Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([C:8]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:18]([NH2:22])([NH2:21])(=[O:20])=[O:19]>CO>[C:2]1([C:8]2[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:22][S:18](=[O:20])(=[O:19])[N:21]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NS(N)(=O)=O
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CO
Product: O=S1(=O)N=C(c2ccccc2)C(c2ccccc2)=N1
Temperature: 25 °C
Yield: 84416 %

Procedure:
Hydrogen chloride is bubbled through a solution of benzil (24 g, 0.11 mmol) and sulfamide (11 g, 0.11 mmol) in methanol (120 mL) for 2 h followed by heating to reflux for 2 h. The reaction mixture is cooled to RT, and the precipitate that formed is filtered to give 25.1 g of the product 14.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1.CCOCC.[ClH:27]>C(Cl)Cl>[ClH:27].[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2CO)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: OCc1ccccc1C1CCNCC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
260 mg (0.89 mmol) of 4-(2-hydroxymethylphenyl)-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester were dissolved in 20 mL of CH2Cl2, 4 mL of a saturated Et2O/HCl solution were added and the reaction mixture was stirred at room temperature for 45 min. The solvent was removed in vacuo and the resulting crude solid was triturated with CH2Cl2, filtered and dried, yielding 180 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([Mg]Br)#[CH:16]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:15]#[CH:16])([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Solvent: C1CCOC1
Product: C#CC1(O)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
A solution of 3-oxo-piperidine-1-carboxylic acid tert-butyl ester (112 mg, 0.56 mmol) in THF (1 mL) was added dropwise to a solution of ethynylmagnesium bromide (0.5 M, 2.2 mL) in THF (1 mL) at 0° C. and the resulting mixture was stirred at 0° C. for 4 hours. The reaction was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated to afford 3-ethynyl-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (119 mg, 94%) as yellow oil. MS: m/z=226 amu (M++H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)=[C:6]([C:21]#[N:22])[CH:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.O>[OH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][N:12]=2)=[C:6]([CH:5]=1)[C:21]#[N:22]
Reactant: COC(=O)c1ccc(Oc2ccc(C(F)(F)F)cn2)c(C#N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(CO)ccc1Oc1ccc(C(F)(F)F)cn1
Temperature: -55 °C
Reaction time: 0.33 h
Yield: 60.7 %

Procedure:
To a solution of 3-cyano-4-(5-trifluoromethyl-pyridin-2-yloxy)-benzoic acid methyl ester (23 g, 0.070 mol) in anhydrous THF (200 mL) was added portionwise LiAlH4 (4.07 g, 0.11 mmol) at −78° C. The reaction mixture was warmed to −55° C. slowly and stirred for 20 mins, diluted with water (3 mL 0.16 mmol, slow addition), filtered and concentrated. Purification via column chromatography on silica gel (petroleum ether/ethyl acetate=10/1 to 5/1) afforded the title product (12.5 g) as a colorless oil. LCMS: rt=2.81 min, [M+H+]=295.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH:11]3C[CH2:12]3)[CH:10]=[C:6]2[N:5]=[C:4]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[CH:3]=1.[C:27]([N:30]1[CH2:36][CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])[CH3:28]>CN1C(=O)CCC1>[C:27]([N:30]1[CH2:36][CH2:35][CH2:34][N:33]([C:2]2[N:7]3[N:8]=[C:9]([CH2:11][CH3:12])[CH:10]=[C:6]3[N:5]=[C:4]([NH:14][C:15](=[O:26])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([OH:25])([CH3:23])[CH3:24])=[CH:18][CH:17]=3)[CH:3]=2)[CH2:32][CH2:31]1)(=[O:29])[CH3:28]
Reactant: CC(=O)N1CCCNCC1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nc(C4CC4)cc3n2)cc1
Solvent: CN1CCCC1=O
Product: CCc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCCN(C(C)=O)CC3)n2n1
Temperature: 25 °C
Yield: 51.3 %

Procedure:
In a 2 mL microwave vial was placed N-(7-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2H, 75 mg, 0.21 mmol) and N-acetylhomopiperazine (59 mg, 0.42 mmol). To the sealed vial was then added NMP (2 ml) and the mixture was then heated in the microwave at 120° C. for 30 minutes. After cooling to room temperature, the reaction mixture was partitioned between brine and EtOAc. The aqueous layer was extracted once more with EtOAc, and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by recrystallization from ether and EtOAc to give the titled compound (50 mg, 51% yield) as an off-white solid. ESI-MS: m/z 465 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH3:19])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:20]([O-])=[O:21].[Na+]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:20]=[O:21])[C:5]([N:7]([CH3:19])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=CO
Product: CN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h
Yield: 45.6 %

Procedure:
1.2 g of 1-(2-chloroethyl)-3-methyl-3-D-glucopyranosylurea are dissolved in 10 ml of formic acid, and 0.56 g of sodium nitrite is added thereto at 0° to 5° C. for one hour under stirring. The mixture is further stirred at the same temperature for 1.5 hours. After the reaction, the mixture is freeze-dried. The residue thus obtained is purified by silica gel chromatography(Solvent: chloroform-ethyl acetate-methanol(2:1:1)). 0.6 g of 1-(2-chloroethyl)-1-nitroso-3-methyl-3-D-glucopyranosylurea is thereby obtained as a pale yellow powder.
Reaction SMILES: I[Si](C)(C)C.[F:6][C:7]1[C:8]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:16]=2)=[CH:9][C:10]([O:13]C)=[N:11][CH:12]=1.CO.C([O-])(O)=O.[Na+]>C(#N)C>[F:6][C:7]1[C:8]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:16]=2)=[CH:9][C:10](=[O:13])[NH:11][CH:12]=1
Reactant: COc1cc(-c2ccnc(NC3CCOCC3)n2)c(F)cn1
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: O=c1cc(-c2ccnc(NC3CCOCC3)n2)c(F)c[nH]1
Temperature: 80 °C
Yield: 31 %

Procedure:
Iodotrimethylsilane (0.186 mL, 1.30 mmol) was added dropwise to a solution of 4-(5-fluoro-2-methoxypyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine (0.0992 g, 0.3260 mmol) in acetonitrile (6 mL) in a vial at room temperature. The sealed vial was heated at 80° C. overnight. The reaction mixture was treated with MeOH (about 2 mL) and some saturated aqueous NaHCO3. The mixture was concentrated, and the aqueous residue was treated dropwise with 1M HCl until a tan precipitate formed (pH 2). This was extracted with 2 portions 10% isopropyl alcohol (“IPA”) in DCM. The combined organics were dried over MgSO4, filtered, and evaporated to yield 5-fluoro-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.0293 g, 0.1009 mmol, 30.96% yield) as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[Br:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][N:31]=[C:30]2[CH:36]=O.N1CCCCC1>CO>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:36]/[C:30]3[C:29]4[C:33](=[CH:34][CH:35]=[C:27]([Br:26])[CH:28]=4)[NH:32][N:31]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1n[nH]c2ccc(Br)cc12
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2n[nH]c4ccc(Br)cc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
A solution of tert-butyl 4-[1-(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.287 mmol) in methanol (1.2 mL) was added with 5-bromo-1H-indazole-3-carbaldehyde (0.0646 g, 0.287 mmol), and piperidine (0.00244 g, 0.0287 mmol) at room temperature, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was added with methanol (4 mL), suspended in methanol and thereby washed, and then the solid was collected by filtration to obtain tert-butyl (Z)-4-({6-hydroxy-3-oxo-2-[(5-bromo-1H-indazol-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0700 g, 44%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.N1C=CC=CC=1.[CH3:17][C:18](OC(C)=O)=[O:19]>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:18](=[O:19])[CH3:17])[N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1n[nH]c2ccccc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)n1nc(C)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
3-Methylindazole (1.00 g, 7.6 mmol) was dissolved in 10 ml THF and stirred at RT under a blanket of argon. Pyridine (0.64 ml, 7.9 mmol) was added followed by Ac2O (0.79 ml, 8.3 mmol) and catalytic DMAP (90 mg, 0.7 mmol). The reaction proceeded for 2 h and was then partitioned between 1N HCl and dichloromethane. The organic phase was dried over MgSO4 and concentrated in vacuo to a tan solid (1.2 g, 91% yield).
Reaction SMILES: [C:1]1([CH:7]2[CH2:9][CH:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[N:19]=[N:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])=[O:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1>>[C:1]1([CH:7]2[CH2:9][CH:8]2[C:10]([N:13]([C:14]2[N:19]=[N:18][C:17]([N:20]3[CH2:21][CH2:22][N:23]([C:26](=[O:27])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:36])[F:35])[CH2:24][CH2:25]3)=[CH:16][CH:15]=2)[C:10]([CH:8]2[CH2:9][CH:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:11])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: O=C(Cl)C1CC1c1ccccc1
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(N(C(=O)C3CC3c3ccccc3)C(=O)C3CC3c3ccccc3)nn2)CC1

Procedure:
Following the procedure of Example 6, making variations only as required to use 2-phenylcyclopropanecarbonyl chloride in place of phenoxyacetyl chloride to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)-methanone, both compounds were obtained from the reaction. 2-Phenylcyclopropanecarboxylic acid (2-phenylcyclopropanecarbonyl) {6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazin-3-yl}amide was isolated by column chromatography eluting with EtOAc:hexane=40:60 and obtained as a white powder (20% yield). 1H NMR (300 MHz, CDCl3) δ 7.73, 7.62, 7.54, 7.34, 7.22, 7.16, 7.04, 6.84, 3.99, 3.82, 3.63, 3.28, 2.62, 2.31, 1.76, 1.38. MS (ES+) m/z 640.3 (M+1). 2-Phenylcyclopropanecarboxylic acid {6-[4-(2-trifluoromethyl-benzoyl)piperazin-1-yl]pyridazin-3-yl}amide was isolated by column chromatography eluting with EtOAc:hexane=50:50 and obtained as a white powder (16% yield). 1H NMR (300 MHz, CDCl3) δ 10.36, 8.39, 7.76, 7.64, 7.57, 7.34, 7.18, 7.12, 3.92, 3.52, 3.37, 3.18, 2.64, 2.30, 1.34. MS (ES+) m/z 496.3 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:6][OH:7])[C:3]([OH:5])=[O:4].[C:9](Cl)(=[O:11])[CH3:10].Cl>N1C=CC=CC=1>[CH3:1][C:2]([CH3:8])([CH2:6][O:7][C:9](=[O:11])[CH3:10])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(CO)C(=O)O
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)OCC(C)(C)C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 632.7 %

Procedure:
2,2-dimethyl-3-hydroxypropionic acid (11.8 g, 100 mmol) was dissolved in pyridine (30 mL), and the reaction solution was cooled to 0° C. Acetyl chloride (11.8 g, 15.0 mmol) was slowly added dropwise, the temperature was then raised to room temperature, and the reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, 1N HCl (30 mL) was added to adjust pH to 3-4, and then the reaction mixture was extracted with EtOAc. The organic extracts were washed with 1N HCl, 4-5 times, dried over MgSO4, and concentrated in vacuo, give the title compound (15.2 g, 95.0%)
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([S:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[C:25]([O:28][CH2:29][CH:30]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[CH2:31][CH2:32]I)(=[O:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:25]([O:28][CH2:29][CH:30]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[CH2:31][CH2:32][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH2:1])=[N:3][C:4]=2[S:11][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:27])[CH3:26]
Reactant: Nc1nc(SC(c2ccccc2)c2ccccc2)c2[nH]cnc2n1
Reactant: CC(=O)OCC(CCI)COC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCC(CCn1cnc2c(SC(c3ccccc3)c3ccccc3)nc(N)nc21)COC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
A mixture of 2-amino-6-[(diphenylmethyl)thio]purine (6.7 g), 2-acetoxymethyl-4-iodobut-1-yl acetate (7.0 g) and anhydrous potassium carbonate (4.14 g) in N,N-dimethylformamide (100 cm3) was stirred at ambient temperature overnight. The reaction mixture was filtered and the residue washed with N,N-dimethylformamide (100 cm3). Evaporation of the filtrate gave a pale coloured oil. Purification via column chromatography on silica (450 g) [eluant 3% methanol-dichloromethane] gave the title compound 9.3 g (89%) as a viscous gum and 1.1 g (10.5%) of 7-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-amino-6-(diphenylmethyl)thio]purine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:14]2[CH:15]=[N:16][CH:17]=[N:18][CH:19]=2)=[N:8][NH:9][C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5])[CH3:2].[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:14]2[CH:15]=[N:16][CH:17]=[N:18][CH:19]=2)=[N:8][N:9]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][C:21]([F:20])([F:32])[F:33])[CH:24]=2)[C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5])[CH3:2]
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: CCOC(=O)c1c(-c2cncnc2)n[nH]c1C1CC1
Product: CCOC(=O)c1c(-c2cncnc2)nn(-c2cccc(OC(F)(F)F)c2)c1C1CC1
Yield: 31 %

Procedure:
In analogy to the procedure described in Example 162C], 5-cyclopropyl-3-pyrimidin-5-yl-1H-pyrazole-4-carboxylic acid ethyl ester (Example 177B]) and 3-(trifluoromethoxy)benzeneboronic acid gave the title compound as a yellow oil (31%). MS: 419.0 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:14])([F:13])[F:12])[CH:5]=[O:6].[OH:15]O.Cl>CO.[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:12])([F:13])[F:14])[C:5]([OH:15])=[O:6]
Reactant: OO
Reactant: O=Cc1ccc(OC(F)(F)F)c(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OC(F)(F)F)c(Br)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To an ice-cooled solution of 3-bromo-4-(trifluoromethoxy)benzaldehyde (3.00 g, 11.2 mmol, 1 eq.) in MeOH (14 mL), a solution of hydrogen peroxide (30% wt solution in water, 14 mL, 11.2 mmol, 1 eq.) in 15% aq. NaOH soln. (14 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 1 hour and further at r.t. for 18 hours. The reaction mixture was acidified by addition of conc. HCl. The suspension was filtered off and the filter cake was rinsed with H2O. The resulting white solid was dried under h.v. to give the title compound. The product was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:12]3[F:19])[C:6]=2[N:7]=1.Cl.[OH-:22].[Na+]>>[NH2:1][C:2]1[NH:3][C:4](=[O:22])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:12]3[F:19])[C:6]=2[N:7]=1
Reactant: [OH-]
Reactant: Nc1nc(Cl)c2ccn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3F)c2n1
Agent: Cl
Agent: [Na+]
Product: Nc1nc2c(ccn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1

Procedure:
A mixture of the compound from Step I (4 mg, 0.08 mmol) in 2N aqueous NaOH (1.2 mL) was stirred at reflux temperature for 1.5 h. The solution was cooled in an ice-bath, neutralized with 2 N aqueous HCl and evaporated to dryness. The residue was suspended in MeOH, mixed with silica gel and evaporated. The solid residue was placed onto a silica gel column (packed in a solvent system of CH2Cl2/MeOH: 10/1) which was eluted with a solvent system of CH2Cl2/MeOH: 10/1. The fractions containing the product were collected and evaporated to dryness to yield the title compound (20 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH3:16])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[NH2:19][C:20]1[CH:28]=[C:27]2[C:23]([CH:24]=[N:25][NH:26]2)=[CH:22][CH:21]=1>C(O)C>[CH2:15]([O:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:19][C:20]3[CH:28]=[C:27]4[C:23]([CH:24]=[N:25][NH:26]4)=[CH:22][CH:21]=3)=[C:3]([C:17]#[N:18])[CH:4]=[N:5]2)=[CH:10][C:9]=1[O:12][CH3:13])[CH3:16]
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1ccc2cn[nH]c2c1
Solvent: CCO
Product: CCOc1cc2ncc(C#N)c(Nc3ccc4cn[nH]c4c3)c2cc1OC
Yield: 80 %

Procedure:
A mixture of 500 mg (1.90 mmol) 4-chloro-7-ethoxy-6-methoxy-quinoline-3-carbonitrile, 30 ml ethanol, and 304 mg (2.28 mmol) 6-aminoindazole was heated to reflux under N2. Removed heat at 4 hours and made basic with saturated sodium bicarbonate. Stripped solvents, slurried residue with hexane, collected solids and dried. Washed with water and dried in vacuo, giving 546 mg of tan solid: mass spectrum (electrospray m/e): M+H=359.9.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[C:7]([S:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[S:6][C:5]=1[N:18]1[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=[O:25])[CH2:20][CH2:19]1)([O-])=O.[Sn](Cl)Cl.O>C(OCC)(=O)C>[NH2:1][C:4]1[CH:8]=[C:7]([S:9]([N:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)(=[O:11])=[O:10])[S:6][C:5]=1[N:18]1[CH2:19][CH2:20][CH:21]([C:24]([OH:26])=[O:25])[CH2:22][CH2:23]1
Reactant: O=C(O)C1CCN(c2sc(S(=O)(=O)N3CCCCC3)cc2[N+](=O)[O-])CC1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(S(=O)(=O)N2CCCCC2)sc1N1CCC(C(=O)O)CC1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
The solution of 300 mg of 1-(3-nitro-5-piperidine-1-sulfonylthiophen-2-yl)piperidine-4-carboxylic acid in 20 ml of ethyl acetate is admixed with 1.0 g of tin(II) chloride and stirred at 65° C. for 8 h. After cooling, it is stirred with 30 ml of water and filtered off with suction through Celite, and the ethyl acetate phase is removed, dried and concentrated under reduced pressure. This crude product is used further without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]([C:14]1([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:16][CH2:15]1)=[O:13])[CH2:6][CH2:5]2.[CH3:24][O:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O)=[O:27].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Pd](Cl)Cl>[CH3:24][O:25][C:26](=[O:27])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]([C:14]1([NH:17][C:18](=[O:23])[C:19]([F:20])([F:21])[F:22])[CH2:15][CH2:16]1)=[O:13])[CH2:6][CH2:5]2
Reactant: O=C(NC1(C(=O)NC2CCc3cc(Br)ccc32)CC1)C(F)(F)F
Reactant: COC(=O)c1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccccc1-c1ccc2c(c1)CCC2NC(=O)C1(NC(=O)C(F)(F)F)CC1
Temperature: 50 °C
Yield: 92.1 %

Procedure:
1-(2,2,2-Trifluoro-acetylamino)-cyclopropanecarboxylic acid ((rac)-5-bromo-indan-1-yl)-amide (intermediate A-1 [B]) (0.20 g, 511 μmol) and 2-(methoxycarbonyl)phenylboronic acid (184 mg, 1.02 mmol) were dissolved in dioxane (9.0 ml); then, sodium carbonate (163 mg, 1.53 mmol), dissolved in water, was added while stirring. Subsequently, (1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) (18.7 mg, 25.6 μmol, eq: 0.05) was added and the reaction mixture was heated up to 50° C. for 5 hours. It was then poured into H2O (50 ml) and extracted with EtOAc (2×25 mL). The organic layers were dried over MgSO4, filtered and concentrated in vacuo to give a crude product (0.296 g) which was purified by flash chromatography (silica gel, 20 g, 0% to 2% MeOH in CH2Cl2) to yield the title compound (0.21 g, 91%) as light brown oil. MS: 445.1 (M−H−).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:12]1([O:17][C:18](=[O:29])[C@@H:19]([NH2:28])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>ClCCl>[CH:12]1([O:17][C:18](=[O:29])[C@@H:19]([NH:28][C:37](=[O:39])[CH3:38])[CH2:20][C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1ccc(C[C@H](N)C(=O)OC2CCCC2)cc1
Reactant: CC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@@H](Cc1ccc(C)cc1)C(=O)OC1CCCC1
Yield: 93 %

Procedure:
To (S)-2-Amino-3-p-tolyl-propionic acid cyclopentyl ester p-toluenesulfonic acid salt prepared in the above stage (10 g, 0.022 mol) was added dichloromethane 200 ml) under nitrogen. Triethylamine (6.29 ml, 0.044 mol) was added dropwise with stirring. Acetyl chloride (1.72 ml, 0.022 mol) in dichloromethane (50 ml) was added dropwise to the reaction. Acetyl chloride (0.1 ml) in DCM (0.5 ml) was added after 20 mins and the reaction reached completion after 1 hr. The organic phase was washed with saturated sodium bicarbonate (3×200 ml), dried (Na2SO4) and the solvent removed in vacuo. The required product was obtained 6.62 g, 93% yield and was used in the next step without further purification. m/z 321 [M++H]+