Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[P+](C)(C1C=CC=CC=1)C1C=CC=CC=1.[C:32]1(CC(Cl)=O)[CH:37]=CC=C[CH:33]=1>>[C:15]1([CH2:16][C:17]2[O:2][C:3]3[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=3[CH:12]=2)[CH:14]=[CH:13][CH:37]=[CH:32][CH:33]=1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1-c1cc([N+](=O)[O-])ccc1O
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Br-]
Product: O=[N+]([O-])c1ccc2oc(Cc3ccccc3)cc2c1
Yield: 58.5 %

Procedure:
40 g (81 mmol) of (2-hydroxy-5-nitrophenyl)-methyltriphenylphosphonium bromide and 21.4 g (162 mmol) of phenylacetyl chloride are treated under the conditions described in step 1 of Example 1. 12 g of product are obtained. Melting point: 100° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[C@H:26]1[C@H:21]([CH2:22][CH2:23][CH2:24][CH2:25]1)[N:20]=[C:19]2[C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1>C(Cl)Cl.C(N(CC)CC)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[C@H:26]1[C@H:21]([CH2:22][CH2:23][CH2:24][CH2:25]1)[N:20]=[C:19]2[C:32]1[CH:33]=[CH:34][C:35]([N:38]([S:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)(=[O:11])=[O:12])[S:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)(=[O:12])=[O:11])=[CH:36][CH:37]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(N(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.45 g of 4-nitrobenzenesulfonyl chloride in 20 ml of methylene chloride are added dropwise to a solution of 2.0 g of (+/-)-cis-8,9-dimethoxy-6-(4-aminophenyl)-1,2,3,4,4a,10b-hexahydrophenanthridine in 50 ml of methylene chloride and 1.0 ml of triethylamine. The solution is stirred overnight at RT, extracted with water, and the organic phase is dried and concentrated. The residue is chromatographed on silica gel using a mixture of petroleum ether/ethyl acetate in the ratio 3:2. After concentration of the corresponding eluate fractions, the title compound of m.p. 234.5° C. is obtained.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5].[CH:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1)=[CH2:15].C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:2]([CH3:1])[CH2:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5])=[CH:18][CH:17]=1)=[CH2:15]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: C=Cc1ccc(CN(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)cc1
Temperature: 4 °C
Yield: 89.9 %

Procedure:
N-Methylglucamine (9.76 g, 50 mmol) was dissolved in hot methanol (200 mL), whereupon 4-vinylbenzylchloride (7.63 g, 50 mmol) and sodium carbonate (6 g) were added to the reaction. The mixture was allowed to reflux overnight. The solution was filtered, the methanol was removed, the residue taken up in hot chloroform and filtered. A precipitate formed in the eluent, which was heated until all solids dissolved and the solution was allowed to cool to 4° C. Filtration gave 14 g (90% yield) of white powder. 1H-NMR (90 MHz, DMSO-d6, δ): 7.33-7.28 (d, 4H); 6.86-6.83 (dd, 1H); 5.85-5.64 (d, 1H); 5.25-5.12 (d, 1H); 2.11 (s, 3h).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4](P(=O)(OC)OC)[O:3]1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27].C(N(CC)CC)C>O1CCCC1>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2](=[O:1])[O:3]2)=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COP(=O)(OC)C1OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1OC(=Cc2ccc(Cl)c([N+](=O)[O-])c2)c2ccccc21
Temperature: 15 °C
Reaction time: 1 h

Procedure:
A stirred solution of dimethyl 3-oxo-1,3-dihydroisobenzofuran-1-ylphosphonate (4.84 g, 0.02 mol; prepared in a manner similar to that described in Example 23) and 4-chloro-3-nitrobenzaldehyde (3.71 g, 0.02 mol) in tetrahydrofuran (30 ml) was cooled to 15° C. and a solution of triethylamine (2.02 g, 0.02 mol) in tetrahydrofuran (3 ml) was added dropwise at <25° C. The mixture was stirred at ambient temperature for 1 hour, allowed to stand at this temperature for a further 16 hours and the resulting solid was collected by filtration. The filtrate was concentrated in vacuo, the residue was triturated with water (5 ml) and the resulting solid was collected by filtration. The two crops of solid were combined and suspended in water (30 ml). The mixture was stirred at ambient temperature for 30 minutes and the resulting solid was collected by filtration and dried in vacuo for 24 hours to give crude 3-(4-chloro-3-nitrobenzylidene)-3H-isobenzofuran-1-one as a pale yellow solid, m.pt. 198–204° C., still slightly wet with water, which was used directly in the next stage.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([F:11])=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.[Al+3].[Cl-].[Cl-].[Cl-].[Cl-].C(C1NC=C[N+]=1C)C.Cl[C:26](=[O:31])[C:27]([O:29]C)=[O:28]>O>[Br:1][C:2]1[N:3]=[CH:4][C:5]([F:11])=[C:6]2[C:10]([C:26](=[O:31])[C:27]([OH:29])=[O:28])=[CH:9][NH:8][C:7]=12
Reactant: Fc1cnc(Br)c2[nH]ccc12
Reactant: COC(=O)C(=O)Cl
Agent: CCc1[nH]cc[n+]1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C(O)C(=O)c1c[nH]c2c(Br)ncc(F)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridine (2.0 g, 9.3 mmol) was added to a mixture of AlCl3 (7.5 g, 55.8 mmol) and ethylmethylimidazolium chloride (2.7 g, 18.6 mmol). Methyl chlorooxoacetate (2.1 mL, 18.6 mmol) was added slowly to the above solution and the mixture was stirred at room temperature for 3 h. Reaction flask was placed in an ice bath and water was slowly added until a white precipitate formed. The solid was collected by filtration and washed with water to afford 2-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (2.4 g, 92%). LCMS: m/e 287 (M+H)+, ret time 0.91 min (method 1).
Reaction SMILES: [CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([C@@H:11]([C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=2)[C@@H:6]([CH3:24])[CH2:5]1)[CH:2]=[CH2:3].C1(C)C=CC(C([C@@](C(O)=O)(O)[C@@](C(C2C=CC(C)=CC=2)=O)(O)C(O)=O)=O)=CC=1>C(O)C>[CH2:1]([N:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C@H:11]([C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=2)[C@H:6]([CH3:24])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1C[C@H](C)N([C@@H](c2ccsc2)c2cccc(O)c2)C[C@H]1C
Agent: Cc1ccc(C(=O)[C@](O)(C(=O)O)[C@@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Solvent: CCO
Product: C=CCN1C[C@@H](C)N([C@H](c2ccsc2)c2cccc(O)c2)C[C@@H]1C
Yield: 7.7 %

Procedure:
(±)-3-((R*)-((2S*,5R*)-4-Allyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)phenol (2.74 g, 8.0 mmol, Example 63) was added to a solution of 6.18 g (16 mmol) of (-)-di-p-toluoyl-L-tartaric acid in 20 mL of absolute ethanol. The mixture was warmed to complete solution, cooled and allowed to crystallize at room temperature. After four recrystallizations, the salt was dissolved in 20 mL of 1N aqueous sodium hydroxide, and the solution was titrated to pH 8 with 6N hydrochloric acid. The precipitated amine was collected by filtration and recrystallized from absolute ethanol to give 0.21 g of (-)-3-((S)-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)phenol as white crystals, mp 193°-194° C. [α]D20 =-3.2° (ethyl acetate, c=1.4). HPLC on β-cyclodextrin with methanol:0.1M ammonium acetate/1:1 gave one peak at tR =7.8 min. Calc. for C20H26N2OS: C, 70.14; H, 7.65: N, 8.18: S, 9.36. Found: C, 70.24; H, 7.69; N, 8.23; S, 9.42.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:35])=[C:4]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])[CH:5]=[CH:6][CH:7]=1.[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[F:1][C:2]1[C:3]([CH3:35])=[C:4]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:22])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(F)cccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cccc(F)c3C)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 36.1 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(3-fluoro-2-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (125 mg, 0.26 mmol) obtained in step 2 and ethanesulfonamide (139 mg, 1.32 mmol), the title compound (53 mg, 36%) was obtained.
Reaction SMILES: C(O[CH2:9][C@@H:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:11]([OH:13])=[O:12])C1C=CC=CC=1.CC[OH:21]>[Pd]>[OH:21][CH:16]([CH2:17][CH3:18])[CH2:15][CH2:14][C@@H:10]([CH3:9])[C:11]([OH:13])=[O:12]
Reactant: CCO
Reactant: CCCCC[C@H](COCc1ccccc1)C(=O)O
Agent: [Pd]
Product: CCC(O)CC[C@@H](C)C(=O)O
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of (R)-3-benzyloxy-2-pentyl-propionic acid (1.54 g, 6.16 mmol) in EtOH (100 mL) was added 10% Pd/C (310 mg). The reaction mixture was subjected to hydrogenation overnight at room temperature. After the reaction was completed, the reaction mixture was filtered through a pad of Celite, and washed with EtOH (50 mL×3). Removal of the solvent provided the title compound (0.92 g, 93%). No further purification was required. 1H NMR (400 MHz, CHCl3) δ 6.30 (br s, 1H), 3.81 (d, J=5.4 Hz, 2H), 2.64 (m, 1H), 1.69 (m, 1H), 1.56 (m, 1H), 1.41–1.27 (m, 6H), 0.91 (t, J=7.7 Hz, 3H). Mass spectrum ES+: 161 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH:42]([NH:45][C@@H:46]([CH2:53][CH2:54][CH3:55])[CH2:47][N:48]1[CH2:51][CH:50]([OH:52])[CH2:49]1)([CH3:44])[CH3:43]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:45]([C@@H:46]([CH2:53][CH2:54][CH3:55])[CH2:47][N:48]2[CH2:51][CH:50]([OH:52])[CH2:49]2)[CH:42]([CH3:44])[CH3:43])=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CCC[C@@H](CN1CC(O)C1)NC(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC[C@@H](CN1CC(O)C1)N(C(=O)c1ccc(Cl)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
To a mixture of 4-chlorobenzoic acid (0.067 g, 0.43 mmol) and TBTU (0.137 g, 0.43 mmol) in DCM (2 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.222 mL, 1.28 mmol). The suspension was stirred at rt for 30 min. A solution of (S)-1-(2-(isopropylamino)pentyl)azetidin-3-ol (Compound O2.1) (0.142 g, 0.43 mmol) in DCM (1 mL) was added and the reaction mixture was stirred at rt overnight. The reaction was washed with saturated NaHCO3 solution (2 ml). The organic phase was concentrated using a vacuum centrifuge. The residue was dissolved in MeOH (2 ml) and 1M NaOH (aq., 0.5 ml) was added. The mixture was stirred at rt for 1.5 h. Acetic acid (110 mg) was added and the mixture was concentrated. The residue was dissolved in DCM (3.5 ml) and washed with saturated NaHCO3 solution (2 ml). The organic phase was concentrated using a vacuum centrifuge and the residue purified by preparative HPLC affording the title compound (20 mg, 14%). Mixture of rotamers: 1H NMR (600 MHz, DMSO-d6) δ 0.62-0.78, 0.76-0.93, 0.93-1.14, 1.14-1.54, 1.67-1.93, 2.24-2.40, 2.41-2.77, 2.76-2.97, 2.96-3.15, 3.16-3.45, 3.45-3.75, 3.96-4.20, 5.12-5.31, 7.17-7.35, 7.38-7.52. Number of protons: 27. HRMS (M+H)+: calculated 339.1839. found 339.1866
Reaction SMILES: [Li]CCCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH3:16])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1.[C:17]1([CH2:23][CH2:24][CH2:25][CH2:26]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1.C1(C)C=CC=CC=1>[CH3:15][O:14][C:12]1[CH:11]=[C:10]([CH3:16])[CH:9]=[C:8]([O:7][CH3:6])[C:13]=1[CH2:26][CH2:25][CH2:24][CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1cc(C)cc(OC)c1
Reactant: BrCCCCc1ccccc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc(C)cc(OC)c1CCCCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 1347.9 %

Procedure:
A solution of nBuLi in hexanes (1.7 M, 14 mL, 24 mmol) was added over 15 min to a solution of 3,5-dimethoxytoluene (2.93 mL, 20 mmol) in THF (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h then at room temperature for 3 h. The reaction was cooled to 0° C. and a solution of the 4-phenylbutylbromide (4.13 mL, 1.2 mmol) in toluene (15 mL) was added over 5 min. The reaction mixture was allowed to warm to room temperature and heated to 80° C. for 3-4 h. The reaction was quenched slowly with water and partitioned over Et2O (100 mL) and water (100 mL). The phases were separated and the aqueous phase was extracted with Et2O (3×100 mL). The pooled organics were washed with brine (120 mL), dried over Na2SO4, and concentrated under vacuum and the crude product was purified by flash chromatography (silica-gel, petroleum ether/EtOAc 200:1) to afford the product as a clear oil (4.6 g, 81%). 1H NMR (CDCl3): δ 1.53-1.67 (m, 4H), 2.31 (s, 3H), 2.60-2.64 (m, 4H), 3.76 (s, 6H), 6.34 (s, 2H), 7.13-7.22 (m, 5H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][CH2:14][CH2:15][CH2:16]Br.C(N(CC)CC)C.[Cl-].[Na+]>CN(C)C=O>[Cl:13][CH2:14][CH2:15][CH2:16][N:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: ClCCCBr
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: ClCCCN1CCC(c2ccccc2)CC1
Reaction time: 1 h

Procedure:
24 Grams of 4-phenylpiperidine, 24 g of 1-chloro-3-bromopropane and 15 g of triethylamine were mixed with 100 ml of dimethylformamide and stirred at 50°-60° C. for 1 hour. The reaction mixture was poured into 200 ml of saturated sodium chloride aqueous-solution and the organic layer was extracted with chloroform. Then the chloroform layers was washed with water, dried and the chloroform was removed by distillation. The residue thus obtained was purified by a silica-gel column chromatography (to obtain only the main product at the upper-most portion in the column). 15.3 Grams of 1-chloro-3-(4-phenylpiperidinyl)propane was obtained as in the form of colorless oily substance. Then this oily substance was distilled under a reduced pressure to obtain 11 g of a fraction of distillate having the boiling point of 112°-115° C. (0.1 mmHg). A part of this distillate was made as in the form of hydrochloride and recrystallized from ethanol to obtain 1-chloro-3-(4-phenyl-1-piperidyl)propane monohydrochloride having the melting point of 167°-169° C. as in the form of colorless needle-like crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.CN(C1C=CC=CN=1)C.[CH3:27][N:28]([CH3:32])[C:29](Cl)=[O:30]>C(Cl)Cl>[CH3:27][N:28]([CH3:32])[C:29]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)=[O:30]
Reactant: CN(C)C(=O)Cl
Reactant: COC(=O)c1ccc(N)cc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)N(C)C)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 12.1 %

Procedure:
Methyl 4-aminobenzoate (Aldrich, 5.0 g, 33 mmol) was dissolved in 120 mL of anhydrous methylene chloride containing pyridine (3.2 mL, 39.6 mmol), and dimethylaminopyridine (DMAP, 500 mg) was added. To the ice-cooled mixture was added dimethylcarbamyl chloride (3.34 mL, 36.3 mmol) while stirring. The stirring was continued for 16 h at room temperature. The reaction was quenched with water (50 mL) and the organic layer separated. The aqueous layer was extracted with chloroform (50 mL). The combined organic extract was dried over sodium sulfate. The volatiles were evaporated on a rotoevaporator to give a residue, which was applied to a column of silica gel (2 cm dia, 16.5 cm high, 42 g). Chloroform (1.2 L) eluted the starting material (3 g) while the desired material was washed with 1% methanol in chloroform (700 mL) and crystallized from chloroform-methanol-hexane. The white solid was separated, dried in air followed by drying in a pistol at acetone reflux in vacuo to give 885 mg (30% based on starting material consumed) of methyl 4-(N,N-dimethylcarbamyl)aminobenzoate, mp 169°-170° C.
Reaction SMILES: [ClH:1].Cl.[C:3]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18]2[N:27]=[C:26]([N:28]3[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH2:13]1)=[O:11].N1C=CC=CC=1.[C:47](OC(=O)C)(=[O:49])[CH3:48]>C(Cl)(Cl)Cl>[ClH:1].[C:47]([N:31]1[CH2:32][CH2:33][CH2:34][N:28]([C:26]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[C:18]([NH:17][C@H:14]3[CH2:15][CH2:16][N:12]([C:10](=[O:11])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:13]3)[N:27]=2)[CH2:29][CH2:30]1)(=[O:49])[CH3:48]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Cc1ccccc1-c1ccccc1)N1CC[C@H](Nc2nc(N3CCCNCC3)c3ccccc3n2)C1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)N1CCCN(c2nc(N[C@H]3CCN(C(=O)Cc4ccccc4-c4ccccc4)C3)nc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 113.9 %

Procedure:
t-Butyl 4-(2-((S)-1-(2-biphenyl-2-ylethanoyl)pyrrolidin-3-ylamino)quinazolin-4-yl)-[1,4]diazepane-1-carboxylate (0.53 g) synthesized in the same manner as in Example 1 was dissolved in ethyl acetate (3 mL), followed by addition of a solution (2.2 mL) of 4 M HCl in ethyl acetate, and the mixture was stirred overnight. Precipitated solids were collected by filtration and then washed with hexane to obtain 2-biphenyl-2-yl-1-((S)-3-(4-[1,4]diazepan-1-ylquinazolin-2-ylamino)pyrrolidin-1-yl)ethanone dihydrochloride (0.15 g). (2) 2-Biphenyl-2-yl-1-((S)-3-(4-[1,4]diazepan-1-ylquinazolin-2-ylamino)pyrrolidin-1-yl)ethanone di hydrochloride (40 mg) was suspended in chloroform (3 mL), followed by addition of pyridine (12 mg) and acetic anhydride (8.5 mg), and the mixture was stirred at room temperature for 3 h. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (chloroform/methanol=10:1) to obtain the title compound (compound 1-210) (46 mg). The resulting purification product was dissolved in ethyl acetate (1.0 mL), followed by addition of a solution (0.015 mL) of 4 M HCl in ethyl acetate, and the mixture was stirred to obtain the title compound (compound 1-212) (12 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O-:9])=[O:8].[Na+].[C:11]([O:17][CH2:18]Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>C(N(CC)CC)C>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:9][CH2:18][O:17][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:8]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C([O-])c1cnccn1
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OCOC(=O)c1cnccn1

Procedure:
The process for producing pivaloyloxymethyl pyrazinecarboxylate is now described taking the use of the sodium salt as an example of said alkali metal pyrazinecarboxylate. Thus, pyrazinecarboxylic acid is dissolved in an aqueous solution containing an equimoler amount, with respect to the acid, of sodium hydroxide, water is then distilled off, and the residue is dried to give sodium pyrazinecarboxylate. To this sodium pyrazinecarboxylate is added 1-2 molar equivalents, with respect to sodium pyrazinecarboxylate, of chloromethyl pivalate, and, as the catalyst, 0.1-0.3 molar equivalent, with respect to sodium pyrazinecarboxylate, of a tertiary amine, e.g. triethylamine, and the reaction is conducted at 90°-120° C. for 3-10 hours, whereby pivaloyloxymethyl pyrazinecarboxylate is produced. As an alternative, pivaloyloxymethyl pyrazinecarboxylate can also be obtained without the aid of a catalyst by conducting the reaction in a solvent in which sodium pyrazinecarboxylate is at least partially soluble and which is inert to the reaction, for example dimethylformamide or N-methyl-2-pyrrolidone.
Reaction SMILES: [C:1](=[N:14][C:15]1[CH:16]=[CH:17][C:18]([F:29])=[C:19]([C@@:21]2([CH3:28])[NH:26][C:25](=S)[CH2:24][O:23][CH2:22]2)[CH:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:30].C(OO)(C)(C)C>CO.O>[C:1](=[N:14][C:15]1[CH:16]=[CH:17][C:18]([F:29])=[C:19]([C@:21]2([CH3:28])[CH2:22][O:23][CH2:24][C:25]([NH2:30])=[N:26]2)[CH:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: C[C@@]1(c2cc(N=C(c3ccccc3)c3ccccc3)ccc2F)COCC(=S)N1
Agent: CC(C)(C)OO
Solvent: CO
Solvent: O
Product: C[C@@]1(c2cc(N=C(c3ccccc3)c3ccccc3)ccc2F)COCC(N)=N1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A suspension of (R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-morpholine-3-thione [Building block H, step b)] (1.25 g, 3.09 mmol) in methanol (57 ml) was treated with a solution of ammonia in methanol (26.5 ml, 185 mmol) and a solution of tert-butyl-hydroperoxide (4.28 ml, 30.9 mmol). After stirring at room temperature for 40 hours, the reaction mixture was diluted with water and extracted three times with dichloromethane. The combined organic layers were washed with water, dried over sodium sulfate, evaporated, and dried at high vacuum at room temperature to yield the crude (R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine as a light brown foam which was dissolved in dioxane (20 ml) and treated with hydrochloric acid (1 M, 3.09 ml). After 40 minutes at room temperature the reaction mixtures was diluted with a saturated solution of hydrogen-carbonate and water. The mixture was extracted three times with ethyl acetate, then the aqueous phase basified with a solution of sodium hydroxide (28%). After four extractions with dichloromethane, the organic layers were combined, dried over sodium sulfate and evaporated. The (R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine was obtained as an off-white waxy solid (445 mg, 64% of theory).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[C:18](=[O:33])[O:19][C:20](=O)[C:21]=2[C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:31])[CH:23]=2)=[CH:9]1)(=O)C.O.C[N:36](C=O)C>N>[OH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[C:18](=[O:33])[NH:36][C:20](=[O:19])[C:21]=2[C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:31])[CH:23]=2)=[CH:9]1
Reactant: CN(C)C=O
Reactant: CC(=O)OCCCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)OC2=O)c2ccccc21
Agent: N
Solvent: O
Product: Cn1cc(C2=C(c3cn(CCCO)c4ccccc34)C(=O)NC2=O)c2ccccc21

Procedure:
A solution of 200 mg of 3-[1-(3-acetoxypropyl)-3-indolyl]-4-(1-methyl-3-indolyl)furan-2,5-dione in 1 ml of DMF and 2 ml of 33% aqueous ammonia was heated to 100° C. for 2 hours. 50 ml of water were added and the resulting solid was filtered off, dried and recrystallized from ethyl acetate to give 85 mg of 3-[1-(3-hydroxypropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 185°-187° C.