturated with MeOH to yield a white solid (0.024 g, 46% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]=[C:14]=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[ClH:16].Cl.[Cl:18][C:19]1[CH:36]=[CH:35][C:22]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][SH:34])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:18].[ClH:16].[CH3:12][O:11][C:7]1[CH:6]=[C:5]([NH:13][C:14](=[SH:34][CH2:33][CH2:32][CH2:31][N:28]2[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][C:22]3[CH:21]=[CH:20][C:19]([Cl:18])=[CH:36][CH:35]=3)[CH2:26][CH2:27]2)[OH:15])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: SCCCN1CCN(CCc2ccc(Cl)cc2)CC1
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(NC(O)=[SH]CCCN2CCN(CCc3ccc(Cl)cc3)CC2)cc(OC)c1OC
Yield: 46.4 %

Procedure:
The procedure described in Example 2 was followed, using 2.5 g of 3,4,5-trimethoxyphenyl isocyanate, 4.4 g of 3-[4-(4-chlorophenethyl)piperazin-1-yl]propanethiol dihydrochloride, 1.2 g of triethylamine and 50 ml of methylene chloride, to give 1.6 g (23% of theory) of N-(3,4,5-trimethoxyphenyl)-S-{3-[4-(4-chlorophenethyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 239°-241° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:12]=[CH:13]OCC)[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].[CH3:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)C>>[OH:1][C:2]1[CH:3]=[C:4]([N:12]=[CH:13][N:18]([CH3:17])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOC=Nc1ccc(C(=O)OC)c(O)c1
Reactant: CNc1ccccc1
Solvent: CCO
Product: COC(=O)c1ccc(N=CN(C)c2ccccc2)cc1O

Procedure:
A mixture of ethyl N-(3-hydroxy-4-methoxycarbonylphenyl)formimidate (6.6 g, 0.03 mol) and N-methylaniline (3.2 g, 0.03 mol) were heated at 150° until 1.7 mol of ethanol had been collected by distillation. The pale yellow oil was flash distilled to yield the desired product, bp≈200° C. (0.1 mm). ##STR16##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.N[C@H](C([NH:19][CH:20]1[C:26](=[O:27])[N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24]2[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=2[N:22]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:21]1=[O:44])=O)C>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:19][C@H:20]([C:26]([C:20]2([NH2:19])[C:21](=[O:44])[N:22]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:23]3[CH:37]=[CH:36][CH:35]=[CH:34][C:24]=3[N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:26]2=[O:27])=[O:27])[CH3:21])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](N)C(=O)NC1C(=O)N(c2ccccc2)c2ccccc2N(c2ccccc2)C1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: Cl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)C(=O)N(c2ccccc2)c2ccccc2N(c2ccccc2)C1=O

Procedure:
Following General Procedure I above using 3,5-difluorophenylacetic acid (Lancaster) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-W), the title compound was prepared as a white solid (melting point=139-141° C.). Purification was by flash chromatography eluting with CH2Cl2/EtOAc (1:1). Rf=0.46 (CH2Cl2/EtOAc, 1:1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:24](Cl)(=[O:27])[CH2:25][CH3:26]>>[C:24]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:27])[CH2:25][CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1ccc2[nH]cc(C3CCNCC3)c2n1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.005 mL (0.062 mMol) propionyl chloride, the title compound was prepared.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH:11]2[C:15]3=[CH:16][CH:17]=[N:18][C:19]4[CH:20]=[CH:21][C:22](=[O:23])[N:13]([C:14]=43)[CH2:12]2)[CH2:6][CH2:5]1.[S:24]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25]1>>[ClH:1].[S:24]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:3][CH:4]3[CH2:9][CH2:8][N:7]([CH2:10][CH:11]4[C:15]5=[CH:16][CH:17]=[N:18][C:19]6[CH:20]=[CH:21][C:22](=[O:23])[N:13]([C:14]=65)[CH2:12]4)[CH2:6][CH2:5]3)[N:29]=[CH:28][C:27]=2[O:26][CH2:25]1
Reactant: NC1CCN(CC2Cn3c(=O)ccc4nccc2c43)CC1
Reactant: O=Cc1cc2c(cn1)OCS2
Agent: Cl
Product: O=c1ccc2nccc3c2n1CC3CN1CCC(NCc2cc3c(cn2)OCS3)CC1

Procedure:
The free base of the title compound was synthesised from 4-[(4-amino-1-piperidinyl)methyl]-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one dihydrochloride salt and [1,3]oxathiolo[5,4-c]pyridine-6-carbaldehyde (for a synthesis see WO2004058144, Example 61) according to the general method of Example 2(h).
Reaction SMILES: [C:1]([C:4]1[C:5]([N:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:8]=1[CH3:9])(=[O:3])[CH3:2].[CH2:24](I)[CH3:25]>>[C:1]([C:4]1[C:5]([N:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:24][CH3:25])[C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: CCI
Reactant: CC(=O)c1c(C)[nH]c(-c2ccccc2)c1N=Cc1ccccc1
Product: CCn1c(C)c(C(C)=O)c(N=Cc2ccccc2)c1-c1ccccc1

Procedure:
By procedure (a) of Example 49 and starting from the compound of Example 46 and ethyl iodide, the 4-acetyl-3-benzylideneamino-1-ethyl-5-methyl-2-phenylpyrrole is obtained, m.p. 139°-141° C. (from isopropanol/water). This compound is hydrolyzed as in procedure (b) of Example 49. Overall yield of the title compound: 54%, m.p. 107°-108° C. (from ethanol).
Reaction SMILES: [I-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:13]2[CH:18]=[CH:17][N+:16]([CH2:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11].[BH4-].[Na+]>CO.CCOC(C)=O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH:14]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: CCC[n+]1ccc(-c2ccc([N+](=O)[O-])c(OC)c2)cc1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCN1CC=C(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To 4-[3-(methyloxy)-4-nitrophenyl]-1-propylpyridinium iodide (5.7 g, 14.24 mmol) in 75 mL of MeOH at 0° C. was added, NaBH4 (1.62 g, 42.73 mmol) over 1 h. The mixture was allowed to come to rt over 2 h. The solvent was reduced to approximately 20 mL and then diluted with EtOAc, washed with conc. NaHCO3, dried (Na2SO4), filtered, rotovaped down, and purified by flash chromatography to give the title compound of step C (3.33 g, 12.05 mmol, 85%). 1H NMR (400 MHz, CDCl3) δ ppm 7.84 (d, J=8.42 Hz, 1H), 7.02 (s, 1H), 6.99-7.02 (m, 1H), 6.19 (ddd, J=3.43, 1.92, 1.79 Hz, 1H), 3.95 (s, 3H), 3.20 (q, J=2.81 Hz, 2H), 2.72 (t, J=5.68 Hz, 2H), 2.54-2.60 (m, 2H), 2.41-2.48 (m, 2H), 1.54-1.64 (m, 2H), 0.94 (t, J=7.42 Hz, 3H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:33])[C:12]2[O:18][C:17]3[C:19]([Cl:29])=[CH:20][C:21]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:22][C:16]=3[CH2:15][S:14](=[O:31])(=[O:30])[C:13]=2[CH:32]=1)=[O:8].N1C=CC=CC=1>ClCCl>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:33])[C:12]2[O:18][C:17]3[C:19]([Cl:29])=[CH:20][C:21]([N:23]4[CH2:24][CH2:25][N:26]([C:1](=[O:3])[CH3:2])[CH2:27][CH2:28]4)=[CH:22][C:16]=3[CH2:15][S:14](=[O:30])(=[O:31])[C:13]=2[CH:32]=1)=[O:8]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCNCC3)cc(Cl)c1O2
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(C(C)=O)CC3)cc(Cl)c1O2
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
Acetyl chloride (0.15 mL, 2.06 mmol) was added to a solution of 4-chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester (free base of example 16, 0.3 g, 0.68 mmol) in dichloromethane (15 mL) and stirred at 20° C., for 10 min. To this, pyridine (0.33 mL, 4.12 mmol) was added and the mixture was stirred further for 18 h. The solvent was removed from the mixture and water (15 mL) was added. The pH of the reaction mixture was adjusted to 3 using aqueous hydrochloric acid (10%). The solid obtained was filtered and the crude obtained was purified by column chromatography (silica gel, 2% methanol in chloroform) to obtain the title compound. Yield: 0.3 g, (91%); 1H NMR (DMSO-d6, 300 MHz): δ 2.02 (s, 3H, CH3), 2.63 (s, 3H, CH3), 3.15 (s, 2H, CH2), 3.17 (s, 2H, CH2), 3.55 (s, 4H, 2CH2), 3.85, (s, 3H, OCH3), 5.16 (s, 2H, CH2), 7.09 (d, 1H, Ar), 7.15 (d, 1H, Ar), 8.08 (t, 1H, Ar), 8.15 (t, 1H, Ar); MS: m/e (ES+) 479 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[C:10]2[C:5]([C:6]([CH2:17][CH2:18][CH3:19])=[CH:7][C:8](=[O:16])[O:9]2)=[C:4]2[O:20][C:21]([CH3:25])([CH3:24])[CH:22]=[CH:23][C:3]=12.C(=O)([O-])[O-].[K+].[K+].[C:32](OCCBr)(=[O:34])[CH3:33]>CN(C=O)C>[OH:34][CH2:32][CH2:33][O:1][C:2]1[C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[C:10]2[C:5]([C:6]([CH2:17][CH2:18][CH3:19])=[CH:7][C:8](=[O:16])[O:9]2)=[C:4]2[O:20][C:21]([CH3:25])([CH3:24])[CH:22]=[CH:23][C:3]=12
Reactant: CCCc1cc(=O)oc2c(C(=O)CC)c(O)c3c(c12)OC(C)(C)C=C3
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1cc(=O)oc2c(C(=O)CC)c(OCCO)c3c(c12)OC(C)(C)C=C3
Temperature: 25 °C
Reaction time: 48 h
Yield: 31.8 %

Procedure:
To a solution of 5-hydroxy-2,2-dimethyl-6-propionyl-10-propyl-2H-pyrano[2,3-f]chromen-8-one (30) (3.40 g, 10 mmol, 1.0 eq) in DMF (60 mL) was added potassium carbonate (13.8 g 100 mmol, 10.0 eq) followed by 2-bromoethyl acetate (5 g, 30 mmol, 3.0 eq). The reaction mixture was stirred for 2 days at ambient temperature, which was partitioned between water (600 mL) and ethyl acetate (300 ml). The organic layer was washed with an additional portion of water (600 mL), dried and concentrated. The solid residue was re-dissolved in methanol (200 mL) followed by addition of 2 N aqueous sodium hydroxide (20 mL). The mixture was stirred for 2 h at room temperature, pH adjusted to 6.0 with concentrated hydrochloric acid and concentrated under vacuum. The residue was partitioned between water (200 mL) and ethyl acetate (200 mL). The organic layer was separated, washed successively with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The solid residue was crystallized from cyclohexane/ethanol 80/20 and re-crystallized from methanol/water 95/5, affording 1.23 g of 31e (32% yield). 1H NMR (CDCl3): 1.05 (t, J=7.5 Hz, 3H), 1.21 (t, J=7.5 Hz, 3H), 1.52 (s, 6H), 1.67 (m, 2H), 2.92 (m, 4H), 3.29 (t, J=6.5 Hz, 1H), 3.81 (m, 2H), 4.13 (m, 2H), 5.66 (d, J=10.0 Hz, 1H), 6.03 (s, 1H), 6.54 (J=10.0 Hz, 1H); 13C NMR (CDCl3): 7.99, 13.89, 23.04, 27.60, 38.50, 38.54, 62.01, 78.08, 78.41, 106.17, 110.77, 112.63, 116.92, 117.04, 128.47, 152.27, 153.12, 154.78, 157.39, 159.38, 203.60; IR: 1708 cm−1; MS (ACPI+): 387 (M+1); Anal. Calcd. for C22H26O6: C 68.38, H 6.78; Found: C 68.21, H 6.90.
Reaction SMILES: II.[Br-:3].COC(=O)[C@@H]1CCCN1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH4+].[Cl-]>C1COCC1.CCOCC>[Br:3][C:13]1[CH:18]=[CH:17][C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:15][CH:14]=1
Reactant: [Br-]
Reactant: COC(=O)[C@@H]1CCCN1Cc1ccccc1
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Brc1ccc(-c2ccccc2)cc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-bromobiphenyl (7.42 g, 31.87 mmol) in 40 mL THF was prepared, and 10 mL was added to Mg (0.85 g, 35.05 mmol) and one crystal of I2 in THF (10 mL). The Grignard reaction was initiated with the aid of gentle warming by a heat gun. After the iodine color had dissipated, the remaining 30 mL of bromide solution was added dropwise to the reaction mixture. After the reflux subsided, the solution was warmed over an oil bath (70° C.), for 30 minutes, then cooled to 0° C. N-benzyl-(S)-proline methyl ester (5, 2.18 g, 9.96 mmol) in THF (10 mL) was added. After the addition, the solution was allowed to warm to room temperature and stirred for another 8 hours. Saturated NH4Cl (150 mL) was added and the resulting mixture was diluted with Et2O (200 mL). The phases were separated and the organic phase was washed with H2O and brine, dried (MgSO4), and concentrated. The residue was purified over a short silica gel column using 5 to 20% EtOAc/pet ether to a give a white solid, which was recrystalized with CH2Cl2/pet ether to obtain white needles (4.106 g, 83%): mp 85-86° C., 1H NMR (300 MHz, CDCl3) δ 1.60-1.74 (m, 2H), 1.76-1.88 (m, 1H), 1.94-2.08 (m, 1H), 2.40 (dd, J=16.6, 9.0 Hz, 1H), 2.92-3.00 (m, 1H), 3.10 (d, J=12.7 Hz, 1H), 3.38 (d, J=12.5 Hz, 1H), 4.06 (dd, J=9.3, 4.6 Hz, 1H), 5.04 (s, 1H), 7.04-7.60 (m, 14H), 7.68 (d, J=8.3 Hz, 2H), 7.82 (d, J=8.3 Hz, 2H).
Reaction SMILES: [CH:1]([NH:5][C:6](=[O:9])[CH2:7]Cl)([CH2:3][CH3:4])[CH3:2].[OH-:10].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH:1]([N:5]1[CH2:7][C:6](=[O:10])[N:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[CH2:7][C:6]1=[O:9])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)NC(=O)CCl
Reactant: [OH-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC(C)N1CC(=O)N(C(C)CC)CC1=O
Temperature: 75 °C
Yield: 61.9 %

Procedure:
Toluene (75 ml), N-sec-butyl-2-chloracetamide (14.9 g, 0.10 mol), tetrabutylammonium hydrogen sulfate (1.7 g, 5×10-3 mol), and powdered sodium hydroxide (16.0 g, 0.40 mol) were charged into a 500 ml Morton flask equipped with a mechanical stirrer, thermometer and condenser. The reaction mixture was vigorously stirred and heated to 75° C. for one hour. The reaction mixture was cooled, filtered and solvent removed under reduced pressure. The resulting solids were recrystallized from ether to give 7.0 g (62%) of 1,4-di-sec-butyl-2,5-diketopiperazine as an off-white colored solid, mp 95.5°-97.5° C. Analytical results on the product were as follows: 1H NMR (CDCl3, TMS, 90 MHz) δ4.54 (septet, J=7 Hz, 2H), 3.78 (s, 4H), 1.45 (q, J=6 Hz, 4H), 1.10 (d, J=6 Hz, 6H), 0.83 (t, J=7 Hz, 6H) Mass spectrum, m/e =226 (parent). Anal. calcd. for C12H22N2O2 :C, 63.68; H, 9.80; N, 12.38. Found: C, 63,51; H, 9.82; N, 12.30.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH:9][C:10]1[C:14]([C:15]([O:17]C)=O)=[CH:13][S:12][CH:11]=1)=[O:8].Cl.[F:20][C:21]([F:35])([F:34])[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[F:35][C:21]([F:20])([F:34])[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:15](=[O:17])[C:14]4=[CH:13][S:12][CH:11]=[C:10]4[NH:9][C:7]3=[O:8])[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: COC(=O)c1cscc1NC(=O)NCCCCBr
Agent: Cl
Product: O=c1[nH]c2cscc2c(=O)n1CCCCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 34.2 %

Procedure:
The above urea (12.41 g, 37.5 mmol) was reacted with 1-(3-trifluoromethylphenyl)piperazine hydrochloride (15 g, 56.2 mmol) as described in Example 12 to produce 5.8 g (34%) of the known 3-[4-[4-(3-trifluoromethylphenyl)piperazin-1-yl]butyl]thieno[3,4-d]pyrimidine-2,4-dione (J. Press and R. Russell, U.S. Pat. No. 4,670,560) after recrystallization from CH2Cl2 /hexane as a white solid, mp 126°-128° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH2:44][CH2:45][O:46][CH2:47][CH2:48][OH:49])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:41]3[CH2:40][CH2:39][N:38]([CH2:44][CH2:45][O:46][CH2:47][CH2:48][OH:49])[CH2:43][CH2:42]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: OCCOCCN1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCOCCO)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 2-(2-piperazin-1-yl-ethoxy)-ethanol (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C37H48Cl2N5O4 [(M+H)+] 696.3078, observed 696.3076.