Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH3:26])=[CH:19][C:18]=1[OH:27])[CH3:16]>CN(C=O)C>[CH2:7]([O:27][C:18]1[CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH3:26])[CH:21]=[CH:22][C:17]=1[CH2:15][CH3:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: CCCOc1ccc(CC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(CC)c(OCc2ccccc2)c1
Temperature: 45 °C
Reaction time: 15 h
Yield: 52.6 %

Procedure:
Potassium carbonate (17.8 g, 0.13 mol) followed by benzyl bromide (5.12 mL, 42.9 mmol) were added to a solution of 2-ethyl-5-propoxy-phenol (7.74 g, 42.9 mmol) in DMF (60 mL). The mixture was stirred at 45° C. for 15 hours and then partitioned between H2O and EtOAc. The organic layer was washed with 1N HCl, brine, dried over Na2SO4 and concentrated to a brown oil. Purification by flash column chromatography (0% to 20% EtOAc in hexanes) gave the product as a clear oil (6.1 g, 55%). 1H NMR (400 MHz, CDCl3): δ 1.02 (t, J=7.6 Hz, 3 H), 1.19 (t, J=7.6 Hz, 3 H), 1.78 (q, J=7.6 Hz, 2 H), 2.63 (q, J=7.6 Hz, 2 H), 3.88 (t, J=6.6 Hz, 2 H), 5.05 (s, 2 H), 6.44 (dd, J=8.1, 2.3 Hz, 1 H), 6.51 (dd, J=2.3 Hz, 1 H), 7.05 (d, J=8.3 Hz, 1 H), 7.31 (m, 1 H), 7.38 (m, 2 H), 7.44 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:17]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)c2ccc(Cl)cc2)cc1
Yield: 19.3 %

Procedure:
In a manner similar to that described in Example 3, 4-chloro-benzoyl chloride (0.058 g, 0.00033 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.016 g of 4-[4-(4-chloro-benzoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; MS-(AP+) MH+332.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1>>[Cl:9][C:4]1[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: NCCc1ccncc1
Product: Clc1nc(Cl)nc(NCCc2ccncc2)n1

Procedure:
Following the general procedure A 2,4,6-trichloro-1,3,5-triazine was coupled with 4-(2-Aminoethyl)pyridine with reaction time of 2 h. Purification by column chromatography gave the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[Br:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.C(Cl)(Cl)Cl>[Br:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12]
Reactant: O=C1CCCc2c(O)cccc21
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: O=C1CCCc2c(OCCCBr)cccc21
Yield: 57 %

Procedure:
32.43 g (0.2 mol) 5-hydroxy-1-oxotetraline and 120.14 g (0.6 mol) 1,3-dibromopropane were, while stirring, heated to the boil in 200 ml anhydrous isopropanol and thereafter 41.46 g (0.3 mol) pulverized anhydrous potassium carbonate were added thereto over the course of about three hours. Subsequently, the reaction mixture was vigorously stirred for six hours at reflux temperature, then filtered with suction and the filter cake washed out with isopropanol. The filtrate was evaporated in a vacuum and excess 1,3-dibromopropane was substantially stripped off. The oily evaporation residue obtained was taken up in chloroform, the chloroform solution was extracted several times with a dilute aqueous solution of sodium hydroxide, then shaken with water until neutral and dried. After distilling off the chloroform, the oily residue was distilled at oil pump vacuum. Between 145°-155°C/0.05 mm Hg, there were obtained 32.3 g (57.1% of theory) 5-(3-bromopropoxy)-1-oxotetraline, which was then further worked up.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:10]([CH2:12][C:13](OCC)=[O:14])#[N:11].N1CCCCC1>C(O)C>[OH:14][C:13]1[C:12]([C:10]#[N:11])=[CH:4][C:3]2[C:2](=[N:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: Nc1ncccc1C=O
Reactant: CCOC(=O)CC#N
Solvent: C1CCNCC1
Solvent: CCO
Product: N#Cc1cc2cccnc2nc1O
Reaction time: 1 h

Procedure:
A mixture of 2-aminonicotinaldehyde (2.44 g., 0.02 m), ethyl α-cyanoacetate (4.52 g., 0.04 m.), absolute ethanol (50 ml.) and piperidine (0.5 ml) is stirred under reflux. After 1 hour, the solution is cooled to 0°-4° C. The yellow solid is filtered and dried to yield 2.5 g. (73%) of 2-hydroxy-3-cyano-1,8-naphthyridines, m.p. 300° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:12]=2[F:19])[O:8][N:7]=1)=[O:5])C.[Li+].[OH-]>O1CCCC1>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:8][N:7]=[C:6]([C:4]([OH:5])=[O:3])[N:10]=2)=[C:12]([F:19])[CH:13]=1)#[N:18]
Reactant: CCOC(=O)c1noc(-c2ccc(C#N)cc2F)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2nc(C(=O)O)no2)c(F)c1

Procedure:
The title compound is prepared from 5-(4-cyano-2-fluoro-phenyl)-[1,2,4]oxadiazole-3-carboxylic acid ethyl ester by treatment with aqueous LiOH solution in tetrahydrofuran. LC (method 15): tR=0.69 min; Mass spectrum (ESI+): m/z=234 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]2([CH2:11][CH2:10][C@H:9]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[CH2:8]2)[NH:4][C:3]1=[O:20].[NH2:21][OH:22]>C(O)C.O>[OH:22]/[N:21]=[C:16](\[NH2:17])/[C:15]1[CH:18]=[CH:19][C:12]([C@H:9]2[CH2:10][CH2:11][C:5]3([NH:4][C:3](=[O:20])[N:2]([CH3:1])[C:6]3=[O:7])[CH2:8]2)=[CH:13][CH:14]=1
Reactant: CN1C(=O)NC2(CC[C@H](c3ccc(C#N)cc3)C2)C1=O
Reactant: NO
Solvent: CCO
Solvent: O
Product: CN1C(=O)NC2(CC[C@H](c3ccc(/C(N)=N/O)cc3)C2)C1=O
Temperature: 60 °C
Yield: 97.9 %

Procedure:
4-((7S)-3-methyl-2,4-dioxo-1,3-diazaspiro[4.4]nonan-7-yl)benzonitrile (0.88 g, 3.27 mmol) was suspended in ethanol (20 ml). To this was added hydroxylamine (0.240 ml, 3.59 mmol) as 50% weight solution in water, and the reaction was heated to 60° C. under an atmosphere of nitrogen for about 20 hours. The reaction mixture was left to cool down to ambient temperature. Solvent was partially removed. The resulting white precipitate was filtered, rinsed with cold ethanol and vacuum-dried to afford (Z)-N′-hydroxy-4-{(7S)-3-methyl-2,4-dioxo-1,3-diazaspiro[4.4]nonan-7-yl}benzimidamide as light brown solid (1.12 g, 3.20 mmol).
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH2:12][C:13]([NH2:15])=[O:14])=[C:9]([Br:16])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:17]1(=O)[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[CH2:18]1>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[Br:1][C:2]1[C:10]([O:11][CH2:12][C:13]([NH2:15])=[O:14])=[C:9]([Br:16])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:17]1[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[CH:18]=1)=[O:5]
Reactant: O=C1CCCC(=O)C1
Reactant: NC(=O)COc1c(Br)ccc(C(=O)O)c1Br
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: NC(=O)COc1c(Br)ccc(C(=O)OC2=CC(=O)CCC2)c1Br

Procedure:
0.400 g (1.10 mmol) of 2,4-dibromo-3-(aminocarbonylmethoxy)benzoic acid, 0.140 g (1.20 mmol) of cyclohexane-1,3-dione, 0.222 g (1.10 mmol) of N′-(3-dimethyl-aminopropyl) -N-ethylcarbodiimide hydrochloride and 0.001 g of DMAP was stirred for 14 hours at RT in 15 ml of CH2Cl2. The mixture was subsequently diluted with CH2Cl2 and with 0.5 N HCl, and washed with water, with saturated NaHCO3 solution and again with water. After the combined organic phases have been dried over Na2SO4 and concentrated completely, 3-oxo-1-cyclohexenyl 2,4-dibromo-3-(aminocarbonylmethoxy)benzoate was obtained as a yellow resin, which had sufficient purity for the subsequent reaction.
Reaction SMILES: C([Li])CCC.[CH2:6]([Cl:8])[Cl:7].[C:9]1([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:16][C@H:17]([C:25](O)=[O:26])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[NH4+]>CCCCCC.O1CCCC1.C(OCC)C.O>[Cl:7][CH:6]([Cl:8])[C:25](=[O:26])[C@@H:17]([N:16]=[C:15]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCCl
Reactant: O=C(O)[C@H](Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: O=C(C(Cl)Cl)[C@H](Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Reaction time: 0.17 h
Yield: 96 %

Procedure:
A mixed solution of dehydrated tetrahydrofuran (6.2 ml) and diethyl ether (3.1 ml) was cooled to −78° C. 1.53 M solution (3.3 ml) of n-butyllithium in hexane and then a solution of methylene chloride (0.40 ml) in dehydrated tetrahydrofuran (3.3 ml) were added to the mixed solution and they were stirred for 10 minutes. Then a solution of methyl ester of N-(diphenylmethylene)-L-phenylalanine (0.86 g) in diethyl ether (3.3 ml) was added to the obtained solution. They were stirred for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction solution to terminate the reaction. The temperature was elevated to room temperature. After the addition of water followed by the extraction with ethyl acetate twice, the obtained solutions in ethyl acetate were combined together and washed with saturated aqueous sodium chloride6solution. The obtained solution in ethyl acetate solvent was dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered out. The solvent was evaporated under reduced pressure to obtain the intended (3S)-1,1-dichloro-3-(diphenylmethylene) amino-4-phenyl-2-butanone (0.95 g) in a yield of 96%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:14]3[C:13]([NH:15][C@H:16]([C:18]4[N:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:22](=[O:30])[C:21]5=[C:31]([CH3:34])[CH:32]=[CH:33][N:20]5[N:19]=4)[CH3:17])=[N:12][CH:11]=[N:10][C:9]=3[N:8]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:7]=2)=[N:2]1.[CH3:43][O:44][C:45]1[CH:46]=[C:47]([CH:49]=[C:50](B2OC(C)(C)C(C)(C)O2)[CH:51]=1)[NH2:48].N1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:48][C:47]1[CH:49]=[C:50]([N:1]2[CH:5]=[CH:4][C:3]([C:6]3[C:14]4[C:13]([NH:15][C@H:16]([C:18]5[N:23]([C:24]6[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=6)[C:22](=[O:30])[C:21]6=[C:31]([CH3:34])[CH:32]=[CH:33][N:20]6[N:19]=5)[CH3:17])=[N:12][CH:11]=[N:10][C:9]=4[N:8]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:42])[CH3:41])[CH:7]=3)=[N:2]2)[CH:51]=[C:45]([O:44][CH3:43])[CH:46]=1
Reactant: COc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc[nH]n3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COc1cc(N)cc(-n2ccc(-c3cn(COCC[Si](C)(C)C)c4ncnc(N[C@@H](C)c5nn6ccc(C)c6c(=O)n5-c5ccccc5)c34)n2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 14 %

Procedure:
(S)-2-(1-((5-(1H-Pyrazol-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (67 mg, 0.12 mmol) was treated with 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (57 mg, 0.23 mmol), Cu(AcO)2 (32 mg, 0.18 mmol) and pyridine (20 μl, 0.25 mmol) in DMF (1.5 ml). The reaction mixture was submitted at vacuum-argon cycles and stirred at 100° C. under microwave conditions for 2 h. More pyridine and Cu(AcO)2 were added, and the reaction mixture stirred at 100° C. until the reaction was over. The solvent was cooled at room temperature and poured into ice-water, basified with potassium carbonate and extracted with ethyl acetate (×3). The organic phase was successively washed with water and brine, dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure. The residue (15.3 mg, 14% yield, 75% purity) was used in the next synthetic step without further purification.
Reaction SMILES: Cl[C:2]1[C:3]2[S:13][C:12]3[N:14]=[C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:16]=[C:17]([CH3:18])[C:11]=3[C:4]=2[N:5]=[C:6]([S:8][CH2:9][CH3:10])[N:7]=1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>O1CCCC1>[CH2:9]([S:8][C:6]1[N:7]=[C:2]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:3]2[S:13][C:12]3[N:14]=[C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:16]=[C:17]([CH3:18])[C:11]=3[C:4]=2[N:5]=1)[CH3:10]
Reactant: CCSc1nc(Cl)c2sc3nc(-c4ccccc4)cc(C)c3c2n1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: CCSc1nc(N2CCNCC2)c2sc3nc(-c4ccccc4)cc(C)c3c2n1

Procedure:
0.63 g (1.7 mmol) 4-chloro-2-ethylthio-9-methyl-7-phenyl-pyrido-[3′,2′:4,5]thieno[3,2-d]pyrimidine is stirred with 0.29 g (3.4 mmol) piperazine in 10 ml tetrahydrofuran at room temperature for 1 h. The precipitate is sucked off, washed with some water and suck dried. Thereafter, the precipitate is suspended in about 300 ml dichloromethane, fully stirred, filtrated and the solvent of the filtrate is removed. 0.67 g (93%) of the title substance is obtained. ESI-MS [m/z]: 422, melting point: 150-154° C.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].O.[F:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[CH:25][CH:26]=1>O1CCCC1>[C:15]([O:14][C:12]([NH:7][C@H:6]([CH2:10][CH2:9][C:8]([C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([F:20])[CH:26]=1)=[O:11])[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: Fc1cccc([Mg]Br)c1
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@H](CCC(=O)c1cccc(F)c1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (4.0 g) in tetrahydrofuran (100 mL), 3-fluorophenylmagnesium bromide (1.0 M solution in tetrahydrofuran; 17.1 mL) was added dropwise at −40° C. over 10 minutes, and the reaction solution was stirred at −40° C. to 0° C. for one hour. Water was added to the solution in small portions at 0° C., followed by extraction from the reaction solution with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 5.5 g of the title compound as a colorless oil. The property values of the compound are as follows.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]2[CH2:21][CH2:20][S:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)=[O:5].[Cl:27][C:28]1[N:32]([CH3:33])[N:31]=[C:30]([CH3:34])[C:29]=1[S:35](Cl)(=[O:37])=[O:36]>N1C=CC=CC=1>[Cl:26][C:23]1[CH:24]=[CH:25][C:2]([NH:1][S:35]([C:29]2[C:30]([CH3:34])=[N:31][N:32]([CH3:33])[C:28]=2[Cl:27])(=[O:36])=[O:37])=[C:3]([CH:22]=1)[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([N:16]2[CH2:21][CH2:20][S:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:11][CH:12]=1)=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(S(=O)(=O)N2CCSCC2)cc1
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)Nc1ccc(Cl)cc1C(=O)Nc1ccc(S(=O)(=O)N2CCSCC2)cc1

Procedure:
250 mg (0.60 mmol) of 2-amino-5-chloro-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide were dissolved in 10 ml of dry pyridine, and a solution of 195 mg (0.85 mmol) 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride in 5 ml of pyridine was added dropwise at 0° C. After 2 h the mixture was poured onto ice, the precipitated solid was filtered off with suction and purified by chromatography over silica with methylene chloride/methanol (98:2). 250 mg (69%) of the title compound having a melting point of 215-216° C. were obtained.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]([C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:19]3[C:26]([CH3:27])=[CH:25][N:24]([S:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)(=[O:30])=[O:29])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:14][CH2:13]1)=[O:11])(C)(C)C.Cl.O>O1CCOCC1.C(OCC)C>[NH2:7][CH2:8][CH:9]([C:37]1[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=1)[C:10]([N:12]1[CH2:13][CH2:14][N:15]([C:18]2[C:19]3[C:26]([CH3:27])=[CH:25][N:24]([S:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)(=[O:30])=[O:29])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:16][CH2:17]1)=[O:11]
Reactant: Cc1cn(S(=O)(=O)c2ccccc2)c2ncnc(N3CCN(C(=O)C(CNC(=O)OC(C)(C)C)c4ccc(Cl)cc4)CC3)c12
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: C1COCCO1
Product: Cc1cn(S(=O)(=O)c2ccccc2)c2ncnc(N3CCN(C(=O)C(CN)c4ccc(Cl)cc4)CC3)c12
Reaction time: 4 h
Yield: 77.6 %

Procedure:
The [3-[4-(7-benzenesulfonyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-2-(4-chlorophenyl)-3-oxo-propyl]-carbamic acid tert-butyl ester (295 mg, 0.464 mmol) was dissolved in 2.3 mL of 1,4-dioxane and treated with 4M HCl in 1,4-dioxane (2.3 mL, 9.29 mmol). The mixture was allowed to stir for 4 hours to completion affording a yellow precipitate. The suspension was diluted with diethyl ether and poured into water. More diethyl ether was added, and the layers were shaken. The ether wash was discarded, and the aqueous was treated with saturated NaHCO3 solution until basic to pH paper (about 10) to afford a white precipitate. The aqueous was extracted with ethyl acetate, and the organics were combined. The organic was washed with water, then brine, separated, dried over MgSO4, filtered, and concentrated in vacuo to afford the near-pure 3-amino-1-[4-(7-benzenesulfonyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-2-(4-chlorophenyl)-propan-1-one as a colorless oil (194 mg, 77%). 1H NMR (free-base, CDCl3, 400 MHz) δ 8.44 (s, 1H), 8.16 (d, J=8.4 Hz, 2H), 7.59 (t, J=7.2 Hz, 1H), 7.49 (appt, J=7.6 Hz, 2H), 7.31 (m, 3H), 7.19 (d, J=8.0 Hz, 2H), 3.92 (m, 1H), 3.85 (dd, J=8.4, 5.2 Hz, 1H), 3.61 (m, 1H), 3.56-3.50 (m, 4H), 3.43 (m, 2H), 3.32 (m, 2H), 2.90 (m, 2H), 2.29 (s, 3H). LCMS (APCI+) m/z 539 [M+H]+; Rt=2.40 min.
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[N:7][CH:8]=[N:9][CH:10]=1)=[NH:4].[NH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[C:13]=1[C:14]([OH:16])=O.C(O)(=O)C>CO>[Br:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:12]2[C:13]=1[C:14]([OH:16])=[N:4][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[N:9][CH:10]=1)=[N:11]2
Reactant: Nc1cccc(Br)c1C(=O)O
Reactant: COC(=N)c1cncnc1
Solvent: CC(=O)O
Solvent: CO
Product: Oc1nc(-c2cncnc2)nc2cccc(Br)c12
Reaction time: 16 h
Yield: 27.3 %

Procedure:
To a stirred suspension of methylpyrimidine-5-carbimidate (2.00 g, 14.5 mmol) in methanol (20 mL) was added 2-amino-6-bromobenzoic acid (3.1 g, 14.5 mmol). The mixture was heated to reflux where it stirred for 16 h under the nitrogen atmosphere. At the conclusion of this period, acetic acid (2.72 ml, 47 mmol) was added drop wise. Upon completion of addition, methanol was evaporated under reduced pressure to yield a residue. The residue was triturated with ether (100 mL), ethyl acetate (50 mL) and the resulting solid was dried to yield 5-bromo-2-(pyrimidin-5-yl)quinazolin-4-ol (1.2 g, 27%) as an off-white solid. The crude product was used without further purification. 1H NMR (400 MHz, DMSO-d6, δ): 7.64 (dd, J=7.2 Hz, 8.4 Hz, 1H); 7.73-7.75 (m, 2H); 9.35 (s, 1H); 9.46 (s, 2H); 12.9 (br s, 1H). ES-MS: [M++1]=303 and [M++3]=305.
Reaction SMILES: C(=O)([O-])OC.[Mg+2].COC(=O)[O-].[C:12]1([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([CH3:21])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[N:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=1.Cl>CO>[C:22]1([CH:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:19](=[O:20])[CH2:21][CH:33]2[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C1=NCCCC1
Reactant: CC(=O)C(c1ccccc1)c1ccccc1
Agent: COC(=O)[O-]
Agent: Cl
Agent: [Mg+2]
Solvent: CO
Product: O=C(CC1CCCCN1)C(c1ccccc1)c1ccccc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 37 %

Procedure:
Magnesium methyl carbonate (1.2 moles, 2 N in dimethylformamide) is heated to 120°C. under an atmosphere of carbon dioxide. The compound 1,1-diphenylacetone, 63.0 g (0.3 moles), is added and the mixture is stirred at 120°C. for a period of 4 hours under a stream of nitrogen to form the chelate, allowing the methyl alcohol that forms to escape. The mixture is cooled to room temperature under an atmosphere of carbon dioxide and 30.0 g (0.36 moles) of 2,3,4,5-tetrahydropyridine (as α-tripiperidein) is added and stirring continued at room temperature for a period of 6 days under an atmosphere of carbon dioxide. The reaction mixture is poured into 375 ml of concentrated HCl on 400 g of ice and the resulting mixture is extracted with methylene dichloride. The extracts are combined, dried over anhydrous sodium sulfate and the solvent is removed. The crude oil is recrystallized twice from an aqueous isopropyl alcohol solution to yield 37.9 g (37% yield) of 1,1-diphenyl-3-(2-piperidyl)propan- 2-one as the hydrochloride salt having a M.P. of 197-9°C. (dec.)
Reaction SMILES: C(N)C1C=CC=CC=1.C(OC([NH:19][C@H:20]([C:22]([NH:24][C@H:25]([C:28]([NH:30][C@H:31]([P:33](=[O:36])([OH:35])[OH:34])[CH3:32])=[O:29])[CH2:26][OH:27])=[O:23])[CH3:21])=O)C1C=CC=CC=1>>[NH2:19][C@H:20]([C:22]([NH:24][C@H:25]([C:28]([NH:30][C@H:31]([P:33](=[O:34])([OH:36])[OH:35])[CH3:32])=[O:29])[CH2:26][OH:27])=[O:23])[CH3:21]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)P(=O)(O)O
Solvent: NCc1ccccc1
Product: C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)P(=O)(O)O

Procedure:
In a manner analogous to that described in Example 3(ii), from the monobenzylamine salt of (1R)-1-[(N-benzyloxycarbonyl-L-alanyl-L-seryl)amino]-ethylphosphonic acid there was obtained (1R)-1-(L-alanyl-L-serylamino)-ethylphosphonic acid of melting point 234°-235° C. (decomposition).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[NH:23][CH2:22][CH2:21][C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][C:18]=3[CH:28]=2)=[CH:10][CH:9]=1)[CH2:2][CH3:3].[O:29]1[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[O:29]1[CH:33]=[CH:32][C:31]([CH2:34][N:23]2[C:17]3[CH:16]=[CH:15][C:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][O:4][CH2:1][CH2:2][CH3:3])=[CH:9][CH:10]=4)=[CH:28][C:18]=3[CH:19]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH2:21][CH2:22]2)=[CH:30]1
Reactant: O=Cc1ccoc1
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccoc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a solution of methyl 7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (300 mg) and 3-furaldehyde (378 mg) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (416 mg), and the mixture was stirred under nitrogen atmosphere at room temperature overnight. Then, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) to give methyl 1-(3-furylmethyl)-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (362 mg) as yellow oil.