Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[CH:13]=[N:14][N:15]([CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])[CH:16]=1)=[CH:7][CH:6]=2.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]([CH2:34][CH:35]3[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]3)[C:32]([CH3:48])=[N:31][CH:30]=2)=[CH:25][C:24]=1[O:49][CH3:50].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:50][O:49][C:24]1[CH:25]=[C:26]([C:29]2[N:33]([CH2:34][CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:32]([CH3:48])=[N:31][CH:30]=2)[CH:27]=[CH:28][C:23]=1[NH:22][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[CH:13]=[N:14][N:15]([CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])[CH:16]=1)=[CH:7][CH:6]=2
Reactant: CC(C)(O)Cn1cc(-c2ccc3cnc(Cl)cc3c2)cn1
Reactant: COc1cc(-c2cnc(C)n2CC2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(-c2cnc(C)n2CC2CCNCC2)ccc1Nc1cc2cc(-c3cnn(CC(C)(C)O)c3)ccc2cn1
Temperature: 160 °C
Reaction time: 2 h
Yield: 8.8 %

Procedure:
A suspension of 1-(4-(3-chloroisoquinolin-6-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Preparation 22, 15 mg, 0.050 mmol), tert-butyl 4-((5-(4-amino-3-methoxyphenyl)-2-methyl-1H-imidazol-1-yl)methyl)piperidine-1-carboxylate (Preparation 79, 19.9 mg, 0.050 mmol), xantphos (17.3 mg, 0.030 mmol), Pd2(dba)3 (4.6 mg, 0.005 mmol) and Cs2CO3 (130 mg, 0.398 mmol) in toluene/DMF (3/1 mL) was stirred at 160° C. under microwave irradiation for 2 hours. The reaction mixture was filtered, diluted with NaCl solution and extracted with EtOAc. The organic solution was purified by elution through an SCX-2 column using 2M NH3/MeOH followed by preparative HPLC. The residue was dissolved in DCM (6 mL) and cooled to 0° C. TFA (0.2 mL) was added and the reaction stirred at room temperature for 16 hours. The reaction was concentrated in vacuo and purified by elution through an SCX-2 column using 2M NH3/MeOH followed by preparative HPLC to afford the title compound as a yellow oil (2.5 mg, 59%).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].O.OC1C2N=NNC=2C=CC=1.C(N=C=NCCCN(C)C)C.[F:32][C:33]([F:51])([F:50])[C:34]1[CH:35]=[CH:36][C:37]([NH:40][C@@H:41]2[CH2:49][N:44]3[CH2:45][CH2:46][NH:47][CH2:48][C@@H:43]3[CH2:42]2)=[N:38][CH:39]=1>ClCCl.CN(C)C=O>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([N:47]1[CH2:46][CH2:45][N:44]2[CH2:49][C@@H:41]([NH:40][C:37]3[CH:36]=[CH:35][C:34]([C:33]([F:51])([F:32])[F:50])=[CH:39][N:38]=3)[CH2:42][C@H:43]2[CH2:48]1)=[O:6]
Reactant: FC(F)(F)c1ccc(N[C@H]2C[C@H]3CNCCN3C2)nc1
Reactant: O=C(O)CCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CCC(F)(F)F)N1CCN2C[C@@H](Nc3ccc(C(F)(F)F)cn3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solutions of 4,4,4-trifluorobutanoic acid (99 mg, 0.7 mmol) and hydroxybenzotriazole hydrate (54 mg, 0.35 mmol) in dichloromethane (4 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (163 mg, 1.05 mmol) in dichloromethane (1 mL). After 5 minutes, a solution of Example 20 (200 mg, 0.7 mmol) in dimethylformamide (1.5 mL) was added. The mixture was stirred at room temperature for 3 days and then concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/methanol=10:1) to give the title compound. 1H NMR(400 MHz, DMSO-d6) δ ppm 1.30 (m, 1H), 1.80-2.10 (m, 2H), 2.35-2.70 (m, 6H), 2.80-2.97 (m, 3H), 3.10 (m, 1H), 3.82-4.00 (m, 1H), 4.30 (m, 1H), 4.35-4.50 (m, 1H), 6.60 (d, 1H, J=7 Hz), 7.55 (m, 1H), 7.60 (d, 1H, J=7 Hz), 8.28 (s, 1H); MS (ESI) m/z 411 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([F:17])=[CH:15][C:14]([Cl:18])=[C:13](F)[N:12]=2)[CH:9]=1)[C:5]#[N:6].[NH2:20][CH2:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[NH:24][N:23]=1>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([F:17])=[CH:15][C:14]([Cl:18])=[C:13]([NH:20][CH2:21][C:22]3[C:30]4[C:25](=[N:26][CH:27]=[CH:28][CH:29]=4)[NH:24][N:23]=3)[N:12]=2)[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(Cl)cc(Oc2nc(F)c(Cl)cc2F)c1
Reactant: NCc1n[nH]c2ncccc12
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1cc(Cl)cc(Oc2nc(NCc3n[nH]c4ncccc34)c(Cl)cc2F)c1
Temperature: 90 °C
Reaction time: 7 h

Procedure:
A solution of 50 mg (0.166 mmol) of 1-6 and 25 mg (0.166 mmol) of 1-3 in 1.5 mL of dry NMP was heated with stirring at 90° C. under nitrogen. After 7 hours, the reaction was stopped and cooled. The reaction mixture was diluted with water, and extracted twice with EtOAc. The combined EtOAc extracts were washed with water and brine, dried, filtered, and concentrated in vacuo to give a crude oil. The crude product was purified by reversed phase preparative HPLC on a Gilson apparatus to give the title product as a white amorphous solid. MS M+1=430. 1H NMR (CDCl3): 4.77 (d, 2H), 5.60 (br m, 1H), 7.17 (q, 1H), 7.34 (m, 1H), 7.36 (m, 1H), 7.39 (m, 1H), 7.50 (d, 1H), 8.01 (dd, 1H), 8.53 (m, 1H), 10.5-11.5 (br, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[CH:10].C([Li])CCC.[CH3:16][Si:17]([CH3:20])([CH3:19])Cl.C(O)(=O)C>CCOCC.CCCCCC.O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][Si:17]([CH3:20])([CH3:19])[CH3:16]
Reactant: C[Si](C)(C)Cl
Reactant: C#CCOC1CCCCO1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: CCOCC
Product: C[Si](C)(C)C#CCOC1CCCCO1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
To a stirred -20° C. solution of 125 g (0.89 mol.) of 3-tetrahydropyranyloxy-1-propyne (Example 56) in 450 ml of ether, under a nitrogen atmosphere, is added dropwise, over one hour, a solution of 45 ml (0.89 mol.) of 2.0 N n-butyllithium in hexane. After 150 ml of dry ether is added and the mixture stirred at -20° C. for 30 minutes, a solution of 98 g (0.89 mol.) of trimethylchlorosilane in 73 ml of ether is added dropwise. Stirring is continued for 30 minutes at -20° C. and at ambient temperature for 18 hours. The reaction mixture is again cooled to -20° C., and a solution of 90 ml of acetic acid in 300 ml of ether is added dropwise, followed by 90 ml of water. It is then diluted with 500 ml of water, and extracted 3 times with 300 ml of 5% sodium bicarbonate solution. The organic phase is separated, washed with 500 ml of a saturated brine solution, dried over sodium sulfate, and evaporated at 40° C. under vacuum (12 mm.). The crude product is fractionally distilled, bp 120°-125° C. (18 mm.), to yield 120 g of an oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1)=[O:7].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:11]2[N:10]=[N:9][C:8]([C:6](=[O:7])[NH:5][CH2:4][CH2:3][CH:2]([CH3:15])[CH3:1])=[CH:13][CH:12]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (3-methylbutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazine-1-carboxylic acid t-butyl ester, the title compound was obtained as a white solid (83% yield). 1H NMR (500 MHz, CDCl3) δ8.03, 7.86, 6.97, 3.75, 3.56-3.63, 3.49, 1.65-1.76, 1.52, 0.94. MS (ES+) m/z 378 (M+1).
Reaction SMILES: C(N[C@H](C(O)=O)CC(C)C)(OC(C)(C)C)=[O:2].[CH2:17]([O:24][C:25](=[O:42])[CH:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[N:27]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:28][CH:29]=[CH2:30])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(Br)C=C>C1COCC1>[CH2:17]([O:24][C:25](=[O:42])[CH:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[N:27]([C:31]([CH3:32])([CH3:33])[CH3:34])[CH2:28][CH2:29][CH2:30][OH:2])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C=CCN(C(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(C)(C)C
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: C1CCOC1
Solvent: C=CCBr
Product: CC(C)(C)OC(=O)C(C(=O)OCc1ccccc1)N(CCCO)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
BOC-L-leucine is converted to racemic BOC-(2-isobutyl)-allyl glycine benzyl ester using essentially the procedures of Example 20, Steps A and B, substituting allyl bromide in the alkylation step. The benzyl ester (2.07 g, 5.73 mmol) is dissolved in THF (40 ml), under nitrogen, 0.5M 9-borabicyclo[3.3.1]-nonane (9-BBN)in hexanes (46 ml, 23 mmol) is added and mixture stirred at room temperature for 16 hours. The reaction mixture is quenched with water (1 ml) and a mixture of 1N aqueous sodium hydroxide solution (51 ml) and 30% hydrogen peroxide solution (18 ml) is added dropwise. The mixture is stirred for 1 hour at room temperature, saturated with solid sodium chloride, then extracted with ether. The organic layer is washed with saturated sodium bicarbonate solution, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product is purified by flash chromatography, eluting with 20% ethyl acetate/hexanes to give BOC-(2-isobutyl)-3-hydroxypropyl glycine benzyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16]S(C3C=CC(C)=CC=3)(=O)=O)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:37]([CH:39]([CH2:42][CH2:43][CH2:44]C)[CH2:40]O)C>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH:43]([CH2:42][CH:39]([CH3:40])[CH3:37])[CH3:44])=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCCCC(CC)CO
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)cc1
Product: CC(C)CC(C)Oc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 178, starting with 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 4-methyl-2-pentanol for 2-ethyl-1-hexanol (yield: 115 mg, 50%). mp 132-133° C. 1H NMR (300 MHz, DMSO-d6) δ 0.80 (d, J=7 Hz, 3H), 0.87 (d, J=7 Hz, 3H), 1.10 (d, J=7 Hz, 3H), 1.26 (m, 1H), 1.50 (m, 1H), 1.63 (m, 1H), 3.30 (s, 3H), 5.31 (m, 1H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.90 (d, J=9 Hz, 2H), 8.08 (d, J=9 Hz, 2H), 8.22 (s, 1H). MS (APCI+) m/z 463 (M+H)+; (APCI−) m/z 497 (M+Cl)−. Anal. calc. for C23H24F2N2O4S: C, 59.72; H, 5.23; N, 6.05. Found: C, 59.44; H, 5.26; N, 5.99.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.C([O-])([O-])=O.[K+].[K+].[CH2:18]([NH:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21]>CS(C)=O.O>[CH2:18]([N:22]([CH2:23][CH2:24][CH2:25][CH3:26])[C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[F:1])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCNCCCC
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCN(CCCC)c1ccc([N+](=O)[O-])cc1F
Temperature: 90 °C
Yield: 75.1 %

Procedure:
To a solution of 3,4-difluoronitrobenzene (3.18 g, 20 mmol) in DMSO (25 mL) were added K2CO3 (6.08 g, 44 mmol) and di-n-butylamine (2.84 g, 22 mmol) with stirring. The mixture was heated at 90° C. overnight, then cooled to rt, diluted with water (100 mL) and extracted with CH2Cl2 (80 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/CH2Cl2 (V/V)=10:1) to give the title compound as yellow oil (4.03 g, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].C[C:25]1[C:33]([N+:34]([O-:36])=[O:35])=[C:32]([O:37][CH2:38][CH2:39][NH2:40])[CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28].CCN(CC)CC.Cl>CN(C=O)C>[N+:34]([C:33]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:37][CH2:38][CH2:39][NH:40][C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:27]([OH:29])=[O:28])([O-:36])=[O:35]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: Cc1c(C(=O)O)ccc(OCCN)c1[N+](=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(CC(=O)NCCOc2ccc(C(=O)O)cc2[N+](=O)[O-])ccc1NC(=O)Nc1ccccc1C
Reaction time: 8 h
Yield: 3 %

Procedure:
To a stirred solution of pentafluorophenyl ester of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (1.86 g, 3.87 mmol) and methyl 3-nitro-4-(2-aminoethoxy)benzoic acid (0.93 g, 3.87 mmol) in DMF (27 mL) was added Et3N (0.90 mL, 6.46 mmol), and the resulting mixture was stirred overnight. The mixture was poured into 0.5 N HCl and the resulting solid was collected. The crude solid was dissolved in THF-0.25 N NaOH (1/1, 20 mL) and the resulting mixture was heated under reflux overnight. The mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, and evaporated. The crude solid was recrystallized from CHCl3—EtOH to give 60 mg (3% for 2 steps) 3-nitro-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]aminoethoxy]benzoic acid 257 as a yellow crystalline solid. mp 112-115° C.; 1H-NMR (DMSO-d6) d 2.24 (s, 3 H), 3.37-3.66 (m, 7 H), 3.84 (s, 3 H), 4.27-4.30 (m, 1 H), 6.74-8.56 (series of m, total 12 H); MS (FAB) m/z 523 (M++1); Anal. Calcd. for C26H26N4O8.3/2H2O: C, 56.83; H, 5.32; N, 10.20. Found: C, 56.66; H, 4.90; N, 9.33.
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:13]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:14][CH:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)C=CC=CC=1.FC(F)(F)C(O)=O.[CH3:35][O:36][CH2:37][C:38]1([CH3:44])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(N(CC)C(C)C)(C)C>ClC(Cl)C.O1CCCC1>[CH3:20][O:19][C:16]1[C:17]2[N:18]=[C:10]([NH:9][C:8]([N:41]3[CH2:42][CH2:43][C:38]([CH2:37][O:36][CH3:35])([CH3:44])[CH2:39][CH2:40]3)=[O:27])[S:11][C:12]=2[C:13]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[N:14][CH:15]=1
Reactant: COCC1(C)CCNCC1
Reactant: COc1cnc(N2CCOCC2)c2sc(NC(=O)Oc3ccccc3)nc12
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCC1(C)CCN(C(=O)Nc2nc3c(OC)cnc(N4CCOCC4)c3s2)CC1

Procedure:
From (7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-carbamic acid phenyl ester with 4-methoxymethyl-4-methyl-piperidine trifluoroacetate and N,N-diisopropylethylamine in dichloroethane and tetrahydrofuran. ES-MS m/e (%): 436 (M+H+, 100).
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:8]#[N:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[H-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CN(C=O)C.[Cl-].[Na+].O>[CH2:12]([O:1][CH2:2][C:3]1([C:8]#[N:9])[CH2:7][CH2:6][CH2:5][CH2:4]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CC1(CO)CCCC1
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC1(COCc2ccccc2)CCCC1
Reaction time: 0.33 h
Yield: 76.6 %

Procedure:
To a solution of 1-(hydroxymethyl)cyclopentanecarbonitrile (0.30 g, 2.0 mmol) in DMF (4 mL) was added sodium hydride (60% dispersion in mineral oil, 0.101 g, 2.52 mol). The resulting mixture was stirred for 20 minutes, followed by the addition of benzyl bromide (0.28 mL, 2.4 mmol). The reaction was stirred at ambient temperature for 64 hours. Additional sodium hydride (60% dispersion in mineral oil, 0.060 g, 1.5 mmol) and benzyl bromide (0.18 mL, 1.5 mmol) were added and the reaction was stirred for an additional 30 minutes. Water was then added to the mixture, followed by brine, and the aqueous layer was extracted with ethyl acetate. The extracts were combined and dried over sodium sulfate, and the solvent was then removed in vacuo. To the resulting residue was added water. The product was isolated by extraction with diethyl ether. The ethereal extracts were dried over sodium sulfate, and the solvent was evaporated. Flash column chromatography (eluting with a gradient from 0-30% ethyl acetate in hexanes) afforded product (330 mg, 64%).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:18][O:19][C:20]1[C:29]([O:30][CH3:31])=[N:28][C:27]2[C:26]([C:32](Cl)=[O:33])=[C:25]([CH3:35])[C:24]([N+:36]([O-:38])=[O:37])=[CH:23][C:22]=2[N:21]=1>O1CCCC1>[C:2]([O:6][C:7](=[O:10])[CH2:8][NH:9][C:32]([C:26]1[C:27]2[N:28]=[C:29]([O:30][CH3:31])[C:20]([O:19][CH3:18])=[N:21][C:22]=2[CH:23]=[C:24]([N+:36]([O-:38])=[O:37])[C:25]=1[CH3:35])=[O:33])([CH3:5])([CH3:4])[CH3:3]
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Cl)c2nc1OC
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)NCC(=O)OC(C)(C)C)c2nc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of glycine tert-butyl ester hydrochloride 104 mg (0.67 mmol) and triethylamine in 3 mL anhydrous tetrahydrofuran 0.26 mL (1.69 mmol) under an atmosphere of nitrogen was added dropwise a solution of 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl chloride (13) 200 mg (0.64 mmol) in 7 mL anhydrous tetrahydrofuran at 0° C. After the addition was complete (approximately 5 minutes), the reaction mixture was stirred at room temperature for 24 hours, filtered, and concentrated. The residue was taken up in ethyl acetate and the organic solution was washed with water, saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated. The crude product was purified by elution through a flash column (silica gel 60, 230-400 mesh, 3:2 hexanes/ethyl acetate) to give a yellow oil which crystallized on standing, 200 mg (77%), mp 125-126° C.; 1H NMR (CDCl3): δ 8.32 (s, 1H, 8-H), 6.32 (br s, 1H, amide NH), 4.14 (d, 2H, J=5.1 Hz), 4.09 (s, 3H), 3.99 (s, 3H), 2.54 (s, 3H), 1.47 (s, 9H, tert-butyl protons); MS (APCI): m/z 407 (M+H). Anal. Calcd. for C18H22N4O7: C, 53.20; H, 5.46; N, 13.79. Found: C, 53.24; H, 5.45; N, 13.55.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:16])=[CH:11][CH:10]=2)=[O:7])[CH2:3][CH2:2]1.[F:23][C:24]([F:41])([F:40])[C:25]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)([OH:30])[C:26]([F:29])([F:28])[F:27].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>[CH:1]1([CH2:4][NH:5][C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([C:35](=[O:36])[C:34]4[CH:33]=[CH:32][C:31]([C:25]([OH:30])([C:24]([F:23])([F:40])[F:41])[C:26]([F:27])([F:28])[F:29])=[CH:39][CH:38]=4)[CH2:19][CH2:18]3)=[O:16])=[CH:13][CH:14]=2)=[O:7])[CH2:2][CH2:3]1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)N2CCNCC2)cc1
Reactant: O=C(O)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1CC1)Nc1ccc(C(=O)N2CCN(C(=O)c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Reaction time: 2 h
Yield: 19 %

Procedure:
To a solution of 1-(cyclopropylmethyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea (1.654 mmol, 500 mg), 4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzoic acid (1.654 mmol, 476 mg) and triethylamine (4.96 mmol, 0.691 mL, 502 mg) in dichloromethane (50 mL) was added 1-propanephosphonic acid cyclic anhydride (2.480 mmol, 0.738 mL, 789 mg; 50% solution in ethyl acetate). The reaction mixture was stirred for 2 hours then was diluted with ethyl acetate and sodium carbonate (aqueous). The organic layer was separated, dried (magnesium carbonate) and concentrated under reduced pressure. The residue was chromatographed on silica eluting with a gradient of dichloromethane to ethyl acetate to give the title compound (180 mg). MS (ESI) m/z 571.0 [M−H]−
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH:9]([C:12]([NH2:14])=O)[CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl>C1COCC1>[F:1][C:2]1[C:11]2[O:10][CH:9]([CH2:12][NH2:14])[CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)C1CNc2cccc(F)c2O1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NCC1CNc2cccc(F)c2O1
Temperature: 60 °C

Procedure:
To a solution of 4b (0.75 g, 3.83 mmol) in anhydrous THF (20 mL) held at ambient temperature in an inert atmosphere, is added dropwise a solution of LiAlH4 in THF (13.4 mL, 13.4 mmol). When addition is completed, the mixture is heated to 60° C. for 11 h. The mixture obtained is cooled to 0° C. then an aqueous solution of hydrochloric acid (1N) is added slowly until a pH of 3 is reached. The mixture is concentrated under reduced pressure then the residue is made alkaline through the addition of an aqueous NaOH solution (1N). The mixture is extracted with ethyl acetate, the organic phase is washed with water then with salt water, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by silica gel chromatography using a dichloromethane-methanol mixture (85:5) as eluting solvent. The title compound is obtained in oil form (1.1 g, 59%).
Reaction SMILES: C[Si](Cl)(C)C.[BH4-].[Li+].[NH2:8][CH:9]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:10](O)=[O:11]>C1COCC1>[NH2:8][CH:9]([CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:10][OH:11]
Reactant: NC(CC(F)(F)F)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC(CO)CC(F)(F)F
Reaction time: 0.08 h
Yield: 38.2 %

Procedure:
A solution of trimethylsilyl chloride (1.38 g, 12.73 mmol) was added to a solution of lithium borohydride (3.2 mL, 2.0 M in THF) and THF (5 mL) at 25° C. After stirring 5 min, 2-amino-4,4,4-trifluoro-butyric acid (0.50 g, 3.18 mmol) was added portionwise over a 5 min period. The reaction was allowed to stir 48 h. The reaction was quenched by cautious addition of MeOH (5 mL) dropwise. The solvent was evaporated and the residue treated with potassium hydroxide (KOH) solution (20%, 6 mL). The aqueous phase was extracted using dichloromethane, 3 times (10 mL each). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration the solvent was evaporated to afford the 2-amino-4,4,4-trifluoro-butan-1-ol as an oil (0.174 g, 38%). This oil was used directly in the next reaction without further purification.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[I-].[Na+].Cl[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH:19]([CH2:23][C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[O:25])[CH2:18]1>O1CCCC1>[C:3]([CH:2]([CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH:19]([CH2:23][C:24]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[O:25])[CH2:18]1)[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: O=C(CC1CCCN(CCCl)C1)c1ccc(F)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCN1CCCC(CC(=O)c2ccc(F)cc2)C1)C(C)=O
Yield: 45 %

Procedure:
A solution of 6.2 g of ethyl acetoacetate is added at 0° C. to a suspension of 1.13 g of sodium hydride in 150 ml of tetrahydrofuran. After 15 minutes at this temperature, 7.1 g of anhydrous sodium iodide are added, followed by the addition at 0° C. of l3.5g of the product obtained in Stage B. The mixture is then brought to reflux for 12 hours and the whole is thereafter concentrated, the residue is taken up in water and the product is extracted with dichloromethane. The 16.9 g of oil obtained are purified by chromatography on 900 g of silica (70-230 mesh), using a mixture of dichloromethane and methanol (98:2 V/V) as eluant.