Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[C:2]12([C:12]3[CH:13]=[CH:14][C:15](Br)=[C:16]([CH3:18])[CH:17]=3)[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[C:20]12([C:30]3[CH:35]=[CH:34][C:33](Br)=[CH:32][CH:31]=3)[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2.Cl>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:2]12([C:12]3[CH:13]=[CH:14][C:15]([C:33]4[CH:32]=[CH:31][C:30]([C:20]56[CH2:21][CH:22]7[CH2:28][CH:26]([CH2:25][CH:24]([CH2:23]7)[CH2:29]5)[CH2:27]6)=[CH:35][CH:34]=4)=[C:16]([CH3:18])[CH:17]=3)[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1Br
Reactant: Brc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1-c1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Yield: 79 %

Procedure:
In a 1 L recovery flask, 3.19 g of magnesium (131 mmol), g of 5-(1-adamantyl)-2-bromotoluene (131 mmol), 200 mL of tetrahydrofuran and a stirrer were charged and refluxed under a nitrogen atmosphere for two hours to prepare a Grignard reagent. Next, in another 1 L recovery flask, 38.2 g of 4-(1-adamantyl)-bromobenzene (131 mmol), 9.19 mg of bis(triphenylphosphine)palladium dichloride (13.1 mmol), 300 mL of tetrahydrofuran and a stirrer were charged. A tetrahydrofuran solution, which is the above-prepared Grignard reagent, was added thereto under nitrogen flow and the mixture was refluxed for 12 hours. Then, 60 mL of 10% hydrochloric acid aqueous solution was added thereto and the mixture was refluxed for 30 minutes. After an aqueous layer was separated and removed therefrom, the reaction solution was washed with 200 mL of saturated sodium hydrogencarbonate aqueous solution, followed by removal of solvent under reduced pressure. Solid thus obtained was refined by alumina column chromatography, thus obtaining 45.1 g of 4,4′-di(1-adamantyl)-2-methyl-1,1′-biphenyl (103.5 mmol; yield: 79.0%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(O)(=O)C.O>[C:11]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Cc2ccccc2N1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)N1C(=O)Cc2ccccc21
Temperature: 25 °C
Yield: 79.2 %

Procedure:
A solution of oxindole (5.0 g, 37.5 mmol) in acetic anhydride (7.1 mL, 75.1 mmol) and acetic acid (25 mL) was refluxed for 20 h. After cooling to room temperature, the reaction mixture was diluted with water (200 mL). The resulting solids were filtered, washed with water and dried to give N-acetyl oxindole as a white solid (5.2 g, 79%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[CH:5]=[CH:4][C:3]=1[OH:12].[C:13]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Cl:11][C:6]1[CH:5]=[CH:4][C:3]([O:12][CH3:13])=[C:2]([Cl:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1c(Cl)ccc(O)c1Cl
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(Cl)c([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
To a solution of 2,4-dichloro-3-nitro-phenol (600 mg, 2.9 mmol, 1.0 eq) in acetone (30 mL), was added K2CO3 (1.2 g, 8.7 mmol, 3.0 eq) and the solution was stirred at room temperature for 30 min. Methyl iodide (1.2 g, 8.7 mmol, 3.0 eq) was added and the reaction was stirred at room temperature overnight. The reaction was filtered to remove the inorganic salts and the organic phase was evaporated in vacuo to give the title compound (550 mg, 86%).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([CH2:17][NH2:18])[CH:3]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[NH:31][N:30]=[C:29]([CH:32]3[CH2:34][CH2:33]3)[CH:28]=2)[CH:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:32]1([C:29]2[NH:30][N:31]=[C:27]([NH:26][C:24]3[CH:23]=[CH:22][N:21]=[C:20]([NH:18][CH2:17][C:4]4[CH:3]=[C:2]([F:1])[C:7]5[N:8]([CH:11]6[CH2:16][CH2:15][CH2:14][CH2:13][O:12]6)[CH:9]=[N:10][C:6]=5[CH:5]=4)[N:25]=3)[CH:28]=2)[CH2:34][CH2:33]1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: NCc1cc(F)c2c(c1)ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Fc1cc(CNc2nccc(Nc3cc(C4CC4)[nH]n3)n2)cc2ncn(C3CCCCO3)c12
Temperature: 120 °C
Yield: 62.6 %

Procedure:
A tube was charged with 270 (260 mg, 1.04 mmol), 53 (100 mg, 0.57 mmol), DIPEA (0.5 ml) in IPA (3 mL), degassed, sealed and heated at 120° C. overnight. The solvent was evaporated under reduced pressure to afford 160 mg (34%) N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-((7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)methyl)pyrimidine-2,4-diamine (272) as yellow solid: MS (ESI) m/z=449.2 [M+1]+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH2:8]([O:10][C:11]([C:13]1[CH:17]=[CH:16][S:15][C:14]=1[NH2:18])=[O:12])[CH3:9]>C(O)=O>[CH2:8]([O:10][C:11]([C:13]1[CH:17]=[CH:16][S:15][C:14]=1[NH:18][CH:1]=[O:3])=[O:12])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1ccsc1N
Solvent: O=CO
Product: CCOC(=O)c1ccsc1NC=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To acetic anhydride (4.7 ml) under ice cooling, formic acid (4.7 ml) was added dropwise, to which 2-aminothiophene-3-carboxylic acid ethyl ester (2.8 g, 16.4 mmol) was added and stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, ether was added, and the precipitate that deposited was filtered off. Ether was distilled off under reduced pressure to obtain 2-formylaminothiophene-3-carboxylic acid ethyl ester (3.0 g, 15.3 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[C:11](=[O:13])[N:10]([O:14]CC1C=CC=CC=1)[CH2:9]2)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[C:11](=[O:13])[N:10]([OH:14])[CH2:9]2
Reactant: [H][H]
Reactant: O=C1c2c(cccc2[N+](=O)[O-])CN1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc2c1C(=O)N(O)C2
Yield: 609.2 %

Procedure:
To a solution of 7-nitro-2-benzyloxy-2,3-dihydro-1H-isoindol-1-one (Compound 186B, 2.3 g, 1.2 mmol) in methanol (30 mL) in a Parr hydrogenation flask was added 200 mg of 5% Pd/C. The mixture was hydrogenated under 40 psi hydrogen pressure at room temperature overnight. The reaction mixture was filtered through a glass filter paper and the filtrate was concentrated to afford 1.2 g of the pure product (90%). 1H NMR (CDCl3, 600 MHz): δ=4.57 (s, 2 H), 5.04 (br, 2 H), 6.57 (d, J=7.8 Hz, 1 H) 6.65 (d, J=7.5 Hz, 1 H), 7.25 (dd, J=7.5, 7.8 Hz, 1 H), 10.2 (s, br, 1 H).
Reaction SMILES: [CH2:1]([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/[CH:27]=[CH:28]/[C:29]([O:31][CH3:32])=[O:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].CCO>[Pd].CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][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][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4/C=C/C(=O)OC)cc3)cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)OC)cc3)cc2)CC1
Reaction time: 4 h

Procedure:
1-{4′-[4-((E)-2-Methoxycarbonyl-vinyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (1.249 g, 2.89 mmol) and 10% palladium on carbon (0.135 g) were combined in EtOAc (25 mL) and stirred under H2 atmosphere for 4 hours. EtOH (25 mL) was added, along with additional 10% palladium on carbon (one spatula), and the reaction was stirred under H2 for 2 days, replacing the balloon of H2 as needed. When no starting material was seen by analytical LCMS, the mixture was filtered through Celite and the filtrate was concentrated to give the title compound.
Reaction SMILES: C([O:4][C:5]1[C:6]([O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[N:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[OH:4][C:5]1[C:6]([O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[N:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)COc1nc(OC)ccc1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)COc1nc(OC)ccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-acetoxy-6-methoxy-2-(methoxycarbonyl)methoxypyridine, potassium carbonate and methanol is stirred for 3 hours at room temperature. The reaction solution is poured into water, and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, and concentrated. The residue is subjected to silica gel column chromatography to obtain 3-hydroxy-6-methoxy-2-(methoxycarbonyl)methoxypyridine.
Reaction SMILES: F[C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C@H:8]2[CH2:24][N:12]3[CH2:13][CH2:14][N:15]([C:17]4[CH:22]=[CH:21][C:20](N)=[CH:19][CH:18]=4)[CH2:16][C@@H:11]3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N(OCCC(C)C)=O>C1COCC1>[O:6]([CH2:7][C@H:8]1[CH2:24][N:12]2[CH2:13][CH2:14][N:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:16][C@@H:11]2[CH2:10][CH2:9]1)[C:5]1[CH:25]=[CH:26][CH:2]=[CH:3][CH:4]=1
Reactant: Nc1ccc(N2CCN3C[C@H](COc4ccc(F)cc4)CC[C@H]3C2)cc1
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: c1ccc(OC[C@@H]2CC[C@H]3CN(c4ccccc4)CCN3C2)cc1
Yield: 16.5 %

Procedure:
A solution of 0.400 g (1.13 mmol) of (7R,9aS)-7-(4-fluorophenoxy)methyl-2-(4-aminophenyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine in 20 mL of THF was added dropwise to a solution of 0.33 mL (2.48 mmol) of isoamyl nitrite in 15 mL of THF. After the addition was complete, the solution was refluxed for 24 h. The solvent was evaporated, the residue dissolved in ethyl acetate, washed with 1 M sodium hydroxide (3×), washed with brine (1×), dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with ethyl acetate gave 0.060 g (16%) of the title compound. mp (—HCl) 247-252° C. HRMS calcd for C21H25FN2O: 340.1951, found: 340.1989.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[N:14]=[C:13]([C:15](N(OC)C)=[O:16])[N:12]([CH3:21])[C:11]=2[CH:22]=1>C1COCC1>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[N:14]=[C:13]([C:15]([CH:1]3[CH2:2][CH2:3]3)=[O:16])[N:12]([CH3:21])[C:11]=2[CH:22]=1
Reactant: CON(C)C(=O)c1nc2ccc(Br)cc2n1C
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: Cn1c(C(=O)C2CC2)nc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Cyclopropylmagnesium bromide (0.70 M in THF, 7.19 ml) was added dropwise to a solution of 6-bromo-N-methoxy-N,1-dimethyl-1H-benzimidazole-2-carboxamide (1.00 g) in THF (3 ml) at 0° C. The mixture was stirred at 0° C. under Ar atmosphere for 30 min. The mixture was quenched with saturated NH4Cl solution and extracted with EtOAc twice. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc), and the resulting solid was washed with hexane to give the title compound (0.625 g) as a white solid.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[CH:4]=[N:3][CH:2]=1.[Br:10]Br>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Br:10][C:9]1[C:5]2[CH:4]=[N:3][CH:2]=[N:1][C:6]=2[NH:7][CH:8]=1
Reactant: BrBr
Reactant: c1ncc2cc[nH]c2n1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Brc1c[nH]c2ncncc12
Reaction time: 1.5 h

Procedure:
5-Bromo-7H-pyrrolo[2,3-d]pyrimidine (7) is prepared by dissolving 7H-pyrrolo[2,3-d]pyrimidine (6) in chloroform and slowly adding Br2 in carbon tetrachloride at 0° C. After stirring for 1-2 hours, the reaction may be quenched in aqueous hydrochloric acid. Isolation by conventional means (e.g. extraction and silica gel chromatography) provides compound 7.
Reaction SMILES: [CH2:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:20])=O>>[CH2:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:20])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCc1ccc(C(=O)O)cc1
Product: CCCCCCCCc1ccc(C(=O)Cl)cc1

Procedure:
20 g. of p-n-octylbenzoic acid and 100 ml. of thionyl chloride are boiled at reflux for 1 hour. The excess thionyl chloride is removed by distillation at normal pressure. The residue is mixed with absolute toluene and concentrated under vacuum. The obtained crude p-n-octylbenzoic acid chloride can be used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([NH:11][C:12]3[C:13]([O:18][CH:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:25]([O:27]C)=[O:26].CO.[OH-].[Na+].Cl>C(Cl)Cl>[CH3:1][C:2]1[C:10]2[C:9]([NH:11][C:12]3[C:13]([O:18][CH:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:25]([OH:27])=[O:26]
Reactant: COC(=O)c1sc2ncnc(Nc3cccnc3OC3CCOCC3)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC3CCOCC3)c12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Methyl 5-methyl-4-(2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-ylamino)thieno[2,3-d]pyrimidine-6-carboxylate (0.921 g, 2.30 mmol) was added into a solution of MeOH (8 mL) and 2M aqueous sodium hydroxide (2.0 mL). The reaction was stirred at 60° C. for two hours. The mixture was cooled to ambient temperature and acidified with concentrated hydrochloric acid. On addition of DCM a precipitate formed which was collected and washed with water. The product was purified by reverse phase preparative HPLC to yield off-white solid which was used in the next step without further purification.
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[CH:7]=[C:8]([C:12]2[CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])[CH3:3]>O1CCOCC1.ClCCl>[NH:15]1[CH2:14][CH:13]=[C:12]([C:8]2[CH:7]=[C:6]([NH:5][C:2](=[O:4])[CH3:3])[CH:11]=[CH:10][CH:9]=2)[CH2:17][CH2:16]1
Reactant: CC(=O)Nc1cccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)Nc1cccc(C2=CCNCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4 M HCl in dioxane (10 mL) was added to tert-butyl 4-[3-(acetylamino)phenyl]-1,2,3,6-tetrahydro-1-pyridinecarboxylate (8.25 mmol) in dichloromethane (30 mL). The reaction mixture was stirred at room temperature overnight, concentrated in vacuo, giving the desired product as the hydrochloride salt (2.1 g): 1H NMR (CDCl3) δ 7.41–7.00 (m, 4H), 6.10 (br, 1H), 3.55 (m, 2H), 3.16 (t, 2H, J=5.7 Hz), 2.44 (m, 2H), 2.19 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](OC)(OC)[CH2:9]Br)[CH:3]=1.[NH2:15][C:16]1[CH:28]=[C:27]([CH3:29])[C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:18]([Cl:30])[N:17]=1>ClC1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:15]=[C:16]3[CH:28]=[C:27]([CH3:29])[C:19]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])=[C:18]([Cl:30])[N:17]3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(N)nc(Cl)c1C(=O)OC(C)(C)C
Reactant: COC(CBr)(OC)c1cccc(Br)c1
Solvent: Clc1ccccc1
Product: Cc1cc2nc(-c3cccc(Br)c3)cn2c(Cl)c1C(=O)OC(C)(C)C
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 79.3 %

Procedure:
A flask charged with chlorobenzene (300 ml) was heated to reflux (140° C. oil bath) and to this was added sequentially 1-bromo-3-(2-bromo-1,1-dimethoxyethyl)benzene (56.05 g, 173 mmol) as an oil, and tert-butyl 6-amino-2-chloro-4-methylnicotinate (33.91 g, 140 mmol) as a powder, rinsing both with additional chlorobenzene (70 mL total) to facilitate transfer. The reaction was returned to reflux and heated for 90 min, then cooled and poured slowly into vigorously stirred Et2O (1500 mL). The resulting suspension was stirred for 15 min, then solids were collected by vacuum filtration to afford the product (47 g, 111 mmol, 64.4% yield) as a tan powdery solid. A 3 g sample of product was first purified by biotage (80 g SiO2, 0% (3 CV), 0-60% (15 CV), 60% (2 CV), EtOAc in hexanes), then recrystallized from hot acetonitrile to afford a high purity sample for spectra. 1H NMR (500 MHz, CDCl3) δ 8.14 (t, J=1.7 Hz, 1H), 8.02 (d, J=0.5 Hz, 1H), 7.89 (dq, J=7.7, 0.9 Hz, 1H), 7.48 (ddd, J=8.0, 2.0, 1.1 Hz, 1H), 7.41-7.39 (m, 1H), 7.32 (t, J=7.9 Hz, 1H), 2.45 (d, J=0.9 Hz, 3H), 1.65 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 164.3, 145.6, 145.2, 135.3, 133.6, 131.3, 130.3, 129.2, 124.7, 123.9, 123.0, 121.7, 115.4, 107.6, 83.9, 28.1, 19.9. LCMS (M+H)=421.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7]O)[CH2:4][O:3]1.CCN(CC)CC.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl>[CH3:9][C:2]1([CH3:1])[O:6][CH:5]([CH2:7][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[CH2:4][O:3]1
Reactant: CC1(C)OCC(CO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)CC2COC(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.9 %

Procedure:
To a solution of solketal (2.00 mL, 16.0 mmol) in CH2Cl2 (50 mL) was added Et3N (4.50 mL, 32 mmol). A solution of p-toluensulfonyl chloride (4.30 g, 22 mmol) in CH2Cl2 (30 mL) was then added dropwise at 0° C. The resulting solution was stirred at 25° C. for 6 h, then was diluted with CH2Cl2 (50 mL). This solution was washed with HCl (5w, 100 mL) and brine (100 mL), dried and concentrated in Vacuo to afford the crude product. This was purified by flash-chromatography on silica gel using EtOAc/n-hexane as eluant to give the title compound as a colorless oil (2.03 g, 45%): 1H NMR (CDCl3) δ1.31 (s, 3H), 1.34 (s, 3H), 2.45 (s, 3H), 3.77 (q, J=5.1 and 8.7 Hz, 1H), 3.90-4.10 (m, 3H), 4.28 (p, J=5.7 Hz, 1H), 7.35 (d, J=8.1 Hz, 2H), 7.80 (d, J=8.1 Hz, 2H);
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[OH-].[Na+].Cl[C:11]1[N:16]=[C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:14]=[C:13]([N:23]2[C:28]([CH3:30])([CH3:29])[CH2:27][C:26]3([O:34][CH2:33][CH2:32][O:31]3)[CH2:25][C:24]2([CH3:36])[CH3:35])[N:12]=1>O.C1(C)C(C)=CC=CC=1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[C:11]1[N:16]=[C:15]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[N:14]=[C:13]([N:23]2[C:24]([CH3:36])([CH3:35])[CH2:25][C:26]3([O:31][CH2:32][CH2:33][O:34]3)[CH2:27][C:28]2([CH3:30])[CH3:29])[N:12]=1
Reactant: OCCNCCO
Reactant: CC1(C)CC2(CC(C)(C)N1c1nc(Cl)nc(N3CCOCC3)n1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: CC1(C)CC2(CC(C)(C)N1c1nc(N(CCO)CCO)nc(N3CCOCC3)n1)OCCO2
Reaction time: 14 h

Procedure:
5.3 g of diethanolamine and a solution of 1 g of NaOH in 3 ml of water are added to a solution of 20 g of 2-chloro-4-morpholino-6-(4,4-ethylenedioxy-2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine (product from Example 44) in 50 ml of xylene. 1 g of NaOH in 3 ml of water is again added after 1.75 hours with stirring under reflux. After 14 hours, 7.9 g of diethanolamine are added, after which the mixture is stirred under reflux for a further 28 hours. It is then allowed to cool and washed with water, and the organic phase is separated off. After drying over Na2SO4, evaporating and recrystallizing twice from toluene, the above product is obtained as a white powder which melts at 135°-140°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH:15]1([CH2:19][CH2:20][NH:21][C:22]([C:24]2[N:25]=[N:26][C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:28][CH:29]=2)=[O:23])[CH2:18][CH2:17][CH2:16]1>>[CH:15]1([CH2:19][CH2:20][NH:21][C:22]([C:24]2[N:25]=[N:26][C:27]([N:30]3[CH2:31][CH2:32][N:33]([C:7](=[O:8])[C:6]4[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[C:11]([F:14])([F:13])[F:12])[CH2:34][CH2:35]3)=[CH:28][CH:29]=2)=[O:23])[CH2:18][CH2:17][CH2:16]1
Reactant: O=C(NCCC1CCC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(Cl)c1cc(F)ccc1C(F)(F)F
Product: O=C(NCCC1CCC1)c1ccc(N2CCN(C(=O)c3cc(F)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 5-fluoro-2-(trifluoromethyl)benzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclobutylethyl)amide, the title compound was obtained as a white powder (71% yield). 1H NMR (300 MHz, CDCl3) δ 8.03, 7.83-7.71, 7.20, 7.06, 6.95, 4.01, 3.88-3.67, 3.40-3.28, 2.35, 1.89-1.57. 13C NMR (300 MHz, CDCl3) δ166.0, 162.8, 162.6, 159.9, 145.5, 137.0, 19.7, 127.2, 125.1, 121.5, 116.9, 116.6, 115.0, 114.7, 112.6, 46.4, 44.6, 44.4, 41.3, 37.6, 36.5, 33.7, 28.3, 18.6. MS (ES+) m/z 480.5 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=2[NH2:17])=[CH:4][CH:3]=1.C(Cl)(Cl)[Cl:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[C:14]([Cl:20])[CH:13]=[C:12]([CH3:16])[C:11]=2[NH2:17])=[CH:6][CH:7]=1
Reactant: Cc1cccc(C(=O)Nc2ccc(Cl)cc2)c1N
Reactant: ClC(Cl)Cl
Product: Cc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cc2)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(4-chlorophenyl)-2-amino-3-methylbenzamide (0.40 g, 1.5 mmol) in chloroform (3 mL) at 0° C. was added SO2Cl2 (0.31 g, 2.3 mmol). The mixture was warmed to ambient temperature and stirred for 1 hour. Concentration of all volatiles in vacuo afforded N-(4-chlorophenyl)-2-amino-3-methyl-5-chlorobenzamide as a yellow solid; NMR (DMSO-d6) 10.2 (s, 1), 7.8 (d, 2), 7.6 (s, 1), 7.4 (d, 2), 7.2 (s, 1), 6.2 (br, 2), 2.1 (s, 3) ppm.
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].C([Li])CCC.[C:14](Cl)(=[O:18])/[CH:15]=[CH:16]/[CH3:17].C([O-])(O)=O.[Na+]>O1CCCC1.O>[C:14]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])(=[O:18])/[CH:15]=[CH:16]/[CH3:17]
Reactant: CC(C)(C)OC(N)=O
Reactant: C/C=C/C(=O)Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C/C=C/C(=O)NC(=O)OC(C)(C)C
Temperature: -78 °C
Yield: 27.9 %

Procedure:
1,1-Dimethylethyl carbamate (5 g, 42.7 mmol) was dissolved in tetrahydrofuran (THF) (100 mL) In a 500 mL 3 necks round bottom flask and cooled at −78° C. under nitrogen. n-Butyl lithium (1.6 M in THF, 26.7 mL, 42.7 mmol) and (2E)-2-butenoyl chloride (4.55 mL, 42.7 mmol) were added in slow successive additions as follow: 1) n-Butyl lithium: 13.4 mL and (2E)-2-butenoyl chloride 2.28 mL; 2) n-Butyl lithium: 6.8 mL and (2E)-2-butenoyl chloride 1.14 mL; 3) n-Butyl lithium: 3.34 mL and (2E)-2-butenoyl chloride 0.57 mL; 4) n-Butyl lithium: 1.67 mL and (2E)-2-butenoyl chloride 0.28 mL (2×). A five to ten min waiting time was observed between each double addition, and the final mixture was stirred for an extra 30 minutes period at −78° C. The temperature was kept below −60° C. during the additions. The reaction mixture was then slowly poured into a stirred saturated NaHCO3 aqueous solution (250 mL). The aqueous layer was extracted with AcOEt (2×250 mL). The combined organic phases were washed with brine (150 mL), dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 50 to 100% AcOEt in Hexanes) gave 1,1-dimethylethyl (2E)-2-butenoylcarbamate (2.21 g, 11.93 mmol, 28%) as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=1)([CH3:6])[CH3:5].Cl[C:17]1[C:26]2[C:21](=[C:22]([F:27])[CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1>CN(C=O)C>[C:4]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][O:15][C:17]2[C:26]3[C:21](=[C:22]([F:27])[CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)=[CH:11][CH:12]=1)([CH3:3])([CH3:5])[CH3:6]
Reactant: CC(C)(C)c1ccc(CCO)cc1
Reactant: Fc1cccc2c(Cl)ccnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CCOc2ccnc3c(F)cccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.3 %

Procedure:
To a mixture of 1.1 g of sodium hydride in 50 mL of DMF was added 4.0 g of 2-[4-(1,1-dimethylethyl)phenyl]ethyl alcohol, and the mixture was stirred for one hour at room temperature. Then 4.0 g of 4-chloro-8fluoroquinoline in 20 mL of DMF were added, and the mixture was stirred at room temperature overnight. Then the mixture was poured into an ice/water mixture, and the solid was collected and recrystallized from ethyl acetate/pentane to give 2.3 g of the title product. Yield 32.4%. M.P. 81°-82° C.