Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH:18](O)[CH2:19][O:20]C(C2C=CC(OC)=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:3][CH:2]=1.CCCCCC.CN(C)[CH:57]=[O:58]>O1CCCC1>[C:1]1([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH:18]([O:58][CH3:57])[CH2:19][OH:20])=[CH:3][CH:2]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(C(OCC(O)COCCCCCCCCOc2ccc(-c3ccccc3)cc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(CO)COCCCCCCCCOc1ccc(-c2ccccc2)cc1
Reaction time: 8 h

Procedure:
A solution of 7.6 g of 1-[[8-([1,1'-biphenyl]-4-yloxy)octyl]oxy]-3-[(4-methoxyphenyl)diphenylmethoxy]-2-propanol in 20 ml of dimethylformamide and 20 ml of tetrahydrofuran was added dropwise to a solution of 849 mg of hexane washed 50% sodium hydride in 50 ml of dimethylformamide containing 5.02 g of methyl iodide over 35 minutes under argon. The mixture was stirred overnight then ice was cautiously added followed by 300 ml of iced water. This mixture was extracted three times with ether, the extracts combined, washed with water, dried and evaporated. The residue was taken up in 65 ml of chloroform and 130 ml of methanol, heated to boiling, 8 g of Amberlite® IR-4B ion exchange resin added, stirred for 2 hours, filtered and evaporated. The residue was purified by chromatography, giving 1.27 g of 3-[[8-([1,1'-biphenyl]-4-yloxy]octyl]oxy]-2-methoxy- 1-propanol.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:9]([CH:10](Cl)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:9]([CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:8][CH:7]=1
Reactant: C1CNCCN1
Reactant: COCCOc1ccc(C(Cl)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(C(c2ccccc2)N2CCNCC2)cc1

Procedure:
For the preparation of the compound of Example 27, 4-(2-methoxyethoxy)benzophenone is obtained by reaction of 4-hydroxybenzophenone with 2-methoxyethyl chloride at 100° C. in the presence of sodium hydride in dimethylformamide. Further reaction takes place in accordance with Example 1-5. 4-(2-Methoxyethoxy)benzophenone is reduced to 4-(2-methoxyethoxy)benzhydrol using sodium borohydride. 4-(2-Methoxyethoxy)benzhydrol is reacted with thionyl chloride in chloroform to give 4-(2-methoxyethoxy)benzhydryl chloride. 4-(2-methoxyethoxy)benzhydryl chloride is reacted with piperazine in dimethylformamide in the presence of potassium carbonate to give 1-((4-(2-methoxyethoxy)phenyl)phenylmethyl)piperazine.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10][C@@H:9]([NH:24][C:25](=[O:42])[C@@H:26]([NH:34]C(OC(C)(C)C)=O)[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]1=[O:43])(=[O:3])[CH3:2].C(OCCN1C2C=CC=CC=2C(C2C=CC=CC=2)=N[C@H](NC(=O)[C@@H](NC(OC(C)(C)C)=O)CC2C=CC=CC=2)C1=O)(=O)C.Cl>C(OCC)(=O)C>[C:1]([O:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10][C@@H:9]([NH:24][C:25](=[O:42])[C@@H:26]([NH2:34])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]1=[O:43])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCN1C(=O)[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)N=C(c2ccccc2)c2ccccc21
Agent: CC(=O)OCCN1C(=O)[C@@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)N=C(c2ccccc2)c2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)OCCN1C(=O)[C@H](NC(=O)[C@@H](N)Cc2ccccc2)N=C(c2ccccc2)c2ccccc21
Yield: 98.3 %

Procedure:
To a solution of a mixture (0.7 g) of (3R)-1-(2-acetoxyethyl) -1,3-dihydro-5-phenyl-3-[((2S)-2-tert-butoxycarbonylamino-3-phenylpropanoyl)amino]-2H-1,4-benzodiazepine-2-one and (3S)-1-(2-acetoxyethyl)-1,3-dihydro-5-phenyl-3-[((2S)-2-tert-butoxycarbonylamino-3-phenylpropanoyl)amino]-2H-1,4-benzodiazepine-2-one in ethyl acetate (20 ml) was introduced hydrogen chloride gas under cooling in an ice-bath with stirring. After the solution was saturated with hydrogen chloride, the mixture was stirred for 30 minutes under the same temperature and for 1 hour at ambient temperature. After removal of the hydrogen chloride by bubbling dried nitrogen gas, the mixture was evaporated under reduced pressure. To the residue was added water and the mixture was neutralized with a saturated aqueous solution of sodium bicarbonate. The mixture was extracted with ethyl acetate twice and the extract was washed with water and dried over magnesium sulfate. Removal of the solvent afforded a mixture (0.57 g) of (3R)-1-(2-acetoxyethyl)-3-[((2S)-2-amino-3-phenylpropanoyl)amino]-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one and (3S)-1-(2-acetoxyethyl)-3-[((2S)-2-amino-3phenylpropanoyl)amino]-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:13][CH:14]1[NH:18][C:17](=[O:19])[CH2:16][CH2:15]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCCCCC.O1CCCC1>[C:20]([N:18]1[CH:14]([O:13][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:15][CH2:16][C:17]1=[O:19])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCCCCCCOC1CCC(=O)N1
Reactant: O=C(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCOC1CCC(=O)N1C(=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
16.5 cm3 of a 15% solution butyllithium in hexane is added at -60° C. to 4.98 g of 5-n-heptyloxy pyrrolidin-2-one in solution in 100 cm3 of tetrahydrofuran. After 20 minutes of agitation at -60° C., 3.5 g of benzoyl chloride in 25 cm3 of tetra-hydrofuran is added at this temperature. Agitation is carried out for 4 hours, allowing the mixture to return to ambient temperature. After concentration at 40° C., the residue is taken up in water, extracted with ether and concentrated to dryness. The residue is chromatographed on silica (eluent: toluene-ethyl acetate 8-2) and 1.2 g of the product sought is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH:10]([CH3:12])[CH3:11])[N:3]=1.[CH3:13][C:14]1([CH3:22])[CH2:19][CH2:18][CH2:17][C:16]([CH3:21])([CH3:20])[NH:15]1.CCCCCC>C1(C)C(C)=CC=CC=1>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH:10]([CH3:12])[CH3:11])[N:3]=[C:2]([N:15]2[C:16]([CH3:21])([CH3:20])[CH2:17][CH2:18][CH2:19][C:14]2([CH3:22])[CH3:13])[N:7]=1
Reactant: CC(C)Oc1nc(Cl)nc(Cl)n1
Reactant: CC1(C)CCCC(C)(C)N1
Solvent: CCCCCC
Solvent: Cc1ccccc1C
Product: CC(C)Oc1nc(Cl)nc(N2C(C)(C)CCCC2(C)C)n1

Procedure:
104.0 g of 2,4-dichloro-6-isopropyloxy-1,3,5-triazine and 148.3 g of 2,2,6,6-tetramethylpiperidine are reacted in 300 ml of xylene as described in Example 1 and worked up. 2-Chloro-4-isopropyloxy-6-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine is obtained by crystallization from hexane as colorless crystals having a melting point of 111°-112°.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1.[F:14][C:15]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:18]=[CH:17][C:16]=1[C:30]1[N:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=1>CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+]>[F:14][C:15]1[CH:20]=[C:19]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[CH:13]=[N:12][CH:11]=[CH:10][N:9]=2)[CH:18]=[CH:17][C:16]=1[C:30]1[N:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: Clc1ccccc1-c1cnccn1
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2cccc(P(C3CCCCC3)C3CCCCC3)c2)c(C(C)C)c1
Agent: Nc1ccccc1-c1[c-]cccc1
Product: Nc1cnc(-c2ccc(-c3ccccc3-c3cnccn3)cc2F)cn1
Temperature: 45 °C

Procedure:
2-(2-Chlorophenyl)pyrazine (58 mg, 0.31 mmol), 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine (88 mg, 0.28 mmol) and chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (4.4 mg, 0.0060 mmol) were placed into a sealable 5 mL vial equipped with a stir-bar. The vial was sealed, evacuated and backfilled with argon three times. To this vial was added separately deoxygenated THF (0.56 mL) and K3PO4 (1.1 mL, 0.5 M). The vial was then heated at 45° Celsius for 1 hour before cooling to rt diluting with brine (5 mL), and extracting with EtOAc (1×5 mL, 3×10 mL). The combined organic extracts were then dried with sodium sulfate, filtered, and concentrated to dryness. The crude product was purified via FCC to provide the title compound. MS (ESI): mass calcd. for C20H14FN5, 343.12; m/z found, 344.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.65-8.59 (dd, J=2.6, 1.6, 1H), 8.47-8.42 (d, J=2.6, 1H), 8.33-8.31 (dd, J=2.2, 1.4, 1H), 8.31-8.29 (d, J=1.5, 1H), 8.04-8.02 (d, J=1.5, 1H), 7.79-7.73 (m, 1H), 7.72-7.69 (m, 1H), 7.64-7.53 (m, 3H), 7.11-6.87 (m, 2H).
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=O.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[CH2:14]([N:21]1[C:1](=[O:13])[CH2:2][C:3]2[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5]1=[O:7])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)Cc1ccccc1C(=O)O
Reactant: NCc1ccccc1
Solvent: O
Product: O=C1Cc2ccccc2C(=O)N1Cc1ccccc1

Procedure:
A mixture consisting of homophthalic acid (25 g, 0.139 mol) and benzylamine (15.2 ml, 14.91 g, 0.139 mol) was heated at 165°-180° C. for two hours, producing a vigorous release of water vapor. Cooling afforded a hard green solid which was pulverized, triturated with diethyl ether, and isolated by filtration to afford the title compound as a light-green granular solid (29.4 g) used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[CH3:6][O:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10]Cl>>[CH3:6][O:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][NH:1][CH2:2][CH2:3][CH2:4][OH:5]
Reactant: NCCCO
Reactant: COc1ccccc1CCl
Product: COc1ccccc1CNCCCO
Yield: 55.8 %

Procedure:
In a similar manner to Reference Example 23, 3-amino-1-propanol (27.0 g) was reacted with 2-methoxybenzylchloride (5.00 g) to obtain 3-(2-methoxybenzylamino)-1-propanol (3.48 g, 50%).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH3:28])([CH3:27])[C:24](O)=[O:25])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1C=CC=CC=1>[CH2:5]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH3:28])([CH3:27])[C:24]([Cl:3])=[O:25])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(CCCCCCCCCCOCc1ccccc1)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)(CCCCCCCCCCOCc1ccccc1)C(=O)Cl

Procedure:
1.2 ml of thionyl chloride was added to a solution of 3.34 g of the obtained carboxylic acid in 5 ml of anhydrous benzene, and the mixture was reacted at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to give 3.53 g of 12-benzyloxy-2,2-dimethyldodecanoyl chloride as a colorless oily material.
Reaction SMILES: S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][C:50]([O:52][CH3:53])=[O:51])(C1C=CC(C)=CC=1)(=O)=O.[NH2:54][C:55]1[CH:56]=[C:57]([CH2:63][OH:64])[CH:58]=[C:59]([CH2:61][OH:62])[CH:60]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:62][CH2:61][C:59]1[CH:60]=[C:55]([NH:54][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][C:50]([O:52][CH3:53])=[O:51])[CH:56]=[C:57]([CH2:63][OH:64])[CH:58]=1
Reactant: Nc1cc(CO)cc(CO)c1
Reactant: COC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCNc1cc(CO)cc(CO)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a stirred mixture of methyl 1-(tosyloxy)-3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxanonatriacontan-39-oate (265b)(700 mg, 0.890 mmol) and (5-amino-1,3-phenylene)dimethanol (26) (150 mg, 0.978 mmol) in anhydrous DMF (2.0 ml) was added potassium carbonate (184 mg, 1.334 mmol). The reaction was stirred at 80° C. overnight. The mixture was cooled to room temperature, quenched with water and extracted with 10% Methanol/Methylene chloride. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (eluted with 5→15% MeOH/CH2Cl2) to give methyl 1-(3,5-bis(hydroxymethyl)phenylamino)-3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxanonatriacontan-39-oate (265c) (285 mg, 42%). 1H NMR (400 Hz, CDCl3): δ 6.62 (s, 1H), 6.51 (s, 2H), 4.52 (s, 4H), 3.72 (t, J=6.4 Hz, 2H), 3.65 (s, 3H), 3.61 (m, 48H), 2.94 (s, 2H), 2.63 (s, 1H), 2.57 (t, J=6.4 Hz, 2H); MS (m/z), found 790.4 (M+Na)−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:59])[NH:7][CH:8]([CH2:50][C:51]1[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][C:52]=1[Cl:58])[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[CH2:13][CH:12]1[CH2:29][CH2:30][CH2:31][NH:32][C:33]([NH:42]C(OC(C)(C)C)=O)=[N:34]C(OC(C)(C)C)=O)=[O:10])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:59])[NH:7][CH:8]([CH2:50][C:51]1[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][C:52]=1[Cl:58])[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[CH2:13][CH:12]1[CH2:29][CH2:30][CH2:31][NH:32][C:33]([NH2:42])=[NH:34])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N=C(NCCCC1CN(CCc2ccc3ccccc3c2)CCN1C(=O)C(Cc1ccc(Cl)cc1Cl)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1Cl)C(=O)N1CCN(CCc2ccc3ccccc3c2)CC1CCCNC(=N)N
Yield: 30.5 %

Procedure:
Alternatively, 20 mg (0.033 mmol) of the crude product H was reacted with 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (10 mg, 1.1 eq) and silver nitrate (6 mg, 1.1 eq) and NMM (2.2 eq) in 5 mL of acetonitrile at room temperature for 24 hrs, followed by evaporation to remove the solvent and column chromatography purification to afford 4.5 mg of the product [2-[2-[3-(N′, N″-Di-tert-butoxycarbonyl-guanidino)-propyl]-4-(2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-1-(2,4-dichloro-benzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (J). Product J (4.5 mg) was treated with 33% TFA in DCM at room temperature for 2 hours and the reaction mixture was concentrated and purified with HPLC to give 1.05 mg {1-(2,4-Dichloro-benzyl)-2-[2-(3-guanidino-propyl)-4-(2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (K).
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([CH3:22])([S:18]([CH3:21])(=[O:20])=[O:19])[C:13]([O:15]CC)=[O:14])=[CH:6][CH:5]=1.O1CCCC1CO.O.Cl>O>[Br:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([CH3:22])([S:18]([CH3:21])(=[O:20])=[O:19])[C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(C)(CCc1ccc(Br)nc1)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: OCC1CCCO1
Product: CC(CCc1ccc(Br)nc1)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.4 %

Procedure:
A solution of lithium hydroxide (357 mg, 8.5 mmol, 4.0 equiv) and ethyl 4-(6-bromopyridin-3-yl)-2-methyl-2-(methylsulfonyl)butanoate (775 mg, 2.1 mmol, 1.0 equiv) in 1:1:1 tetrahydrofuran-methanol-water (3 mL) was allowed to stir at room temperature for 2 h. The reaction was diluted with water (150 mL), acidified (to pH=2) with 0.5 M hydrochloric acid, and then was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound (716 mg, 98%). MS (LCMS) m/z 334.1 (M−1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.56 (s, 3H) 2.03 (td, J=12.78, 5.27 Hz, 1H) 2.31 (td, J=12.68, 4.68 Hz, 1H) 2.51 (td, J=12.98, 4.49 Hz, 1H) 2.59-2.70 (m, 1H) 2.96 (s, 3H) 7.30-7.39 (m, 2H) 8.07 (d, J=1.56 Hz, 1H).
Reaction SMILES: C(N[S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:16]([CH:19]=1)[C:17]#[N:18])(=[O:11])=[O:10])C1C=CC=CC=1.[ClH:33].Cl[O-].[Na+]>ClCCl>[C:22]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][C:15]1[CH:14]=[CH:13][C:12]([S:9]([Cl:33])(=[O:11])=[O:10])=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: Cl
Reactant: N#Cc1cc(S(=O)(=O)NCc2ccccc2)ccc1Oc1ccccc1-c1ccccc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: N#Cc1cc(S(=O)(=O)Cl)ccc1Oc1ccccc1-c1ccccc1

Procedure:
A mixture of 5-benzylsulfamyl-2-(biphenyl-2-yloxy)-benzonitrile (Preparation 56, 6.06 g, 15.4 mmol), dichloromethane and aq HCl was stirred vigorously with cooling (ice bath). Sodium hypochlorite was added dropwise over 30 minutes and stirring continued with cooling for 1 hour. The layers were separated, the aqueous extracted with dichloromethane (2×100 ml), and the organic collected, dried (MgSO4) and concentrated in vacuo. The residue was purified using silica gel column chromatography (ethyl acetate:Heptane 10/90 to 20/80) to furnish 4.58 g of the title compound. 1HNMR (CDCl3): δ 6.7 (m, 1H), 7.2-7.6 (m, 9H), 7.85 (m, 1H), 8.15 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH2:12][C:13]2([CH3:18])OCC[O:14]2)[CH:3]=1>C(O)(=O)C.O>[OH:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH2:12][C:13](=[O:14])[CH3:18])[CH:3]=1
Reactant: CC1(CCc2cc(O)n3nccc3n2)OCCO1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)CCc1cc(O)n2nccc2n1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
The compound obtained in step (1), 22 g, was dissolved in 500 ml of acetic acid-water (4:1) and stirred at 50° C. for 3 days. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the remaining acetic acid-water was azeotropically distilled off with benzene. The residue was recrystallized from ethanol-n-hexane to provide 11 g of 7-hydroxy-5-(3-oxobutyl)pyrazolo[1,5-a]pyrimidine as colorless crystals.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:25][C:24]=1[CH3:33]>CCOC(C)=O>[Br:8][CH2:33][C:24]1[CH:25]=[C:26]([CH2:29][C:30]([OH:32])=[O:31])[CH:27]=[CH:28][C:23]=1[O:22][CH3:21]
Reactant: COc1ccc(CC(=O)O)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: COc1ccc(CC(=O)O)cc1CBr
Temperature: 80 °C
Reaction time: 2 h

Procedure:
NBS (2.72 g) and AIBN (0.136 g) were added in one portion to a solution of 2-(4-methoxy-3-methylphenyl)acetic acid (2.99 g) in EtOAc (50 ml) and stirred at 80° C. for 2 h. Another portion of AIBN (0.136 g) was added and the suspension stirred for a further 2 h. The reaction mixture was diluted with EtOAc, washed with sat. sodium thiosulfate solution, 2M HCl, water, and sat. brine. The organic phase was dried, filtered and evaporated to afford the subtitle compound, 4.10 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[N:23]=[C:22]([NH:24][C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[N:29]=[CH:28]4)[C:21]3[C:16](=[CH:17][C:18]([O:42][CH3:43])=[C:19]([OH:41])[CH:20]=3)[N:15]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[CH2:45][CH2:46][Cl:47].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:47][CH2:46][CH2:45][O:41][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:42][CH3:43])[N:15]=[C:14]([C:4]1[CH:5]=[CH:6][C:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[C:2]([F:1])[CH:3]=1)[N:23]=[C:22]2[NH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[N:29]=[CH:28]2
Reactant: ClCCBr
Reactant: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCCl
Temperature: 85 °C
Yield: 54.5 %

Procedure:
A mixture of tert-butyl 5-(2-(3-fluoro-4-(phenyl)phenyl)-6-hydroxy-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.61 g, 1.06 mmol), 1-bromo-2-chloro ethane (0.475 g, 3.31 mmol) and K2CO3 (0.533 g, 3.86 mmol) in DMF (5 mL) was heated at 85° C. for 2.5 h. the mixture was allowed to cool to RT upon which, it was poured into water. A solid separated out which was collected via filtration and dried under vacuum. The residue was purified via preparative TLC (SiO2, CH2Cl2:MeOH 9:1) to give the desired compound tert-butyl 5-(6-(2-chloroethoxy)-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.37 g, 0.578 mmol, 55%). MS 640.3 (M+1 Cl isotope pattern).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([C:24]([OH:26])=O)[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:28][O:29][C:30](=[O:33])[CH2:31][NH2:32].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.C(OC(N1CCCN(C2C=CC([N+]([O-])=O)=C(C(NCC(O)=O)=O)C=2)CC1)=O)(C)(C)C>C(Cl)Cl.Cl.COC(=O)CN>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([C:24]([NH:32][CH2:31][C:30]([O:29][CH3:28])=[O:33])=[O:26])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CN
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc([N+](=O)[O-])c(C(=O)O)c2)CC1
Agent: CC(C)(C)OC(=O)N1CCCN(c2ccc([N+](=O)[O-])c(C(=O)NCC(=O)O)c2)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CNC(=O)c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
4-(3-Carboxy-4-nitro-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (37.27 g, 102 mmol) and 107.1 mmol of glycine methyl ester hydrochloride salt were suspended in methylene chloride. To this suspension was added 102 mmol of N-hydroxybenzotriazole and the mixture was cooled with an ice-water bath. Triethylamine (214 mmol) was added, effecting a solution. At this time 1.1 equivalents of 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride was added. This mixture was stirred at 0° C. for 1 hour and then at room temperature for 3 days. At this time, thin layer chromatography indicated the presence of 4-[3-(carboxymethyl-aminocarbonyl)-4-nitro-phenyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester. An additional 5.1 mmol each of glycine methyl ester hydrochloride salt and N-hydroxybenzotriazole as well as 10.3 mmol of triethylamine were added. The reaction mixture was stirred at room temperature for another 24 hour. At this time, the reaction mixture was diluted with methylene chloride, washed with water, with 10% (wt/vol) KHSO4 solution, with water again, with saturated sodium bicarbonate aqueous solution, with water again, and finally with brine. The methylene chloride solution was concentrated to dryness in vacuo, resulting in a dark brown oil. The oil was purified by flash column chromatography: the column was loaded with a methylene chloride solution, followed by elution with ethyl acetate:hexane (7:3), and then finally with ethyl acetate. In this manner, fractions were collected and concentrated in vacuo to provide 42.05 g (94.4%) of 4-[3-(methoxycarbonylmethyl-aminocarbonyl)-4-nitro-phenyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester.