Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][CH:9]([CH3:11])[O:10][C:6]=2[C:5]([Cl:12])=[CH:4][CH:3]=1.Cl.[N:14]([O-])=O.[Na+].[C:18]([CH2:20][C:21]([NH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:22])#[N:19]>O.N1C=CC=CC=1>[Cl:12][C:5]1[C:6]2[O:10][CH:9]([CH3:11])[CH2:8][C:7]=2[C:2]([NH:1][N:14]=[C:20]([C:18]#[N:19])[C:21]([NH:23][C:24](=[O:25])[O:26][CH2:27][CH3:28])=[O:22])=[CH:3][CH:4]=1
Reactant: CCOC(=O)NC(=O)CC#N
Reactant: CC1Cc2c(N)ccc(Cl)c2O1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)NC(=O)C(C#N)=NNc1ccc(Cl)c2c1CC(C)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 9.18 g of 32A, 10 mL of 12N hydrochloric acid and 10 mL of water was heated on a steam bath for 1 hour, then 10 mL of water was added and the mixture was stirred at room temperature overnight. Then 30 mL of water was added, the mixture was cooled to 0° C. and stirred while a solution of 3.45 g of sodium nitrite in 10 mL of water was added dropwise over 15 minutes, then was stirred for 1 hour at 0° C. The resulting mixture was added slowly to a stirred mixture of 7.8 g of N-cyanoacetylurethane, 35 mL of pyridine and 900 mL of water, at 0° C. The resulting mixture was stirred at 0° C. for 1.5 hours, and filtered. The collected solid phase was washed with water, dried under reduced pressure and recrystallized from acetone/petroleum ether to give ethyl N-((7-chloro-2,3-dihydro-2-methyl- 4-benzofuranylhydrazono)cyanoacetyl)carbamate (32B), as a solid, m.p.: 175°-177° C. (with decomposition).
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[C:2]([N:6]([C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:7])([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)N(N)C(=O)c1ccccc1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of t-butylhydrazine hydrochloride (1 g, 0.008M) in toluene (30 ml) at room temperature was added dropwise a 50% aqueous solution of sodium hydroxide (0.64 g, 0.008M). After 15 min., the reaction mixture was cooled to 5° C. and a solution of benzoyl chloride (1.12 g, 0.008M) in toluene (5 ml) and a solution of aqueous 50% sodium hydroxide (0.64 g, 0.008M) were added dropwise simultaneously from separate addition funnels while maintaining the temperature at or below 10° C. Following the addition, the reaction mixture was warmed to room temperature and stirred for 1 hr. The reaction was diluted with hexane and the solid N'-t-butyl-N'-benzoylhydrazine was isolated by filtration.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22]([O:25][C:26]3[C:31]([F:32])=[C:30]([F:33])[C:29]([F:34])=[C:28]([F:35])[C:27]=3[F:36])(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2.[C:37]([Zn]C#N)#[N:38]>>[C:37]([C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22]([O:25][C:26]3[C:31]([F:32])=[C:30]([F:33])[C:29]([F:34])=[C:28]([F:35])[C:27]=3[F:36])(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2)#[N:38]
Reactant: N#C[Zn]C#N
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Br
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Temperature: 25 °C
Yield: 91.8 %

Procedure:
A round bottom flask was charged with perfluorophenyl 4-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (see EXAMPLE 46, STEP 1) (391 mg, 0.647 mmol), dicyanozinc (380 mg, 3.24 mmol), and palladum (0) bis(tri-tert-butylphosphine) (33.1 mg, 0.065 mmol). The flask was flushed with Ar (g), then DMAC (3235 μL) was added. A reflux condenser was attached, and the flask was lowered into a 60° C. heating bath overnight. The mixture was cooled to room temperature and diluted with water and EtOAc. A small portion of brine was added to break up an emulsion, and the layers were separated. The aq. layer was extracted with EtOAc (2×), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The product was purified by chromatography on silica gel (40 g, 0 to 30% EtOAc/Heptane) to give perfluorophenyl 4-(2-cyano-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (327 mg, 0.594 mmol) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.50 (d, J=2.2 Hz, 1 H), 8.26-8.13 (m, 1 H), 7.85 (d, J=8.5 Hz, 1 H), 7.43 (d, J=2.2 Hz, 1 H), 7.33 (dd, J=2.3, 8.8 Hz, 1 H), 6.80 (d, J=8.8 Hz, 1 H), 4.45-4.40 (m, 2 H), 3.94 (t, J=4.2 Hz, 2 H). m/z (ESI) 573.2 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClCl.[CH2:22]([O:29][C:30]([NH:32][C:33]1[S:34][CH:35]=[C:36]([C:38](=[C:42](Cl)[CH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[O:47])[C:39]([OH:41])=[O:40])[N:37]=1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:22]([O:29][C:30]([NH:32][C:33]1[S:34][CH:35]=[C:36]([C:38](=[CH:42][CH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)=[O:47])[C:39]([OH:41])=[O:40])[N:37]=1)=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(CCCC(Cl)=C(C(=O)O)c1csc(NC(=O)OCc2ccccc2)n1)OCc1ccccc1
Agent: ClCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCCC=C(C(=O)O)c1csc(NC(=O)OCc2ccccc2)n1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 67 %

Procedure:
To a solution of triphenylphosphine (284 mg) in tetrahydrofuran (4 ml) cooled at -15° C. are added a 0.85M solution of chlorine in carbon tetrachloride (1.27 ml), triethylamine (0.152 ml), and a solution of ketodiester (4) (160 mg) in tetrahydrofuran (2 ml). The mixture is warmed to room temperature, stirred for 6.5 hours, subjected to usual work-up, and silica gel chromatography to give chlorodiester (5). Yield: 67%.
Reaction SMILES: C(N(CC)CC)C.C(Cl)Cl.[O:11]([CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[C:24](\[CH3:27])/[CH2:25][OH:26])[Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>CS(C)=O>[O:11]([CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[C:24](\[CH3:27])/[CH:25]=[O:26])[Si:12]([C:15]([CH3:17])([CH3:18])[CH3:16])([CH3:14])[CH3:13]
Reactant: C/C(=C\CCCCO[Si](C)(C)C(C)(C)C)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: C/C(C=O)=C\CCCCO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 94.9 %

Procedure:
After the addition of triethylamine (36.5 ml) to a methylene chloride solution (53 ml) of Alcohol 5 (13.6 g) and cooling to 0° C., a dimethylsulfoxide solution (53 ml) of SO3-pyridine (25 g) is added thereto at 0° C. and the whole is stirred for 1.5 hours. After stirring, the resultant solution is quenched using a buffer solution (5 ml) and the organic compound is extracted three times with ethyl acetate, followed by the wash of the organic layer in a saturated saline solution and drying over anhydrous sodium sulfate. After anhydrous sodium sulfate is filtered and the solvent is distilled off under reduced pressure, the residue is separated and purified by column chromatography to produce Aldehyde 6 (12.8 g) of 94% in yield.
Reaction SMILES: C1(O)CCC1.C(N(CC)CC)C.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N+]([O-])=O)=CC=1)=[O:15].[CH3:26][S:27]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([C:39]1[CH:44]=[C:43]([O:45][CH:46]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)[N:42]=[CH:41][N:40]=1)[CH2:34][CH2:33]2)(=[O:29])=[O:28]>C(Cl)Cl>[CH:17]1([O:16][C:14]([N:49]2[CH2:50][CH2:51][CH:46]([O:45][C:43]3[CH:44]=[C:39]([N:35]4[C:36]5[C:32](=[CH:31][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:38][CH:37]=5)[CH2:33][CH2:34]4)[N:40]=[CH:41][N:42]=3)[CH2:47][CH2:48]2)=[O:15])[CH2:22][CH2:21][CH2:20]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCNCC2)ncn1
Agent: OC1CCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCN(C(=O)OC3CCC3)CC2)ncn1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of the cyclobutanol (0.48 mmol, 4 eq) and triethylamine (0.3 mL, 4.4 eq) in 1 mL of DCM, was added 4-nitrophenyl chloroformate (0.1 g, 4.2 eq) and the mixture was stirred at room temp for 17 h. This solution was then added to a vial containing 4b (0.12 mmol) and the reaction mixture was stirred for 5 h at room temperature. The solvent volume was reduced to 0.7 mL under a stream of nitrogen and the residue was purified by preparative HPLC to afford 5-1, LCMS 473.4 (MH+).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][NH2:23])=[O:21])=[CH:16][CH:15]=3)[C:10]([CH3:13])=[CH:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[Cl:24][CH2:25][C:26](OCC)(OCC)OCC>>[Cl:24][CH2:25][C:26]1[O:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:9]3[C:10]([CH3:13])=[CH:11][CH:12]=[C:7]([C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:6])[CH:8]=3)=[CH:15][CH:16]=2)=[N:22][N:23]=1
Reactant: CCOC(CCl)(OCC)OCC
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NN)cc1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CCl)o2)cc1

Procedure:
N-Cyclopropyl-4′-(hydrazinocarbonyl)-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 40) (150 mg) in 2-chloro-1,1,1-triethoxyethane (5 ml) was heated at 150° C. for 18 hours. The reaction was applied to a biotage cartridge (silica, 90 g) and eluted with an ethyl acetate/cyclohexane gradient. The product fractions were reduced to dryness under vacuum to give 4′-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]1([CH:14]([N:18]2[CH:22]=[C:21](B3OC(C)(C)C(C)(C)O3)[CH:20]=[N:19]2)[CH2:15][C:16]#[N:17])[CH2:13][CH2:12][CH2:11][CH2:10]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.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:1][C:2]1[N:7]=[C:6]([C:21]2[CH:20]=[N:19][N:18]([CH:14]([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[CH2:15][C:16]#[N:17])[CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC1(C)OB(c2cnn(C(CC#N)C3CCCC3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: N#CCC(C1CCCC1)n1cc(-c2ccnc(Cl)n2)cn1
Temperature: 100 °C
Yield: 67.3 %

Procedure:
A mixture of 2,4-dichloropyrimidine (0.28 g, 1.9 mmol), 3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile (0.500 g, 1.59 mmol), tetrakis(triphenylphosphine)palladium (100 mg, 0.1 mmol), and potassium phosphate (1.0 g, 4.8 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was heated at 100° C. overnight. After cooling to room temperature, the mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, concentrated. The residue was purified on silica gel, eluting with 0 to 80% EtOAc in hexanes, to give the desired product (323 mg, 67%). LCMS (M+H) 302.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.O/[N:53]=[C:54](\[NH2:62])/[CH2:55][S:56]([CH2:59][CH2:60][CH3:61])(=[O:58])=[O:57]>ClCCl.O>[NH2:62]/[C:54](=[N:53]\[O:10][C:9]([C@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:21])=[O:11])/[CH2:55][S:56]([CH2:59][CH2:60][CH3:61])(=[O:58])=[O:57]
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Reactant: CCCS(=O)(=O)C/C(N)=N/O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: CCCS(=O)(=O)C/C(N)=N/OC(=O)[C@H](CCCC1CCCCC1)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.8 %

Procedure:
A solution of (2R)-2-(2-tert-butoxy-2-oxoethyl)-5-cyclohexylpentanoic acid (Preparation 1) (500 mg, 1.67 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (354 mg, 1.85 mmol), N-methylmorpholine (203 □1,1.85 mmol) and 1-hydroxybenzotriazole hydrate (227 mg, 1.67 mmol) in dichloromethane (20 ml) was treated with (1Z)-N′-hydroxy-2-(propylsulfonyl)ethanimidamide (300 mg, 1.67 mmol) and stirred at room temperature for 18 hours. The reaction mixture was diluted with water (10 ml) and stirred for 20 minutes. The layers were separated via a 5 micron filter cartridge. The organic solvent was removed under reduced pressure to afford the title compound as a yellow solid (760 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:20](=O)[CH3:21])[C:15](OCC)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][NH2:24]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:15](=[O:16])[NH:23][NH:24][C:20]=2[CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(C(C)=O)C1CCN(C(=O)OC(C)(C)C)CC1
Product: Cc1[nH][nH]c(=O)c1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
A solution of 595 mg (1.9 mmol) of ethyl 2-(R/S)-(1-tert-butoxycarbonyl-piperidin-4-yl)-3-oxo-butanoate (from Step B) and 0.06 mL (1.9 mmol) of hydrazine in 10 mL of xylenes was heated at reflux for 2 h. The resulting mixture was cooled to rt and the solid that precipitated was filtered and dried to afford the title compound. 1H-NMR (500 MHz, CD3OD) δ 1.45 (s, 9H), 1.60 (app d, J=12.0, 2H), 1.83 (dq, J=4.0, 13.0, 2H), 2.14 (s, 3H), 2.52–2.58 (m, 1H), 2.65–2.85 (br s, 2H), 4.13 (d, J=13.5, 2H), 4.81 (s, 2H).
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.Cl[C:18](Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[N:2]([C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5])=[C:18]=[O:20]
Reactant: COC(=O)C(C)(C)N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)N=C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of the methyl 2-amino-2-methylpropanoate hydrochloride(65.5 g) in THF (650 mL) was treated with triethylamine (60 mL), heated to reflux, stirred for 30 minutes, cooled to room temperature, treated dropwise with a solution of triphosgene (43.2 g) in THF (250 mL) over 5 minutes, heated to reflux, stirred for 4 hours, cooled to 15° C., treated with triethylamine (120 mL) over 7 minutes, heated to reflux, stirred for 40 minutes, cooled to room temperature, and filtered. The solid was washed with THF and the filtrate was collected to provide a solution of methyl 2-isocyanato-2-methylpropanoate in THF.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=1)=O.[C:15]([NH:17][C:18]([NH2:20])=[NH:19])#[N:16].C[O-].[Na+].Cl>C(O)C.CO>[CH3:13][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([C:5]2[CH:4]=[CH:3][N:20]=[C:18]([NH:17][C:15]#[N:16])[N:19]=2)[CH:12]=1
Reactant: N#CNC(=N)N
Reactant: Cc1ccnc(C(=O)C=CN(C)C)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: Cc1ccnc(-c2ccnc(NC#N)n2)c1
Yield: 37.5 %

Procedure:
To a suspension of 3-dimethylamino-1-(4-methylpyridin-2-yl)prop-2-en-1-one (0.78 g) and cyanoguanidine (1.38 g) in ethanol (8 ml) was added a solution of sodium methoxide in methanol (28%, 1.49 ml), and the mixture was refluxed for 2 hours. The mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate and tetrahydrofuran (3:1). The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 75 g, 10% methanol in dichloromethane). The solid obtained was triturated with 2-propanol, filtered and dried to give N-(4-(4-methylpyridin-2-yl)-pyrimidin-2-yl)cyanamide (325 mg).
Reaction SMILES: [C:1]([C@@H:4]1[CH2:7][C@H:6]([C:8]([OH:10])=[O:9])[C:5]1([CH3:12])[CH3:11])(=[O:3])[CH3:2].C1COCC1.C1CCC(N=C=NC2CCCCC2)CC1.[C:33](O)([CH3:36])([CH3:35])[CH3:34]>CCOC(C)=O>[C:1]([C@@H:4]1[CH2:7][C@H:6]([C:8]([O:10][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:9])[C:5]1([CH3:12])[CH3:11])(=[O:3])[CH3:2]
Reactant: CC(C)(C)O
Reactant: CC(=O)[C@@H]1C[C@H](C(=O)O)C1(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)[C@@H]1C[C@H](C(=O)OC(C)(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 36 h
Yield: 70 %

Procedure:
To a stirred ice cooled solution of (1S,3R)-3-acetyl-2,2-dimethylcyclobutanecarboxylic acid (16.0 g, 94.117 mmol) in THF (160 ml) DMAP (1.148 g, 9.409 mmol) and DCC (23.265 g, 112.93 mmol) were added, followed by t-butyl alcohol (27.63 ml, 282.34 mmol) was added drop wise. The reaction mixture was stirred at room temperature for 36 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc and filtered through a celite bed and washed with EtOAc. The filtrate was as such concentrated and purified by silica gel column (100-200 mesh, elution 10% EtOAc in hexane) to afford the title compound as a solid. Wt: 15.0 g: Yield: 70%; 1H NMR (300 MHz, CDCl3): δ 2.86-2.74 (m, 1H), 2.70-2.50 (m, 2H), 2.04 (s, 3H), 1.89-1.78 (m, 1H), 1.42, 1.40 (2s, 12H), 0.91 (s, 3H); Mass: [M+Na]+ 249 (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7][CH2:6]2.[C:13](Cl)(=[O:17])[C:14](Cl)=[O:15].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10]3=[C:11]([C:13](=[O:17])[C:14](=[O:15])[N:9]3[CH2:8][CH2:7][CH2:6]2)[CH:12]=1
Reactant: COc1ccc2c(c1)CCCN2
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc2c3c(c1)C(=O)C(=O)N3CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
A solution of 6-methoxy-1,2,3,4-tetrahydroquinoline (10 g, 61.3 mmol) 600 mL CH2Cl2 was slowly added to a solution of oxalyl chloride (8.4 mL, 94.5 mmol) in 100 mL CH2Cl2 at 0° C. After addition the reaction mixture was at 0° C. for 0.5 h, aluminum chloride (24.5 g, 184 mmol) was than added to the reaction mixture, the resulting mixture was warmed up to room temperature, stirred over night. The reaction mixture was poured on ice, diluted with 1N HCl, the aqueous layer was extracted with CHCl3 (3×150 mL), the combined organic layers was washed with brine, dried over Na2SO4. The solvent was concentrated, the crude product was purified by flash chromatography (Hexane/EtOAc), obtained 10.0 g (75%) of pure title compound: 1H NMR (300 MHz, CDCl3) 2.01-2.05 (m, 2H), 2.74 (t, 2H, J=6.0 Hz), 3.73 (t, 2H, J=5.8 Hz), 3.77 (s, 3H), 6.92-6.93 (m, 2H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([C:10]#[C:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1)=[N:5]2.[F:19][C:20]1[CH:28]=[C:27](C)[CH:26]=[CH:25][C:21]=1[C:22]([OH:24])=O.Cl.[CH3:31]N(C)CCCN=C=NCC>ClC(Cl)C.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:19][C:20]1[CH:28]=[CH:27][C:26]([CH3:31])=[CH:25][C:21]=1[C:22]([NH:16][C:15]1[CH:14]=[CH:13][C:12]([C:11]#[C:10][C:6]2[CH:7]=[CH:8][C:9]3[N:4]([CH:3]=[CH:2][N:1]=3)[N:5]=2)=[CH:18][CH:17]=1)=[O:24]
Reactant: Nc1ccc(C#Cc2ccc3nccn3n2)cc1
Reactant: Cc1ccc(C(=O)O)c(F)c1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: Cc1ccc(F)c(C(=O)Nc2ccc(C#Cc3ccc4nccn4n3)cc2)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To the solution of 4-(imidazo[1,2-b]pyridazin-6-ylethynyl)aniline (93.6 mg, 0.4 mmol, 1 eq) and 2-fluoro-4-methylbenzoic acid (62.3 mg, 1 eq) in anhydrous dichloroethane (3 mL) under nitrogen atmosphere at room temperature was added 4-(dimethylamino)pyridine (10 mg, 0.2 eq) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (92.2 mg, 1.2 eq). After the reaction was stirred at 60° C. for 3 hours, it was diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, brine, and lastly dried with anhydrous sodium sulfate. The upper solution was decanted, concentrated, and the solid residue was triturated with EtOAc-Hex (2:1) to yield 2-fluoro-N-[4-(imidazo[1,2-b]pyridazin-6-ylethynyl)phenyl]-5-methylbenzamide as a slightly yellow solid in amount of 122 mg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C:13]([CH:18]([CH3:20])[CH3:19])([OH:17])[CH2:14][CH:15]=[CH2:16])[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:14]([C:13]1([CH:18]([CH3:20])[CH3:19])[O:17][C:29](=[O:31])[N:10]([C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH3:9])[CH2:11][CH2:12]1)[CH:15]=[CH2:16]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCC(O)(CCN[C@@H](C)c1ccc(Br)cc1)C(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC1(C(C)C)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.1 %

Procedure:
To a solution of 1-((S)-1-(4-bromophenyl)ethylamino)-3-isopropylhex-5-en-3-ol (802 mg, 2.366 mmol) and triethylamine (139 mg, 2.366 mmol) in CH2Cl2 (20 mL) was added triphosgene (348 mg, 1.18 mmol) at 0° C. under N2, and the mixture was stirred at rt overnight. The reaction mixture was quenched with water, and extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by column chromatography to give 6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-1,3-oxazinan-2-one (480 mg, 56% yield),
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:18](I)[CH3:19].Cl>O.C1(C)C=CC=CC=1.CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH2:18][CH3:19])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(CC)c1ccc([N+](=O)[O-])cc1

Procedure:
The starting material is prepared as follows: To the mixture of 104 g ethyl 4-nitrophenyl-acetate, 350 ml dimethylformamide and 350 ml toluene, 19 g 50% sodium hydride in mineral oil are added during 3/4 hour at 10° while stirring. After 11/2 hours, 78 g ethyl iodide are added during 1 hour while stirring. After 11/2 hours, some water is added dropwise and the mixture acidified with 10% hydrochloric acid. The mixture is extracted with diethyl ether, the extract dried and evaporated, to yield the ethyl α-(4-nitrophenyl)-butyrate.