Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH:10]([C@H:13]1[O:22][C@@H:16]2[O:17][C:18]([CH3:21])(C)[O:19][C@@H:15]2[CH2:14]1)[CH2:11][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:26]C(=O)C)(=[O:25])[CH3:24].S(=O)(=O)(O)O>C(O)(=O)C.C(Cl)(Cl)Cl.CCOC(C)=O>[C:1]([O:9][CH:10]([C@@H:13]1[CH2:14][C@@H:15]([O:19][C:18](=[O:17])[CH3:21])[CH:16]([O:26][C:23](=[O:25])[CH3:24])[O:22]1)[CH2:11][CH3:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(OC(=O)c1ccccc1)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCC(OC(=O)c1ccccc1)[C@@H]1C[C@@H](OC(C)=O)C(OC(C)=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propyl benzoate (compound 26a, 6.73 g, 22.0 mmol) and acetic anhydride (11 mL) in acetic acid (44 mL) and chloroform (11 mL) was added concentrated sulfuric acid (200 uL) dropwise. After being stirred at room temperature overnight, the resulted mixture was diluted with EtOAc (100 mL) and washed with a saturated aqueous solution of NaHCO3 (100 mL) three times. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:20 to 1:10 EtOAc in petroleum ether) to afford 5.1 g 1-[(2S,4R)-4,5-diacetoxytetrahydrofuran-2-yl]propyl benzoate (compound 26b) as a viscous oil.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[N:23]1([C:29]([N:31]2[CH2:36][CH:35]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=3)[CH2:34][CH:33]([C:47]([NH2:49])=O)[CH2:32]2)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[N:23]1([C:29]([N:31]2[CH2:36][CH:35]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=3)[CH2:34][CH:33]([C:47](=[S:10])[NH2:49])[CH2:32]2)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: NC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
45 mg (0.11 mmol) of Lawesson reagent (2,4-bis[4-methoxyphenyl] 1,3-dithia-2,4-diphosphetane 2,4-disulphide) were added to a solution of 10 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxamide (Example 52A) in 1 ml of dioxane, and the reaction mixture was stirred at 60° C. for 30 minutes and then at room temperature for 3 h. After addition of saturated aqueous sodium bicarbonate solution and removal of the dioxane, the residue was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure. This gave 43 mg (100% of theory) of crude product, which was reacted without any further purification steps.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[CH2:17]([O:16][C:14]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([Cl:7])[CH:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#Cc1ccc(O)cc1Cl
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
Potassium carbonate (66.3 g, 480 mmol) was added to a mixture of 2-chloro-4-hydroxybenzonitrile (25 g, 160 mmol) and benzyl bromide (19.3 mL, 161 mmol) in acetonitrile (300 mL) and the mixture was stirred for 18 hours at room temperature. The reaction mixture was then filtered and the filtrate was concentrated in vacuo. Trituration of the residue with heptanes afforded the title compound as an off-white solid in 99% yield, 38.65 g.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH:18]([OH:24])[CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])[C:9]=2[C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].Cl>CO>[OH:24][CH:18]([CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])[CH2:17][O:16][C:12]1[C:9]2[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[O:7][C:8]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1oc2cccc(OCC(O)CNC(C)C)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)O)oc2cccc(OCC(O)CNC(C)C)c12
Reaction time: 8 h
Yield: 86.2 %

Procedure:
A solution of 4-(2-hydroxy-3-isopropylamino-propoxy)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (100 mg) in methanol (5 ml) was treated with 5 N NaOH solution (1 ml) at room temperature, and the resulting mixture was stirred overnight at the same temperature. The solution was acidified with 1N HCl solution (6 ml) and concentrated in vacuo. The residue was dissolved in H2O and passed through Sep-Pak Cartridge (C18) which was developed with H2O-MeOH. The fractions containing the target compound were collected and concentrated in vacuo to give 4-(2-hydroxy-3-isopropylamino-propoxy)-3-methyl-benzofuran-2-carboxylic acid (79 mg) as a white powder. FAB-MS: m/z 308 (MH+); 1H-NMR (DMSO-d6): δ 1.05 (6H, d, J=6 Hz), 2.65 (3H, s), 2.73 (1H, dd, J1=12 Hz, J2=7 Hz), 2.86 (2H, m), 3.99 (1H, m), 4.16 (2H, d, J=5 Hz), 6.68 (1H, d, J=8 Hz), 7.01 (1H, d, J=8 Hz), 7.17 (1H, t, J=8 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[CH:6][C:5]=1[CH3:18])([O-])=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:31].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:31].[ClH:31].[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[CH:6][C:5]=1[CH3:18]
Reactant: Cc1cc(NCCCCCCO)ccc1[N+](=O)[O-]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Cc1cc(NCCCCCCO)ccc1N

Procedure:
The 6-(4-nitro-3-methylphenylamino)hexan-1-ol (9) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]CC)=O.[CH3:13][C:14]1([CH3:26])[CH2:19][CH:18]([CH3:20])[CH2:17][CH:16]([CH3:21])[N:15]1[CH2:22][CH2:23][CH2:24][NH2:25]>>[CH3:26][C:14]1([CH3:13])[CH2:19][CH:18]([CH3:20])[CH2:17][CH:16]([CH3:21])[N:15]1[CH2:22][CH2:23][CH2:24][NH:25][C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: CC1CC(C)N(CCCN)C(C)(C)C1
Reactant: CCOC(=O)CN1CCCC1=O
Product: CC1CC(C)N(CCCNC(=O)CN2CCCC2=O)C(C)(C)C1

Procedure:
From 8.5 g. of ethyl 2-oxo-1-pyrrolidineacetate and 14 g. of 3-(2,2,4,6-tetramethyl-1-piperidinyl)propylamine (U.S. Pat. No. 3,446,811), following the procedure of Example 9, there is obtained N-[3-(2,2,4,6-tetramethyl-1-piperidinyl)propyl]-2-oxo-1-pyrrolidineacetamide; m.p. 85°-87° C. after recrystallization from ethyl ether.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH3:13][O:14][CH2:15]CO>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH2:13][O:14][CH3:15])=[O:8])=[CH:11][CH:12]=1
Reactant: COCCO
Reactant: COC(=O)c1ccc(O)cc1
Agent: [Na]
Product: COCCOC(=O)c1ccc(O)cc1

Procedure:
In the first step (as in the Example 4) 1 g (43 mmol) of sodium was dissolved in 25 ml of 2-methoxyethanol. An amount of 3.0 g (22 mmol) of methyl 4-hydroxy-benzoate was added, producing 2-methoxyethyl 4-hydroxybenzoate, as a colourless oil, in essentially quantitative yield.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-])=O.[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[O:21]>C(OC)(C)(C)C.[Pd]>[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20](=[O:21])[NH:1][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: Cc1ccccc1N=C=O
Agent: [Pd]
Solvent: COC(C)(C)C
Product: Cc1ccccc1NC(=O)Nc1ccc(CO)cc1
Reaction time: 0.5 h

Procedure:
30.6 g (200 mmol) of 4-nitrobenzyl alcohol were hydrogenated with ice cooling over 1.0 g of palladium/carbon (10% strength; 50% water) in 500 ml of methyl tert-butyl ether. After the absorption of hydrogen was complete, the catalyst was filtered off and 24.8 ml (200 mmol) of 2-methylphenyl isocyanate were added to the filtrate at 15° C. with stirring in the course of 30 minutes. The precipitated solid was filtered off with suction and washed with methyl tert-butyl ether. Yield: 46.9 g (92%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:34]2[C:35](=[O:48])[N:36]([CH3:47])[C:37]([NH:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[N:38][CH:39]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15](CC3C=CC(OC)=CC=3)[N:16]=[C:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:10]=12>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]([C:34]2[C:35](=[O:48])[N:36]([CH3:47])[C:37]([NH:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[N:38][CH:39]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][N:16]=[C:17]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[C:10]=12
Reactant: COc1ccc(Cn2nc(-c3ccc(F)cc3)c3c(Oc4ccc(-c5cnc(Nc6ccccc6)n(C)c5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(Nc2ccccc2)ncc(-c2ccc(Oc3ccnc4[nH]nc(-c5ccc(F)cc5)c34)c(F)c2)c1=O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
5-(3-fluoro-4-(3-(4-fluorophenyl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (0.024 g, 0.037 mmol) was dissolved in TFA (1 mL) and the reaction mixture was stirred at 60° C. for 3 hours and then at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and saturated NaHCO3. The layers were separated and the aqueous layer was re-extracted with EtOAc (1×). The combined EtOAc layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography, eluting with 10:1 CH2Cl2/MeOH. The product was obtained (15.2 mg; 78%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 13.97 (br s, 1H), 9.02 (br s, 1H), 8.38 (d, 1H), 8.09 (s, 1H), 8.03 (m, 2H), 7.85 (dd, 1H), 7.69-7.48 (m, 4H), 7.38 (t, 2H), 7.32 (t, 2H), 7.17 (t, 1H), 6.38 (d, 1H), 3.58 (s, 3H). LRMS (APCI pos) m/e 523 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7])[CH3:2].S(Cl)([Cl:14])=O>CN(C)C=O>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:14])=[O:7])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCc1cccc(C(=O)O)c1
Solvent: CN(C)C=O
Product: CCc1cccc(C(=O)Cl)c1

Procedure:
3-Ethylbenzoic acid (9.40 g, 62.6 mmol) was slowly added to thionyl chloride (45 mL) at 0° C. and N,N-dimethylformamide (3 drops) was added dropwise. The obtained reaction mixture was heated under reflux for 2 hrs. The reaction mixture was concentrated and used for the next reaction without purification.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:12]([NH:20][C:21](=[O:29])[NH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.O>CN(C)C=O>[C:12]([NH:20][C:21]([NH:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)[CH2:25][CH2:24]1)=[O:29])(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)c1ccc(CCl)cc1
Reactant: O=C(NC(=O)c1ccccc1)NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ccc(CN2CCC(NC(=O)NC(=O)c3ccccc3)CC2)cc1

Procedure:
4-Isopropylbenzyl chloride (0.84 g, 0.005 m), 4-benzoylureidopiperidine (1.28 g, 0.005 m) and triethylamine (0.6 g) in dimethylformamide (25 cm3) were stirred at room temperature for 24 hours. Water was added and the precipitated solid filtered off. The solid was suspended in isopropylalcohol and acidified with ethanolic HCl. The title compound was filtered off and dried (1.2 g), m.p. 240°-242° C. as the hydrochloride salt, hemihydrate.
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[C:31]=2[Cl:40])[CH2:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][CH:5]=1.O[Li].O>O1CCCC1.O>[Cl:40][C:31]1[C:32]([C:36]([F:37])([F:38])[F:39])=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][N:14]([CH2:15][CH:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:13][CH2:12][CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:41])=[O:2])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzoic acid methyl ester (0.20 g, 0.34 mmol) in tetrahydrofuran (7.5 mL) and H2O (2.5 mL) at ambient temperature was treated with LiOH.H2O (0.029 g, 0.68 mmol). The mixture was stirred overnight at ambient temperature. The mixture was then treated with additional LiOH.H2O (0.058 g, 1.37 mmol) and heated at 50° C. overnight. The reaction was cooled to 0° C. and was quenched with H2O (5 mL). The mixture was the acidified to a pH=2 with 1 N HCl (aq.). The mixture was then extracted three times with EtOAc, dried, filtered and concentrated in-vacuo to afford the carboxylic acid product. The acid was purified via reverse-phase HPLC (TMC CombiPrep PDS, 75×30 mm, 25 mL/min, acetonitrile:H2O, UV detection at 254 nm) to yield the title compound, 0.140 g (72%); MS (ESI) m/e 569 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].C(N(CC)CC)C.[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[CH:20]=[CH:19]2.O>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][S:26]([C:21]1[CH:20]=[CH:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]([Cl:15])[CH:17]=2)[CH:22]=1)(=[O:27])=[O:28]
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Reactant: COC(CN)OC
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(CNS(=O)(=O)c1ccc2cc(Cl)ccc2c1)OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,2-dimethoxyethylamine (3 g) and triethylamine (4.318 g) in tetrahydrofuran (120 ml) was treated portionwise at 0° C. with 6-chloronaphthalene-2-sulfonyl chloride (7.45 g) and stirred at 0° C. for 30 minutes. The reaction mixture was combined with water and ethyl acetate to separate the organic phase, which was washed with an aqueous solution of citric acid and brine, dried and concentrated to obtain N-(2,2-dimethoxyethyl)-6-chloro-2-naphthalenesulfonamide as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[N:3]=1.[CH3:16][O:17][CH2:18][CH2:19][NH2:20].C(O)C>O>[Cl:8][C:6]1[CH:7]=[C:2]([NH:20][CH2:19][CH2:18][O:17][CH3:16])[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[N:5]=1
Reactant: COCCN
Reactant: Cc1ccc(-c2nc(Cl)cc(Cl)n2)cc1
Solvent: CCO
Solvent: O
Product: COCCNc1cc(Cl)nc(-c2ccc(C)cc2)n1

Procedure:
A solution of 7.2 g. of 4,6-dichloro-2-(p-tolyl)pyrimidine and 4.5 g. of β-methoxyethylamine in 35 ml. of absolute ethanol is refluxed for 15 minutes. Pouring of the resulting solution into 700 ml. of water causes separation of a gummy material which solidifies on standing. The crude product weighs 7.3 g. and recrystallization from n-heptane affords 4-chloro-6-[2-(methoxy)ethylamino]-2-(4-tolyl)pyrimidine, 70°-72°C.
Reaction SMILES: CO[C:3]([C:5]1([CH3:31])[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[N:17]=[C:18]4[C:24]([C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:23][NH:22][C:19]4=[N:20][CH:21]=3)[CH:11]=2)[CH2:6]1)=[O:4].[OH-].[K+].C(C1NC=CN=1)([C:36]1[NH:37]C=CN=1)=O.CN>CN(C)C=O.CO>[CH3:36][NH:37][C:3]([C:5]1([CH3:31])[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[N:17]=[C:18]4[C:24]([C:25](=[O:30])[C:26]([CH3:27])([CH3:29])[CH3:28])=[CH:23][NH:22][C:19]4=[N:20][CH:21]=3)[CH:11]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1(C)CCN(c2cccc(-c3cnc4[nH]cc(C(=O)C(C)(C)C)c4n3)c2)C1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: CN
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CNC(=O)C1(C)CCN(c2cccc(-c3cnc4[nH]cc(C(=O)C(C)(C)C)c4n3)c2)C1
Temperature: 65 °C

Procedure:
1-{3-[7-(2,2-Dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenyl}-3-methyl-pyrrolidine-3-carboxylic acid methylamide was prepared by treating 1-{3-[7-(2,2-dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenyl}-3-methyl-pyrrolidine-3-carboxylic acid methyl ester (190 mg, 0.3 mmol) with methanol (3 mL) and potassium hydroxide (2 mL, 0.5 M aqueous). Upon partitioning the mixture between 10% aqueous acetic acid and ethyl acetate, the desired acid (110 mg, 0.27 mmol) was dissolved in N,N-dimethylformamide (3 mL) and treated with carbonyl diimidazole (46 mg, 0.28 mmol) and heated to 65° C. for 2 hours. Methylamine (2 mL) was condensed at −20° C. in heavy-walled vessel. The mixture above was added and the vessel was immediately sealed and heated to 50° C. for 5 days. Upon cooling, the volatiles were removed in vacuo and the residue partitioned between 2% aqueous acetic acid and ethyl acetate. The combined organic layers were aged over anhydrous sodium sulfate. The title compound was obtained as a powder (26 mg) following silica gel chromatography (eluant: 40 to 100% ethyl acetate-hexanes): m.p. 252-254° C.; MS m/z 419 (M+H).
Reaction SMILES: [Cl:1]C(C=O)C(OCC)=O.BrC1C=C(Cl)N=NC=1N.Br[C:20]1[C:21]2[N:22]([C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:29]=2)[N:23]=[C:24]([Cl:26])[CH:25]=1>>[Cl:26][C:24]1[CH:25]=[C:20]([Cl:1])[C:21]2[N:22]([C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:29]=2)[N:23]=1
Reactant: CCOC(=O)C(Cl)C=O
Reactant: CCOC(=O)c1cnc2c(Br)cc(Cl)nn12
Agent: Nc1nnc(Cl)cc1Br
Product: CCOC(=O)c1cnc2c(Cl)cc(Cl)nn12
Temperature: 90 °C
Yield: 29 %

Procedure:
To a 250 mL round-bottomed flask was added ethyl 2-chloro-3-oxopropanoate (4.33 g, 28.8 mmol) and 4-bromo-6-chloropyridazin-3-amine (5 g, 23.99 mmol). The solution was heated to 90° C. for 16 hours. The solution was quenched with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was purified by ISCO (10% ethyl acetate/dichloromethane; 80 g column) to give a mixture of ethyl 8-bromo-6-chloroimidazo[1,2-b]pyridazine-3-carboxylate and ethyl 6,8-dichloroimidazo[1,2-b]pyridazine-3-carboxylate (2.1 g, 29% yield). LC/MS, m/z 256.96 (M+1). HPLC Rt, 2.54 min. LC/MS, m/z 303.92 (M+1). HPLC Rt, 2.63 min. Waters Sunfire C18 column (4.6×50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[N:41]1([CH2:47][CH2:48][NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:38])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:44]3[CH2:45][CH2:46][N:41]([CH2:47][CH2:48][NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH2:42][CH2:43]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)NCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCNS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with N-(2-piperazin-1-yl-ethyl)-methanesulfonamide dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). LR-MS: 739.3 [(M+H)+]
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[OH:8].NCC1CCN(CC2C=CC(Cl)=C(Cl)C=2)C1.[NH2:29][CH2:30][C@@H:31]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=2[Cl:44])[CH2:32]1>>[Cl:44][C:38]1[C:39]([Cl:43])=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][N:33]1[CH2:34][CH2:35][C@@H:31]([CH2:30][NH:29][C:10](=[O:12])[CH2:9][C:4]2[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=2)[CH2:32]1
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Reactant: NC[C@@H]1CCN(Cc2cccc(Cl)c2Cl)C1
Agent: NCC1CCN(Cc2ccc(Cl)c(Cl)c2)C1
Product: O=C(Cc1ccc(O)c(F)c1)NC[C@@H]1CCN(Cc2cccc(Cl)c2Cl)C1

Procedure:
Proceeding as described above but substituting 4-(2,5-dimethylphenyl)-4-oxobutyric acid with 2-(3-fluoro-4-hydroxyphenyl)acetic acid and 3-aminomethyl-1-(3,4-dichlorobenzyl)pyrrolidine with 3-(S)-aminomethyl-1-(2,3-dichlorobenzyl)pyrrolidine gave N-[1-(2,3-dichlorobenzyl)pyrrolidin-3-(S)-ylmethyl]-2-(3-fluoro-4-hydroxyphenyl)-acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O)=[CH:5]2.CCN=C=[N:25][CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30].C1C=NC2N(O)N=NC=2C=1.CN(CCCN)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH:25][CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])=[O:16])=[CH:5]2
Reactant: O=C(O)c1ccccc1-c1cc2cc(Cl)c(Cl)cc2[nH]1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)CCCN
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CN(C)CCCNC(=O)c1ccccc1-c1cc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 50 °C
Yield: 30 %

Procedure:
A mixture of crude 2-(5,6-dichloro-1H-indol-2-yl)benzoic acid (0.19 g, 0.62 mmol), WSC (0.13 g, 0.68 mmol), HOAT (0.093 g, 0.68 mmol), dimethylamino propylamine (0.13 g, 1.3 mmol) in DMF (2 ml) was heated at 50° C. for 16 h. The mixture was then poured on water and extracted with ethyl acetate. The organic phase was washed twice with water, dried over MgSO4, concentrated in vacuo and the residue was purified by column chromatography (SiO2, CH2Cl2/CH3OH/NH4OH; 9/1/0.1) to afford the title compound as an oil, which crystallised by trituration in diisopropyl ether obtaining, after filtration, 0.072 g (0.18 mmol yield 30%) of the title compound as white crystals, mp=169° C.