Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[CH2:11]([O:18][C:19]1[CH:26]=[C:25]([CH3:27])[C:22](C=O)=[C:21]([CH3:28])[CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+].[O:31]1CCC[CH2:32]1>>[CH2:11]([O:18][C:19]1[CH:26]=[C:25]([CH3:27])[C:22]([C:3]2[CH:4]=[CH:5][O:1][C:2]=2[CH2:32][OH:31])=[C:21]([CH3:28])[CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C1CCOC1
Reactant: c1ccoc1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Product: Cc1cc(OCc2ccccc2)cc(C)c1-c1ccoc1CO
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of furan (10.9 ml, 150 mmol) in dry tetrahydrofuran (200 ml) is added dropwise, under nitrogen, n-butyllithium (2.5 M solution in hexane, 50 ml, 125 mmol) at −78° C. When the addition is complete, the reaction is stirred for 30 minutes at −78° C. A solution of 4-benzyloxy-2,6-dimethylbenzaldehyde (23.0 g, 96 mmol) in dry tetrahydrofuran (100 ml) is added dropwise over 30 minutes. On completion of the addition, the reaction is allowed to warm to room temperature and stirring is continued for 2 hours. A solution of saturated aqueous ammonium chloride solution (300 ml) is added and the reaction mixture is extracted with dichloromethane (3×250 ml). The organic extract are combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The product, ([4-benzyloxy-2,6-dimethylphenyl]furan-2-yl)methanol (32 g) is used without further purification in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:7]=1.Br[CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.[H-].[Na+]>CN(C=O)C.CC(=O)OCC>[F:12][S:8]([F:13])([F:9])([F:10])([F:11])[C:6]1[CH:5]=[C:4]([C:14](=[O:16])[CH3:15])[CH:3]=[C:2]([O:1][CH2:18][CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:7]=1
Reactant: CC(=O)c1cc(O)cc(S(F)(F)(F)(F)F)c1
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1cc(OCCOC2CCCCO2)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
1-[3-Hydroxy-5-(pentafluorosulfanyl)phenyl]ethanone (O3.050; 700 mg) and 2-(2-bromo-ethoxy)tetrahydropyran (670 mg) were dissolved in DMF (15 ml), and sodium hydride (77 mg) was added. After stirring at RT for 2 h, the mixture was heated to 50° C. for 4 h and left to stand over the weekend. Then the DMF was drawn off and the residue was taken up in EA. The EA phase was washed with water, dried, filtered and concentrated. The crude product was purified using silica gel (100 g, n-heptane/EA 4:1). 813 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([N:11]=[C:12]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([OH:21])=[CH:16][C:15]=3[CH3:22])[N:13]=2)[CH:10]=1)=[O:4].[CH3:23][S:24]([CH2:27][CH2:28][CH2:29]OS(C1C=CC(C)=CC=1)(=O)=O)(=[O:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([N:11]=[C:12]([C:14]3[C:15]([CH3:22])=[CH:16][C:17]([O:21][CH2:29][CH2:28][CH2:27][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:18][C:19]=3[CH3:20])[N:13]=2)[CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc2nc(-c3c(C)cc(O)cc3C)nn2c1
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc2nc(-c3c(C)cc(OCCCS(C)(=O)=O)cc3C)nn2c1
Temperature: 100 °C
Yield: 70.5 %

Procedure:
To a solution of 2-(4-hydroxy-2,6-dimethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid methyl ester (0.2 g, 0.673 mmol) in acetonitrile (5 mL) is added toluene-4-sulfonic acid 3-methanesulfonyl-propyl ester (0.196 g, 0.673 mmol) and potassium carbonate (0.278 g, 2.019 mmol) at room temperature and the reaction mixture is heated at 100° C. for 16 hours. The reaction mixture is diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts are washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The crude material is purified by silica gel chromatography (combiflash purifier 24 g redisep column) and is eluted with 40-60% EtOAc in hexane to give the title compound as a light yellow solid (198 mg, 70%). LCMS m/z 418 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([S:8][CH3:9])=[N:6][N:5]2[C:10]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([NH:23]C(=O)OC(C)(C)C)[CH2:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)[N:12]=[C:4]2[C:3]=1[CH3:37].CO.Cl.O1CCOCC1>C(Cl)Cl>[CH3:1][C:2]1[C:7]([S:8][CH3:9])=[N:6][N:5]2[C:10]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([C:19]4([NH2:23])[CH2:22][CH2:21][CH2:20]4)=[CH:17][CH:18]=3)[N:12]=[C:4]2[C:3]=1[CH3:37]
Reactant: CSc1nn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c(C)c1C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: CSc1nn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2c(C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a mixture of the tert-butyl (1-{4-[7,8-dimethyl-6-(methylsulfanyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-35 (95 mg, 0.190 mmol, 1.0 eq) in DCM (1.19 mL) and MeOH (0.75 mL) was added a solution of 4 M hydrogen chloride in dioxane (0.92 mL, 3.69 mmol, 20.0 eq) and the mixture was stirred overnight at rt. The mixture was poured onto ice, made alkaline, treated with DCM and filtered through a phase separator. The volatile components of the organic phase were removed in vacuo to give 75 mg (94% yield) of the title compound.
Reaction SMILES: C([NH:4][OH:5])(=O)C.CC(C)([O-])C.[K+].C1COCC1.F[C:18]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]([N:35]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:29]3[N:30]([CH:32]=[CH:33][N:34]=3)[N:31]=2)=[CH:22][C:19]=1[C:20]#[N:21]>CN(C=O)C.CO>[CH3:50][O:49][C:46]1[CH:45]=[CH:44][C:43]([CH2:42][N:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:28]2[C:29]3[N:30]([CH:32]=[CH:33][N:34]=3)[N:31]=[C:26]([C:23]3[CH:24]=[CH:25][C:18]4[O:5][N:4]=[C:20]([NH2:21])[C:19]=4[CH:22]=3)[CH:27]=2)=[CH:48][CH:47]=1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(-c3ccc(F)c(C#N)c3)nn3ccnc23)cc1
Reactant: CC(=O)NO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2ccccc2)c2cc(-c3ccc4onc(N)c4c3)nn3ccnc23)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of acetohydroxamic acid (42 mg, 0.556 mmol) in DMF (1 mL) was added a solution of potassium t-butoxide in THF (0.56 mL, 0.56 mmol). The reaction solution was stirred at RT for 15 minutes and then a solution of 2-fluoro-5-(8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-yl)benzonitrile (25 mg, 0.056 mmol) from (1b) in DMF (1 mL) was added. The reaction solution was stirred at RT for 24 hours. The solution was diluted with methanol and purified by preparative HPLC to give 5-(8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-yl)benzo[d]isoxazol-3-amine. LC/MS, m/e 463 (M+1). HPLC Rt, 3.13 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[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([B:16]4[O:20]C(C)(C)C(C)(C)[O:17]4)=[CH:12][N:11]3[CH:25]=2)=[CH:4][CH:3]=1.Cl.C(OCC)C>CC(C)=O.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([B:16]([OH:20])[OH:17])=[CH:12][N:11]3[CH:25]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2ccc3nc(-c4ccc(Cl)cc4)cn3c2)OC1(C)C
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Solvent: CCOCC
Product: OB(O)c1ccc2nc(-c3ccc(Cl)cc3)cn2c1
Yield: 199 %

Procedure:
3.60 g of 2-(4-chlorophenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine are dissolved in 112 ml of acetone and 56 ml of water; 101 ml of 1N hydrochloric acid are added thereto, dropwise and with stirring, and the mixture is stirred at ambient temperature for 24 h. The reaction mixture is then concentrated under reduced pressure. The solid obtained is titurated with diethyl ether and recovered by filtration, and then dried in an oven under reduced pressure at 60° C. 3.12 g of compound are obtained.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([Br:26])[CH:24]=2)[NH:19][CH:18]=1)=O)C1C=CC=CC=1.Br.C(O)(=O)C>>[NH3:11].[Br:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[CH2:16][C@H:12]1[CH2:13][CH2:14][CH2:15][NH:11]1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Agent: Br
Solvent: CC(=O)O
Product: Brc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Product: N
Yield: 59.5 %

Procedure:
To 3-(1-benzyloxycarbonylpyrrolidin-2(R)-ylmethyl)-5-bromo-1H-indole (see Preparation 35B) (10.0 g, 24.2 mmol) was added dropwise hydrogen bromide/acetic acid (36% w/w) (17 ml) at 0° C., with stirring. After 50 minutes at 0° C. the solvent was removed by evaporation under reduced pressure, and the residue azeotroped with toluene. The resulting oil was partitioned between dichloromethane and 2M aqueous sodium carbonate. The separated aqueous phase was re-extracted with dichloromethane and the combined organic phases dried (Na2SO4) and evaporated under reduced pressure. Purification by column chromatography on silica gel, eluting with a gradient of dichloromethane: methanol:0.88 aqueous ammonia (95:5:0 to 95:5:2), yielded the title compound as an oil (2.01 g). Found: C,54.75; H,5.41; N,9.63. C13H15BrN2.1/5CH2Cl2 requires: C,54.84; H,5.37; N,9.67%.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1.Br[CH:23]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]2[C:36]1=[O:45])[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(N(CC)CC)C>C(#N)C>[CH2:27]([O:26][C:24]([C@H:23]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[C:36](=[O:45])[C:37]2=[CH:44][CH:43]=[CH:42][CH:41]=[C:38]2[C:39]1=[O:40])=[O:25])[CH3:28]
Reactant: CCOC(=O)C(Br)CCCCCCN1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)COc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H](CCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 80 °C
Yield: 25.8 %

Procedure:
In 100 ml of acetonitrile are dissolved 2.8 g of tert-butyl 3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate and 7.6 g of ethyl 2-bromo-8-phthalimidooctanoate, and 1.3 g of triethylamine is added to the solution. After heating at 80° C. for 3 days, the reaction solution is concentrated under reduced pressure, diluted with 200 ml of water and extracted with 200 ml of ethyl acetate. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethyl acetate (10 ml) and oxalic acid (2.8 g) are added to the residue, and 200 ml of petroleum ether is added to the solution. After shaking, the resulting solution is allowed to stand. The supernatant is removed by decantation and 150 ml of water and 200 ml of ethyl acetate are added to the precipitate. The mixture is neutralized with sodium bicarbonate and the ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The oily product is separated and purified by silica gel column chromatography to give 1.5 g of tert-butyl 3(S)-[1(R)-ethoxycarbonyl-7-phthalimidoheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate from the first fraction.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH3:2].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:21][C:22]#[N:23]>>[CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[C:21](/[C:20]2[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:18]([O:17][CH3:16])[CH:19]=2)\[C:22]#[N:23])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Reactant: COc1ccc(CC#N)cc1OC
Product: CCOC(OCC)c1ccc(/C=C(\C#N)c2ccc(OC)c(OC)c2)cc1
Yield: 89.1 %

Procedure:
4-Diethoxymethyl-benzaldehyde (4.16 g) and 3,4-dimethoxybenzyl cyanide (3.54 g) were subjected to condensation in accordance with process A of (production process 2), to thereby produce (Z)-3-(4-diethoxymethyl-phenyl)-2-(3,4-dimethoxy-phenyl)-acrylonitrile (6.54 g, yield: 89%). The thus-produced (Z)-3-(4-diethoxymethyl-phenyl)-2-(3,4-dimethoxy-phenyl)-acrylonitrile (1.84 g) was dissolved in methanol, and water and 2N sulfuric acid were added to the resultant solution, followed by stirring, to thereby produce the target product (1.20 g, yield: 82%).
Reaction SMILES: C(NC[C@@H]1C[C@H](O)C1)C1C=CC=CC=1.[OH:15][C@@H:16]1[CH2:19][C@H:18]([CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17]1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl.O>[CH3:37][S:38]([O:15][C@H:16]1[CH2:19][C@@H:18]([CH2:20][N:21]([C:22]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:28])[CH3:29])[CH2:17]1)(=[O:40])=[O:39]
Reactant: CN(C[C@H]1C[C@@H](O)C1)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: O[C@H]1C[C@@H](CNCc2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CN(C[C@H]1C[C@@H](OS(C)(=O)=O)C1)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
Intermediate 5, tert-Butyl [(cis-3-hydroxycyclobutyl)methyl]methylcarbamate (22.6 g, 105 mmol) and triethylamine (36 mL, 250 mmol) were dissolved in CH2Cl2 (50 mL). MsCl (9.75 mL, 126 mmol) was added dropwise at −20° C. under stirring in argon. The temperature was brought to ambient within 1 h. Water (100 mL) was added, and the layers were separated. The organic one was washed with water, brine, dried with Na2SO4, and evaporated. The title compound (29 g, 96%) was obtained as a yellow oil. This crude product was used for the next stage without additional purification. 1H NMR-data (DMSO-d6): 4.76-4.88 (m, 1H); 3.23 (d, 2H, CH2, J=6.6 Hz); 3.12 (s, 3H, MS); 2.76 (s, 3H, NCH3); 2.38-2.48 (m, 2H); 2.00-2.12 (m, 1H); 1.86-97 (m, 2H); 1.38 (s, 9H, Boc).
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=O)=[CH:13][CH:12]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([N:17]([OH:19])[C:14]2[CH:13]=[CH:12][C:11]([N:5]3[CH:6]=[N:7][C:8]4[C:4]3=[N:3][CH:2]=[N:1][CH:9]=4)=[CH:16][CH:15]=2)=[O:29])=[CH:23][C:22]=1[C:30]([F:31])([F:32])[F:33]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: c1ncc2[nH]cnc2n1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)N(O)c1ccc(-n2cnc3cncnc32)cc1

Procedure:
The title compound can be synthesized from purine, 4-fluoronitrobenzene and 4-chloro-3-(trifluoromethyl)phenyl isocyanate by using the same techniques as in Example 45.
Reaction SMILES: [C:1]([C:9]1[CH:13]=[C:12]([CH3:14])[N:11]([CH:15]([CH3:18])[CH2:16][OH:17])[C:10]=1[CH3:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.C(Cl)(Cl)Cl>C(Cl)Cl>[C:20]([O:17][CH2:16][CH:15]([N:11]1[C:12]([CH3:14])=[CH:13][C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]1[CH3:19])[CH3:18])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc(C(=O)c2ccccc2)c(C)n1C(C)CO
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cc(C(=O)c2ccccc2)c(C)n1C(C)COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.8 %

Procedure:
In 10 ml of methylene chloride were dissolved 140 mg (0.54 mmole) of 2-(3-benzoyl-2,5-dimethylpyrrol-1-yl) 2-methylethanol and 383 mg (2.75 mmoles) of benzoyl chloride. Triethylamine (1 ml) was added to the solution, and the mixture was stirred at room temperature for 20 hours. Chloroform was added to the reaction mixture. The mixture was washed with dilute hydrochloric acid and then with an aqueous solution of sodium hydrogen carbonate, and the resulting extract was dried over anhydrous magnesium sulfate, and concentrated to afford 860 mg of a crude product. The product was chromatographed on a column of silica gel using cyclohexane/ethyl acetate (3/1) as an eluent to afford compound (314) (150 mg, 0.42 mmole, 77.8%).
Reaction SMILES: C[CH:2]([N:11](C([O-])=O)[C:12]([O:14][C:15](C)(C)C)=[O:13])[C:3]1[C:4]([CH3:10])=[N:5][C:6]([Cl:9])=[CH:7][CH:8]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:15][O:14][C:12](=[O:13])[NH:11][CH2:2][C:3]1[C:4]([CH3:10])=[N:5][C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: Cc1nc(Cl)ccc1C(C)N(C(=O)[O-])C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)NCc1ccc(Cl)nc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl methyl[(6-chloro-2-methylpyridin-3-yl)methyl]imidodicarbonate (830 mg, 2.64 mmol) was taken up in a mixture of CH2Cl2 (8.0 ml) and TFA (2.0 ml) and stirred at room temperature for 1 h. The solution was concentrated, diluted with EtOAc, and washed with saturated NaHCO3. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Flash chromatography (25-100% EtOAc/hexanes) afforded the title compound as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][C:28]#[N:29])=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:30]=[N+:31]=[N-:32].[Na+].Cl>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][C:28]4[NH:32][N:31]=[N:30][N:29]=4)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCC#N)ccc23)CC1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCc4nnn[nH]4)ccc23)CC1
Temperature: 100 °C
Reaction time: 6.5 h
Yield: 44.8 %

Procedure:
A mixture of 4-[7-(3-Cyano-propoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester (24.5 mg, 62 μmol), as prepared in the preceding step, NaN3 (13.4 mg, 206 μmol), TEA.HCl (25.5 mg, 185 μmol), and toluene (100 μL) was tightly capped and stirred at 100° C. for 6.5 hr. The reaction was then allowed to cool to rt, partitioned with EtOAc (1 mL) and 0. 1 M HCl (1 mL). The aqueous layer was then extracted with EtOAc (2×1 mL), the organic layers were combined, dried (Na2SO4), and concentrated. The residue was purified via flash silica chromatography (3:2 EtOAc/acetone) to yield the title intermediate as an off-white solid (12.2 mg, 44%). LC/MS (ESI) calcd mass 439.2, found 440.1 (MH)+.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.Cl[C:16]1[N:21]=[N:20][C:19]([Cl:22])=[C:18]2[CH:23]=[N:24][CH:25]=[CH:26][C:17]=12.CCN(C(C)C)C(C)C.CN1C(=O)CCC1>O>[Cl:22][C:19]1[C:18]2[CH:23]=[N:24][CH:25]=[CH:26][C:17]=2[C:16]([N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3][C@H:2]2[CH3:1])=[N:21][N:20]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Clc1nnc(Cl)c2cnccc12
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1nnc(Cl)c2cnccc12
Temperature: 100 °C
Yield: 2 %

Procedure:
To (R)-tert-butyl 3-methylpiperazine-1-carboxylate (3.30 g, 16.5 mmol) and 1,4-dichloropyrido[4,3-d]pyridazine 3 (3.00 g, 15.0 mmol), suspended in Hünig's base (9.14 ml, 52.5 mmol) was added NMP (6 ml). The reaction was stirred at 100° C. The reaction contents were poured into water (120 mL) and extracted with dichloromethane (3×50 mL). Silica gel chromatography (gradient elution 20 to 80% EtOAc in hexanes) afforded 110 mg of (R)-tert-butyl 4-(4-chloropyrido[4,3-d]pyridazin-1-yl)-3-methylpiperazine-1-carboxylate 26 eluting after the 1-substitution product. 1H NMR (500 MHz, CDCl3) δ ppm 9.66 (s, 1H) 9.06 (d, J=6.1 Hz, 1H) 7.77 (d, J=5.5 Hz, 1H) 3.28-4.23 (m, 7H) 1.51 (s, 9H) 1.28 (d, J=6.7 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH3:20])[C:10]([NH:12][C:13]([NH:15]C(C)(C)C)=[O:14])=[NH:11].Cl>>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:9]([CH3:20])[C:10]([NH:12][C:13]([NH2:15])=[O:14])=[NH:11]
Reactant: Cc1cccc(C)c1N(C)C(=N)NC(=O)NC(C)(C)C
Agent: Cl
Product: Cc1cccc(C)c1N(C)C(=N)NC(N)=O

Procedure:
A mixture of 27 g. (0.106 mole) of 1-(2,6-dimethylphenyl-N-methylamidino)-3-(t-butyl)urea and 200 ml. of conc. hydrochloric acid is refluxed for 178 hour. The reaction mixture is cooled, the precipitated solid filtered and washed with 10 ml. of 1:1 HCl/H2O and dried. The product is then recrystallized from ethanol-ether to obtain 1-(2,6-dimethylphenyl-N-methylamidino)urea.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[N:10]=[C:11]([N:20]([CH:28]2[CH2:30][CH2:29]2)[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:12]2[N:13]([C:15]([CH:18]=[O:19])=[CH:16][N:17]=2)[CH:14]=1.[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33]>CN(C=O)C.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.[Cu]I>[CH:28]1([N:20]([C:11]2[C:12]3[N:13]([C:15]([CH:18]=[O:19])=[CH:16][N:17]=3)[CH:14]=[C:9]([C:36]#[C:35][Si:32]([CH3:34])([CH3:33])[CH3:31])[N:10]=2)[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:30][CH2:29]1
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N(c1nc(Br)cn2c(C=O)cnc12)C1CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(c1nc(C#C[Si](C)(C)C)cn2c(C=O)cnc12)C1CC1
Temperature: 65 °C
Yield: 70.7 %

Procedure:
Triethylamine (912 μL, 6.56 mmol) was added to tert-butyl 6-bromo-3-formylimidazo[1,2-a]pyrazine-8-yl(cyclopropyl)carbamate (250 mg, 0.66 mmol) dissolved in anhydrous DMF (2.2 mL) in a 15 mL pressure tube. The solution was degassed with a stream of N2 for 10 min. Trimethylsilylacetylene (927 μL, 6.56 mmol), Pd(PPh3)4 (76 mg, 0.07 mmol), and copper(I) iodide (25 mg, 0.13 mmol) were added and the reaction was sealed and heated to 65° C. for 24 h. The reaction was diluted with EtOAc (50 mL) and then washed with 10% brine (4×50 mL) and brine (50 mL). The organics were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified via flash column chromatography (30% EtOAc/hexanes) to give tert-butyl cyclopropyl(3-formyl-6-((trimethylsilyl)ethynyl)imidazo[1,2-a]pyrazin-8-yl)carbamate (186 mg, 71%) as a brown foamy solid. LCMS (ES): >95% pure, m/z 400 [M+1]+.