Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:5][C@H:6]([C:21]2[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[C:23]([CH3:29])[CH:22]=2)[C:7](N([C@H](C)[C@H](O)C2C=CC=CC=2)C)=[O:8])[CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)[OH:31]>O1CCOCC1.O>[CH:1]1([CH2:5][C@H:6]([C:21]2[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[C:23]([CH3:29])[CH:22]=2)[C:7]([OH:8])=[O:31])[CH2:2][CH2:3][CH2:4]1
Reactant: O=S(=O)(O)O
Reactant: CSc1ccc([C@@H](CC2CCC2)C(=O)N(C)[C@H](C)[C@H](O)c2ccccc2)cc1C
Solvent: O
Solvent: C1COCCO1
Product: CSc1ccc([C@@H](CC2CCC2)C(=O)O)cc1C
Temperature: 110 °C
Yield: 77 %

Procedure:
A solution of (R)-3-cyclobutyl-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-2-(3-methyl-4-methylsulfanyl-phenyl)-propionamide (300 mg, 0.73 mmol) in dioxane (4 mL) was treated with a 9 N aqueous sulfuric acid solution (2 mL). The resulting solution was then heated at 110° C. for 16 h. The reaction was then cooled and diluted with water (75 mL) and extracted with a chloroform/methanol solution (3:2, 2×50 mL) and then concentrated. The resulting residue was then dissolved in methylene chloride and concentrated with silica gel (2 g) and purified on Biotage Flash chromatography system (40S column, silica gel, 80% ethyl acetate/hexanes) to afford (R)-3-cyclobutyl-2-(3-methyl-4-methylsulfanyl-phenyl)-propionic acid (148 mg, 77%): [α]30589=−48.3° (c=0.18, methylene chloride); EI-HRMS m/e calcd for C15H20O2S (M+) 264.1184, observed 264.1183; 1H NMR (300 MHz, DMSO-d6) δ 1.47-2.14 (m, 9H, CH and 4×CH2), 2.21 (s, 3H, ArCH3), 2.43 (s, 3H, SCH3), 3.30 (t, J=7.4 Hz, 1H, ArCHCO), 7.05-7.15 (m, 3H, Ar), 12.28 (s, 1H, CO2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[N:17]=[N:18][C:19]([Cl:23])=[CH:20][C:21]=2[CH3:22])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[N:17]=[N:18][C:19]([Cl:23])=[CH:20][C:21]=1[CH3:22]
Reactant: Cc1cc(Cl)nnc1-c1c(-c2ccc(Cl)cc2)c(C)n[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)nnc1-c1c(Cl)nnc(C)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 82.3 %

Procedure:
0.30 g of 5-(4-chlorophenyl)-4-(6-chloro-4-methyl-3-pyridazinyl)-6-met hyl-2H-pyridazin-3-one and 5 g of phosphorus oxychloride were mixed. The mixture was stirred for 1.5 hours on an oil bath of 110° C. The reaction mixture was allowed to cool to room temperature, the, concentrated under reduced pressure. To the resultant residue were added ethyl acetate and ice-cooled sodium bicarbonate water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.31 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.26 g of 3-chloro-5-(4-chlorophenyl)-4-(6-chloro-4-methyl-3-pyridazin yl)-6-methylpyridazine (hereinafter, described as compound (13) of the present invention(13).).
Reaction SMILES: [NH:1]1[CH2:9][C@H:7]([OH:8])[CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C([O-])(O)=O.[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[C:32]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1)=[O:17]>O.O1CCOCC1.C1(C)C=CC=CC=1>[C:16]([N:1]1[CH2:9][C@H:7]([OH:8])[CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])([O:18][CH2:19][CH:20]1[C:21]2[C:28](=[CH:29][CH:24]=[CH:23][CH:22]=2)[C:27]2[C:32]1=[CH:31][CH:30]=[CH:25][CH:26]=2)=[O:17]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: O=C(Cl)OCc1cccc2c1Cc1ccccc1-2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 8 h

Procedure:
Hydroxyproline (5.00 g, 38.2 mmol) and NaHCO3 (8.00 g, 95.2 mmol) were suspended in 150 ml H2O/Dioxane (1:1). Fluorenylmethyl chloroformate (11.4 g, 44.0 mmol) in 25 ml toluene was added dropwise. The temperature of the reaction was not allowed to rise above 25° C. during the addition. The mixture was stirred vigorously overnight, and then quenched with 50 ml saturated NaHCO3 solution and 50 ml water. The solution was then extracted with 100 ml diethyl ether. The aqueous layer was acidified to pH 1 with concentrated HCl, and extracted twice with ethyl acetate, and the organic extracts washed with brine. The solution was dried with MgSO4, filtered and the solvent removed in vacuo. The pure product crystallized from the concentrated solution. Yield: 13.4 g (100%). 1H NMR: (CDCl3, 200 MHz) δ 7.75-7.15 (8H, m, ArH), 4.55-4.05 (5H, m, ArCHCH2, H2, H4), 3.65-3.45 (2H, m, 2 H5), 2.35-2.10 (2H, m, 2 H3).
Reaction SMILES: C([N:8]1[CH2:14][CH:13]2[N:15]([CH2:16][CH2:17][CH2:18][NH:19][C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)C1C=CC=CC=1.Cl.C(Cl)Cl>C(#N)C>[CH:10]12[N:15]([CH2:16][CH2:17][CH2:18][NH:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=3)[CH:13]([CH2:12][CH2:11]1)[CH2:14][NH:8][CH2:9]2
Reactant: N#Cc1ccc(NCCCN2C3CCC2CN(Cc2ccccc2)C3)cc1
Agent: Cl
Solvent: CC#N
Solvent: ClCCl
Product: N#Cc1ccc(NCCCN2C3CCC2CNC3)cc1
Reaction time: 0.25 h
Yield: 42.9 %

Procedure:
To a cold solution of 4-{[3-(3-benzyl-3,8-diazabicyclo[3.2.1]oct-8-yl)propyl]amino}benzonitrile (6.26 g, 17.4 mmol; from step (c) above) in acetonitrile (100 mL) was added 12 M HCl (5.8 mL). The reaction mixture was stirred for 15 minutes, concentrated in vacuo and dried under high vacuum overnight. The resulting hydrochloride salt was added to a suspension of 10% Pd/C (800 mg) in methanol (250 mL). The reaction was then stirred under hydrogen (1 atmosphere of pressure) for 50 min. The mixture was filtered through Celite® and the filtrate was concentrated in vacuo. The resulting residue was partitioned with saturated NaHCO3 (100 mL) and CH2Cl2 (200 mL). The organic layer was dried (Na2SO4), filtered and concentrated ill vacuo to give the crude product. Flash chromatography on silica gel eluting with a gradient of CH2Cl2:CMA (4:1 to 2:1) gave 2.02 g (43%) of the title compound.
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:21])[C@H:8]([CH2:17][CH2:18][S:19][CH3:20])[NH:9]C(OC(C)(C)C)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>ClCCl>[CH:1]1([O:6][C:7](=[O:21])[C@H:8]([CH2:17][CH2:18][S:19][CH3:20])[NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC1CCCC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCC[C@H](N)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of N-tert-butoxycarbonyl L-methionine cyclopentyl ester (53 g.), TFA (200 ml.), triethylsilane (39 g.) and dichloromethane (2 L.) was stirred at ambient temperature for 2 hours, evaporated to dryness and then converted to the hydrochloride salt to give L-methionine cyclopentyl ester as a white crystalline solid (40.5 g.).
Reaction SMILES: C(N)C1C=CC=CC=1.[CH2:9]([N:12](C(OCC1C=CC=CC=1)=O)[CH2:13][C:14]([NH:16][C@H:17]([C:19]([NH:21][C@H:22]([C:24]([NH:26][C@H:27]([P:29](=[O:32])([OH:31])[OH:30])[CH3:28])=[O:25])[CH3:23])=[O:20])[CH3:18])=[O:15])[CH:10]=[CH2:11]>>[CH2:9]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:19]([NH:21][C@H:22]([C:24]([NH:26][C@H:27]([P:29](=[O:30])([OH:32])[OH:31])[CH3:28])=[O:25])[CH3:23])=[O:20])[CH3:18])=[O:15])[CH:10]=[CH2:11]
Reactant: C=CCN(CC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)P(=O)(O)O)C(=O)OCc1ccccc1
Solvent: NCc1ccccc1
Product: C=CCNCC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)P(=O)(O)O

Procedure:
In a manner analogous to that described in Example 7 (A)(ii), from the monobenzylamine salt of (1R)-1-[(N-allyl-N-benzyloxycarbonyl-glycyl-L-alanyl-L-alanyl)amino]-ethylphosphonic acid [prepared as described in Example 20(B)(i)] there was obtained (1R)-1-(N-allyl-glycyl-L-alanyl-L-alanylamino)-ethylphosphonic acid of melting point 251°-253° C. (decomposition); [α]D20 =-110°; [α]36520 =-394° (c=1% in water).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([CH2:22][OH:23])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([CH:22]=[O:23])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1

Procedure:
7.7 g (25.3 mmol) of 1-benzyl-3-(5-hydroxymethyl-2-furyl)indazole and 11 g (126.5 mmol) of activated manganese(IV) oxide in 200 ml of dry carbon tetrachloride were stirred under reflux for 4.5 h. For work-up, the mixture was filtered off with suction and the filtrate was washed with water, dried and concentrated using a rotary evaporator. The crude product was recrystallized from isopropanol. This gave 4.8 g (63%) of the title compound. m.p.: 108° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]([CH:10]1[CH2:15][CH:14]2[CH2:16][CH2:17][CH:11]1[CH2:12][N:13]2[C:18](OCC)=O)=[N+]=[N-]>C1COCC1>[NH2:7][CH:10]1[CH2:15][CH:14]2[CH2:16][CH2:17][CH:11]1[CH2:12][N:13]2[CH3:18]
Reactant: CCOC(=O)N1CC2CCC1CC2N=[N+]=[N-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CC2CCC1CC2N
Yield: 73.1 %

Procedure:
To a stirred suspension of LiAlH4 (2 g) in dry THF (100 was added a solution of the (±)-5-azido-2-carbethoxy-2-azabicyclo[2,2,2]octane (D3a) (3.5 g) under dry nitrogen and the mixture heated under reflux for 5 hrs. Normal basic work-up afforded the crude (±) 5-amino-2-methyl-2-azabicyclo[2,2,2]octane (D4a) (1.6 g, 70%), purified by distillation (b.p. 75°/5 mmHg).
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[C:4]1[N:8]2[CH2:9][CH2:10][NH:11][CH2:12][C:7]2=[N:6][N:5]=1.C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.[C:46]([O:50][C:51]([NH:53][C@H:54]([CH2:59][C:60]1[CH:65]=[C:64]([F:66])[C:63]([F:67])=[CH:62][C:61]=1[F:68])[CH2:55][C:56](O)=[O:57])=[O:52])([CH3:49])([CH3:48])[CH3:47].C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[C:46]([O:50][C:51]([NH:53][C@H:54]([CH2:59][C:60]1[CH:65]=[C:64]([F:66])[C:63]([F:67])=[CH:62][C:61]=1[F:68])[CH2:55][C:56]([N:11]1[CH2:10][CH2:9][N:8]2[C:4]([C:3]([F:13])([F:2])[F:14])=[N:5][N:6]=[C:7]2[CH2:12]1)=[O:57])=[O:52])([CH3:49])([CH3:47])[CH3:48]
Reactant: FC(F)(F)c1nnc2n1CCNC2
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 27.5 °C
Reaction time: 12 h

Procedure:
To a solution of 3-trifluoromethyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (11) (1.0 eq, 28.0 gm), diisopropylethylamine (2.0 eq, 31.0 gm), 1-hydroxybenzotriazole (1.2 eq, 22.0 gm), and EDC-HCl (1.2 eq, 28.0 gm) in N,N-dimethylformamide (4.0 vol, 160.0 ml), a solution of (3R)-3-[N-(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (07) (40.0 gm, 0.12 mol) in N,N-dimethylformamide (4.0 vol, 160.0 ml) was charged at 0-5° C. within 1 hour. The clear pale yellow solution was further stirred for 12 hours at 25-30° C. After stirring for 12 hours, the N,N-dimethylformamide was distilled out completely at 55-65° C. under reduced pressure to give a brown coloured residue. The brown coloured residue was further basified with 10% Na2CO3 solution (1.0 vol, 40.0 ml) and the product was extracted in ethyl acetate (3×10.0 vol, 3×400.0 ml). The combined ethyl acetate layers were washed with water, charcoalized and filtered, and the ethyl acetate was distilled out completely to give a white coloured product. The product was triturated with hexane (10.0 vol, 400.0 ml) and filtered at 25-30° C. The crude Boc-protected sitagliptin free base (12) was further purified by crystallising it from a mixture of isopropanol (20.0 vol) and water (2.0 vol).
Reaction SMILES: [C:1]([C:9]1[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=1[NH:11][C:12](=O)C(Cl)Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]#[N:22].[K+]>C(O)C.O>[NH2:22][C:12]1[C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([OH:8])[C:9]2[C:10](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:11]=1
Reactant: O=C(c1ccccc1)c1ccccc1NC(=O)C(Cl)Cl
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: NC1=Nc2ccccc2C1(O)c1ccccc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
2'-Benzoyl-2,2-dichloroacetanilide (50 g.) was suspended in 91% ethanol (750 ml) and treated with a solution of potassium cyanide (30 g) in water (50 ml). The reaction was stirred at room temperature for 40 hours. The crystalline precipitate was filtered off and the mother liquors diluted with water to provide further crops of 2-amino-3-phenyl-3H-indol-3-ol. Total 37 g. The product could be recrystallized from acetonitrile or aqueous dimethylformamide and had a m.p. of 204°-6°C (decomp).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:24])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:7])(C)(C)C.[CH2:25]([O:32][C:33]([N:35]1[CH2:42][CH2:41][CH2:40][C@H:36]1C(O)=O)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>Cl.O1CCOCC1>[CH2:25]([O:32][C:33]([N:35]1[CH2:42][CH2:41][CH2:40][C@H:36]1[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:24])[CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)=[O:7])=[O:34])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: COc1ccc(OCC(O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(OCC(O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To (2S)-1-[t-butoxycarbonyl)-2-[1-hydroxy-2-(4-methoxyphenoxy)ethyl]pyrrolidine (14.03 g) was added 4N hydrochloric acid/1,4-dioxane (220 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness, and the residue was dissolved in DMF (100 ml), followed by condensation reaction as in Example 1-C) w i t h known N-benzyloxycarbonyl-L-proline (10.70 g) to give 11.10 g of the title compound.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[CH:7]=[C:6]2[C:14]2[N:18]([CH3:19])[C:17]3[C:20]([O:28][CH3:29])=[CH:21][C:22]([C:24]([O:26]C)=[O:25])=[CH:23][C:16]=3[N:15]=2)[CH2:3][CH2:2]1.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH:1]1([CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[CH:7]=[C:6]2[C:14]2[N:18]([CH3:19])[C:17]3[C:20]([O:28][CH3:29])=[CH:21][C:22]([C:24]([OH:26])=[O:25])=[CH:23][C:16]=3[N:15]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(OC)c2c(c1)nc(-c1cc3cccnc3n1CC1CC1)n2C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)O)cc2nc(-c3cc4cccnc4n3CC3CC3)n(C)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.9 %

Procedure:
Methyl 2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-carboxylate (260 mg, 0.666 mmol) was dissolved in a 1:1 ratio of tetrahydrofuran (THF) (3.2 mL) and water (3.2 mL). To this was added lithium hydroxide monohydrate (140 mg, 3.33 mmol) and the reaction stirred at rt for 16 h. The reaction mixture was acidified by the addition of 2M HCl(aq) (20 mL) and the organics extracted into 10% MeOH/DCM (20 mL). The aqueous layer was washed with 10% MeOH/DCM (2×20 mL) and the combined organics dried (Na2SO4) and concentrated in vacuo to afford a yellow oil which solidified on standing (44 mg). Due to the poor recovery it was assumed the remainder of the product remained in the aqueous layer. The aqueous layer was further extracted with EtOAc (20 mL), DCM (2×20 mL) and 10% MeOH/DCM (8×10 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo. Both crude products were combined together to form 2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid (105 mg, 0.279 mmol, 41.9% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[N:8]([CH2:13][CH3:14])[C:7]2=[O:15].O=P(Cl)(Cl)[Cl:18].CCN(C(C)C)C(C)C.[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:18])[N:8]([CH2:13][CH3:14])[C:7]2=[O:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1c(=O)[nH]c2c(Br)cccc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCn1c(Cl)nc2c(Br)cccc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
A mixture of 8-bromo-3-ethylquinazoline-2,4(1H,3H)-dione (736 mg, 2.74 mmol, 481b), POCl3 (1.5 mL, 16.42 mmol, Sigma Aldrich), and DIPEA (0.9 mL, 5.47 mmol) was heated to reflux. Additional DIPEA (0.9 mL, 5.47 mmol) was added. It was stirred overnight at reflux. The mixture was cooled to RT and poured into rapidly stirred water at 0° C. It was basified to pH 10 with 10 N NaOH (aq.) to give an orange solution. The solution was extracted with DCM, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a yellow orange solid (398 mg, 57%). m/z (ESI, +ve) 286.9 (M+H)+.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:15][CH:16]([Cl:20])[C:17](Cl)=[O:18]>C1C=CC=CC=1>[CH:1]([N:4]([CH:5]([CH3:7])[CH3:6])[C:17](=[O:18])[CH:16]([Cl:20])[Cl:15])([CH3:3])[CH3:2]
Reactant: CC(C)NC(C)C
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)N(C(=O)C(Cl)Cl)C(C)C

Procedure:
To a solution of diisopropylamine (6.8 g) (0.068 mol) and 6.8 g. of triethylamine in 100 ml of anhydrous benzene was added dropwise at 15° C. with stirring and ice-bath cooling, dichloroacetyl chloride (10.0 g, 0.068 mol). The solution was stirred overnight at room temperature. The benzene solution was washed successively with 10% HCl, H2O sodium hydroxide and saturated NaCl solution and was dried over anhydrous MgSO4. The solvent was distilled off, yielding 4.9 g. of liquid product, which infrared absorption spectra indicated to be substantially pure. No further purification was considered to be necessary for the purpose of this invention.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](=O)[CH3:4].BrBr.[CH3:9][CH:10]([CH3:17])[CH2:11][CH2:12][NH:13][C:14]([NH2:16])=[S:15].C([O-])(=O)C.[Na+]>CO>[CH:2]([C:3]1[N:16]=[C:14]([NH:13][CH2:12][CH2:11][CH:10]([CH3:17])[CH3:9])[S:15][CH:4]=1)([CH3:6])[CH3:1]
Reactant: CC(C)CCNC(N)=S
Reactant: CC(=O)C(C)C
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCNc1nc(C(C)C)cs1
Temperature: 25 °C
Yield: 21.2 %

Procedure:
A solution of 3-methyl-2-butanone (2.64 g) in methanol (30 ml) was cooled to −30° C. bromine (4.8 g) was added, and heated to room temperature with stirring. To the obtained colorless solution were added N-(3-methylbutyl)thiourea (2.92 g) and sodium acetate (2.40 g) and the mixture was stirred with heating under reflux for 2 hrs. The reaction mixture was concentrated, diluted with ethyl acetate and washed with water. The ethyl acetate layer was concentrated, and the residue was purified by silica gel column chromatography with ethyl acetate-hexane (gradient of 1:9 to 2:1 by volume ratio) to give the title compound (0.90 g, yield 21%) as a yellow oil.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([NH:12][C:13](=[NH:17])[NH:14][CH2:15][CH3:16])=[O:11].[CH3:18]OC(OC)N(C)C>CC#N>[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:18]=[N:17][C:13]([NH:14][CH2:15][CH3:16])=[N:12][C:10]1=[O:11]
Reactant: COC(OC)N(C)C
Reactant: CCNC(=N)NC(=O)Nc1ccccc1C
Agent: Cl
Solvent: CC#N
Product: CCNc1ncn(-c2ccccc2C)c(=O)n1

Procedure:
To a magnetically stirred suspension of 9.02 g (35.2 mmol) of 1-(2-methylphenyl)-3-ethylamidinourea hydrochloride in 30 ml of CH3CN, was added 8.40 g (70.5 mmol) of N,N-dimethylformamide dimethylacetal and 20 ml of CH3CN. All of the solid dissolved. The reaction mixture was refluxed for two hours, allowed to come to ambient temperature, and partitioned between CHCl3 and H2O.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[CH:8][C:7]=1[Cl:30].[OH-].[Na+].Cl>C(O)C>[Br:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([C:23]2[CH:24]=[CH:25][C:26]([Br:29])=[CH:27][CH:28]=2)=[CH:14][CH2:13][S:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:31])=[O:2])=[C:7]([Cl:30])[CH:8]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)COc1ccc(SCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1ccc(SCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)cc1Cl
Temperature: 5 °C
Reaction time: 18 h

Procedure:
{4-[3,3-Bis-(4-bromo-phenyl)-allylsulfanyl]-2-chloro-phenoxy}-acetic acid methyl ester (350 mg, 0.6 mmol, example 23) was dissolved in ethanol (10 ml). 1N NaOH (3 ml, 3 mmol) was added at room temperature and the reaction mixture was stirred for 18 h at 5° C. after which it was treated with 1N HCl (15 ml) and extracted with dichloromethane (2×20 ml). The combined organic phases were dried and evaporated to give the title compound in 230 mg (68%) yield.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([N:33]1[CH2:34][CH2:35][CH:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[O:23][CH3:22])[CH2:31][CH2:32]1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc2c(Br)cnn2c1NCc1ccccc1
Reactant: COc1ccccc1C1CCNCC1
Product: COc1ccccc1C1CCN(C(=O)c2cnc3c(Br)cnn3c2NCc2ccccc2)CC1
Yield: 85 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-bromopyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.150 g, 0.400 mmol) obtained in step 3 and 4-(2-methoxyphenyl)piperidine (0.091 g, 0.480 mmol), the title compound (0.177 g, 80%) was obtained.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl.Cl[CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][N:22]([CH2:30][C:31]5[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=5)[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CN(Cc3ccncc3)C2=O)CC1
Yield: 68 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride (2.4 equivalents) and 4-(chloromethyl)pyridine hydrochloride, to give the desired product as a light yellow foam (68%).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=1>C(O)(=O)C.CCOC(C)=O>[O:11]=[C:1]1[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:6])[N:12]1[C:13]1[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cccc(CC(=O)O)c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)Cc1cccc(N2C(=O)c3ccccc3C2=O)c1

Procedure:
A solution of phthalic anhydride (1.2 g, 8.3 mmol) and (3-aminophenyl)acetic acid (1.0 g, 6.9 mmol) in acetic acid (25 mL) was heated to reflux for 16 hours. The reaction was cooled, and diluted with 25 mL of EtOAc. A lot of solids crashed out from the solution. The solids were collected by filtration, and identified as the desired [3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]acetic acid. LC-MS (IE, m/z): 282 [M+1]+.