Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O>C(O)(=O)C.CO>[Br:20][C:16]1[CH:17]=[CH:18][C:19]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(-n2c3ccccc3c3ccccc32)cc1
Solvent: CO
Solvent: CC(=O)O
Product: Brc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.1 %

Procedure:
Into a 2 L Meyer flask was put 24.3 g (100 mmol) of 9-phenylcarbazole, and dissolved in 600 mL of glacial acetic acid. Then, 17.8 g (100 mmol) of N-bromosuccinimide was slowly added thereto, followed by stirring at room temperature for about 12 hours. This glacial acetic acid solution was dropped into 1 L of ice water while being stirred. A white solid substance was precipitated and collected by suction filtration, and then the white solid substance was washed with water three times while being suction filtered. This solid substance was dissolved in 150 mL of diethyl ether, and this solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and water. The resulting organic layer was dried with magnesium sulfate. This mixture was suction filtered, and the obtained filtrate was concentrated to give an oily substance. This oily substance was dissolved in about 50 mL of methanol. The resulting solution was left still to precipitate a white solid. This solid substance was collected by suction filtration and dried. Then, 28.4 g (88% yield) of 3-bromo-9-phenylcarbazole was obtained as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1I.[CH3:13][N:14]1[C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=[N:15]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:18]1[N:14]([CH3:13])[N:15]=[CH:16][CH:17]=1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: FC(F)(F)c1ccc(Br)c(I)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cn1nccc1-c1cc(C(F)(F)F)ccc1Br
Temperature: 60 °C
Reaction time: 48 h
Yield: 68 %

Procedure:
A round-bottom flask was charged with 1-bromo-2-iodo-4-(trifluoromethyl)benzene (5.00 g, 14.25 mmol; Combi-blocks, San Diego, Calif.), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (3.41 g, 16.39 mmol), potassium phosphate (6.05 g, 28.5 mmol) and Pd(dppf)Cl2CH2Cl2 (1.164 g, 1.425 mmol). The flask was flushed with Ar, and DMF (47.5 mL) was then added. The flask was sealed, heated to 60° C. for 12 h, and then stirred at room temperature for 48 h. The mixture was diluted with water and extracted with EtOAc (three times). The combined organics were washed with brine, dried and concentrated under a vacuum. The product was purified by chromatography using silica gel (0 to 100% EtOAc/Heptane) to yield 5-(2-bromo-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazole (2.956 g, 9.69 mmol) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=8.06 (td, J=0.7, 8.1 Hz, 1H), 7.86-7.73 (m, 2H), 7.53 (d, J=2.0 Hz, 1H), 6.41 (d, J=2.0 Hz, 1H), 3.64 (s, 3H); m/z (ESI) 305.0 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][C:23]([NH:26][C:27]([NH:29][CH:30]([CH3:32])[CH3:31])=[O:28])([CH3:25])[CH3:24])[C:20]([CH2:33][O:34][CH2:35][CH3:36])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)C1C=CC=CC=1>[Pd].C(O)C>[CH2:35]([O:34][CH2:33][C:20]1[N:21]([CH2:22][C:23]([NH:26][C:27]([NH:29][CH:30]([CH3:31])[CH3:32])=[O:28])([CH3:25])[CH3:24])[C:13]2[C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:19]=1)[CH3:36]
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOCc1nc2cnc3cc(O)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Yield: 101.7 %

Procedure:
A mixture of N-{2-[7-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-N′-isopropylurea (3.82 g, 7.80 mmol) and 10% palladium on carbon (0.92 g) in ethanol (100 mL) was hydrogenated at 50 psi (3.5×105 Pa) overnight on a Parr apparatus. The mixture was filtered through CELITE filter agent and the filtrate was concentrated under reduced pressure to yield 3.17 g of N-{2-[2-(ethoxymethyl)-7-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-N′-isopropylurea as a yellow solid.
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([C:10]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][C:11]=1[O:12][CH2:13][C@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][NH2+:15]1)#[N:9].C(N(CC)CC)C.[C:34](Cl)(=[O:38])[CH2:35][CH2:36][CH3:37]>C(Cl)Cl>[C:34]([N:15]1[CH2:16][CH2:17][CH2:18][CH2:19][C@@H:14]1[CH2:13][O:12][C:11]1[CH:20]=[CH:21][CH:22]=[C:23]([N+:24]([O-:26])=[O:25])[C:10]=1[C:8]#[N:9])(=[O:38])[CH2:35][CH2:36][CH3:37]
Reactant: CCCC(=O)Cl
Reactant: N#Cc1c(OC[C@H]2CCCC[NH2+]2)cccc1[N+](=O)[O-]
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)N1CCCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N
Temperature: 0 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
To a solution of (R)-2-((2-cyano-3-nitrophenoxy)methyl)piperidin-1-ium 2,2,2-trifluoroacetate (Example 16c, 2.26 g, 6.03 mmol) in anhydrous DCM (50 mL) was added triethylamine (4.2 mL, 30.1 mmol) at room temperature. The reaction mixture was cooled down to 0° C. and butyryl chloride (0.95 mL, 9.05 mmol) was added and the solution stirred at room temperature overnight. The solvent was then removed under reduced pressure and the residue was diluted with EtOAc (150 mL), the organic layer was washed successively with water, brine and dried over Na2SO4, filtered and evaporated. The residue was purified by Biotage SP-1 (40s column) eluting with EtOAc/Hexane (10%-70%) to give the desired product (1.5 g, 75%). MS 332 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[O:14])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:27][NH:28][CH3:29]>C(O)C>[CH3:27][N:28]([CH3:29])[C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[O:14])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CNC
Reactant: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2c(Cl)nccc12
Solvent: CCO
Product: CN(C)c1nccc2c(NC(=O)NCc3ccc(C(F)(F)F)cc3)cccc12
Temperature: 100 °C

Procedure:
N-(1-Chloroisoquinolin-5-yl)-N′-(4-trifluoromethylbenzyl)urea (Example 69; 60 mg) was suspended in ethanol (5 ml). Ethanolic dimethylamine (33%, 2 ml) was added and the mixture heated to 100° C. in a sealed tube for 16 hours after which time TLC indicated complete reaction. The reaction mixture was evaporated and the residue purified by preparative thin layer chromatography (5% methanol-dichloromethane eluant) to give the title compound (20 mg). m/z (ES+) 389 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=1>C(#N)C.C(Cl)Cl>[N+:21]([C:20]1[C:15]([N:1]2[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=[CH:2]2)=[N:16][CH:17]=[CH:18][CH:19]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: C1CNCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: O=[N+]([O-])c1cccnc1N1C=CC=NC=C1
Reaction time: 4 h

Procedure:
Homopiperazine (15.58 g) is dissolved in 100 ml of acetonitrile. Potassium carbonate (8.7 g) is added and then the 2-chloro-3-nitropyridine (5.0 g) dissolved in 25 ml of acetonitrile is added dropwise. The reaction is stirred at 20°-25° 4 hr, then diluted with methylene chloride, washed with water (2×), saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound, NMR (300 MHz, CDCl3) 8.30, 8.08, 6.66, 3.60, 3.41, 3.10, 2.89 and 1.93 δ.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[C:9](Cl)(=O)CC>>[O:4]=[C:3]([CH2:5][CH3:9])[CH2:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: CCC(=O)Cl
Reactant: COC(=O)CC(C)=O
Product: CCC(=O)CC(=O)OC
Yield: 45.5 %

Procedure:
According to the method described in Jikken Kagaku Koza, Vol. 19, p. 441, 121 g of methyl 3-ketopentanoate was synthesized from 326 g of methyl acetoacetate and 189 g of propionyl chloride and then subjected to enantioselective hydrogenation using (+)-2,2'-bis[di(p-tolylphosphino)-1,1'-binaphthyl]tetrachlorodiruthenium-triethylamine [Ru2Cl4 (T-BINAP)2Et3N] according to the method disclosed in JP-A-63-310847, to obtain 110 g of methyl R-(-)-3-hydroxypentanoate. 100 g of this compound was treated in the same manner as in Step 1 of Example 1, to obtain 19 g of the desired compound having a boiling point of 60° to 65° C./1 mmHg and a chemical purity, as measured by GC, of 88.2%. The percent yield was 36.3%.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].[F:36][CH:37]([F:40])[CH2:38]Br>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[N:13]([CH2:38][CH:37]([F:40])[F:36])[C:12]2=[O:24])[CH2:25][CH2:26]1)=[O:7]
Reactant: Cc1ccccc1N1C(C)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Reactant: FC(F)CBr
Product: Cc1ccccc1N1C(C)N(CC(F)F)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=564.2 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and 2,2-difluoroethyl bromide.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:10]1([C:16]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:24]3[C@H:20]([CH2:21][NH:22][CH2:23]3)[C:19](=[O:25])[CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCl.C(N(CC)CC)C>[CH2:1]([N:22]1[CH2:21][C@H:20]2[C@H:24]([C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:17][CH2:18][C:19]2=[O:25])[CH2:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CN(Cc3ccccc3)C[C@H]12
Temperature: 20 °C
Reaction time: 2 h

Procedure:
7.9 cm3 of benzyl bromide are added to a solution, cooled to 0° C., of 21.7 g of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride in 300 cm3 of dichloromethane and 18.5 cm3 of triethylamine. After stirring for 1 hour at 0° C. and 2 hours at 20° C., the reaction mixture is washed with 50 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.04-0.06 mm, diameter 5 cm, height 40 cm), eluting under a nitrogen pressure of 0.6 bar with an ethyl acetate and cyclohexane mixture (75/25 by volume) and collecting fractions of 250 cm3. Fractions 3 to 6 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). 22.1 g of (3aR, 7aR)-2-benzyl-7,7-diphenyl-4-perhydroisoindolone are obtained in the form of a white solid; melting point 124° C. [α]20 =-279° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:3][CH:2]=1.[CH:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)([CH3:23])[CH3:22].N1C=CC=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH:21]([C:24]1[CH:29]=[CH:28][C:27]([O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][NH:11][C:4]3[C:5]4[C:10](=[N:9][CH:8]=[CH:7][N:6]=4)[N:1]=[CH:2][N:3]=3)=[CH:15][CH:16]=2)=[CH:26][CH:25]=1)([CH3:23])[CH3:22]
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: Oc1ccc(CCNc2ncnc3nccnc23)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)c1ccc(Oc2ccc(CCNc3ncnc4nccnc34)cc2)cc1
Reaction time: 20 h
Yield: 10.7 %

Procedure:
4-[2-(Pteridin-4-ylamino)-ethyl]-phenol (500 mg, 1.9 mmol), 4-isopropylphenylboronic acid (400 mg, 2.4 mmol), anh. Cu(OAc)2 (360 mg, 2.0 mmol) and powdered, freshly activated 4 Å molecular sieves (approximately 1 g) were combined in CH2Cl2 (15 mL), treated with pyridine (920 μL, 900 mg, 11.4 mmol) and sealed and stirred for 20 h with a moisture trap. The reaction was suction filtered and the filtrate shaken with dilute aqueous NH4OH. The organic phase was washed with H2O and brine and concentrated in vacuo. The residue was purified by preparative RP-HPLC using 80% MeCN/H2O to yield {2-[4-(4-isopropylphenoxy)-phenyl]-ethyl}-pteridin-4-yl-amine (78 mg, 11%) as a tan solid: mp 105-106.5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]2[CH2:7][CH2:8][CH2:9][C@@H:10]([NH2:11])[C@@H:4]2[O:3]1.[CH3:13][C:14]1([CH3:38])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]2[CH:19]=[C:18]([C:26]3[N:27]=[C:28]([N:31]4[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]4)[S:29][CH:30]=3)[CH:17]=[CH:16][C:15]1=2>C1COCC1>[CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]2[CH2:7][CH2:8][CH2:9][C@@H:10]([NH:11][CH:34]3[CH2:35][CH2:36][N:31]([C:28]4[S:29][CH:30]=[C:26]([C:18]5[CH:17]=[CH:16][C:15]6[C:14]([CH3:38])([CH3:13])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]=6[CH:19]=5)[N:27]=4)[CH2:32][CH2:33]3)[C@@H:4]2[O:3]1
Reactant: CC1(C)O[C@H]2[C@H](N)CCC[C@H]2O1
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(=O)CC4)n3)ccc21
Solvent: C1CCOC1
Product: CC1(C)O[C@H]2[C@H](NC3CCN(c4nc(-c5ccc6c(c5)C(C)(C)CCC6(C)C)cs4)CC3)CCC[C@H]2O1

Procedure:
The preparation is carried out analogously in THF starting from 27 mg (0.16 mmol) of (3aS,4R,7aR)-2,2-dimethylhexahydrobenzo-1,3-dioxol-4-ylamine and 60 mg (0.16 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-one. The purification is carried out by means of flash chromatography on silica gel.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([OH:22])=[C:18]([CH:21]=2)[CH:19]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1C(=O)CCC1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:19][C:18]=3[CH:21]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)c(C=O)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)c1cc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2o1
Reaction time: 3 h

Procedure:
520 mg of 5-(4-tert-butoxycarbonylpiperazin-1-yl)-2-hydroxybenzaldehyde are added at 20° under nitrogen with stirring to 5 ml of NMP, and 0.25 g of potassium carbonate and 0.2 ml of ethyl bromoacetate are added to the solution. The mixture is stirred at 105° for 3 hours and then cooled to 25°. The batch is added to 30 ml of water (10°) with stirring, the aqueous phase is extracted at 10° with 3 times 30 ml of ethyl acetate, and the combined organic phases are washed with 30 ml of saturated NaCl solution and with 30 ml of water and then freed from solvent under reduced pressure (0.6 g of orange oil with crystal components). After chromatography on 30 g of silica gel (MTB ether/heptane 5:1), 0.45 g of pale-yellow crystals can be isolated (70%), m.p. 116-117°; MS 374 (M+), 318 (100%), 244, 232.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([S:18]([CH3:21])(=[O:20])=[O:19])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[C:22]([O:26][C:27]([CH2:29][C@H:30]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[Cl:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][C@H:30]([C:31]([N:15]2[CH2:16][CH2:17][N:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[S:18]([CH3:21])(=[O:19])=[O:20])[CH2:13][CH2:14]2)=[O:32])[CH2:29][C:27]([O:26][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:28])=[CH:40][CH:39]=1
Reactant: CS(=O)(=O)N(CC1CC1)c1ccccc1N1CCNCC1
Reactant: CC(C)(C)OC(=O)C[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2N(CC2CC2)S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65 %

Procedure:
To a solution of (cyclopropylmethyl)(methylsulfonyl)-(2-piperazinyl-phenyl)amine (HCl salt, 2.3 g, 6.0 mmol), (2S)-3-[(tert-butyl)oxycarbonyl]-2-[(4-chlorophenyl)-methyl]propanoic acid (1.8 g, 6.02 mmol, Step 4), HOBt (0.81 g, 6.0 mmol, Novabiochem), and TEA (1.67 mL, 12.0 mmol) in 20 mL of CH2Cl2 at 0° C. was added EDC (1.73 g, 9.03 mmol, Advanced Chemtech). The reaction was warmed to RT and stirred for 12 h. The reaction was quenched with satd NaHCO3, extracted with 80 mL of EtOAc and the organic solution was washed with brine, dried over Na2SO4 and concentrated in vacuo. The compound was further purified by silica gel column chromatography (50% EtOAc in hexane) to provide 2.3 g of tert-butyl (3S)-3-[(4-chlorophenyl)-methyl]-4-(4-{2-[(cyclopropylmethyl)(methylsulfonyl)-amino]phenyl}-piperazinyl)-4-oxobutanoate as a white foam. MS (ESI, pos. ion) m/z: 590.6 (M+1). Calc'd for C30H40ClN3O5S: 589.24. Anal. Calcd for C30H40ClN3O5S: C, 61.05; H, 6.83; N, 7.12; Cl, 6.01. Found: C, 60.91; H, 6.69; N, 7.09; Cl, 6.16.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[H-].[Na+].Cl[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22].O>C1COCC1>[N+:21]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:15]=1[O:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])([O-:23])=[O:22]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1ccncc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a cooled solution (0° C.) of tert-butyl 2-hydroxyethylcarbamate (1.1 eq) in THF, NaH (1.3 eq) was added, stirred for 1 hr, and then 4-chloro-3-nitropyridine (1.0 eq) was added. The reaction mixture was stirred at RT overnight, poured into cold water, and extracted with EtOAc. Organic layer was dried over Na2CO3, filtered, and concentrated to yield tert-butyl 2-(3-nitropyridin-4-yloxy)ethylcarbamate. LCMS (m/z): 284.1 (MH+); LC Rt=2.09 min.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([CH2:17][C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[CH:20][C:19]=2[Cl:25])=[N:7][N:6]=1>C(O)C>[Cl:25][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:24])[C:18]=1[CH2:17][C:8]1[C:9]2[C:14](=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([NH:2][NH2:3])=[N:6][N:7]=1
Reactant: NN
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Solvent: O
Solvent: CCO
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(NN)c2c1
Yield: 109.1 %

Procedure:
Hydrazine hydrate (0.81 ml, 0.84 g, 16.8 mmoles) was added to a solution under N2 of 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (2 g, 5.6 mmoles), obtained as described in example 13, in ethanol (30 ml), and the mixture was kept under reflux for 24 hours, then cooled in ice and the resultant precipitate was filtered, washed with ethanol and ethyl ether and dried under vacuum at 50° C. to give 2.14 g of the title compound (stoichiometric yield). m.p.: 297-299° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)=[C:13]([CH:17]=1)[C:14](O)=[O:15].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[CH:24][CH:25]=2)=[C:13]([CH:17]=1)[C:14]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: N#Cc1ccc(COc2ccc(Br)cc2C(=O)O)cc1
Reactant: Nc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: N#Cc1ccc(COc2ccc(Br)cc2C(=O)Nc2cccnc2)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Solid pyridin-3-amine (82 mg, 0.873 mmol) was added in one charge to a stirred solution of 5-bromo-2-{[(4-cyanophenyl)methyl]oxy}benzoic acid (may be prepared as described in Description 24; 145 mg, 0.44 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmol) and 1-Hydroxybenzotriazole (70.8 mg, 0.52 mmol) in DMF (15 ml) under nitrogen at 20° C. The reaction mixture was stirred at 20° C. for 16 h. The organic phase was washed with water (25 ml), extracted with ethyl acetate (3×30 ml), dried over sodium sulphate, evaporated in vacuo and purified by column chromatography (petroleum ether:ethyl acetate=2:1) to yield the title compound as a white solid. 100 mg.
Reaction SMILES: [C:1]1([CH:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:36][N:37]=[C:38]=[O:39]>C(Cl)Cl>[CH3:36][NH:37][C:38]([N:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:9]1[CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:39]
Reactant: COc1cc2c(cc1OC)C(CC(c1ccccc1)c1ccccc1)NCC2
Reactant: CN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)N1CCc2cc(OC)c(OC)cc2C1CC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A stirred solution of 1-(2,2-diphenyleth-1-yl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (487.6 mg, 1.306 mmoles) in methylene chloride (5 mL) at 0° C. was treated with triethylamine (0.24 mL, 1.3 equiv.) and methyl isocyanate (0.10 mL, 1.3 equiv.). The mixture was immediately allowed to warm to room temperature. After 4 hours, the mixture was evaporated and the residue partitioned between ether and 2% phosphoric acid. The organic phase was washed with 1M sodium hydroxide and brine, dried over sodium sulfate, and evaporated to give a solid foam that was triturated with hexane to give the product as a white solid (494.8 mg, 88%). 1H-NMR (CDCl3) δ 2.45 (m, 1H), 2.65-3.10 (m, 3H), 2.73 (s, 3H), 3.38 (m, 1H), 3.79 (s, 3H), 3.85 (s, 3H), 3.90 (m, 2H), 4.03 (t, 1H), 4.45 (m, 1H), 6.38 (s, 1H), 6.58 (s, 1H), 7.32 (m, 10H). Mass spec. 431.2 (MH)+. Anal. Calc. for C27H30N2O3: C-75.32, H-7.02, N-6.51. Found: C-75.04, H-7.13, N-6.35.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:24])[CH2:15][O:16]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:5]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:25])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:24])[CH2:15][OH:16])=[CH:9][CH:8]=1)[CH3:5]
Reactant: COC(=O)C(C)Oc1ccc(NC(=O)COCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C)Oc1ccc(NC(=O)CO)cc1
Reaction time: 10 h
Yield: 36.1 %

Procedure:
2-[4-(2-Benzyloxyacetylamino)-phenoxy]-propionic acid methyl ester 51 (15 gm, 43.7 mmol) was dissolved in methanol (150 ml) in a pressure vessel. Palladium on carbon (5%, 8 g) was added and the mixture stirred under a hydrogen atmosphere (2.5 kg) for 10 hrs. Catalyst was removed by filtration and the methanol distilled off. The crude 52 was recrystallised in chloroform:hexane (1:6) to give pure 52 (4 g, 36.3%) as a white powder with an m.p. between 111-112.6° C.