Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][O:11][CH3:12])[C:4]=1[O:13][CH3:14].C([Li])CCC.C(O[B:24]1[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]1)(C)C>C(OCC)C>[CH3:14][O:13][C:4]1[C:5]([O:9][CH2:10][O:11][CH3:12])=[C:6]([B:24]2[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: COCOc1cccc(OC)c1OC
Agent: [Li]CCCC
Solvent: CCOCC
Product: COCOc1c(B2OC(C)(C)C(C)(C)O2)ccc(OC)c1OC
Temperature: -78 °C
Reaction time: 2 h

Procedure:
The MOM-protected phenol 1a (10 g; 0.0505 mol) was dissolved in 1000 ml of dry diethyl ether and cooled to −78° C. A solution of n-butyl lithium (22.2 ml of 2.5 M) was then added via syringe. The cooling bath was removed and the solution was allowed to warm to room temperature. After stirring the solution at room temperature for two hours, a yellow precipitate was observed. The mixture was cooled to −78° C., and 15 ml of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.080 mol) was added via syringe. The cooling bath was removed after two hours. Stirring was continued for four hours at room temperature. The mixture was then poured into 300 ml of water and extracted several times with diethyl ether (3×300 ml), dried (Na2SO4), and concentrated to a yellow oil (12.37 g, 76%) that was used without further purification: 1H NMR: (300 MHz, CDCl3): 7.46 (d, 1H, J=8.4 Hz); 6.69 (d, 1H, J=8.4 Hz); 5.15 (s, 2H); 3.87 (s, 3H); 3.83 (s, 3H); 1.327 (s, 12H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[OH-:9].[Na+]>>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]([NH2:2])=[O:9]
Reactant: [OH-]
Reactant: N#Cc1ccccn1
Agent: [Na+]
Product: NC(=O)c1ccccn1

Procedure:
As to preparative methods for these compounds, cyanopyridines have frequently been hydrolyzed in batch and continuous processes with catalytic to stoichiometric excesses of a base. A majority of the methods reported have been batch processes. For example, 4-cyanopyridine in the presence of sodium hydroxide at a molar ratio of 1:(0.03-0.075) and at 120°-170° C. is reported to give isonicotinamide. See U.S.S.R. SU 1,553,531 (1990); CA:113:78174f (1990). Similarly, 2-cyanopyridine is reported to react with sodium hydroxide at a molar ratio of 1:(0.03-0.20) and at temperatures ranging from 100°-130° C. to give 2-picolinamide. See U.S.S.R. SU 1,553,530 (1990); CA:113:78173e (1990). With a molar ratio of 4-cyanopyridine:sodium hydroxide of 1:(1.5-1.75) and a hydrolysis temperature of 50°-80° C., the reported hydrolysis product was isonicotinic acid. See U.S.S.R. SU 1,288,183; CA:106:176187n (1987). The hydrolysis of 3-cyanopyridine with excess ammonia at 107°-109° C. for 12 hours was reported to give mixtures of nicotinamide and niacin. See J. Am Chem. Soc. 65, at pages 2256-7 (1943). In still another variation, the hydrolysis of 3-cyanopyridine has been reported with a polymeric base, Dowex 1X4 (in the hydroxide form), to yield nicotinamide. See Dutch Patent Application No. 7706612-A; CA:90:186814e. U.S. Pat. No. 4,314,064 describes the continuous hydrolysis of 3-cyanopyridine with 0.3 to 3.0 moles of an alkali metal hydroxide for each 100 moles of cyanopyridine at pressures of between 3 to 20 bars and with heating or cooling to maintain the prescribed reaction temperature. Similarly, 3-cyanopyridine is reported to react in a continuous process with aqueous ammonia at a molar ratio of 1:0.5 and a contact time of 40-50 minutes at 200°-260° C. to give nicotinamide. See Journal of Applied Chemistry of the USSR (English Translation: 45:2716-2718 (1972).
Reaction SMILES: [C:1]1([O:7][C:8](=[O:34])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][C:27]=3[F:33])[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43]([C:45]2([C:48](O)=[O:49])[CH2:47][CH2:46]2)=[O:44])=[CH:38][CH:37]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]1([O:7][C:8](=[O:34])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:48]([C:45]4([C:43](=[O:44])[NH:42][C:39]5[CH:38]=[CH:37][C:36]([F:35])=[CH:41][CH:40]=5)[CH2:46][CH2:47]4)=[O:49])=[CH:28][C:27]=3[F:33])[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: Nc1ccc(Oc2ccnc(N(C(=O)Oc3ccccc3)C(=O)Oc3ccccc3)c2)c(F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reaction time: 8 h
Yield: 43 %

Procedure:
A crude product of [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (1.617 g) was dissolved in N,N-dimethylformamide (25 ml). 1-(4-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid (1.26 g), triethylamine (0.786 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.49 g) were added thereto under a nitrogen atmosphere at room temperature, followed by stirring overnight. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (3 times) and brine in this order and dried over anhydrous sodium sulfate. The solvent was removed to give residue, which was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=1:1) to provide the titled compound as white powder (1.007 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:16]=[C:15]([C:17]([OH:19])=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1.Cl.[CH3:21][O:22][C:23]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:16]=[C:15]([C:17]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:23]=4[O:22][CH3:21])[CH2:28]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1
Reactant: COc1ccc2c(c1OC)CCNC2
Reactant: O=C(O)c1nc(-c2cccnc2)nc2ccccc12
Agent: Cl
Product: COc1ccc2c(c1OC)CCN(C(=O)c1nc(-c3cccnc3)nc3ccccc13)C2
Yield: 7 %

Procedure:
Reaction of 2-(3-pyridinyl)quinazoline-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 86 (7% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.73 and 2.99 (2t, 2H), 3.51 and 4.03 (2t, 2H), 3.68-3.81 (4s, 6H), 4.44 and 4.94 (2s, 2H), 6.62 and 7.01 (2d, 1H), 6.80 and 7.08 (2d, 1H), 7.59-8.22 (m, 5H), 8.76-8.83 (m, 2H), 9.61-9.66 (m, 1H); MS (ESI) m/z 427 ([M+H]+).
Reaction SMILES: [F:1][C@@H:2]1[CH2:4][C@H:3]1[C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:21]=[C:22]([NH2:33])[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([N+:30]([O-:32])=[O:31])[CH:24]=1>CN1C(=O)CCC1>[F:1][CH:2]1[CH2:4][CH:3]1[C:5]1[O:7][N:33]=[C:22]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([N+:30]([O-:32])=[O:31])[CH:24]=2)[N:21]=1
Reactant: O=C(O)[C@@H]1C[C@H]1F
Reactant: Cc1ccc(C(N)=NO)cc1[N+](=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2noc(C3CC3F)n2)cc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 0.05 h

Procedure:
To a stirring solution of trans-2-Fluoro-cyclopropanecarboxylic acid (0.38 g, 3.68 mmol) in anhydrous NMP (12 mL) was added 1,1′-carbonyldiimidazole (CDI) (0.59 g, 3.68 mmol). The reaction was stirred for 3 minutes. N′-hydroxy-4-methyl-3-nitrobenzimidamide (27) (0.72 g, 3.68 mmol) was added and the reaction was stirred for minutes then heated in the microwave at 120° C. for 15 minutes. The crude product was extracted with ethyl acetate. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate. The solvent was concentrated and the crude product was purified on silica gel using ethyl acetate and hexane to yield 5-(2-fluorocyclopropyl)-3-(4-methyl-3-nitrophenyl)-1,2,4-oxadiazole (129). MS m/z 264.1 (M+1)+.
Reaction SMILES: [NH2:1]OS(=O)=O.[H-].[Na+].[C:8]1(=[O:19])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][CH2:10][NH:9]1.[Na+].[Cl-]>CN(C)C=O.O1CCCC1>[NH2:1][N:9]1[CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:8]1=[O:19]
Reactant: NO[SH](=O)=O
Reactant: O=C1NCCCc2ccccc21
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NN1CCCc2ccccc2C1=O
Reaction time: 1 h

Procedure:
A solution of 2.7 g of O-amino-sulfonic acid and 1.25 g of a 55% oily suspension of sodium hydride in 30 ml of dimethylformamide and 30 ml of tetrahydrofuran was gradually added at a temperature of 10° C. to a suspension of 9.66 g (0.0176 mol) 4,5-dihydro-2-benzazepine-1(2H,3H)-one. After standing for 1 hour at room temperature the mixture was poured into a saturated aqueous solution of NaCl, then the organic layer was separated and the mother liquors were extracted with 300 ml (3×100 ml) of an 1:1 (v:v) mixture of tetrahydrofuran and dimethylformamide. The organic phases were combined and brought to dryness. The obtained residue was subsequently taken up with 500 ml of ethyl acetate and the resulting organic solution was extracted with 200 ml (5×40 ml) of a 3% aqueous solution of HCl. The acidic extract was made alkaline with 5% aqueous sodium hydroxide and subsequently extracted with ethyl acetate. After evaporating the solvent, an oily residue was obtained which was distilled under reduced pressure. Yield: 10 g. of the title compound. B.p. 120° C./0.2 mmHg
Reaction SMILES: [C:1]([CH:5]([C:8]#[N:9])[C:6]#[N:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:11][NH2:12]>C(O)CCC>[C:1]([C:5]1[C:8]([NH2:9])=[N:11][NH:12][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C(C#N)C#N
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: CC(C)(C)c1c(N)n[nH]c1N
Temperature: 25 °C
Reaction time: 19 h
Yield: 100.1 %

Procedure:
A mixture of tert-butylmalononitrile (5.01 g, 41.0 mmol) and hydrazine monohydrate (10.0 mL, 205 mmol) in 1-butanol (40 mL) was heated to reflux and stirred overnight (19 hours). The mixture was cooled to ambient temperature. Concentration afforded 6.33 g (100%) of the title compound. MS (DCI) m/z 155 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([CH3:38])[CH3:37])[C:31]=1[N:39]=[C:40]=[O:41])([CH3:29])[CH3:28].Cl>ClCCl>[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([CH3:37])[CH3:38])[C:31]=1[NH:39][C:40]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]1[CH2:10][CH2:11][C@@H:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:14]1)=[O:41])([CH3:28])[CH3:29]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: c1ccc(CN[C@H]2CC[C@@H](c3ccccc3)CC2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)c1cccc(C(C)C)c1NC(=O)N(Cc1ccccc1)[C@H]1CC[C@@H](c2ccccc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 400 mg of cis-N-benzyl-N-(4-phenylcyclohexyl)amine in 20 ml of dichloromethane were added 2 ml of pyridine and then a solution of 310 mg of 2,6-diisopropylphenylisocyanate in 5 ml of dichloromethane dropwise. The mixture was stirred at room temperature, poured into diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, aqueous sodium hydrogencarbonate solution and saturated brine and then dried over magnesium sulfate. The solvent was distilled away in vacuo to give crude crystals. The crystals were recrystallized from the mixture of ethyl acetate and hexane to give 460 mg of cis-N-(2,6-diisopropylphenyl)-N'-benzyl-N'-(4-phenylcyclohexyl)urea, melting at 153°-154° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]([CH:27]([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f61) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.OS(O)(=O)=O.[CH3:17]O>>[Br:1][C:2]1[C:3]([C:9]([O:11][CH3:17])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)c1nc(Cl)ccc1Br
Agent: O=S(=O)(O)O
Product: COC(=O)c1nc(Cl)ccc1Br
Yield: 93 %

Procedure:
To a stirred solution of 3-bromo-6-chloropyridine-2-carboxylic acid (2.00 g, 8.46 mmol) in MeOH (40 ml) was added H2SO4 (189 μl, 3.55 mmol) and the solution was heated to reflux for 16 h. The reaction was cooled and the MeOH removed under reduced pressure, the resulting solid was dissolved in EtOAc (100 ml) and washed with saturated NaHCO3 solution (2×50 ml) followed by brine (50 ml), dried (Na2SO4) and evaporated under reduced pressure to afford the title compound as an off-white solid (1.97 g, 93%) which was used without any further purification. LC-MS 98%, m/z=249.8/251.7/253.7
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:15]([O:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9].[N+:25]([O-])([OH:27])=[O:26].S(=O)(=O)(O)O>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:15]([O:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])=[CH:14][C:13]([N+:25]([O-:27])=[O:26])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COCCOc1c(OC(=O)c2ccccc2)cccc1C(=O)OC
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COCCOc1c(OC(=O)c2ccccc2)cc([N+](=O)[O-])cc1C(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
Methyl 2-{[2-(methyloxy)ethyl]oxy}-3-[(phenylcarbonyl)oxy]benzoate (8.0 g, 24.2 mmol) was added drop wise over 15 minutes to a mixture of 90% nitric acid (15 mL) and concentrated sulfuric acid (3 mL) at −5° C. The resulting mixture was stirred for an additional 15 minutes then it was poured into a mixture of ice (200 g) and dichloromethane (200 mL). The organic portion was separated, washed with saturated sodium bicarbonate solution, brine (100 mL each) dried over sodium sulfate, filtered and concentrated to give methyl 2-{[2-(methyloxy)ethyl]oxy}-5-nitro-3-[(phenylcarbonyl)oxy]benzoate (8.1 g, 21.6 mmol, 89% yield). 1H NMR (400 MHz, CDCl3): 8.63-8.62 (d, 1H), 8.27-8.26 (d, 1H), 8.21-8.19 (m, 2H), 7.69-7.67 (d, d, 1H), 7.55-7.51 (d, d, 2H), 4.26-4.24 (m, 2H), 3.96 (s, 3H), 3.58-3.56 (m, 2H), 3.12 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[CH:6][CH:5]=1.[CH3:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[C:27]=1[S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>ClCCl>[CH3:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[C:27]=1[S:34]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:6][CH:5]=1)(=[O:35])=[O:36]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: COC(=O)CCCC=C(c1ccc(CCN)cc1)c1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(S(=O)(=O)NCCc2ccc(C(=CCCCC(=O)O)c3cccnc3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3.24 g of methyl 6-(4-(2-aminoethyl)phenyl)-6-(3-pyridyl)hex-5-enoate, 2.2 g of 2,4,6-trimethylbenzenesulphonic acid chloride and 100 ml of triethylamine in 50 ml of dichloromethane is stirred for 30 minutes at ambient temperature. Then the reaction mixture is washed twice with water, dried and evaporated down. The residue is purified over a silica gel column using ethyl acetate. The crude product obtain is heated in a mixture of 32 ml of ethanol and 5 ml of 4N sodium hydroxide solution for 30 minutes to 50° to 60° C. The reaction mixture is evaporated down, the residue is taken up in 50 ml of water and washed with ethyl acetate. The aqueous phase is adjusted to pH 5 by the addition of citric acid and extracted twice with ethyl acetate. The organic phase is dried, evaporated down and the residue is chromatographed over a silica gel column using ethyl acetate. The crude product is then recrystallised from ethyl acetate/diisopropyl ether.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])[CH2:10][C@H:9]2[CH3:22])=[C:4]2[N:23]=[CH:24][CH:25]=[CH:26][C:3]=12.[Cl:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[C:30]([F:37])[CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[N:7]=[N:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[O:15])[CH2:10][C@H:9]3[CH3:22])=[C:4]3[N:23]=[CH:24][CH:25]=[CH:26][C:3]=23)=[C:30]([F:37])[CH:29]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(Cl)c2cccnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(-c2ccc(Cl)cc2F)c2cccnc12

Procedure:
Using methods described in Example 6, and starting with (R)-(4-(5-chloropyrido[2,3-d]pyridazin-8-yl)-3-methylpiperazin-1-yl)(phenyl)methanone 79 (180 mg, 489 μmol), 4-chloro-2-fluorophenylboronic acid (128 mg, 734 μmol), tetrakis(triphenylphosphine)palladium (28 mg, 24 μmol), and 2 M sodium carbonate (489 μl, 979 μmol) afforded ((R)-4-(5-(4-chloro-2-fluorophenyl)pyrido[2,3-d]pyridazin-8-yl)-3-methylpiperazin-1-yl)(phenyl)methanone 83 after chromatographic purification. MS 461.1 (calc'd) 462.1 (M+H, found).
Reaction SMILES: C(O[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:5]=1)C.O=P(Cl)(Cl)[Cl:17]>CN(C=O)C>[Cl:17][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:5]=1
Reactant: CCOc1ccnc(N2CCCC2)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1ccnc(N2CCCC2)n1

Procedure:
4-Ethoxy-2-pyrrolidin-1-ylpyrimidine (2.0 g, 10 mol) was added to 15 mL of POCl3, followed by the addition of 0.5 ml of DMF. The reaction mixture was irradiated under microwave at 160° C. for 1.5 h. Most of the solvent was evaporated in vacuo. The residue was added in portions to ice-water containing ammonia. The precipitate was filtered off. The aqueous filtrate was extracted with EtOAc. The organic phase was dried over sodium sulfate, filtered, and concentrated. The solid precipitate was combined with the crude residue and purified by silica gel column chromatography to afford the title compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH:18]=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18][NH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.9 %

Procedure:
A solution of tert-butyl 3-aminopyrrolidine-1-carboxylate (1.5 g; 8.05 mmol; 1.00 eq and 3,4-dichlorobenzaldehyde (1339.00 mg; 7.65 mmol; 0.95 eq.) in methanol (10.00 ml) and acetic acid (1.00 ml) was stirred for 30 minutes at ambient temperature, then sodium cyanoborohydride (9.66 ml; 9.66 mmol; 1.20 eq.) was added. The reaction mixture was stirred for an additional 12 hours at ambient temperature at which time the reaction was quenched by pouring into aqueous ammonia (30 mL). The resulting inorganic precipitate was filtered off, and washed with dichloromethane (50 mL). The organic layer was separated and the remaining aqueous layer was extracted with dichloromethane (50 mL×3). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The resultant oil is purified under flash chromatography using silicon column with gradient of ethyl acetate in hexanes to afford the desired intermediate, tert-Butyl 3-((3,4-dichlorobenzyl)amino)pyrrolidine-1-carboxylate (2.47 g; 7.16 mmol; 88.9%), as a clear viscous oil. LC-MS (M+H=346, obsd.=288 (M-57))
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][OH:11].Cl[C:13]1[CH:14]=[C:15]2[N:22]([CH3:23])[C:21]([CH3:25])([CH3:24])[CH2:20][N:16]2[C:17](=[O:19])[N:18]=1>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:13]1[CH:14]=[C:15]2[N:22]([CH3:23])[C:21]([CH3:25])([CH3:24])[CH2:20][N:16]2[C:17](=[O:19])[N:18]=1
Reactant: OCCc1cccc(F)c1F
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CN1c2cc(OCCc3cccc(F)c3F)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 2-(2,3-difluorophenyl)ethanol and 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [P:1]([O-:36])([O:32][CH2:33][CH2:34]Br)([O:3][CH2:4][CH:5]([O:26][C:27]1[CH:31]=[CH:30][O:29][N:28]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2].[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[P:1]([O-:36])([O:32][CH2:33][CH2:34][N+:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([O:3][CH2:4][CH:5]([O:26][C:27]1[CH:31]=[CH:30][O:29][N:28]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2]
Reactant: c1ccncc1
Reactant: CCCCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCCBr)Oc1ccon1
Product: CCCCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCC[n+]1ccccc1)Oc1ccon1
Reaction time: 11 h

Procedure:
A solution of 0.663 g of crude (2RS)-3-octadecyloxy-2-(3-isoxazolyloxy)propyl 2-bromoethyl phosphate (prepared as described in the first part of Example 2) in 4.5 ml of pyridine was heated on an oil bath kept at 60° C. for 11 hours. After allowing the mixture to cool, excess pyridine was distilled off. The residue was dissolved in 10 ml of chloroform, and the solution was heated under reflux for 1 hour. The mixture was then cooled, and the solvent was evaporated off under reduced pressure. Methanol was then added to the residue, and the resulting insoluble material was filtered off. The filtrate was concentrated by evaporation under reduced pressure, and the residue was subjected to column chromatography through 15 g of silica gel. 0.305 g of the title compound was obtained as a hygroscopic powder, melting at 49°-52° C., from the fractions eluted with a 2:1 by volume mixture of methylene chloride and methanol.