Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][O:11][C@H:10]1[CH2:15][O:16][C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C1C=CC=CC=1>C(O)C.[Pd].[H][H]>[OH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][O:11][C@H:10]1[CH2:15][O:16][C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: [H][H]
Reactant: c1ccc(CO[C@@H]2CCCO[C@H]2COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: O[C@@H]1CCCO[C@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 90.3 %

Procedure:
3.513 g of (2S, 3R)-3-benzyloxy-2-triphenylmethoxymethyltetrahydropyran (prepared as described in Preparation 23) were dissolved in 120 ml of ethanol and hydrogenated at room temperature for 30 hours in the presence of 1.852 g of 10% w/w palladium on activated carbon in a Paal's apparatus at a hydrogen pressure of 4 atmospheres (about 4 bars). The catalyst was filtered off and the filtrate was freed from the solvent by evaporation under reduced pressure. The residue was subjected to column chromatography through 90 g of silica gel, 2.557 g of the title compound were obtained, as a colorless oil, from those fractions eluted with a 7:1 by volume mixture of hexane and ethyl acetate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:11]=1[C:12]([O:14]C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:21]([NH2:24])([CH3:23])[CH3:22]>>[F:20][C:17]1[CH:18]=[CH:19][C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[C:11]([C:12]([NH:24][CH:21]([CH3:23])[CH3:22])=[O:14])[CH:16]=1
Reactant: CC(C)N
Reactant: COC(=O)c1cc(F)ccc1CNC(=O)OC(C)(C)C
Product: CC(C)NC(=O)c1cc(F)ccc1CNC(=O)OC(C)(C)C
Temperature: 70 °C

Procedure:
In an oven-dried high pressure bomb reactor apparatus was placed dry toluene (30 mL) and nitrogen was bubbled through the solution. Methyl 2-{[(tert-butoxycarbonyl)amino]methyl}-5-fluorobenzoate (4.0 g, 14.1 mmol, prepared as described in Example 3C, Step 4) and isopropylamine (12.0 mL, 0.14 mol) were added to the vessel. The bomb was sealed and heated to 70° C. overnight. The vessel was cooled and the reaction was concentrated to dryness in vacuo. The residue was purifed by flash column chromatography (ISCO column, 120 g silica) running a 0-30% acetone/hexane gradient over 30 minutes. The product fractions were concentrated to give the title compound as a white solid.
Reaction SMILES: [NH:1]([N:41]=[N+:42]=[N-:43])[C@H:2]([C:10]([NH:12][C@H:13]([C:29]([NH:31][C@H:32]([C:37]([O:39]C)=O)[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[NH2:45][NH2:46]>CO>[NH:1]([N:41]=[N+:42]=[N-:43])[C@H:2]([C:10]([NH:12][C@H:13]([C:29]([NH:31][C@H:32]([C:37]([NH:45][NH2:46])=[O:39])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])=[CH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccc(NC(=O)OC(C)(C)C)cc1)NC(=O)[C@H](Cc1ccccc1)NN=[N+]=[N-]
Reactant: NN
Solvent: CO
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccc(NC(=O)OC(C)(C)C)cc1)NC(=O)[C@H](Cc1ccccc1)NN=[N+]=[N-])C(=O)NN
Reaction time: 8 h

Procedure:
N3-Phe-Phe(4-NHBoc)-Leu-OMe (160 mg, 276 μmol) was dissolved in MeOH and hydrazine hydrate (800 μl, 16.6 mmol, 60 equiv.) was added and the mixture was stirred overnight. Co-evaporation with toluene (3×) yielded the title compound which was used without further purification. LC/MS: Rt 7.54 minutes (linear gradient 10->90% MeCN+0.1% TFA, 15 minutes), (ESI-MS (m/z): 581.13. 1H NMR (400 MHz, CD3OD): δ ppm 7.40-7.17 (m, 7H), 7.02 (d, J=8.5 Hz, 2H), 4.61 (t, J=7.0 Hz, 1H), 4.35 (t, J=7.3 Hz, 1H), 4.13 (dd, J=8.6, 4.8 Hz, 1H), 3.15 (dd, J=14.0, 4.7 Hz, 1H), 3.00-2.81 (m, 3H), 1.60-1.45 (m, 3H), 1.51 (s, 9H), 0.93 (d, J=6.0 Hz, 3H), 0.89 (d, J=5.9 Hz, 3H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:10]([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C1C=CC=CC=1.[OH-].[Na+]>[C:14]([O:13][C:11](=[O:12])[C@H:10]([CH3:18])[NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: NCc1ccccc1
Reactant: CC(Cl)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: C[C@H](NCc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To 65.0 g of benzylamine in 100 ml of benzene was added with stirring 25.0 g of tert-butyl 2-chloropropionate over a period of 30 minutes, while maintaining the temperature at 30°-70° C. The reaction mixture was held at 70° C for an additional one hour. At the end of this period, the reaction mixture was taken up in 70 ml of 2N NaOH solution and 80 ml of benzene, transferred into a separatory funnel and well shaken. The benzene solution was separated, washed with water, dried over anhydrous sodium sulfate and filtered. After evaporation of benzene, the residue was distilled under reduced pressure to give 33.2 g (90.0 percent) of N-benzylalanine tert-butyl ester, B.P. 164° C/14 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]=[O:13].[H-].[Na+].[CH3:16]I.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:16])[CH:7]=[C:6]2[CH:12]=[O:13]
Reactant: CI
Reactant: COc1ccc2[nH]cc(C=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)c(C=O)cn2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-methoxyindole-3-carboxaldehyde (80 g) in dimethylformamide (1 L) under nitrogen was treated portion-wise with sodium hydride (20.1 g, 60% dispersion in mineral oil) over 15 minutes. After stirring at ambient temperature for 30 minutes the mixture was treated dropwise with methyl iodide (31.3 mL) over 10 minutes and stirring was then continued for a further 2 hours. The reaction mixture was poured cautiously into water then extracted with ethyl acetate. The organic phase was washed with water, then dried over sodium sulfate and then evaporated. The residue was triturated with pentane to give the title compound (76 g) as a pale brown solid, m.p. 133-134° C. 1H NMR [(CD3)2SO]: δ 9.86 (1H, s); 8.20 (1H, s); 7.60 (1H, d, J=2.6 Hz); 7.50 (1H, d, J=8.9 Hz); 6.96 (1H, dd, J=8.9 and 2.6 Hz); 3.86 and 3.80 (6H, s).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.BrCC1CCCCO1.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[C:23]1([C:34]3=[CH:35][C:36]4[O:40][CH2:39][O:38][C:37]=4[CH:41]=[C:33]3[O:32][CH2:31]1)[C:24](=[O:30])[NH:25]2>>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[C:23]1([C:34]3=[CH:35][C:36]4[O:40][CH2:39][O:38][C:37]=4[CH:41]=[C:33]3[O:32][CH2:31]1)[C:24](=[O:30])[N:25]2[CH2:2][C:3]1[O:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: O=C1Nc2cccc(Cl)c2C12COc1cc3c(cc12)OCO3
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(Cl)c2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-bromomethyl-5-(trifluoromethyl)furan to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 4′-chlorospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 4′-chloro-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1H)-one was obtained (43%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 7.36 (dd, J=8.0, 8.0 Hz, 1H), 7.20-7.18 (m, 2H), 7.08 (dd, J=0.7 Hz, 8.0 Hz, 1H), 6.77 (d, J=3.4 Hz, 1H), 6.66 (s, 1H), 6.12 (s, 1H), 5.94 (s, 2H), 5.09 (ABq, 2H), 4.92 (d, J=9.8 Hz, 1H), 4.75 (d, J=9.8 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 176.1, 156.1, 152.7, 148.6, 143.4, 141.5, 139.5 (q, 2JCF=42 Hz), 130.5, 129.7, 127.9, 123.6, 118.8 (q, 1JCF=267 Hz), 116.6, 114.0 (d, 3JCF=3 Hz), 109.9, 108.2, 102.2, 101.4, 92.9, 76.9, 57.9, 36.7; MS (ES+) m/z 464.3 (M+1), 466.3 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N+:5]([O-:43])[CH:6]=[C:7]([Cl:42])[C:8]=1[CH2:9][C@@H:10]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:36])[F:35])=[C:29]([O:37][CH2:38][CH:39]2[CH2:41][CH2:40]2)[CH:28]=1)[O:11][C:12](=[O:26])[CH2:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl.Cl>[Cl:42][C:7]1[CH:6]=[N+:5]([O-:43])[CH:4]=[C:3]([Cl:2])[C:8]=1[CH2:9][C@@H:10]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:36])[F:35])=[C:29]([O:37][CH2:38][CH:39]2[CH2:40][CH2:41]2)[CH:28]=1)[O:11][C:12](=[O:26])[CH2:13][N:14]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[S:45]([CH3:44])(=[O:47])=[O:46]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CNCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OC
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(CN(CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)S(C)(=O)=O)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.3 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3,4-dimethoxybenzylamino)acetoxy)ethyl)pyridine 1-oxide hydrochloride (42 mg, 0.064 mmol) was dissolved in DCM (1.5 ml). Py (500 μl, 6.18 mmol) and methanesulfonyl chloride (5.96 μl, 0.076 mmol) were added, and the reaction was stirred at RT for 2 hours to achieve completion. The reaction mixture was diluted with HCl 1M and extracted with DCM. The organic phase was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by preparative reverse-phase HPLC to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(N-(3,4-dimethoxybenzyl)methylsulfonamido)-acetoxy)ethyl)pyridine 1-oxide (20 mg, 44.5% yield).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(N(CC)CC)C.[F:21][C:22]([F:48])([C:26]([F:47])([F:46])[C:27]([F:45])([F:44])[C:28]([F:43])([F:42])[C:29]([F:41])([F:40])[C:30]([F:39])([F:38])[C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])[CH2:23][CH2:24][OH:25].CN(C)C(=O)C>O>[F:21][C:22]([F:48])([C:26]([F:46])([F:47])[C:27]([F:44])([F:45])[C:28]([F:42])([F:43])[C:29]([F:40])([F:41])[C:30]([F:38])([F:39])[C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])[CH2:23][CH2:24][O:25][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 70.1 %

Procedure:
In a flask were charged 1-fluoro-2,4-dinitrobenzene (40.94 g, 0.22 mol), triethylamine (24.29 g, 0.24 mol), 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl alcohol (102.1 g, 0.22 mol), 220 g of N,N-dimethylacetamide and stirred at room temperature for 22 hours under a nitrogen atmosphere. The resultant etherified product was introduced into water with stirring. The solids precipitated were collected and dried at 40° C. under reduced pressure to obtain 97.22 g (yield: 72%) of 4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyloxy)-1,3-dinitrobenzene as yellow crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:7]1([N:11]2[CH2:17][CH2:16][C:15]3[CH:18]=[C:19]([O:22][C:23]4[N:24]=[CH:25][C:26]([C:29](Cl)=[O:30])=[N:27][CH:28]=4)[CH:20]=[CH:21][C:14]=3[CH2:13][CH2:12]2)[CH2:10][CH2:9][CH2:8]1.CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1>ClCCl>[CH:7]1([N:11]2[CH2:17][CH2:16][C:15]3[CH:18]=[C:19]([O:22][C:23]4[N:24]=[CH:25][C:26]([C:29]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[O:30])=[N:27][CH:28]=4)[CH:20]=[CH:21][C:14]=3[CH2:13][CH2:12]2)[CH2:8][CH2:9][CH2:10]1
Reactant: O=C(Cl)c1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Reactant: C1COCCN1
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Solvent: ClCCl
Solvent: C=Cc1ccccc1
Product: O=C(c1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1)N1CCOCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Morpholine (0.17 ml, 2.0 mmol) was added to a stirred solution of the product of step 1 (394 mg, 1 mmol) and diethylaminomethyl polystyrene (1.88 g, 3.2 mmol/g, 6 mmol) in dichloromethane (10 ml). The resulting mixture was allowed to stir at room temperature for 24 hours and the filtered. The filtrate was concentrated in vacuo and the resulting crude residue was purified column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title compound (E123). MS (ES+) m/e 409 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=2)=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:26]1([C:32]2[N:33]=[CH:34][NH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:13])[O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:35]3[CH:36]=[C:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:33]=[CH:34]3)=[CH:19][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(B(O)O)cc2)cc1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(-n3cnc(-c4ccccc4)c3)cc2)cc1
Temperature: 25 °C
Yield: 44.9 %

Procedure:
A mixture of 4-{2-[({[(4-Methylphenyl)sulfonyl]amino}carbonyl)oxy]ethyl}phenylboronic acid (100 mg, 0.28 mmol), 4-phenylimidazole (40 mg, 0.28 mmol), Copper(II) acetate (50 mg, 0.28 mmol), triethylamine (115 μL, 0.83 mmol), molecular sieves 4A (100 mg), and dichloromethane (4 mL) was stirred at room temperature for 1 week. Insoluble materials were removed by Celite pad, the filtrate was diluted with dichloromethane, and washed with water. The combined organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by TLC with dichloromethane/methanol (10:1) to afford 58 mg (46%) of the title compound as white solids: MS (ESI) m/z 462 [M+H]+, 460 [M−H]−, 1H-NMR (DMSO-d6) δ 2.35 (3H, s), 2.88 (2H, t, J=6.5 Hz), 4.23 (2H, t, J=6.5 Hz), 7.22-7.43 (7H, m), 7.62 (2H, d, J=8.3 Hz), 7.74 (2H, d, J=8.3 Hz), 7.86 (2H, d, J=7.3 Hz), 8.26 (1H, s), 8.32 (1H, s).
Reaction SMILES: [CH3:1][N:2]1[C:6]([B:7]2[O:11][C:10]([CH3:13])([CH3:12])[C:9]([CH3:15])([CH3:14])[O:8]2)=[CH:5][CH:4]=[N:3]1.[Cl:16]N1C(=O)CCC1=O>C1COCC1>[Cl:16][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[B:7]1[O:11][C:10]([CH3:13])([CH3:12])[C:9]([CH3:15])([CH3:14])[O:8]1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: Cn1ncc(Cl)c1B1OC(C)(C)C(C)(C)O1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.3 g, 6.3 mmol), N-chlorosuccinimide (0.93 g, 7.0 mmol) and THF (6.6 mL) was stirred at 70° C. for 3 h. The mixture was extracted with EtOAc, dried and concentrated under reduced pressure. The sub-title compound was purified by chromatography on silica gel using 40% EtOAc in hexanes gave the desired compound, 1.456 g, 95%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)=O)[CH3:2].[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([NH:26][C:27](=[O:29])[CH3:28])=[CH:24][CH:23]=1.Cl.N[C:34]1C=CC(NC(=O)C)=C[CH:35]=1.C(O)CCC>O>[CH2:1]([O:3][C:4](=[O:20])[CH:5]=[C:6]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([NH:26][C:27](=[O:29])[CH3:28])=[CH:30][CH:31]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[CH2:2][CH2:34][CH3:35]
Reactant: CCOC(=O)CC(=O)c1ccc(C2CCCCC2)cc1
Reactant: CC(=O)Nc1ccc(N)cc1
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: CCCCOC(=O)C=C(Nc1ccc(NC(C)=O)cc1)c1ccc(C2CCCCC2)cc1
Temperature: 400 °C
Reaction time: 48 h
Yield: 98 %

Procedure:
3-(4-Cyclohexylphenyl)-3-oxo-propionic acid ethyl ester 50.25 g (0.183 moles), 4′-aminoacetanilide 25 g (0.167 moles), 4′-aminoacetanilide hydrochloride salt, 1.55 g (0.008 moles), and 500 mL of dry n-butanol were placed in a 1 liter single neck round bottom flask equipped with a Soxhlet extractor apparatus with condenser, magnetic stirrer and nitrogen inlet. In the Soxhlet thimble (33×118 mm) was placed highly activated 4A sieves (1.7-2.4 mm beads). The sieves were activated immediately before use under high vacuum with heating (400° C. for 30 min). The mixture was then brought to reflux such that the butanol azeotropically removed water, so as to drive the equilibrium reaction, and the water was removed from the butanol by the sieves before being returned to the reaction pot. The reaction was allowed to continue for 48 hrs. The charge of sieves was replaced after the first 24 hrs. Transesterification to the butyl ester along with removal of ethanol occurred concomitantly with enamine formation. After 48 hrs the reaction pot was cooled, placed in a −40° C. freezer and crystals were-allowed to form for 24 hrs. Crystals were collected by vacuum filtration and solids washed with cold ethanol. The product was then dried in a vacuum oven to give 73.8 g (98%) of the desired enamine.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])[N:8]=1)=O.[Cl:23][C:24]1[CH:25]=[C:26]([NH:30]N)[CH:27]=[CH:28][CH:29]=1>>[Cl:23][C:24]1[CH:25]=[C:26]([N:30]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=4)[C:17]#[N:18])[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:27]=[CH:28][CH:29]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C#N)c2)ccc1=O
Product: N#Cc1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc(Cl)c3)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-benzonitrile (A-19) and 3-chloro-phenylhydrazine according to the method described for example 1. MS: M=374.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9](=[O:43])[CH2:10][N:11]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[CH:36]=1)[C:12]([C:14]1[CH:15]=[N:16][N:17]([C@H:23]2[CH2:28][CH2:27][C@H:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]2)[C:18]=1[C:19]([F:22])([F:21])[F:20])=[O:13].N1C=CC=CC=1.[CH3:50][C:51](Cl)=[O:52]>C(Cl)Cl>[C:51]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9](=[O:43])[CH2:10][N:11]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[CH:36]=1)[C:12]([C:14]1[CH:15]=[N:16][N:17]([C@H:23]2[CH2:28][CH2:27][C@H:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]2)[C:18]=1[C:19]([F:22])([F:21])[F:20])=[O:13])(=[O:52])[CH3:50]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CC(=O)c3c(N)cccc3Cl)Cc3cc(F)cc(F)c3)c2C(F)(F)F)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CC(=O)c3c(Cl)cccc3NC(C)=O)Cc3cc(F)cc(F)c3)c2C(F)(F)F)CC1
Reaction time: 2 h

Procedure:
To a stirred solution of compound 11-3 (45 mg, 0.07 mmol) in 1:1 mixture of pyridine and DCM (5 mL) was added CH3COCl (6 μL, 0.08 mmol) at 0° C. and stirred for 2 h. The reaction mixture was quenched with water (20 mL) and extracted with DCM (2×10 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 20% EtOAc/hexane as eluent) to provide compound 13-1 (50 mg, quant.) as a yellow solid.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:16]=2)[C:13](=[O:27])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:28])[N:6]=1)[CH2:3][CH3:4].Cl[C:30]1[CH:35]=[CH:34][N:33]=[C:32]2[NH:36][CH:37]=[CH:38][C:31]=12.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[NH:36]1[C:32]2=[N:33][CH:34]=[CH:35][C:30]([NH:1][C@H:2]([C:5]3[N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([F:26])([F:24])[F:25])[CH:16]=4)[C:13](=[O:27])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=4[F:28])[N:6]=3)[CH2:3][CH3:4])=[C:31]2[CH:38]=[CH:37]1
Reactant: Clc1ccnc2[nH]ccc12
Reactant: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ccnc2[nH]ccc12)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
Under nitrogen, to (S)-2-(1-aminopropyl)-5-fluoro-3-(3-(2,2,2-trifluoroethoxy)phenyl)quinazolin-4(3H)-one (40 mg, 0.10 mmol, 1.0 equiv) in t-BuOH (0.5 mL) at 23° C. is added 4-chloro-1H-pyrrolo[2,3-b]pyridine (23 mg, 0.15 mmol, 1.5 equiv) and diisopropylethylamine (63 μL, 0.36 mmol, 4.0 equiv). After stirring for 48 hr at 120° C. in a sealed tube, the reaction mixture is concentrated in vacuo and the residue is purified by preparative TLC eluting with CH2Cl2/MeOH to afford the title compound (Compound 13A).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7](S(C3C=CC=CC=3)=O)[C:6]=2[N:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH:8]=[CH:7][C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: Cc1ccnc2c1CCCC2S(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccnc2c1CCC=C2
Temperature: 25 °C
Yield: 94.7 %

Procedure:
The crude product of Step 5 (10.8 g, 40.0 mmol) was heated under reflux in toluene (100 m) for 30 min, cooled to room temperature, and extracted with 1N-HCl (3×50 ml). The extracts were basified with 10N-NaOH and extracted with dichloromethane (3×200 ml). The organic extracts were dried (MgSO4) and evaporated in vacuo to give an oil which was purified by chromatography (alumina; ether) to give the product (5.5 g, 95%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[CH:13](C(OC)=O)[C:14](OC)=[O:15].[Cl-].[Na+].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[CH2:13][CH2:14][OH:15]
Reactant: COC(=O)C(C(=O)OC)c1cc(OC)c([N+](=O)[O-])cc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(CCO)c(Cl)cc1[N+](=O)[O-]
Yield: 90.4 %

Procedure:
A solution of dimethyl 2-(2-chloro-5-methoxy-4-nitrophenyl)malonate (15.5 g, 48.7 mmol), sodium chloride (5.70 g, 97.5 mmol) and water (0.876 mL, 48.7 mmol) in DMSO (200 mL) was heated to 120° C. for 2 hours. The cooled reaction mixture was partitioned between water (1000 mL) and EtOAc (200 mL) and the separated aqueous phase was extracted with EtOAc (200 mL). The combined organic extracts were washed with brine (150 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by column chromatography on neutral silica gel using 3-10% EtOAc in hexane to give the title compound (10.2 g, 86%) as a solid.
Reaction SMILES: C([SiH](C(C)C)C(C)C)(C)C.[C:11]([C:15]([C:18]([O:21][C:22]([C:28](Cl)=[O:29])([C:24]([F:27])([F:26])[F:25])[F:23])([F:20])[F:19])([F:17])[F:16])([F:14])([F:13])[F:12]>[Pd]>[C:11]([C:15]([C:18]([O:21][C:22]([CH:28]=[O:29])([C:24]([F:26])([F:27])[F:25])[F:23])([F:20])[F:19])([F:17])[F:16])([F:14])([F:13])[F:12]
Reactant: O=C(Cl)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Agent: [Pd]
Agent: CC(C)[SiH](C(C)C)C(C)C
Product: O=CC(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 75 h
Yield: 53.5 %

Procedure:
A 3-necked round bottom flask equipped with a dropping funnel and reflux condenser was charged with 10% Pd/C (0.35 g) and cooled to 0° C. Triisopropylsilane (6.0 g) was added. CF3CF2CF2OCF(CF3)COCl (10.9 g) was added, and the mixture was stirred at 25° C. for 75 hr. During this period, a total of 0.5 g of additional catalyst was added in ca. 0.1 g increments. Vacuum transfer and separation of the lower layer after chilling at -25° C. provided 5.26 g of liquid. 1H NMR (THF-d8 /F11): 9.9 (m). 19F NMR: -79.4 (m), -81.1 (s), -81.4 (t, J=7.2), -129.5 (s), -138.8 (m). 1H-decoupling experiment showed JHCCF ca. 2.5 Hz.