Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:16][C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[N:3]=1)[N:10]=[C:9]([CH3:14])[CH:8]=[C:7]3O.O=P(Cl)(Cl)[Cl:19].[NH4+].[OH-]>CN(C)C=O>[Cl:19][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]3[N:3]=[C:2]([CH3:1])[NH:16][C:5]3=2)[N:10]=[C:9]([CH3:14])[CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)c2c(ccc3nc(C)[nH]c32)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1cc(Cl)c2c(ccc3nc(C)[nH]c32)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 31 g. (0.146 m.) of 2,7-dimethyl-1H-imidazo[4,5-f]quinoline-9-ol and 1336 ml. (223 g. 1455 m.) of POCl3 is added dropwise 267.2 ml. of dimethylformamide. The mixture is stirred overnight at room temperature, then poured into 1000 ml. of ice. The solution is basified to pH 8.0 using conc. NH4OH, keeping the temperature below 20° C. It is then filtered, washed with H2O and air-dried. The crude product is recrystallized from 2000 ml. of MeOH, and concentrated in vacuo to yield 338 g. m.p. 314°-330° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][S:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Li+]>CO.O>[CH3:26][C:23]1[C:22]([CH2:27][S:28][CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:6]4([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]4)=[CH:14][CH:13]=3)=[CH:16][CH:17]=2)[O:25][N:24]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CSCCc4ccccc4)cc3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CSCCc1ccccc1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To 1-[4′-(3-methyl-4-phenethylsulfanylmethyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (1.13 mmol) in MeOH and H2O was added lithium hydroxide (excess) and the reaction was stirred at 70° C. for 3 hours. After acidic workup, the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:18][C:19]#[N:20]>>[C:19](/[C:18](/[C:17]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:15]([O:14][CH3:13])[CH:16]=1)=[CH:1]\[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)#[N:20]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: COC(=O)c1ccc(C=O)cc1
Product: COC(=O)c1ccc(/C=C(\C#N)c2ccc(OC)c(OC)c2)cc1
Yield: 30 %

Procedure:
Methyl 4-formylbenzoate (1.64 g) and 3,4-dimethoxybenzyl cyanide (1.77 g) were subjected to condensation in accordance with process B of (production process 2), to thereby produce the target product (0.97 g, yield: 30%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1COCC1.C(=O)([O-])O.[Na+]>[CH3:8][C:6]1[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=[C:2]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:7]=1
Reactant: COC(=O)Cc1c(C)nc(Cl)nc1-c1ccccc1
Reactant: C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Cc1c(C)nc(N2CCCCC2)nc1-c1ccccc1
Temperature: 110 °C
Yield: 67.2 %

Procedure:
A mixture of methyl 2-(2-chloro-4-methyl-6-phenylpyrimidin-5-yl)acetate (200 mg; 0.723 mmol) and piperidine (0.286 mL; 2.89 mmol) in THF (2 mL) was placed in a sealed tube and heated via microwave irradiation at 110° C. for 1 h. The reaction mixture was diluted with a saturated sodium hydrogen carbonate solution and extracted twice with ethyl acetate. The organic layers were combined, washed with brine, dried over magnesium sulphate and concentrated under vacuum. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (2-20%) in heptane to give 158 mg (63%) of methyl 2-(4-methyl-6-phenyl-2-(piperidin-1-yl)pyrimidin-5-yl)acetate. ESI/APCI(+): 326 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[N:22]=[CH:21][C:20]([CH:23]([OH:46])[CH2:24][CH2:25][O:26][C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:19][CH:18]=2)[CH:10]=1.[C:47](OC(=O)C)(=[O:49])[CH3:48].[Cl-].C(=O)(O)O.[Na+]>N1C=CC=CC=1>[C:47]([O:46][CH:23]([C:20]1[CH:21]=[N:22][C:17]([O:16][CH2:15][C:11]2[CH:10]=[C:9]([C:3]3[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[CH:14]=[CH:13][CH:12]=2)=[CH:18][CH:19]=1)[CH2:24][CH2:25][O:26][C:27]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)(=[O:49])[CH3:48]
Reactant: Cc1cccc(C)c1-c1cccc(COc2ccc(C(O)CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Reactant: CC(=O)OC(C)=O
Agent: O=C(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)OC(CCOC(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(OCc2cccc(-c3c(C)cccc3C)c2)nc1
Temperature: 65 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
1-{6-[(2′,6′-Dimethylbiphenyl-3-yl)methoxy]pyridin-3-yl}-3-(trityloxy)propan-1-ol (250 mg, 0.413 mmol) produced in Example 31 (31C) was dissolved in pyridine (3.0 mL), and acetic anhydride (0.116 mL, 1.24 mmol) was added thereto at 0° C., and then, the resulting mixture was stirred under a nitrogen atmosphere at 65° C. for 4 hours. To the reaction solution, a saturated sodium bicarbonate chloride solution was added, and the organic matter was extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, then dried over anhydrous sodium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 80:20 (v/v)), whereby the objective title compound was obtained (212 mg, yield: 79%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=[O:14])[CH2:11][CH2:10][NH:9]1)=[O:7])([CH3:4])[CH3:3].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>CO>[CH3:4][C:2]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=[O:14])[CH2:11][CH:10]=[N:9]1)=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1NCC[C@H]1C(=O)O
Solvent: CO
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1N=CC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.8 %

Procedure:
To a 50 ml round bottom flask was added (3S)-2-{[(1,1-dimethylethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (431 mg, 1.99 mmol) in methanol (15 mL), followed by iodobenzene diacetate (770 mg, 2.39 mmol). The mixture was stirred at room temperature for 10 min, and LCMS indicated the reaction was complete. The organic solvent was removed under vacuum, and the residue was taken up in 1 M aq. NaHCO3 (30 mL). The aqueous mixture was washed with DCM (3×20 mL), acidified with 6 N HCl to ˜pH 2.0, and then extracted with DCM (3×30 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under vacuum to afford (5S)-1-{[(1,1-dimethylethyl)oxy]carbonyl}-4,5-dihydro-1H-pyrazole-5-carboxylic acid (273 mg, 1.27 mmol, 64% yield) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].Cl[CH2:11][C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.[I-].[K+]>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:11][C:12](=[O:14])[CH3:13]
Reactant: Oc1ccc(F)cc1Cl
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccc(F)cc1Cl
Yield: 98 %

Procedure:
A mixture of 2-chloro-4-fluorophenol (3.00 g, 20.4 mmol), chloroacetone (2.12 mL, 26.6 mmol), potassium carbonate (4.24 g, 30.7 mmol) and potassium iodide (0.20 g, catalytic) in acetone (30 mL) was heated at reflux for 4 h, cooled and filtered. The filtrate was concentrated under reduced pressure to provide the title compound as a yellow solid (4.05 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])[NH:9][C:8]2=O.Cl.C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:34]>>[Cl:34][C:8]1[C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[N:9]=1
Reactant: COc1cccc2c(=O)[nH]c(-c3ccccc3C(F)(F)F)nc12
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1cccc2c(Cl)nc(-c3ccccc3C(F)(F)F)nc12
Yield: 89 %

Procedure:
Prepared from 8-methoxy-2-(2-trifluoromethyl-phenyl)-3H-quinazolin-4-one (1.0 g, 3.12 mmol), triethylamine hydrochloride (472 mg, 3.43 mmol), and POCl3. Purification by flash chromatography afforded a white solid (89% yield). HPLC-Method A, Rt 4.10 min, (98%), MS (m/z) 258.08 (M+H).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([CH:12]=[C:13]1[C:18](=[O:19])[CH2:17][CH2:16][CH2:15][C:14]1=O)C>>[C:1]1([N:7]2[C:14]3[CH2:15][CH2:16][CH2:17][C:18](=[O:19])[C:13]=3[CH:12]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C=C1C(=O)CCCC1=O
Reactant: NNc1ccccc1
Product: O=C1CCCc2c1cnn2-c1ccccc1

Procedure:
Prepared analogously to Example 1 starting from phenylhydrazine and 2-(dimethylaminomethylene)-cyclohexane-1,3-dione.
Reaction SMILES: [OH:1][C:2]1[C:10]2[NH:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:7]3[CH2:17][CH2:18][C:19](=[O:20])[C:5]([C:6]=23)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].O>CS(C)=O>[CH3:32][O:31][C:29]([CH2:28][O:1][C:2]1[C:10]2[NH:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:7]3[CH2:17][CH2:18][C:19](=[O:20])[C:5]([C:6]=23)=[CH:4][CH:3]=1)=[O:30]
Reactant: O=C1CCc2c(-c3ccccc3)[nH]c3c(O)ccc1c23
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)COc1ccc2c3c(c(-c4ccccc4)[nH]c13)CCC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A portion (1.09 g) of the compound obtained in Example 75 was dissolved in dimethylsulfoxide (20 ml) and to the solution were added potassium carbonate (1.14 g) and methyl bromoacetate (0.43 ml). The mixture was stirred for 1 hour at room temperature. After adding water, the reaction mixture was extracted three times with ethyl acetate. The organic layer was washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was crystallized from ether to yield 1.18 g (85%) of the titled compound as a yellowish brown powder.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH:10]([C:24]2[N:28]([CH3:29])[N:27]=[N:26][N:25]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:33]O.Cl>CO.O>[CH3:29][N:28]1[C:24]([CH:10]2[CH2:9][CH:8]([C:6]3[O:7][NH:33][C:4](=[O:3])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])=[N:25][N:26]=[N:27]1
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OCc2ccccc2)C(c2nnnn2C)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1nnnc1C1CC(c2cc(=O)[nH]o2)CCN1C(=O)OCc1ccccc1
Temperature: -40 °C
Reaction time: 0.67 h
Yield: 55.7 %

Procedure:
Benzyl 4-(3-ethoxy-3-oxopropanoyl)-2-(1-methyl-1H-tetrazol-5-yl)piperidine-1-carboxylate (0.947 g, 2.28 mmol) was dissolved in MeOH (10 mL) and cooled to −40° C. 3.8 M NaOH (0.600 mL, 2.28 mmol) dissolved in water (1 mL) was added and the reaction stirred at −40° C. for 40 min. Hydroxylamine (50% by weight in water, 0.140 mL, 2.28 mmol) was added and stirring continued for 3.5 h at −40° C. The reaction mixture was then added to a preheated 80° C. warm solution of 6 M HCl (11.40 mL, 68.38 mmol) and stirred for 20 min. The reaction mixture was partitioned between water and DCM. The aqueous phase was extracted twice with DCM and the combined organic phase was dried and evaporated. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-55% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Benzyl 2-(1-methyl-1H-tetrazol-5-yl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (488 mg, 56%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.86-1.99 (m, 1H), 2.18-2.30 (m, 1H), 2.33-2.54 (m, 2H), 3.01-3.12 (m, 1H), 3.78-4.09 (m, 5H), 5.05 (s, 2H), 5.20-5.30 (m, 1H), 5.67 (s, 1H), 7.20-7.27 (m, 2H), 7.27-7.39 (m, 3H). MS m/z 385 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[C:8]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH2:23][CH3:24])[CH:17]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.O[N:26]1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[Cl-].[NH4+].C(N(CC)CC)C>CN(C)C=O.O>[NH2:1][C:2]1[N:10]=[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[C:8]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH2:23][CH3:24])[CH:17]=2)=[CH:7][C:3]=1[C:4]([NH2:26])=[O:6]
Reactant: CCn1cc(-c2cc(C(=O)O)c(N)nc2-c2ccco2)ccc1=O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCn1cc(-c2cc(C(N)=O)c(N)nc2-c2ccco2)ccc1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.1 %

Procedure:
2-Amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinic acid (20 mg, 61.5 μmol), 1-hydroxybenzotriazole (28 mg, 183 μmol), 3-(3′-dimethylaminopropyl)-1-ethyl carbodiimide (29 mg, 187 μmol), ammonium chloride (16 mg, 299 μmol), and a suspension of triethylamine (43 μL, 309 μmol) in N,N-dimethylformamide (1.0 mL) was stirred at room temperature for 18 hours. After diluting the reaction solution with water, the resulting solid was collected by filtration and washed with water, to give the title compound (9 mg, 45%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[Br:38][C:39]1[CH:40]=[C:41]([C@H:49](O)[CH3:50])[CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1.CN(C1C=CC=CN=1)C>C1(C)C=CC=CC=1.ClCCl>[C:17]1([C:11]2([C:14]([O:16][C@@H:49]([C:41]3[CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=[C:39]([Br:38])[CH:40]=3)[CH3:50])=[O:15])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[C@@H](O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C[C@@H](OC(=O)C1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 1-(tert-butoxycarbonyl)-4-phenylpiperidine-4-carboxylic acid (3.8 g, 10.3 mmol) in a dichloromethane (5 mL) and toluene (30 mL) mixture was treated with 1,3-dicyclohexylcarbodiimide (2.96 g, 14.4 mmol) and stirred for 30 min. The suspension was cooled to 0° C. and treated with (R)-1-(3-bromo-5-(trifluoromethyl)phenyl)ethanol (2.79 g, 10.3 mmol) and dimethylaminopyridine (1.26 g, 10.3 mmol). The ice bath was removed and the suspension stirred at room temperature for 60 h. The reaction mixture was poured into pentane, filtered, and the solids washed several times with pentane. The filtrate was washed with 1 N hydrochloric acid (1×), water (2×), then 1 N sodium hydroxide, then brine (2×), dried over sodium sulfate, and concentrated. Flash chromatography on silica gel (12% ethyl acetate/hexanes) gave 4.8 g (84%) as a light yellow oil. 1H NMR (500 MHz, CDCl3) δ ppm 7.58 (s, 1H), 7.23-7.33 (m, 6H), 7.19 (s, 1H), 5.80 (q, J=6.6 Hz, 1H), 3.82-3.97 (m, 2H), 2.97-3.09 (m, 2H), 2.44-2.53 (m, 2H), 1.76-2.01 (m, 2H), 1.42 (s, 9H), 1.40 (m, 3H). Mass spec.: 558.06 (MH)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[NH:31]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[O:24])=[CH:21][CH:22]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C1CCCNCC1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1
Product: O=C(c1ccc(-c2ccc3oc(CCN4CCCCCC4)cc3c2)cc1)N1CCOCC1

Procedure:
The product from Example 23D and azepane were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.82 (m, 1H), 7.73 (d, J=8.1, 2H), 7.56 (m, 2H), 7.52 (d, J=8.1 Hz, 2H), 6.77 (s, 1H), 3.3-3.8 (m, 16H), 1.6-2.1 (m, 8H); MS (DCI) m/z 433 (M+H)+;
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]([NH2:24])=[N:15][CH:16]=[C:17]([C:19]2[CH:20]=[N:21][NH:22][CH:23]=2)[N:18]=1)[CH3:11].[H-].[Na+].[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37](OS(C)(=O)=O)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].O>CN(C=O)C>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([N:22]2[CH:23]=[C:19]([C:17]3[CH:16]=[N:15][C:14]([NH2:24])=[C:13]([O:12][C@@H:10]([C:3]4[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=4[Cl:1])[CH3:11])[N:18]=3)[CH:20]=[N:21]2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: C[C@@H](Oc1nc(-c2cn[nH]c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](Oc1nc(-c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
To a solution of 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1H-pyrazol-4-yl)-pyrazin-2-ylamine (295 mg, 0.80 mmol) in anhydrous DMF (4 mL) was added NaH (60% in mineral oil, 30.7 mg, 0.80 mmol). The mixture was stirred at ambient temperature under nitrogen for 0.5 h, and then 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (223.5 mg, 0.80 mmol) was introduced. The reaction mixture was heated to 90° C. oil bath for 0.5 h under nitrogen, and cooled to ambient temperature. Water was added slowly to the mixture, which was extracted with EtOAc, washed with brine, and dried over Na2SO4. The crude product was purified on a silica gel column to provide 4-(4-{5-amino-6-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (265 mg, 59% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([NH:19][CH2:20][CH3:21])=[N:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][CH:11]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:20]([NH:19][C:7]1[C:6]([CH2:4][OH:3])=[CH:11][N:10]=[C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1)[CH3:21]
Reactant: CCNc1nc(Nc2ccccc2)ncc1C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNc1nc(Nc2ccccc2)ncc1CO
Reaction time: 0.42 h
Yield: 38.8 %

Procedure:
A solution of 4-ethylamino-2-phenylamino-pyrimidine-5-carboxylic acid ethyl ester (109 mg, 0.38 mmol) in 6 mL of tetrahydrofuran was added dropwise to a room temperature suspension of lithium aluminum hydride (35 mg, 0.92 mmol) in 5 mL of tetrahydrofuran. After 25 minutes, an additional 30 mg of lithium aluminum hydride was added, and stirring was continued for 30 minutes. The reaction was carefully quenched with 120 μL of water, 200 μL of 15% NaOH, and 300 μL of water. After stirring for 1 hour, the white precipitate was removed by filtration washing with ethyl acetate. The filtrate was concentrated in vacuo, and the crude material was purified by flash chromatography eluting with ethyl acetate to provide 36 mg (39%) of (4-ethylamino-2-phenylamino-pyrimidin-5-yl)methanol; mp 174°-176° C.
Reaction SMILES: [H-].[Na+].[Cl-].[CH3:4][S+](C)(C)=O.[CH3:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([C:24]([C:26]4[CH:27]=[C:28]5[C:33](=[CH:34][CH:35]=4)[N:32]=[CH:31][CH:30]=[CH:29]5)=[CH2:25])=[CH:22][N:23]=3)[N:20]=2)[CH:12]=[N:11]1.[OH-].[Na+]>CS(C)=O>[CH3:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([C:24]4([C:26]5[CH:27]=[C:28]6[C:33](=[CH:34][CH:35]=5)[N:32]=[CH:31][CH:30]=[CH:29]6)[CH2:4][CH2:25]4)=[CH:22][N:23]=3)[N:20]=2)[CH:12]=[N:11]1
Reactant: C=C(c1ccc2ncccc2c1)c1cnc2ccc(-c3cnn(C)c3)nn12
Reactant: C[S+](C)(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1cc(-c2ccc3ncc(C4(c5ccc6ncccc6c5)CC4)n3n2)cn1
Reaction time: 0.5 h

Procedure:
NaH 60% (96 mg, 2.41 mmol) was introduced in a round bottom flask and placed under nitrogen. A solution of trimethylsulfoxonium chloride (372 mg, 2.84 mmol) in DMSO (4 mL) was added slowly at rt. It was stirred for 30 min until H2 releasing was over. Then, a solution of 6-{1-[6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-yl]-vinyl}-quinoline (Example 155, 100 mg, 0.284 mmol) in DMSO (3 mL) was added dropwise. The RM was stirred for 1.5 h and then poured into 1 N NaOH. It was extracted twice with EtOAc and the organics were joined and washed with brine, dried over Na2SO4 and concentrated. The residue was again taken up in EtOAc and washed with water 4 times to take away remaining DMSO then washed with brine, dried over Na2SO4 and concentrated. It was purified by preparative HPLC with acetonitrile and water (+0.1% TFA) to give the title compound as a light yellow solid (tR 1.0 min (conditions 1), MH+=367).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([CH3:32])[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]2[C:16]3[N:17]([CH:24]=[C:25]([C:27](O)=[O:28])[CH:26]=3)[N:18]=[CH:19][C:20]=2[C:21](=[O:23])[NH2:22])[C:10]1([CH3:31])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.[NH:63]([C:65]([S:67][CH3:68])=[S:66])[NH2:64]>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:8][C@@:9]1([CH3:32])[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]2[C:16]3[N:17]([CH:24]=[C:25]([C:27]([NH:64][NH:63][C:65]([S:67][CH3:68])=[S:66])=[O:28])[CH:26]=3)[N:18]=[CH:19][C:20]=2[C:21](=[O:23])[NH2:22])[C:10]1([CH3:30])[CH3:31])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CSC(=S)NN
Reactant: CC(C)(C)OC(=O)N[C@@]1(C)CC[C@@H](Nc2c(C(N)=O)cnn3cc(C(=O)O)cc23)C1(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CSC(=S)NNC(=O)c1cc2c(N[C@@H]3CC[C@](C)(NC(=O)OC(C)(C)C)C3(C)C)c(C(N)=O)cnn2c1
Reaction time: 1.5 h
Yield: 75.6 %

Procedure:
To a solution of 4-((1R,3S)-3-(tert-butoxycarbonylamino)-2,2,3-trimethylcyclopentylamino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylic acid (500 mg, 1.122 mmol, from Step 3 of Example 346). HOBT (206 mg, 1.347 mmol) and DIEA (0.490 mL, 2.81 mmol) in DMF (4 mL) were added EDCI (280 mg, 1.459 mmol) and methyl hydrazinecarbodithioate (144 mg, 1.178 mmol) at 23° C. The reaction mixture was stirred for 1.5 hrs followed by the addition of 25 mL of water. The solids were removed. The water phase was extracted with EtOAc (2×30 mL). The combined organic phase was washed with 10% LiCl solution (2×20 mL), 20 mL of brine and dried over Na2SO4. Filtration and concentration gave methyl 2-(4-(((1R,3S)-3-((tert-butoxycarbonyl)amino)-2,2,3-trimethylcyclopentyl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carbonyl)hydrazinecarbodithioate (466.5 mg, 76% yield). MS (ES+) m/z: 550.08 (M+H); HPLC retention time: 3.168 min (analytical HPLC Method F).