Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][NH:15][CH3:16].Cl>[OH-].[Na+]>[CH3:14][N:15]([CH3:16])[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CNC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(C)c1ccc([N+](=O)[O-])cc1C(=O)O
Yield: 57 %

Procedure:
2-Chloro-5-nitrobenzoic acid (2 g, 9.9 mmol) was dissolved in of 8% sodium hydroxide solution (10 ml) at room temperature. 40% dimethyl amine aqueous solution (1.5 eq) was added and the reaction mixture was heated to reflux for 3 days. The reaction mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was dried and evaporated and the residue crystallized with ether/pet ether to give 2-dimethylamino-5-nitro-benzoic acid (1.14 g, 57%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[C:6]([CH2:17][CH3:18])[N:5]=[CH:4][N:3]=1.C(OC([N:26]1[CH2:31][CH2:30][C:29]2([CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:28][CH2:27]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.Cl>C(#N)C>[CH2:30]1[C:29]2([CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:28][CH2:27][N:26]([C:2]2[C:7]([C:8]#[C:9][C:10]3[CH:15]=[CH:14][C:13]([NH2:16])=[N:12][CH:11]=3)=[C:6]([CH2:17][CH3:18])[N:5]=[CH:4][N:3]=2)[CH2:31]1
Reactant: CCc1ncnc(Cl)c1C#Cc1ccc(N)nc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)CC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ncnc(N2CCC3(CCNCC3)CC2)c1C#Cc1ccc(N)nc1
Temperature: 80 °C

Procedure:
The title compound is synthesized according to general procedure GP7 (method 2) starting from 1.0 g (3.87 mmol) 4-chloro-6-ethyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidine and 1.18 g (4.6 mmol) 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester using 1.97 mL (11.6 mmoL) DIPEA in 20 mL acetonitrile. The reaction mixture is stirred at 80° C. over night. 1.6 ml conc. HCl is added the reaction is stirred for 4 hours at 80° C. The solvent is removed under reduced pressure. The residue is taken up to in acetonitrile and K2CO3 is added. The mixture is stirred at 80° C. over night. The solvent is removed and the residue is taken up in DCM/water. After phase separation the organic phase is extracted twice with DCM. The combined organic layers are dried over Na2SO4, filtered and the solvent is removed under reduced pressure yielding 1.08 g (74%) of crude product, which is used without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29]O)=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].C(Br)(Br)(Br)[Br:33].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][Br:33])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2CO)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2CBr)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.3 %

Procedure:
A mixture of N-(2,6-dichlorobenzoyl)-4-[2-(hydroxymethyl)phenyl]-L-phenylalanine methyl ester (0.15 g), CBr4 (0.22 g) and PPh3 (0.173 g) in CH2Cl2 (5 mL) was stirred at room temperature for 18 h. The solvent was evaporated and the residue was purified by flash column chromatography (silica gel; eluent: CH2Cl2/EtOAc 9:1 to 8:1) to yield 0.12 g of N-(2,6-dichlorobenzoyl)-4-[2-(bromomethyl)phenyl]-L-phenylalanine methyl ester. ESMS: m/z 522 (MH+).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]([OH:17])[C:13]([NH:15][CH3:16])=O)[CH2:3][CH2:2]1.B.Cl>O1CCCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]([OH:17])[CH2:13][NH:15][CH3:16])[CH2:3][CH2:2]1
Reactant: CNC(=O)C(O)C(c1ccccc1)N1CCOc2ccccc21
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CNCC(O)C(c1ccccc1)N1CCOc2ccccc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A solution of (2RS,3RS)-3-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2-hydroxy-N-methyl-3 phenylpropanamide (216 mg, 0.692 mmol) in dry tetrahydrofuran (3 mL) under nitrogen was treated dropwise with a solution of borane (1.0 M in tetrahydrofuran, 3.50 mL, 3.50 mmol), and the resulting solution was stirred at 70° C. for 2 hours. After cooling in an ice bath, the reaction mixture was treated with a 2N aqueous solution of hydrochloric acid (1 mL), and the resulting mixture was heated at 50° C. for 30 minutes. Tetrahydrofuran was removed under reduced pressure, and the aqueous residue was dissolved in water (5 mL) and washed with diethyl ether (10 mL). The aqueous layer was made alkaline with solid potassium carbonate and extracted with ethyl acetate (2×10 mL). The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated under reduced pressure to yield 202 mg (98%) (1RS,2SR)-1-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-ol as a colorless oil. This oil was dissolved in ethanol (1 mL) and treated with a solution of hydrochloric acid (0.5 mL, 4M in 1,4-dioxane). All volatiles were again removed under reduced pressure. The resulting white solid was recrystallized (minimal warm ethanol/ethyl ether/−20° C.) to yield 105 mg (41%) (1RS,2SR)-1-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-ol di hydrochloride as a white solid. MS (ESI) m/z 299.0 ([M+H]+); HRMS: calcd for C18H22N2O2+H+, 299.17540; found (ESI, [M+H]+), 299.1755.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:19]=[C:18]2[C:9]([S:10](=[O:25])(=[O:24])[C:11]3[CH:12]=[C:13]([C:21]([NH2:23])=O)[CH:14]=[CH:15][C:16]=3[C:17]2=[O:20])=[CH:8][CH:7]=1>CN(C=O)C>[C:21]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[C:17](=[O:20])[C:18]1[CH:19]=[C:6]([F:5])[CH:7]=[CH:8][C:9]=1[S:10]2(=[O:25])=[O:24])#[N:23]
Reactant: NC(=O)c1ccc2c(c1)S(=O)(=O)c1ccc(F)cc1C2=O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc2c(c1)S(=O)(=O)c1ccc(F)cc1C2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (75 g) was cooled to 5° C. and DMF (150 ml) was added dropwise and the temperature was maintained below 10° C. The amide prepared in (a) supra, 19.1 g, (0.05 mol) was added and the mixture was allowed to warm to room temperature and was stirred for 2 hr. The mixture was poured onto 1 L of ice and was filtered. The solid was washed with H2O, 2×300 ml and dried. The nitrile was dissolved in hot acetic acid (800 ml), treated with charcoal and filtered through a celite bed. The solution was cooled, and the crystals were collected by filtration and dried in vacuo to give 14.48 g of 6-cyano-2-fluorothioxanthene-9-one 10,10-dioxide, m.p.=260°-262°0 C.; TLC on silica gel (butanol:acetic acid:H2O/5:4:1), Rf =0.82.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[N:13]O)[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH2:13])[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(C)=NO)cc1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C(C)N)cc1OC
Yield: 213.1 %

Procedure:
3′,4′-Dimethoxyacetophenone oxime (1 gram, 5.1 mmol) was dissolved in 10 milliliters of glacial acetic acid, the solution was flushed with N2 and the palladium on carbon (0.2 grams, 5%) was added. The mixture was treated with 60 psi of H2 in a Parr Type Shaker for 24 hours. The catalyst was filtered off and the filtrate was concentrated to afford a yellow oil which was taken up in water, basified to pH 12 with a saturated solution of sodium carbonate and extracted with methylene chloride. The combined extracts were dried over magnesium sulfate and concentrated to afford 1.97 grams (82%) of product as a yellow oil: 1H NMR (CDCl3) δ7.02-6.75 (m, 3H), 4.08 (q, J1=6.6 Hz, J2=13.1 Hz, 1 H), 3.89 (s, 3H), 3.87 (s, 3H), 1.37 (d , J=6.6 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:16]2[N:17]=[N:18][N:19]([CH:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])[CH:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:15])[C:16]4[N:17]=[N:18][N:19]([CH:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH3:22])[CH:20]=4)=[CH:6][CH:7]=3)=[CH:39][CH:38]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cn(C(C)c2ccccc2)nn1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cn(C(C)c5ccccc5)nn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(1-phenyl-ethyl)-1H-[1,2,3]triazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[S:10][C:6]=2[C:5]([C:21]#[N:22])=[CH:4][N:3]=1.[CH:23]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:23]1([NH:29][C:2]2[C:7]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([C:17]([CH3:18])([CH3:20])[CH3:19])=[CH:13][CH:12]=4)[S:10][C:6]=3[C:5]([C:21]#[N:22])=[CH:4][N:3]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NC1CCCCC1
Reactant: CC(C)(C)c1ccc(-c2cc3c(Cl)ncc(C#N)c3s2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(-c2cc3c(NC4CCCCC4)ncc(C#N)c3s2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a solution of 4-chloro-7-cyano-2-(4′-t-butylphenyl)-thieno[3,2-c]pyridine (0.05 g, 0.153 mmol) in DMF was added cyclohexylamine (0.017 g, 0.168 mmol) and potassium carbonate (0.023 g, 0.168 mmol). The resulting mixture was stirred under nitrogen at 80° C. for 2 h. After this time the mixture was partitioned between ethyl acetate (10 mL) and saturated aqueous sodium bicarbonate solution (10 mL), and the organic layer washed with water and brine, then dried over magnesium sulphate and concentrated under reduced pressure. Purification by silica gel chromatography (eluent 20% ethyl acetate in hexane) afforded 0.042 g of 102. 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.63 (d, 2H), 7.50 (d, 2H), 7.38 (s, 1H), 5.14 (bs, 1H), 4.20 (bs, 1H), 2.18 (m, 2H), 1.80 (m, 4H), 1.6–1.12 (m, 13H).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10].F[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].Cl>CN1CCCC1=O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH:8]([C:7]([O:14][CH3:15])=[O:13])[C:9]([O:11][CH3:12])=[O:10])=[C:18]([N+:24]([O-:26])=[O:25])[CH:19]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: COC(=O)CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)C(C(=O)OC)c1ccc(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
185 g of potassium-tert-butoxide are added to a solution of 188 ml of dimethyl malonate in 970 ml of N-methylpyrrolidone, while cooling with ice, and the mixture is stirred for 2 hours. 150 ml of 2,5-difluoronitrobenzene are added dropwise to the resulting suspension over a period of 30 minutes and then stirred for 6 hours at 85° C. The mixture is poured onto 4 litres of ice water and 250 ml of concentrated hydrochloric acid and extracted with 2 litres of ethyl acetate. The organic phase is dried with sodium sulphate and evaporated down. The oily residue is stirred twice with water and then taken up in 600 ml ethyl acetate. The solution is dried with sodium sulphate and evaporated to dryness. The crystallised crude product is recrystallised from 600 ml ethyl acetate/hexane=2:8 and dried.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:22]([O:21][C:19]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:20])[CH3:23]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.005 mL (0.053 mMol) ethyl chloroformate, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:3]=1.[ClH:18]>>[ClH:18].[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)[CH:3]=1
Reactant: COC(=O)c1ccc(F)cc1-c1ccncc1
Agent: Cl
Product: O=C(O)c1ccc(F)cc1-c1ccncc1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A mixture of methyl 4-fluoro-2-(pyridin-4-yl)benzoate (0.88 g) and 6 N hydrochloric acid (13 mL) was stirred at 90° C. for 18 hr. The solvent was evaporated under reduced pressure to give the title compound (0.96 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:18])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].N1C=CC=CC=1.[C:25]([O:28][C:29]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32])(=[O:27])[CH3:26]>C(Cl)Cl>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:17]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[NH:18][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:29]=2[O:28][C:25](=[O:27])[CH3:26])=[N:11][CH:12]=1
Reactant: CC(=O)Oc1cc(F)ccc1C(=O)Cl
Reactant: Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(F)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Fluoro-2-amino-N-(5-chloropyridin-2-yl)benzamide (5.32 g, 20 mmol) was added to a solution of 2 mL dry pyridine and 2-acetoxy-4-fluorobenzoyl chloride (21 mmol) in 100 mL dry methylene chloride under dry nitrogen with magnetic stirring. The reaction was allowed to stir overnight at room temperature and then was diluted with 500 mL of methylene chloride. The methylene chloride solution was washed with cold 1 M HCl, cold saturated NaHCO3, and brine; and then was dried over sodium sulfate. The solvent was evaporated, and the crude product was crystallized from acetone to give 2:92 g of off-white product.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:16][C:17](=[O:29])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2[CH:25]=[C:26]([CH3:28])[CH3:27])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[F:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([NH:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[CH:25]=[C:26]([CH3:27])[CH3:28])([C:4]([OH:5])=[O:3])[CH2:14]2
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2C=C(C)C)Cc2ccc(F)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)=Cc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccc(F)cc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101 %

Procedure:
The mixture 5-fluoro-2-[3-methyl-2-(2-methyl-propenyl)-benzoylamino]-indan-2-carboxylic acid ethyl ester (148) (245 mg, 0.62 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (10 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 3 h. After concentration in vacuo, the residue is dissolved in water (30 mL) and acidified with conc. HCl until no more precipitate came out of the water. The precipitate is filtered to give a pure product (149) as white solid (230 mg, 100%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([CH3:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:23]=2)[N:18]([C:33](=[O:54])[CH2:34][C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:42]([NH:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[CH3:51])=[O:43])=[C:37]([O:52][CH3:53])[CH:36]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.[OH-].[Na+]>ClCCl>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][CH:25]([C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[N:18]([C:33](=[O:54])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42]([NH:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[CH3:51])=[O:43])=[C:37]([O:52][CH3:53])[CH:36]=1)[CH2:17][CH2:16][NH:15]2)[CH3:32])[CH3:31]
Reactant: CCOC(=O)CC(C)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CC(C)c1ccc2c(c1)NCCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 87.8 %

Procedure:
Trifluoroacetic acid (574 μl) was added to a stirred solution of 7-(2-ethoxycarbonyl-1-methyl-ethyl)-4-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester (376 mg, Reference Example 18) in dichloromethane (4 ml) at 0° C. After stirring at 0° C. for 2 hours a further aliquot of trifluoroacetic acid (3.5 ml) was added and stirring was continued at 0° C. for a further 4 hours. The reaction mixture was poured onto a mixture of ice (75 ml) and sodium hydroxide solution (55 ml, 1M). The resulting mixture was extracted three times with dichloromethane (50 ml). The combined extracts were washed twice with water (20 ml), then dried over magnesium sulfate and then evaporated (40 mbar, 40° C.). The residue was subjected to flash chromatography (20 g silica, 0.040-0.063 mm particle size) eluting with a mixture of dichloromethane and methanol (99:1, v/v) to give the title compound as a white powder (279 mg). TLC: RF=43/64 (dichloromethane:methanol, 9:1). 1H NMR (250 MHz, (CD3)2SO, at a temperature of 373° K.]: δ1.16 (t, J=7 Hz, 3H); 1.23 (d, J=7.5 Hz, 3H); 2.28 (s, 3H); from 2.45 to 2.55 (m, 2H); 3.06 (m, 1H); 3.25 (m, 2H); 3.69 (m, 2H); 3.82 (s, 2H); 3.85 (s, 3H); 4.05 (q, J=7 Hz, 2H); 5.73 (broad band :1H); 6.43 (dd, J=8 and 2 Hz, 1H); 6.50 (d, J=2 Hz, 1H); 6.70 (dd, J=9 and 1.5 Hz, 1H); 6.81 (d, J=1.5 Hz, 1H); 6.97 (broad t, J=7.5 Hz, 1H); from 7.10 to 7.30 (m, 3H); 7.71 (broad d, J=9 Hz, 1H); 7.98 (d, J=8.5 Hz, 1H); 8.25 (broad s, 1H); 8.29 (broad s, 1H). MS (EI): 544(M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.[I:11]I>C(#N)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[I:11])[CH:7]=1
Reactant: Brc1cnc2ccnn2c1
Reactant: II
Solvent: CC#N
Product: Brc1cnc2c(I)cnn2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of compound 6-bromopyrazolo[1,5-a]pyrimidine (1 eq), ceric ammonium nitrate (0.6 eq), and I2 (0.6 eq) in acetonitrile (10 mL) was stirred over a period of 24 h at room temperature. The formed precipitate was filtered off, washed with acetonitrile, and recrystallized from acetonitrile. The filtrate was evaporated, and the product was extracted with dichloromethane. The latter was evaporated, and the residue was recrystallized from acetonitrile to give 6-bromo-3-iodopyrazolo[1,5-a]pyrimidine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:15][CH2:14][CH:13]([CH2:16][O:17][CH3:18])[O:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][N:3]=1.[I:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>>[I:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[O:15][CH2:14][CH:13]([CH2:16][O:17][CH3:18])[O:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1cccc(I)c1
Reactant: COCC1COc2cc3ncnc(Cl)c3cc2O1
Product: COCC1COc2cc3ncnc(Nc4cccc(I)c4)c3cc2O1
Yield: 72.3 %

Procedure:
The titled compound (260 mg, 94%, m.p. 175-177° C.) was prepared in a similar manner as in Example 8, except for employing 4-chloro-7-methoxymethyl-[1,4]dioxano[2,3-g]quinazoline (175 mg, 0.8 mmol) and 3-iodoaniline (350 mg, 1.6 mmol).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[C:7]([O:11][C:12](=[O:35])[NH:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]=2[N:29]=[C:28]([CH:31]([OH:34])CO)[CH:27]=[CH:26]3)[CH2:17][CH2:16]1)([CH3:10])([CH3:9])[CH3:8]>C(Cl)Cl>[C:7]([O:11][C:12](=[O:35])[NH:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]=2[N:29]=[C:28]([CH:31]=[O:34])[CH:27]=[CH:26]3)[CH2:17][CH2:16]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(C(O)CO)nc23)CC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(C=O)nc23)CC1
Reaction time: 0.17 h

Procedure:
Sodium periodate (0.34 mL, 0.22 mmol was added drop-wise to a slurry of silica gel (0.4 g) in DCM (3 mL)). The reaction was stirred for 10 minutes. tert-Butyl(1-(2-(1,2-dihydroxyethyl)quinolin-8-yl)piperidin-4-yl)methylcarbamate (74 mg, 0.18 mmol) in DCM (2 mL) was then added to the slurry and the reaction was stirred for 30 minutes. The reaction was filtered and the collected solids were washed with DCM (20 mL). The filtrate was concentrated to give the crude product.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:16][CH2:17][CH2:18]CO)[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.NCCC[OH:25]>>[Br:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:16][CH2:17][CH2:18][OH:25])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: NCCCO
Reactant: OCCCCNC1CCCN(c2cccc(Br)n2)CC1
Product: OCCCNC1CCCN(c2cccc(Br)n2)CC1

Procedure:
The preparation is carried out analogously to 4-[1-(6-bromopyridin-2-yl)azepan-4-ylamino]butan-1-ol starting from 127 μl (1.69 mmol) of 3-amino-1-propanol 524 mg, yellow oil, Rt.=1.59 min (method B), LCMS: 329 (M+H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:20][CH:19]4[CH:15]([CH2:16][NH:17][CH2:18]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21]1[N:22]=[C:23]([C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28](O)=[O:29])[NH:24][CH:25]=1>>[C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:14][CH:15]4[CH2:16][N:17]([C:28]([C:27]5[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=5[C:23]5[NH:24][CH:25]=[N:21][N:22]=5)=[O:29])[CH2:18][CH:19]4[CH2:20]3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccnc(N3CC4CNCC4C3)n2)cc1
Reactant: O=C(O)c1ccccc1-c1nnc[nH]1
Product: O=C(c1ccccc1-c1nnc[nH]1)N1CC2CN(c3nccc(-c4ccccc4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 26 and 2-(4H-[1,2,4]triazol-3-yl)benzoic acid. MS (ESI): mass calculated for C25H23N7O, 437.50; m/z found 438.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 12.43 (br s, 1H), 8.36 (d, J=5.2 Hz, 1H), 8.14 (d, J=7.5 Hz, 1H), 8.08-7.91 (m, 3H), 7.60-7.42 (m, 5H), 7.39-7.31 (m, 1H), 6.98 (t, J=6.1 Hz, 1H), 4.01-3.87 (m, 2H), 3.85-3.65 (m, 3H), 3.61-3.40 (m, 2H), 3.28-2.89 (m, 3H).