Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:22][C:23]1[C:24](Cl)=[N:25][CH:26]=[CH:27][CH:28]=1.C(N(C(C)C)C(C)C)C.C(N(CCC)CCC)C>C(O)CCC>[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([CH:16]3[CH2:17][CH2:18][N:19]([N:25]4[CH:26]=[CH:27][CH:28]=[C:23]([F:22])[CH2:24]4)[CH2:20][CH2:21]3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: C1=Cc2ccccc2C(C2CCNCC2)c2ccccc21
Reactant: Fc1cccnc1Cl
Agent: CCCN(CC)CCC
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: FC1=CC=CN(N2CCC(C3c4ccccc4C=Cc4ccccc43)CC2)C1
Reaction time: 24 h

Procedure:
0.50 gram (1.82 millimoles) of 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine, 0.24 gram (1.82 millimoles) of 3-fluoro-2-chloropyridine, 0.47 gram (3.64 mole) of ethyl diisopropylamine and 10 milliliters of n-butanol were heated at reflux temperature protected from atmospheric moisture with a drying tube. After 19.25 hours heating, an additional 240 milligrams of the 3-fluoro-2-chloropyridine was added. After another 24 hours, 300 milligrams of ethyl dipropylamine was added and heating continued. After about 140 hours of refluxing, the mixture was concentrated, diluted with ether, washed successively with 10 percent aqueous sodium hydroxide and brine, dried, and the solvent vaporized to obtain a brown semi-solid residue. The residue was purified by chromatographing on silica gel with 7 percent ether in hexanes to obtain the 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-(3-fluoro-1-pyridyl)piperidine product as a crystalline white solid, which after drying overnight in vacuo and 4 hours at 100° C. at 1 millimeter of mercury pressure had a melting point of 208°-210° C. Elemental analyses were as follows:
Reaction SMILES: Br[C:2]1[N:11]=[C:5]2[CH:6]=[C:7]([Br:10])[CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:12][NH:13][CH:14]1[CH2:16][CH2:15]1>>[Br:10][C:7]1[CH:8]=[CH:9][N:4]2[N:3]=[C:2]([N:13]([CH:14]3[CH2:16][CH2:15]3)[CH3:12])[N:11]=[C:5]2[CH:6]=1
Reactant: Brc1ccn2nc(Br)nc2c1
Reactant: CNC1CC1
Product: CN(c1nc2cc(Br)ccn2n1)C1CC1
Yield: 41 %

Procedure:
2,7-dibromo-[1,2,4]triazolo[1,5-a]pyridine (1.5 g, 5.42 mmol) was refluxed in N-methylcyclopropanamine (3.85 g, 54.2 mmol) for 4 h. The solvent was evaporated and the residue was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and applied on SiO2. Column chromatography over 70 g SiO2 using heptane/ethyl acetate affords (7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropyl-methyl-amine (593 mg, 41%) as white powder. MS: m/z=397.1 (M+H+).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][CH3:3].Cl[P:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N>>[C:13]1([P:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:4][CH2:1][CH2:2][CH3:3])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: CCCO
Agent: N
Product: CCCOP(c1ccccc1)c1ccccc1
Yield: 62.8 %

Procedure:
915 g (15.25 mol) of n-propanol are cooled to -15° C. with stirring under a nitrogen atmosphere. 330 g (1.5 mol) of chloro(diphenyl)phosphine are then added dropwise at this temperature with vigorous stirring in one hour and 15 minutes. 38 g (2.24 mol) of ammonia gas are then introduced at this temperature with further vigorous stirring. The mixture is then stirred for a further ten hours without cooling. After filtering off the ammonium chloride by suction, the filtrate is freed from propanol and excess ammonia in vacuo. The remaining residue is distilled (boiling point 122° C. at 0.4 mbar). 230 g of propyl diphenylphosphinite are obtained. This corresponds to a yield of 63% of theory.
Reaction SMILES: [CH:1]([CH:4]1[NH:8][C:7](=[O:9])[NH:6][C:5]1=[O:10])([CH3:3])[CH3:2].[CH3:11]I>>[CH:1]([CH:4]1[NH:8][C:7](=[O:9])[N:6]([CH3:11])[C:5]1=[O:10])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)C1NC(=O)NC1=O
Product: CC(C)C1NC(=O)N(C)C1=O

Procedure:
Using 5-isopropylimidazolidine-2,4-dione (1.00 g) and methyl iodide (0.46 mL) and by the reaction and treatment in the same manner as in Preparation Example 214, the title compound (0.88 g) was obtained.
Reaction SMILES: [ClH:1].[C:2]([O:6][C:7](=[O:35])[CH2:8][CH:9]([NH2:34])[CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[C:25]([CH3:33])[CH:24]=3)=[CH:17][CH:16]=2)[CH2:11]1)(C)(C)C>CO>[ClH:1].[ClH:1].[CH3:2][O:6][C:7](=[O:35])[CH2:8][CH:9]([NH2:34])[CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[C:25]([CH3:33])[CH:24]=3)=[CH:19][CH:20]=2)[CH2:11]1
Reactant: Cc1cc(COc2ccc(C3=NOC(C(N)CC(=O)OC(C)(C)C)C3)cc2)c2ccccc2n1
Agent: Cl
Solvent: CO
Product: COC(=O)CC(N)C1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Reaction time: 3 h
Yield: 64 %

Procedure:
HCl (g) was bubbled through a solution of the product from step 10d (0.3 g, 0.65 mmol) in methanol (20 mL) at room temperature for 5 minutes and the reaction was stirred for 3 h. This was complete, concentrated in vacuo to give a solid which was triturated into a powder with ethyl ether to give 3-amino-3-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-propionic acid methyl ester di-hydrochloride salt (0.21 g, 64%) as a off white solid. MS found: (M+H)+=420.
Reaction SMILES: [CH2:1]([N:5]1[C:17](=[O:18])[C:8]2[N:9]([CH3:16])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:7]=2[S:6]1(=[O:20])=[O:19])[C:2]([CH3:4])=[O:3].Cl>C[O-].[Na+]>[C:2]([C:1]1[NH:5][S:6](=[O:20])(=[O:19])[C:7]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]([CH3:16])[C:8]=2[C:17]=1[OH:18])(=[O:3])[CH3:4]
Reactant: CC(=O)CN1C(=O)c2c(c3ccccc3n2C)S1(=O)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: CC(=O)C1=C(O)c2c(c3ccccc3n2C)S(=O)(=O)N1
Temperature: 25 °C
Yield: 64.4 %

Procedure:
10 gm (34 millimols) of 2-acetonyl-4-methyl-2H-isothiazolo [4,5-b]-indole-3(4H)-one-1,1-dioxide were added to a methanolic sodium methylate solution [1.6 gm of sodium (0.107 gm-atoms) in 60 ml of anhydrous methanol]. After half an hour of stirring at room temperature, the mixture was heated for 45 minutes on an oil bath at 60° C. Subsequently, the reaction mixture was cooled on an ice bath and acidified with 1 N hydrochloric acid to a pH of 3-4. The precipitate formed thereby was filtered off, washed with ice water, dried and recrystallized from ethylene chloride, yielding 6.4 gm (64% of theory) of 3-acetyl-2,5-dihydro-4-hydroxy-5-methyl-1,2-thiazino[5,6-b ]-indole-1,1-dioxide. M.p.: 210°-211° C.;
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)C.[CH3:17][NH2:18]>>[CH3:17][NH:18][C:4](=[O:3])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: CN
Reactant: CCOC(=O)Cc1ccc2ccccc2c1
Product: CNC(=O)Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of naphthalen-2-yl-acetic acid ethyl ester (42.8 g, 200 mmol) and 64 mL of methylamine (40 wt % in H2O) were stirred at room temperature overnight. Then the white precipitate was filtered off and washed with water. After drying in vacuum the title compound was obtained as a white solid. MS (ES+): 226 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N+:41]([C:44]1[CH:101]=[CH:100][C:47]([CH2:48][O:49][C:50]([N:52]=[C:53]([NH:86][C:87]([O:89][CH2:90][C:91]2[CH:96]=[CH:95][C:94]([N+:97]([O-:99])=[O:98])=[CH:93][CH:92]=2)=[O:88])[NH:54][C@@H:55]([CH3:85])[C:56]([NH:58][C@H:59]2[CH2:63][CH2:62][N:61]([C:64]([C@@H:66]3[CH2:70][C@H:69]([SH:71])[CH2:68][N:67]3[C:72]([O:74][CH2:75][C:76]3[CH:81]=[CH:80][C:79]([N+:82]([O-:84])=[O:83])=[CH:78][CH:77]=3)=[O:73])=[O:65])[CH2:60]2)=[O:57])=[O:51])=[CH:46][CH:45]=1)([O-:43])=[O:42]>>[N+:41]([C:44]1[CH:45]=[CH:46][C:47]([CH2:48][O:49][C:50]([N:52]=[C:53]([NH:86][C:87]([O:89][CH2:90][C:91]2[CH:96]=[CH:95][C:94]([N+:97]([O-:99])=[O:98])=[CH:93][CH:92]=2)=[O:88])[NH:54][C@@H:55]([CH3:85])[C:56]([NH:58][C@H:59]2[CH2:63][CH2:62][N:61]([C:64]([C@@H:66]3[CH2:70][C@H:69]([S:71][C:8]4[C@H:9]([CH3:10])[C@@H:5]5[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:39](=[O:40])[N:6]5[C:7]=4[C:26]([O:28][CH2:29][C:30]4[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=4)=[O:27])[CH2:68][N:67]3[C:72]([O:74][CH2:75][C:76]3[CH:81]=[CH:80][C:79]([N+:82]([O-:84])=[O:83])=[CH:78][CH:77]=3)=[O:73])=[O:65])[CH2:60]2)=[O:57])=[O:51])=[CH:100][CH:101]=1)([O-:43])=[O:42]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: C[C@H](NC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)N[C@H]1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Product: C[C@H](NC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)N[C@H]1CCN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Yield: 81.8 %

Procedure:
By using 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-diphenylphosphoryloxy-1-carbapen-2-em-3-carboxylate (1.21 g) and (2S,4S)-2-[(3S)-3-[(2S)-2-[2,3-di(4-nitrobenzyloxycarbonyl)guanidino]-2-methylacetylamino]-pyrrolidin-1-ylcarbonyl]-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.68 g), reaction and purification were carried out in a similar manner to that described in Example 1-(1), whereby 4-nitrobenzyl (1R,5S,6S)-2-[(2S,4S)-2-[(3S)-3-[(2S)-2-[2,3-di(4-nitrobenzyloxycarbonyl)guanidino]-2-methylacetylamino]pyrrolidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (1.92 g) was obtained as an amorphous substance.
Reaction SMILES: C(=O)(O)[O-].[Na+].[Cl:6][CH2:7][C:8](Br)=[O:9].[CH:11]1([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][CH2:12]1>O.C(Cl)Cl>[Cl:6][CH2:7][C:8]([N:18]1[CH2:19][CH2:20][N:15]([CH:11]2[CH2:14][CH2:13][CH2:12]2)[CH2:16][CH2:17]1)=[O:9]
Reactant: C1CC(N2CCNCC2)C1
Reactant: O=C(Br)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(CCl)N1CCN(C2CCC2)CC1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of sodium bicarbonate (15 mmol) in water (5 mL) and DCM (30 mL) at 0° C. is added chloroacetyl bromide (12 mmol), followed by immediate addition of 1-cyclobutylpiperazine (10 mmol). The mixture is stirred at 0° C. for an additional 40 min. To the mixture is added aqueous sodium bicarbonate (15 mL) and DCM (30 mL). The layers are separated and the organic layer is dried (MgSO4) and solvent is removed in vacuo to give 2-chloro-1-(4-cyclobutyl-piperazin-1-yl)-ethanone, which is used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 4.07 (2H, s), 3.64 (2H, t), 3.52 (2H, t), 2.74 (1H, m), 2.36 (2H, t), 2.31 (2H, t), 1.72-2.08 (6H, m); MS (+VE) m/z 217.1 (M++1).
Reaction SMILES: [N+:1]([CH:3](S(C1C=CC(C)=CC=1)(=O)=O)[CH:4]1[CH2:9][CH2:8][N:7]([S:10]([C:13]2[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:6][CH2:5]1)#[C-:2].C[O-].[Na+].[F:33][C:34]([F:47])([F:46])[C:35]([C:38]1[CH:45]=[CH:44][C:41]([CH:42]=[O:43])=[CH:40][CH:39]=1)([OH:37])[CH3:36]>CO.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[F:33][C:34]([F:46])([F:47])[C:35]([C:38]1[CH:45]=[CH:44][C:41]([C:42]2[O:43][CH:2]=[N:1][C:3]=2[CH:4]2[CH2:5][CH2:6][N:7]([S:10]([C:13]3[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=3)(=[O:11])=[O:12])[CH2:8][CH2:9]2)=[CH:40][CH:39]=1)([OH:37])[CH3:36]
Reactant: [C-]#[N+]C(C1CCN(S(=O)(=O)c2ccc(C)cc2)CC1)S(=O)(=O)c1ccc(C)cc1
Reactant: CC(O)(c1ccc(C=O)cc1)C(F)(F)F
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)N2CCC(c3ncoc3-c3ccc(C(C)(O)C(F)(F)F)cc3)CC2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
4-(Isocyano(tosyl)methyl)-1-tosylpiperidine (260 mg, 0.73 mmol) was dissolved in MeOH (6 mL) and treated with sodium methoxide (1.0 M solution in MeOH, 0.7 mL), and 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzaldehyde (159 mg, 0.73 mmol) was then added. After being stirred at 80° C. for 2 h, the mixture was then cooled to r.t. and diluted with ethyl acetate (80 mL) and saturated aqueous NaHCO3 (30 mL). The separated organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (15% EtOAc/hexane) to provide 1,1,1-trifluoro-2-(4-(4-(1-tosylpiperidin-4-yl)oxazol-5-yl)phenyl)propan-2-ol as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.69-7.65 (m, 2H), 7.51-7.49 (m, 2H), 7.36-7.33 (m, 4H), 3.90 (d, J=11.7 Hz, 2H), 3.30-3.28 (s, 1H), 2.79 (tt, J=3.9 Hz, 11.7 Hz, 1H), 2.45 (s, 3H), 2.37 (td, J=2.3 Hz, 12.1 Hz, 2H), 2.17-2.07 (m, 2H), 1.85 (d, J=12.1 Hz, 2H), 1.80 (s, 3H); MS (ESI) 495.1 (M+H)+.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]#[C:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][CH:26]([CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:25][CH2:24]4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=O)=O)C=CC=CC=1.C1(S(N2C3C(=CC(Br)=CC=3)C=C2)(=O)=O)C=CC=CC=1.C(C1CCN(CCC#C)CC1)C1C=CC=CC=1>N1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:29]([CH:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][C:20]#[C:19][C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[NH:10][CH:11]=[CH:12]3)[CH2:24][CH2:25]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(C#CCCN3CCC(Cc4ccccc4)CC3)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C#CCCN1CCC(Cc2ccccc2)CC1
Agent: O=S(=O)(c1ccccc1)n1ccc2cc(Br)ccc21
Solvent: C1CCNC1
Product: C(#Cc1ccc2[nH]ccc2c1)CCN1CCC(Cc2ccccc2)CC1

Procedure:
1-Benzenesulfonyl-5-[4-(4-benzyl-piperidin-1-yl)-but-1-ynyl]-1H-indole. A mixture of 1-benzenesulfonyl-5-bromoindole (1.34 g, 4 mmol), 4-benzyl-1-(3-butynyl)-piperidine (908 mg, 4 mmol) and tetrakis(triphenylphosphine)palladium (0) (600 mg) is stirred in pyrrolidine (50 mL) at 50° C. under N2 overnight. Most of the pyrrolidine is evaporated and the residue purified by medium-pressure column chromatography on silica gel eluting with 50% increasing to 100% EtOAc/hexanes to give the title compound as a pale yellow oil (1.55 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH2:26][CH3:27])[C:17]([NH:18]C(=O)OC(C)(C)C)=[C:13]2[CH:12]=[CH:11][CH:10]=1.[H-].[Na+].[CH3:30][O:31][CH2:32][CH2:33]Br.Cl.C(OCC)(=O)C.[OH-].[Na+]>CN(C)C=O.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH2:26][CH3:27])[C:17]([NH:18][CH2:33][CH2:32][O:31][CH3:30])=[C:13]2[CH:12]=[CH:11][CH:10]=1
Reactant: CCc1nn2c(-c3ccc(Cl)cc3Cl)cccc2c1NC(=O)OC(C)(C)C
Reactant: COCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1nn2c(-c3ccc(Cl)cc3Cl)cccc2c1NCCOC
Reaction time: 1 h

Procedure:
After dissolving tert-butyl N-[7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]carbamate (57 mg) in N,N-dimethylformamide (2 mL), sodium hydride (60%, 7.3 mg) was added while cooling on ice, and then 2-bromoethyl methyl ether (0.015 mL) was added and the mixture was stirred for 1 hour. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract was washed with brine. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and then the solvent was concentrated under reduced pressure to obtain a crude product. This was dissolved in ethyl acetate (1 mL) without purification, a 4 N hydrochloric acid/ethyl acetate solution (2 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with 5 N aqueous sodium hydroxide while cooling on ice, and then extraction was performed with ethyl acetate and the organic layer was washed with water and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (46 mg) was obtained from the n-hexane:ethyl acetate (5:1) fraction as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:36]=[C:35]([Cl:37])[C:9]([C:10]([NH:12][C@@H:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:34])[C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:33])=[CH:20][CH:19]=2)[C:14]([OH:16])=[O:15])=[O:11])=[C:8]([Cl:38])[CH:7]=1.O=C1CCC(=O)N1[O:46][C:47](=O)[CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][CH2:73][O:74][CH2:75][CH2:76][O:77][CH2:78][CH2:79][O:80][CH2:81][CH2:82][O:83][CH2:84][CH2:85][NH:86][C:87](=[O:97])[CH2:88][CH2:89][N:90]1[C:94](=[O:95])[CH:93]=[CH:92][C:91]1=[O:96].CCN(C(C)C)C(C)C>>[Cl:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([Cl:32])[C:26]=1[C:25]([NH:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][C@H:13]([NH:12][C:10](=[O:11])[C:9]2[C:8]([Cl:38])=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][C:47](=[O:46])[CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][CH2:73][O:74][CH2:75][CH2:76][O:77][CH2:78][CH2:79][O:80][CH2:81][CH2:82][O:83][CH2:84][CH2:85][NH:86][C:87](=[O:97])[CH2:88][CH2:89][N:90]3[C:94](=[O:95])[CH:93]=[CH:92][C:91]3=[O:96])=[CH:36][C:35]=2[Cl:37])[C:14]([OH:16])=[O:15])=[CH:23][CH:22]=1)=[O:34]
Reactant: O=C(CCN1C(=O)C=CC1=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O
Reactant: NCCCOc1cc(Cl)c(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCNC(=O)CCN1C(=O)C=CC1=O)NCCCOc1cc(Cl)c(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)c(Cl)c1

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 11, starting from (S)-2-[4-(3-aminopropoxy)-2,6-dichlorobenzoylamino]-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid (143 mg, 0.2 mmol), 3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[[3-(2,5-dioxo-2,5-dihydro- pyrrol-1-yl)propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propionic acid-2,5-dioxo-pyrrolidin-1-yl ester (173 mg, 0.2 mmol), and DIPEA (258 mg, 348 uL, 2.0 mmol), and after HPLC purification, resulted in a white solid (45 mg, 16.6%). ES(+)-HRMS m/e calcd. for C60H81Cl4N5O21 (M+Na)+ 1370.4070, obsd. 1370.4066.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[C:10]([C:28]2[CH:29]=[N:30][N:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=23)=[N:11][C:12]([NH:15][C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19](F)=[CH:18][C:17]=2[O:26][CH3:27])=[N:13][CH:14]=1>FC(F)(F)CO>[Cl:8][C:9]1[C:10]([C:28]2[CH:29]=[N:30][N:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=23)=[N:11][C:12]([NH:15][C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:18][C:17]=2[O:26][CH3:27])=[N:13][CH:14]=1
Reactant: CN1CCNCC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Solvent: OCC(F)(F)F
Product: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Temperature: 140 °C
Yield: 99.5 %

Procedure:
1-Methylpiperazine (0.267 mL, 2.41 mmol) was added to a suspension of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 20, 500 mg, 1.21 mmol) in 2,2,2-trifluoroethanol (6 mL). The mixture was heated in a microwave at 140° C. for 1 h. The mixture was then loaded onto a SCX column, and the column was washed with CH3OH. The column was then eluted with 2M methanolic ammonia and appropriate fractions were combined and concentrated in vacuo. Further purification by FCC, eluting with 0-10% CH3OH in CH2Cl2 gave the title compound (596 mg, 100%), as an orange foam; 1H NMR: (CDCl3) 2.37 (3H, s), 2.57-2.68 (4H, m), 3.08-3.14 (4H, m), 4.00 (3H, s), 6.64 (1H, s), 6.98 (1H, t), 7.34-7.43 (1H, m), 7.53 (1H, s), 8.41 (1H, s), 8.49 (1H, d), 8.53-8.6 (1H, m), 8.93 (1H, s), 9.04 (1H, s); m/z: ES+ MH+ 495.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[O:2]1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:1]([C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]([OH:2])=[O:10])=[O:11])=[CH:15][CH:14]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Fc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)c1ccccc1C(=O)c1ccc(F)cc1
Reaction time: 1.5 h
Yield: 80.7 %

Procedure:
To a stirred mixture of 25 parts of 1,3-isobenzofurandione and 108.5 parts of fluorobenzene were added portion-wise 50 parts of aluminium chloride. Upon completion, the whole was heated slowly to reflux and stirring was continued for 1.50 hours at reflux temperature. The reaction mixture was cooled and poured onto a mixture of crushed ice and 60 parts of concentrated hydrochloric acid. The product was extracted twice with dichloromethane. The combined extracts were washed with a sodium hydroxide solution 10%. The aqueous phase was separated, washed with 2,2'-oxybispropane and acidified with concentrated hydrochloric acid while cooling. The whole was stirred for 1 hour at room temperature. The precipitated product was filtered off and dissolved in benzene. The solution was distilled azeotropically to dry. The solid residue was stirred in hexane. The product was filtered off and dried in vacuo at about 50° C., yielding 33.5 parts (80.7%) of 2-(4-fluorobenzoyl)benzoic acid; mp. 129.2° C. (intermediate 90).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:13]=[CH:12][C:6]2[O:7][C:8]([F:11])([F:10])[O:9][C:5]=2[CH:4]=1.[C-:14]#[N:15].[Na+].O.CC(OC)(C)C>CS(C)=O>[F:10][C:8]1([F:11])[O:7][C:6]2[CH:12]=[CH:13][C:3]([CH2:2][C:14]#[N:15])=[CH:4][C:5]=2[O:9]1
Reactant: [C-]#N
Reactant: FC1(F)Oc2ccc(CCl)cc2O1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Solvent: O
Product: N#CCc1ccc2c(c1)OC(F)(F)O2
Temperature: 35 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of 5-chloromethyl-2,2-difluoro-1,3-benzodioxole (1 eq) in DMSO (1.25 vol) is added to a slurry of NaCN (1.4 eq) in DMSO (3 vol) maintaining the temperature between 30-40° C. The mixture is stirred for 1 hour then water (6 vol) is added followed by MTBE (4 vol). After stirring for 30 min, the layers are separated. The aqueous layer is extracted with MTBE (1.8 vol). The combined organic layers are washed with water (1.8 vol), dried (Na2SO4), filtered, and concentrated to afford crude (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile (95%) that is used directly in the next step. 1H NMR (500 MHz, DMSO) δ 7.44 (br s, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.22 (dd, J=8.2, 1.8 Hz, 1H), 4.07 (s, 2H).