Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH:23][CH3:24])[CH:17]=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2].[C:25]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=1>>[C:25]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][C:28]([C:31]([N:23]([CH2:22][C:18]2[CH:17]=[C:16]([C:13]3[CH:14]=[CH:15][C:10]([CH2:9][C@H:4]([O:3][CH2:1][CH3:2])[C:5]([O:7][CH3:8])=[O:6])=[CH:11][CH:12]=3)[CH:21]=[CH:20][CH:19]=2)[CH3:24])=[O:32])=[CH:27][CH:26]=1
Reactant: CCO[C@@H](Cc1ccc(-c2cccc(CNC)c2)cc1)C(=O)OC
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: CCO[C@@H](Cc1ccc(-c2cccc(CN(C)C(=O)c3ccc(-c4ccccc4)cc3)c2)cc1)C(=O)OC
Yield: 47.3 %

Procedure:
In a manner similar to Example 1(g), by reacting 500 mg (1.5 mmol) of methyl (S)-2-ethoxy-3-(3′-methylaminomethylbiphenyl-4-yl)propionate with 680 mg (3.1 mmol) of 4-biphenylcarboxylic acid chloride, 360 mg (47%) of the expected product are obtained after purification by chromatography on a silica column eluted with a heptane and ethyl acetate (70/30) mixture.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[N:21]([CH3:22])[C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]=1.CO.ClC1C=CC=C(C(OO)=[O:37])C=1>ClCCl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[N:21]([CH3:22])[C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]=1)=[O:37]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1c(-c2ccccc2Sc2nc3ccccc3[nH]2)nc2ccccc21
Solvent: CO
Solvent: ClCCl
Product: Cn1c(-c2ccccc2S(=O)c2nc3ccccc3[nH]2)nc2ccccc21
Temperature: 25 °C

Procedure:
The product of step (d) above (0.99 g) was dissolved in dichloromethane (60 ml) and methanol (5 ml) and cooled to -10°. 85% m-Chloroperbenzoic acid (0.56 g) was added and the whole was slowly warmed to room temperature with stirring. After 2 hours the reaction mixture was washed with metabisulphate solution, then bicarbonate solution and finally with brine, dried over magnesium sulphate and evaporated to dryness in vacuo and the residue was purified by flash chromatography (SiO2 /CH2Cl2 2:3 ethyl acetate) to afford the title compound as a white solid, mp 164°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([NH2:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C-:22]#[N:23].[K+].[OH-].[NH4+]>C(O)(=O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:22]#[N:23])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: [C-]#N
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: N#CC1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73 %

Procedure:
To a solution of 1-benzyl-4-oxo-piperidine (226.8 g, 1.2 mol) and phenylamine (111.6 g, 1.2 mol) in acetic acid (1000 mL) was added dropwise the solution of potassium cyanide (117 g, 1.8 mol) in water (200 mL). The reaction mixture was stirred at 25° C. for 24 h and then poured into ice-water. The mixture was basified with ammonium hydroxide and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give crude benzyl-4-phenylamino-piperidine-4-carbonitrile (255.36 g, 73.1%), which was used directly in the next step. 1H NMR (300 MHz, CDCl3) δ 7.22-7.36 (m, 7H), 6.90-6.94 (m, 3H), 3.65 (br s, 1H), 3.58 (s, 2H), 2.74-2.86 (m, 2H), 2.44-2.52 (m, 2H), 2.32-2.37 (m, 2H), 1.92-2.00 (m, 2H).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:27])[N:10]([CH3:26])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Br[C:29]1[CH:41]=[CH:40][C:32]([CH:33]=[CH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][CH:30]=1.CN(C)C=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.O>[CH2:1]([NH:8][C:9](=[O:27])[N:10]([C:11]1[CH:12]=[C:13]([C:29]2[CH:41]=[CH:40][C:32]([CH:33]=[CH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][CH:30]=2)[CH:14]=[CH:15][CH:16]=1)[CH3:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCOC(=O)C=Cc1ccc(Br)cc1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C=CC(=O)OCC)cc2)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 74.9 %

Procedure:
308 mg (0.26 mmol, 5 mol %) of tetrakis(triphenylphosphine)palladium are added to a solution of 2 g (5.34 mmol, 1.0 eq) of 3-heptyl-1-methyl-1-[3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]urea and 1.6 g (6.4 mmol, 1.2 eq) of ethyl 4-bromocinnamate in 20 mL of an 8/2 mixture of dimethylformamide and of 2M potassium phosphate solution. The reaction mixture is stirred for 3 hours at 90° C. The reaction is stopped by addition of 50 mL of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 1.69 g of ethyl 3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]acrylate in oil form are obtained. Yield=75%
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]2([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14]3[O:13][C:12]([CH3:22])([CH3:21])[CH2:11][CH2:10][C:9]=3[C:8]2=[O:23])[O:4]1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C>ClCCl>[CH3:24][S:25]([O:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]2([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14]3[O:13][C:12]([CH3:21])([CH3:22])[CH2:11][CH2:10][C:9]=3[C:8]2=[O:23])[O:4]1)(=[O:27])=[O:26]
Reactant: CC1(C)CCC2=C(O1)c1ccccc1C1(OCC(CO)O1)C2=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CCC2=C(O1)c1ccccc1C1(OCC(COS(C)(=O)=O)O1)C2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4′-(hydroxymethyl)-2,2-dimethyl-3,4-dihydro-2H,5H-spiro[benzo[h]chromene-6,2′-[1,3]dioxolan]-5-one (316 mg, 1.0 mmol) in dichloromethane (2 mL) is added methanesulfonyl chloride (0.095 mL, 1.3 mmol) and triethylamine (0.163 mL, 1.24 mmol). The mixture is stirred at room temperature for 2 hours. The reaction mixture is washed with water (2×1.0 mL), dried over sodium sulfate and concentrated to provide (2,2-dimethyl-5-oxo-3,4-dihydro-2H,5H-spiro[benzo[h]chromene-6,2′-[1,3]dioxolan]-4′-yl)methyl methanesulfonate as a white solid (99% by LC/MS, UV 254 nm). The (2,2-dimethyl-5-oxo-3,4-dihydro-2H,5H-spiro[benzo[h]chromene-6,2′-[1,3]dioxolan]-4′-yl)methyl methanesulfonate (197 mg, 0.5 mmol) is dissolved in DMF (2 mL) followed by the addition of sodium azide (97 mg, 1.5 mmol). The reaction is heated at 80° C. for 24 hour and 100° C. for 12 h. The mixture is diluted with CH2Cl2 (4 mL), washed with water (2 ml) and concentrated. The organic layer is dried with sodium sulfate, concentrated under reduced pressure and purified by flash column chromatography (SiO2, 30% EtOAc in hexane) to provide 4′-(azidomethyl)-2,2-dimethyl-3,4-dihydro-2H,5H-spiro[benzo[h]chromene-6,2′-[1,3]dioxolan]-5-one (25 mg, 15%) as a white solid. 400 MHz 1H NMR (CDCl3) δ: 7.78-7.56 (m, 1H), 7.60-7.57 (m, 1H), 7.44-7.40 (m, 2H), 4.68-4.62 (m, 1H), 4.46-4.42 (m, 1H), 4.23 (t, J=8 Hz, 1H). 3.96-3.91 (m, 1H), 3.54-3.49 (m, 1H), 2.48-2.42 (m, 2H), 1.79 (t, J=6.8 Hz, 2H), 1.42 (d, J=3.2 Hz, 6H); LCMS: 342 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:57]=[CH:56][CH:55]=[CH:54][C:3]=1[CH2:4][N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH:7]([C:13]([NH:15][NH:16][C:17]([C:19]1[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=1)[N:24]([C:28]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[N:23]=[C:22]3[C:47]1[CH:52]=[CH:51][N:50]=[C:49]([CH3:53])[CH:48]=1)=O)=[O:14])[CH2:8][CH2:9]2.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[F:1][C:2]1[CH:57]=[CH:56][CH:55]=[CH:54][C:3]=1[CH2:4][N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH:7]([C:13]1[O:14][C:17]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:23]=[C:22]4[C:47]3[CH:52]=[CH:51][N:50]=[C:49]([CH3:53])[CH:48]=3)=[N:16][N:15]=1)[CH2:8][CH2:9]2
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NNC(=O)C4CCC5CCC4N5Cc4ccccc4F)cc23)ccn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(-c4nnc(C5CCC6CCC5N6Cc5ccccc5F)o4)cc23)ccn1
Temperature: 100 °C
Yield: 28.6 %

Procedure:
To N′-(8-(2-fluorobenzyl)-8-azabicyclo[3.2.1]octane-2-carbonyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carbohydrazide (142 mg, 0.19 mmol) in acetonitrile (1.6 mL) was added pyridine (44 mg, 0.56 mmol), followed by phosphoryl trichloride (86 mg, 0.56 mmol). The reaction mixture was heated at 100° C. under microwave condition for 30 min. After quench with saturated NaHCO3, the mixture was extracted with EtOAc. The combined organic layer was dried and concentrated to give 40 mg crude product. The crude was brought to next step without further purification.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:15]=[C:14]([Cl:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[NH2:21][CH2:22][CH:23]([OH:26])[CH2:24][OH:25]>>[ClH:16].[S:1]1[C:5]([C:6]2[CH:15]=[C:14]([NH:21][CH2:22][CH:23]([OH:26])[CH2:24][OH:25])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: Clc1cc(-c2cc3ccccc3s2)nc2ccccc12
Reactant: NCC(O)CO
Product: Cl
Product: OCC(O)CNc1cc(-c2cc3ccccc3s2)nc2ccccc12

Procedure:
The title compound, m.p. 253-255° C., and MS: m/e=386 (M+), was prepared from 2-benzo[b]thiophen-2-yl-4-chloro-quinoline and (RS)-3-amino-1,2-propandiol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(F)cc1Cl
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 5 °C
Reaction time: 2.5 h

Procedure:
A solution of 2-chloro-4-fluorobenzoic acid (24.4 g, 0.142 mol) in 150 ml of concentrated sulfuric acid at 0° C. was treated dropwise with 90% nitric acid (13.2 ml, 20 mol %, 0.284 mol) over a 10 min. period at 10° C., stirred for 2.5 hours at 0 to 10° C., poured onto one liter of ice. The white solid was filtered. The filtercake was air-dried and recrystallized from ethyl acetate/heptane to afford the title compound as off-white needles. Yield: 18.0 g (58.1%); identified by NMR spectral analysis.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][NH:5][C:4](=[O:14])[CH:3]=1.CS(C1C=CNC(=O)C=1)(=O)=O.CS(O[CH:31]1[CH2:36][CH2:35][N:34]([C:37]2[N:42]=[CH:41][C:40]([CH2:43][CH2:44][CH3:45])=[CH:39][N:38]=2)[CH2:33][CH2:32]1)(=O)=O.CS(OC1CCN(C(OC(C)(C)C)=O)CC1)(=O)=O>>[C:8]1([C:7]2[C:2]([O:1][CH:31]3[CH2:36][CH2:35][N:34]([C:37]4[N:38]=[CH:39][C:40]([CH2:43][CH2:44][CH3:45])=[CH:41][N:42]=4)[CH2:33][CH2:32]3)=[CH:3][C:4](=[O:14])[NH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=c1cc(O)c(-c2ccccc2)c[nH]1
Reactant: CCCc1cnc(N2CCC(OS(C)(=O)=O)CC2)nc1
Agent: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: CS(=O)(=O)c1cc[nH]c(=O)c1
Product: CCCc1cnc(N2CCC(Oc3cc(=O)[nH]cc3-c3ccccc3)CC2)nc1

Procedure:
The compound in Step C was prepared according to the procedures described in Example 1 substituting 4-hydroxy-5-phenylpyridin-2(1H)-one for 4-hydroxy-1-(4-(methylsulfonyl)pyridine-2(1H)-one and 1-(5-propylpyrimidin-2-yl)piperidin-4-yl methanesulfonate for tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate in Step D. MS (ESI) 391 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:17]O>>[OH:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: Cc1cc(I)cc(C(=O)O)c1O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(I)cc(C)c1O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 2.0 g (7.19 mmol) 2-hydroxy-5-iodo-3-methyl-benzoic acid in 5.0 mL thionyl chloride (69.0 mmol) is stirred for 20 min at 80° C. Thionyl chloride is eliminated i.vac. and the residue is combined with 20 mL MeOH and stirred for 20 min at RT. The product is precipitated out of the reaction. MeOH is eliminated i.vac. down to 5 mL and the residue is suction filtered. The product is further reacted without any more purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[C:15]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:7][C:6]=1[N+:28]([O-])=O)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:28][C:6]1[CH:7]=[C:8]([NH:11][C:12]([C:14]2[C:15]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])[CH:9]=[CH:10][C:5]=1[C:1]([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1ccc(NC(=O)c2cccnc2NCc2ccccn2)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1ccc(NC(=O)c2cccnc2NCc2ccccn2)cc1N
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of N-[4-(tert-butyl)-3-nitrophenyl]{2-[(2-pyridylmethyl)amino](3-pyridyl)}carboxamide (100 mg, 0.25 mmol, Example 73), iron powder (69 mg, 1.25 mmol) and NH4Cl (10 mg, 0.17 mmol) in EtOH (0.5 mL) and H2O (0.5 ml) was stirred for 4 h at 80° C. The reaction mixture was filtered, concentrated, and purified through column chromatography to give the product. MS (ES+):376 M+H); (ES−):374(M−H). Calc'd. for C22H25N5O—375.21.
Reaction SMILES: [CH2:1]([O:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][C:24](Cl)=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:1]([O:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][C:24]([NH:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)Cl)cc1
Reactant: NCCc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)NCCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.1 %

Procedure:
To a 0° C. solution of 2.3 g of product from Example 87 in 50 ml of methylene chloride is added, dropwise, 0.72 g of 2-(2-aminoethyl)pyridine followed by 1.77 g of pyridine. The reaction is stirred at room temperature for 16 hours, poured into chloroform and saturated sodium bicarbonate and extracted with chloroform. The combined chloroform layers are washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel: 75% ethyl acetate/hexane) to give 2.2 g of the desired product as a colorless solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[O:6])[CH2:3][CH2:2]1.C1(=O)O[C:27](=[O:28])[CH2:26]C1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>C1(C)C=CC=CC=1>[CH:1]1([NH:4][C:5]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:27](=[O:28])[CH3:26])[CH:18]=4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1
Reactant: O=C1CCC(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
N1-Cyclopropyl-5-[(2-amino-4-pyridyl)oxy]-1H-1-indolecarboxamide (830 mg), succinic anhydride (270 mg) and toluene (30 ml) were refluxed together for 30 minutes. After adding 50 ml of acetic anhydride and 82 mg of sodium acetate to the reaction solution, the mixture was stirred at 80° C. for 15 minutes. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate). The second eluted substance was N1-cyclopropyl-5-{[2-(2,5-dioxotetrahydro-1H-1-pyrrolyl)-4-pyridyl]oxy}-1H-1-indolecarboxamide, of which 440 mg was obtained as a colorless powder.
Reaction SMILES: N1C=CC(N)=NC1=O.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.NC1C=CN(C2C=CC(F)=CC=2)C(=O)N=1.[Cl:37][CH2:38][C:39]1[N:40]=[C:41]2[CH:46]=[CH:45][N:44](C3C=CC(F)=CC=3)[C:43](=[O:54])[N:42]2[CH:55]=1>>[Cl:37][CH2:38][C:39]1[N:40]=[C:41]2[CH:46]=[CH:45][N:44]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([F:21])([F:20])[F:9])[CH:12]=3)[C:43](=[O:54])[N:42]2[CH:55]=1
Reactant: O=c1n(-c2ccc(F)cc2)ccc2nc(CCl)cn12
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: Nc1cc[nH]c(=O)n1
Agent: Nc1ccn(-c2ccc(F)cc2)c(=O)n1
Product: O=c1n(-c2cccc(C(F)(F)F)c2)ccc2nc(CCl)cn12

Procedure:
2-chloromethyl-6-(3-trifluoromethyl-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one was prepared from cytosine and 3-(trifluoromethyl)phenylboronic acid using the methods as described above for the preparation of 4-amino-1-(4-fluoro-phenyl)-1H-pyrimidin-2-one and 2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([CH3:20])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2[O:11][N:10]=[C:9]([CH3:20])[C:8]=2[NH2:7])=[CH:18][CH:17]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(-c2ccc(Br)cc2)c1N
Reaction time: 3 h

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid tert-butyl ester (0.38 g, 1.07 mmol) was treated with 50% trifluoroacetic acid in CH2Cl2 and stirred for 3 hours. Once no starting material was seen by analytical LCMS, the mixture was concentrated to give the title compound.
Reaction SMILES: [CH2:1]([C@H:8]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:9][NH:10][C:11](=[O:22])[C@H:12]([NH:14]C(OC(C)(C)C)=O)[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C(O)(C(F)(F)F)=O>ClCCl>[NH2:14][C@@H:12]([C:11]([NH:10][CH2:9][C@@H:8]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:22])[CH3:13]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N)C(=O)NC[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 5 h
Yield: 90 %

Procedure:
To a solution of benzyl [(1S)-1-benzyl-2-({(2R)-2-[(tert-butoxycarbonyl)amino]propanoyl}amino)ethyl]carbamate (1.43 g, 3.14 mmol) from preparation 1 in dichloromethane (30 mL) and methanol (2 mL) was added TFA (20 ml) at 0° C. The reaction mixture was stirred for 5 hours and then concentrated under reduced pressure. The residue was dissolved in methanol (5 mL) and loaded onto a 20 g SCX2 cartridge (pre-wetted with methanol). The cartridge was eluted with methanol to remove non-basic impurities and then eluted with 3M NH3 in methanol. Fractions containing the title compound were combined and concentrated under reduced pressure to afford the title compound as a white solid in 90% yield, 1.01 g. 1H NMR (400 MHz, MeOH-d4) : 1.21 (d, 3H), 2.70 (dd, 1H), 2.78-2.84 (m, 1H), 3.17 (dd, 1H), 3.31-3.44 (m, 3H), 3.88-4.01 (m, 2H), 4.98 (s, 2H), 7.11-7.34 (m, 10H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N:19]([CH3:21])[CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:22]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29])(=[O:24])[CH3:23].CCN=C=NCCCN(C)C.Cl.C(Cl)[Cl:47].CO>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl-:47].[C:22]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N:19]([CH3:21])[CH3:20])[CH:17]=3)[NH+:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1)=[O:29])(=[O:24])[CH3:23]
Reactant: CC(=O)c1cccc(C(=O)O)c1
Reactant: CN(C)c1ccc2nccc(Nc3ccc(N)cc3)c2c1
Reactant: ClCCl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)c1cccc(C(=O)Nc2ccc(Nc3cc[nH+]c4ccc(N(C)C)cc34)cc2)c1
Product: [Cl-]
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
A mixture of N4-(4-Aminophenyl)-N6,N6-dimethyl-4,6-quinolinediamine (181 mg, 0.58 mmol), 3-acetylbenzoic acid (M1) (97 mg, 0.58 mmol) and EDCl (220 mg, 0.1.16 mmol) in DMF (5 mL) was stirred at 20° C. for 5 min. Then DMAP (140 mg, 1.16 mmol) was added and the reaction mixture was stirred at 20° C. for 24 h. The solvent was removed under reduced pressure and residue was stirred in aqueous NaHCO3 for 1 h. The resulting precipitate was filtered and purified by chromatography in SiO2 eluting with a gradient (0-7.5%) of MeOH/DCM to give M2 (113 mg, 42%); mp (DCM/MeOH)>280° C.; 1H NMR [(CD3)2SO] δ 14.02 (br, 1H, N+H), 10.66 (s, 1H, NH), 10.31 (s, 1H, NH), 8.53 (t, J=1.6 Hz, 1H, ArH), 8.28 (d, J=6.7 Hz, 1H, ArH), 8.24 (td, J=8.1, 1.5 Hz, 1H, ArH), 8.19 (td, J=7.8, 2.8 Hz, 1H, ArH), 8.00 (d, J=6.8 Hz, 2H, ArH), 7.87 (d, J=9.4 Hz, 1H, ArH), 7.78 (t, J=7.8 Hz, 1H, ArH), 7.64 (dd, J=9.4, 2.6 Hz, 1H, ArH), 7.51 (d, J=2.5 Hz, 1H, ArH), 7.47 (d, J=8.8 Hz, 2H, ArH), 6.69 (d, J=6.7 Hz, 1H, ArH), 3.09 [s, 6H, (NCH3)2], 2.68 (s, 3H, COCH3); APCl+ve 425.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[PH4+].[N+:7]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)C=O)([O-:9])=[O:8].O1CC[CH2:20][CH2:19]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCC.CCCCCC>[CH:1]([C:12]1[CH:11]=[C:10]([N+:7]([O-:9])=[O:8])[CH:17]=[CH:16][CH:15]=1)=[CH:2][CH2:3][CH2:4][CH2:19][CH3:20]
Reactant: C1CCOC1
Reactant: [Li]CCCC
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [PH4+]
Solvent: CCCCCC
Product: CCCCC=Cc1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 90 %

Procedure:
A suspension of butyltriphenylphosphonium bromide (27.3 g, 0.067 m) in 350 ml of dry tetrahydrofuran was cooled to 0° C. under an inert atmosphere of argon. To this stirred suspension was added 0.9 equivalent (0.06 m) of n-butyl lithium in hexane with continued cooling. The mixture was stirred at 0° and as ylide formation proceeded the solid phosphonium salt dissolved with formation of a red-orange solution. After 30 minutes a solution of one equivalent of 3-nitrobenzaldehyde (10.1 g, 0.067 m) in 200 ml of dry tetrahydrofuran was added dropwise to the ylide solution during 30 minutes. The reaction mixture was stirred and allowed to warm to room temperature. After 1 hour the reaction was quenched into 500 ml of saturated ammonium chloride solution and extracted several times with diethyl ether. The combined ether extracts were washed with water and with saturated sodium chloride solution and dried over magnesium sulfate. Filtration of the drying agent and concentration of the ether solution under vacuum afforded a clear brown oil which was purified by silica gel column chromatography to give 3-(1-hexenyl)nitrobenzene (11.0 g, 90% yield) as a clear, light-yellow oil. NMR of this material showed it to be mostly cis configuration at the double bond with some trans isomer present.