Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20]>CO>[CH2:19]([NH:20][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCC1CO1
Reactant: NCCCCCCN
Solvent: CO
Product: CCCCCCCCCC(O)CNCCCCCCNCC(O)CCCCCCCCC
Reaction time: 8 h

Procedure:
A solution of 1-undecene oxide (88.8 g.), hexamethylenediamine (1,6-hexanediamine, 30.3 g.) and methanol (400 ml.) was allowed to stand at 0° C. overnight, then at room temperature over the weekend. The solid was collected and recrystallized from ethanol, affording N,N'-(1,6-hexylene)-bis[2-hydroxyundecylamine] (I: R= CH3 (CH2)8, R' = X= (CH2)6 ; Z= H)(m.p. 122.6°-129.0° C.).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[C:8]([C:11]#[N:12])[C:9]#[N:10])SC)[CH2:3][CH2:2]1.O.[NH2:14][NH2:15]>CCO>[NH2:10][C:9]1[NH:15][N:14]=[C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)[C:8]=1[C:11]#[N:12]
Reactant: NN
Reactant: CSC(NC1CC1)=C(C#N)C#N
Solvent: CCO
Solvent: O
Product: N#Cc1c(NC2CC2)n[nH]c1N
Temperature: 0 °C

Procedure:
2-((cyclopropylamino)(methylthio)methylene)malononitrile in EtOH (100 mL) and added hydrazine hydrate (1 eq), then heated to reflux until complete by TLC (absence of starting material, 18 hrs). Poured into ice water and filtered to obtain 5-amino-3-(cyclopropylamino)-1H-pyrazole-4-carbonitrile as a yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[N:4][CH:3]=1>C(#N)C.CO.[Pt]>[NH2:12][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[NH:15][CH2:16][C:17]([CH3:18])([OH:19])[CH3:20])=[N:4][CH:3]=[C:2]([Br:1])[CH:11]=2
Reactant: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cc(Br)cnc12
Agent: [Pt]
Solvent: CO
Solvent: CC#N
Product: CC(C)(O)CNc1c(N)cnc2cc(Br)cnc12
Yield: 99.6 %

Procedure:
A Parr vessel was charged with 5% Pt/C (5.8 g) and a suspension of 1-[(7-bromo-3-nitro[1,5]naphthyridin-4-yl)amino]-2-methylpropan-2-ol (58.00 g) in acetonitrile (800 mL) and methanol (400 mL). The vessel was placed under hydrogen pressure (30 psi, 2.1×105 Pa) for 8 hours. The reaction mixture was filtered through a layer of CELITE filter aid. The filtrate was concentrated under reduced pressure to provide 52.70 g of 1-[(3-amino-7-bromo[1,5]naphthyridin-4-yl)amino]-2-methylpropan-2-ol as a yellow foam.
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:45])[CH2:5][CH:6]([CH2:26][O:27][C:28](=[O:44])[C@H:29]([CH:41]([CH3:43])[CH3:42])[NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:7][O:8][C:9](=[O:25])[C@H:10]([CH:22]([CH3:24])[CH3:23])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[I-:46].[Na+]>C(#N)C>[I:46][CH2:2][O:3][C:4](=[O:45])[CH2:5][CH:6]([CH2:26][O:27][C:28](=[O:44])[C@H:29]([CH:41]([CH3:43])[CH3:42])[NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:7][O:8][C:9](=[O:25])[C@H:10]([CH:22]([CH3:24])[CH3:23])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: [I-]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(=O)OCCl
Agent: [Na+]
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(=O)OCI

Procedure:
3,3-bis(N-CBz-L-valyloxymethyl)-propionic acid chloromethyl ester (900 mg, 1.38 mmole) was dissolved in acetonitrile (5 ml). Sodium iodide (289 mg, 1.93 mmole) was added to the solution. After reaction at 70° C. for 3 hr, the reaction mixture was filtered and the residue was dissolved in methylene chloride (5 ml) and refiltered. The solution was dried and gave the titled product. 800 mg.
Reaction SMILES: [CH3:1][S-:2].[Na+].[Br:4][C:5]1[CH:10]=[C:9](I)[CH:8]=[CH:7][C:6]=1[OH:12].Cl.CCOC(C)=O>CN(C=O)C.[Cu-]=O>[Br:4][C:5]1[CH:10]=[C:9]([S:2][CH3:1])[CH:8]=[CH:7][C:6]=1[OH:12]
Reactant: Oc1ccc(I)cc1Br
Reactant: C[S-]
Agent: O=[Cu-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ccc(O)c(Br)c1
Temperature: 80 °C
Yield: 48.4 %

Procedure:
Sodium thiomethoxide (8.64 g) and copper (I) oxide (8.79 g) were mixed with 2-bromo-4-iodophenol (XX, 14.72 g) in anhydrous DMF (100 mL). The mixture was stirred and heated at 80° C. for 48 h under nitrogen atmosphere. Then, the resultant slurry was treated with concentrated HCl (5 mL) and EtOAc (200 mL), and was filtered and rinsed with EtOAc (200 mL). The organic layers were partitioned with 1N HCl (150 mL), water (150 mL) and brine (150 mL) and dried over MgSO4, filtered and solvent removed in vacuo. Product was purified by silica gel column chromatography, the product eluted with dichloromethane/hexane (2:3), to give the desired product (5.22 g, 39%) as a light brown oil.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5]CC)=O.[Na].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1>C(O)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:1](=[O:9])[CH2:2][C:3](=[O:5])[NH:21]2)=[CH:16][CH:15]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: O=C1CC(=O)N(c2ccc(Cl)cc2)N1
Reaction time: 0.25 h

Procedure:
The starting material is prepared as follows: 20.0 g of diethyl malonate are added to 5.8 g of sodium metal dissolved in 100 ml of absolute ethanol. After stirring for 15 minutes, 17.8 g of p-chlorophenylhydrazine are added, and the resulting mixture is stripped to remove excess ethanol. The residue is heated at 110° to 120° for 4.5 hours, then quenched with 500 ml of ice-water. The resulting mixture is washed twice with diethyl ether and the aqueous layer is acidified with conc. hydrochloric acid to a pH below 2. The resulting solid is recrystallized from toluene, to give the 1-(p-chlorophenyl)-pyrazolidin-3,5-dione melting at 189°-193°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[N:3]=1.[C:16]([S:20]([NH:23][C@@H:24]1[CH2:29][CH2:28][C@H:27]([C:30](O)=O)[CH2:26][CH2:25]1)(=[O:22])=[O:21])([CH3:19])([CH3:18])[CH3:17].N[C@@H]1CC[C@H](C(O)=O)CC1.FC(F)(F)C1C=CC(N)=C(N)C=1>>[C:16]([S:20]([NH:23][C@@H:24]1[CH2:25][CH2:26][C@H:27]([C:30]2[NH:8][C:7]3[C:2](=[N:3][C:4]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[F:15])=[N:5][CH:6]=3)[N:1]=2)[CH2:28][CH2:29]1)(=[O:22])=[O:21])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)S(=O)(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: Nc1cnc(-c2ccccc2F)nc1N
Agent: N[C@H]1CC[C@@H](C(=O)O)CC1
Agent: Nc1ccc(C(F)(F)F)cc1N
Product: CC(C)(C)S(=O)(=O)N[C@H]1CC[C@@H](c2nc3nc(-c4ccccc4F)ncc3[nH]2)CC1

Procedure:
By following the same procedure as described in Example 1 except that use was made of 4,5-diamino-2-(2-florophenyl)-pyrimidine and cis-4-tert-butylsulfonylaminocyclohexane-carboxylic acid as prepared from cis-4-aminocyclohexane-carboxylic acid in accordance with the 1st, 2nd and 4th steps of Example 4 described in WO0137826 in place of 4-trifluoromethyl-1,2-phenylenediamine, the title compound was prepared.
Reaction SMILES: C[Si](C)(C)[CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.CCCCCC.C([Li])CCC.[CH3:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)=O.[Cl-].[Na+]>O1CCCC1>[O:31]([C:28]1[CH:27]=[CH:26][C:25]([C:23](=[C:3]2[S:8][CH2:7][CH2:6][CH2:5][S:4]2)[CH3:22])=[CH:30][CH:29]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: C[Si](C)(C)C1SCCCS1
Reactant: CC(=O)c1ccc(Oc2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=C1SCCCS1)c1ccc(Oc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
2-Trimethylsilyl-1,3-dithiane, 1.92 g, was dissolved in 20 ml of tetrahydrofuran and 6.3 ml of 1.6 mole hexane solution of n-butyl lithium was dropwise added to the solution in an argon flow under ice cooling. The mixture was stirred at the same temperature for 30 minutes. Then, a solution of 2.33 g of 4-phenoxyacetophenone in 10 ml of tetrahydrofuran was dropwise added under ice cooling followed by stirring at the same temperature for 30 minutes and at room temperature for an hour. After saturated sodium chloride aqueous solution was added, the mixture was extracted with chloroform. After drying the chloroform phase over magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate : hexane =1 : 10) to give 2.7 g of the oily product.
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5]([C:7]1[N:8]=[C:9]([CH:12]2[CH2:17][CH2:16][CH2:15][NH2+:14][CH2:13]2)[S:10][CH:11]=1)=[O:6])[CH3:3].[CH3:18][C:19]1[N:23]([CH2:24][C:25](O)=[O:26])[N:22]=[C:21]([C:28]([F:31])([F:30])[F:29])[CH:20]=1>>[CH3:18][C:19]1[N:23]([CH2:24][C:25]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:9]3[S:10][CH:11]=[C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[N:8]=3)[CH2:13]2)=[O:26])[N:22]=[C:21]([C:28]([F:30])([F:29])[F:31])[CH:20]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Reactant: CCOC(=O)c1csc(C2CCC[NH2+]C2)n1
Agent: [Cl-]
Product: CCOC(=O)c1csc(C2CCCN(C(=O)Cn3nc(C(F)(F)F)cc3C)C2)n1

Procedure:
3-[4-(Ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (VI-2, 5.32 g) is reacted analogously to Example IV-1 with [5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (4.00 g). This gives, after chromatographic purification, ethyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-3-yl)-1,3-thiazole-4-carboxylate (5.7 g, 69%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:6]=1[C:7]([NH:9][C:10]1[N:14]([CH3:15])[N:13]=[N:12][N:11]=1)=[O:8])(=[O:4])=[O:3].[H-].[Na+].Cl[C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])O.[Na+]>C1COCC1.O>[CH3:1][S:2]([C:5]1[CH:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[CH:16][C:6]=1[C:7]([N:9]([C:10]1[N:14]([CH3:15])[N:13]=[N:12][N:11]=1)[C:27](=[O:28])[O:29][CH3:30])=[O:8])(=[O:3])=[O:4]
Reactant: Cn1nnnc1NC(=O)c1ccc(C(F)(F)F)cc1S(C)(=O)=O
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N(C(=O)c1ccc(C(F)(F)F)cc1S(C)(=O)=O)c1nnnn1C
Reaction time: 0.17 h

Procedure:
To a solution of 175 mg (0.5 mmol) of 2-(methylsulfonyl)-N-(1-methyl-1H-tetrazol-5-yl)-4-(trifluoromethyl)benzamide in 4 ml of THF (abs.) under protective gas at 0° C. are added 14 mg (0.55 mmol) of sodium hydride (95%). After stirring for 10 min, 46 μl (0.6 mmol) of methyl chloroformate are added at 0° C. The reaction mixture is stirred at RT for 1 h. Subsequently, the reaction mixture is adjusted to pH 7 with an aqueous sat. sodium hydrogencarbonate solution, and 10 ml of water are added. Then the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. Yield: 231 mg (57%)
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH2:16])=[CH:4][C:5]([CH3:13])=[C:6]2[C:10]=1[C:9](=[N:11]O)[CH2:8][CH2:7]2.[H][H].[ClH:25]>C(O)(=O)C.C(O)C.[Pt]=O>[ClH:25].[NH2:11][CH:9]1[C:10]2[C:6](=[C:5]([CH3:13])[CH:4]=[C:3]([CH:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:15][CH3:16])[C:2]=2[OH:1])[CH2:7][CH2:8]1
Reactant: C=CC(c1ccccc1)c1cc(C)c2c(c1O)C(=NO)CC2
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CCC(c1ccccc1)c1cc(C)c2c(c1O)C(N)CC2

Procedure:
2.93 Grams of 2,3-dihydro-7-hydroxy-4-methyl-6-(1-phenyl-2-propenyl)-1H-inden-1-one oxime and 0.293 g of platinum oxide were suspended in 200 ml of acetic acid, then the suspension was reduced at room temperature under 3 atmospheric hydrogen pressure for 8 hours. After the completion of hydrogenation, the catalyst was removed by filtration, and the filtrate thus obtain was concentrated to dryness under a reduced pressure. The residue thus obtained was dissolved in 100 ml of ethanol and the pH of the solution was adjusted to about pH=1 by adding an ethanol solution saturated with hydrogen chloride gas, then this solution was again concentrated to dryness under a reduced pressure. The residue thus obtained was recrystallized from ethanoldiethyl ether to obtain 0.88 g of 1-amino-2,3-dihydro-7-hydroxy-4-methyl-6-(1-phenylpropyl)-1H-indene hydrochloride. Colorless powdery crystals. Melting point: 187.5°-189.5° C.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:7][C:8]1[N:9]2[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[N:13]=[C:10]2[S:11][CH:12]=1.[CH2:19](O)[CH3:20]>C(Cl)Cl.O>[CH3:7][C:8]1[N:9]2[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:13]=[C:10]2[S:11][CH:12]=1
Reactant: CCO
Reactant: Cc1csc2nc(C(=O)O)cn12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cn2c(C)csc2n1

Procedure:
To a solution of 6.3 g of phosphorus pentachloride in 120 ml of dry methylene chloride, 5 g of 3-methyl-imidazo-(2,1-b)thiazole-6-carboxylic acid (prepared as described in Example 10) is added and the suspension obtained is refluxed for 3 hours. After vacuum evaporation of the solvent the residue obtained being 3-methyl-imidazo-(2,1-b)thiazole-6-carboxylchloride chlorohydrate is dissolved in 100 ml of abs. ethanol and the solution is refluxed for 4 hours. The solvent is removed and the residue obtained is dissolved in water. The solution obtained is neutralised to pH 7.5 to yield 5 g of 3-methyl-6-carboethoxy-imidazo-(2,1-b)thiazole; m.p. 117°-119°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:12]#[N:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:19]([O-])([OH:21])=[O:20].O>C(O)(=O)C>[CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([N+:19]([O-:21])=[O:20])=[C:11]([CH:10]=1)[C:12]#[N:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C#N)cc1OCc1ccccc1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc([N+](=O)[O-])c(C#N)cc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A solution of 3-benzyloxy-4-methoxybenzonitrile (43.8 g, 0.18 mol) in glacial acetic acid (87 ml) was added dropwise to concentrated nitric acid (70% w/w, 244 ml) with periodic cooling to maintain the reaction temperature below 30° C. Once the addition was complete, the reaction was stirred for a further 30 minutes, after which time the mixture was poured into water (11) and stirred for 30 minutes. The resulting precipitate was isolated by filtration, washed with water and dried under reduced pressure at 50° C. to afford the subtitle compound as a white solid (35.1 g, 68%). Rf 0.70 (EtOAc:hexane 1:1, v/v).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH:24]=2)O1>O1CCOCC1.C(=O)(O)[O-].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:12]([C:4]1[CH:3]=[C:2]([C:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH:24]=2)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(Br)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 128.1 %

Procedure:
Mix 1-bromo-3-nitro-5-(trifluoromethyl)benzene (200 mg, 0.65 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (175 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol) in dioxane and saturated sodium bicarbonate solution (3:1, 10 mL), stir the mixture at 120° C. for 1.5 hrs. Cool to room temperature; concentrate under reduced pressure to give the crude product. Purify by flash chromatography (silica gel, EtOAc:PE=20:1) to afford the product as a yellow solid (310 mg, 82.8%). MS: (M+23): 395.2.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[OH-:12].[K+]>COCCOC.O>[Br:1][C:2]1[N:6]2[NH:7][C:8](=[O:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: [OH-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: O=c1ccc2ncc(Br)n2[nH]1

Procedure:
To a solution of 3-bromo-6-chloro-imidazo[1,2-b]pyridazine [13526-66-4] (425.7 mg, 1.8 mmol) in 1,2-dimethoxyethane (9 mL) was added a solution of potassium hydroxide [1310-58-3] (185.4 mg, 2.8 mmol) in water (9.0 mL) and the stirred resultant solution heated to reflux under N2 for 3d, cooled and partitioned between ethyl acetate and water. The water phase was evaporated to dryness, taken up in methanol, filtered, and evaporated to yield 3-bromo-imidazo[1,2-b]pyridazin-6-one as 340 mg of yellow solid. LRMS (ESI) m/z 214.0/216.0 [(M+H)]+, calc'd for C6H4BrN3O3: 214.02.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:2]=1[F:1]
Reactant: O=C(O)c1cc(F)ccc1F
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(F)ccc1F
Temperature: 60 °C

Procedure:
To a stirred solution of 2,5-difluorobenzoic acid (20 g, 126 mmol) in MeOH (250 mL) is added thionyl chloride (22.5 g, 190 mmol) dropwise at ice-cold conditions. After complete addition the reaction mixture is heated at 60° C. for 3 h. The reaction mixture is concentrated and the residue neutralized with aqueous Na2CO3 solution. It is extracted with CH2Cl2 (3×100 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure to afford the desired 2,5-difluorobenzoic acid methyl ester as a thick liquid (22 g).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].[C:7]([OH:11])([CH3:10])([CH3:9])[CH3:8]>>[C:2]([Cl:4])(=[O:3])[C:1]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)O
Product: CC(C)(C)OC(=O)C(=O)Cl
Yield: 90.8 %

Procedure:
In this example the product was prepared in two synthetic steps. In the first step t-butyl alcohol was reacted with 50% molar excess of oxalyl chloride. Upon completion of the reaction the excess oxalyl chloride was stripped from the product at reduced pressure to produce t-butyl chlorooxalate having an assay of 100% and in a corrected yield of 90.8%. In the second step t-butyl chlorooxalate was reacted with 2,5-dimethyl-2,5-dihydroperoxyhexane, in the presence of pyridine, to yield the product as described below:
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([C:7](=O)[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)=[CH:5][N:6]=1.[CH3:17][NH:18][CH3:19]>C(O)(C)(C)C>[Cl:15][C:10]1[CH:9]=[C:8]([C:7]2[C:4]([OH:3])=[CH:5][N:6]=[C:2]([N:18]([CH3:19])[CH3:17])[N:1]=2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: CNC
Reactant: Nc1ncc(C(=O)c2ccc(Cl)c(Cl)c2)o1
Solvent: CC(C)(C)O
Product: CN(C)c1ncc(O)c(-c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Amino-5-(3', 4'-dichlorobenzoyl)oxazole (2 g, 7.8 mmol) was combined with aqueous dimethylamine (100 ml) in t-butyl alcohol and stirred at room temperature for 4 hours. The solvents were removed in vacuum and the residue was chromatographed on silica gel with hexane and ethylacetate (3:1) as the eluent to yield 1.5 g of the title compound as a crystalline solid, m.p. 188°-189° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:10]=[C:9]([C:11]([OH:13])=O)[S:8][C:6]=2[N:7]=1.C(Cl)(=O)C(Cl)=O.CCN(CC)CC.[NH:33]1[CH2:36][CH:35]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH2:34]1>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:10]=[C:9]([C:11]([N:33]3[CH2:36][CH:35]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)[CH2:34]3)=[O:13])[S:8][C:6]=2[N:7]=1
Reactant: O=C(O)c1nc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: C1CN(C2CNC2)CCO1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1nc2c(N3CCOCC3)nc(Cl)nc2s1)N1CC(N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
To a suspension of 5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine-2-carboxylic acid (301 mg, 1.0 mmol) in DCM (6 mL) was added oxalyl chloride (847 μL, 10.00 mmol) and the resulting mixture allowed to stir at r.t. for 1 h then concentrated in vacuo and azeotroped with toluene. The resulting yellow solid was suspended in a mixture of DCM (6 mL) and NEt3 (418 μL, 3.00 mmol) at 0° C. before the addition of 4-azetidin-3-ylmorpholine (142 mg, 1.00 mmol). The resulting mixture was warmed to r.t. after 1 h then stirred for a further 30 min. The reaction mixture was partitioned between DCM and H2O, the organic phase dried (Na2SO4) and concentrated in vacuo. The resulting residue was triturated with EtOAc and dried in vacuo affording the title compound as an off-white solid (269 mg, 63%). LCMS (method H): RT 2.19 min [M+H]+ 425.3
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([Sn](C)(C)C)=[N:14][N:13]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:10]3=[CH:11][N:12]=2)[CH:2]=1.[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31](Br)[N:30]=1>>[Br:28][C:29]1[N:30]=[C:31]([C:15]2[C:9]3[C:10](=[CH:11][N:12]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:8]=3)[N:13]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:14]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: Brc1cccc(Br)n1
Reactant: C[Si](C)(C)CCOCn1nc([Sn](C)(C)C)c2cc(-c3cccnc3)ncc21
Product: C[Si](C)(C)CCOCn1nc(-c2cccc(Br)n2)c2cc(-c3cccnc3)ncc21
Yield: 67 %

Procedure:
Following the Stille coupling procedure of Example 299, 5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(trimethylstannyl)-1H-pyrazolo[3,4-c]pyridine and 2,6-dibromopyridine were reacted. The mixture was purified via silica gel chromatography using a gradient of ethyl acetate in heptane to afford 81 mg (67%) of 3-(6-Bromopyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine. ESI MS m/z 482.2 (M+1).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]([C:28]1[N:29]=[C:30]([C:33]([OH:35])=O)[S:31][CH:32]=1)([CH3:27])[CH3:26].[O:36]1[C:41]2([CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]2)[CH2:40][NH:39][CH2:38][CH2:37]1.C(N(CC)CC)C>CN(C=O)C>[CH:25]([C:28]1[N:29]=[C:30]([C:33]([N:39]2[CH2:40][C:41]3([CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]3)[O:36][CH2:37][CH2:38]2)=[O:35])[S:31][CH:32]=1)([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCCO2
Reactant: CC(C)c1csc(C(=O)O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1csc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HATU (0.924 g) was added in one portion to a stirred solution at 0° C. of 4-isopropylthiazole-2-carboxylic acid (0.32 g) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 12, step b) (0.547 g) and triethylamine (0.781 mL) in DMF (12 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 30% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.54 g.