Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH2:8])=[O:7])=[N:2]1.[C:9](Cl)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].C(OCC)C>C(N(CC)CC)C>[C:9]([C:5]1[NH:1][N:2]=[C:3]([C:6]([NH2:8])=[O:7])[N:4]=1)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NC(=O)c1nc[nH]n1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)c1nc(C(N)=O)n[nH]1

Procedure:
To a cooled, stirred mixture of 3 g. of 1,2,4-triazole-3-carboxamide and 3.4 g. of pivaloyl chloride in 125 ml. of anhydrous diethyl ether is added rapidly 2.75 g. of triethylamine. The cooling bath is removed and the mixture is stirred at room temperature for 24 hours. The off-white solid is collected by filtration and washed thoroughly with diethyl ether and then cold water. The ether-cold water filtrate deposits another solid almost immediately. This solid is collected by filtration and dried in vacuo for 3.5 hours, yielding 0.22 g. This 0.22 g. is extracted with hot, dry acetonitrile. Concentration of the acetonitrile filtrate to a very small volume gives a colorless, crystalline solid which is collected, washed with a small amount of acetonitrile and dried in vacuo for 2 hours, yielding 50 mg., m.p. 132°-140° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[C:18]([CH3:19])[C:11]=12.Cl[C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[N:24]=[C:23]([NH2:31])[N:22]=1.Cl.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[N:24]=[C:23]([NH2:31])[N:22]=2)[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[C:18]([CH3:19])[C:11]=12
Reactant: Cc1c[nH]c2nccc(Nc3ccc(N)cc3F)c12
Reactant: Nc1nc(Cl)cc(C(F)(F)F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c[nH]c2nccc(Nc3ccc(Nc4cc(C(F)(F)F)nc(N)n4)cc3F)c12
Temperature: 100 °C

Procedure:
123 mg (480 mmol) of 2-fluoro-N1-(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzene-1,4-diamine and 123 mg (620 μmol) of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine are suspended in 3.5 ml of water. 620 μl of 1 M hydrochloric acid are added, and the mixture is heated at 100° C. overnight. Using 1N aqueous sodium hydroxide solution, the suspension is then adjusted to pH 10, resulting in the precipitation of crystals. The solid is filtered off and washed with water. The crude product is purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol (7 M ammonia) 100:1 to 10:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]2[C:26](=[O:27])[N:25]3[CH:21]([CH2:22][CH:23]([O:28][C:29]4[CH:34]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:32]=[C:31]([O:41][CH3:42])[N:30]=4)[CH2:24]3)[C:20](=[O:43])[NH:19][C:18]3([C:44]([OH:46])=O)[CH:16]([CH2:17]3)[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.[CH:60]1([S:63]([NH2:66])(=[O:65])=[O:64])[CH2:62][CH2:61]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]2[C:26](=[O:27])[N:25]3[CH:21]([CH2:22][CH:23]([O:28][C:29]4[CH:34]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:32]=[C:31]([O:41][CH3:42])[N:30]=4)[CH2:24]3)[C:20](=[O:43])[NH:19][C:18]3([C:44]([NH:66][S:63]([CH:60]4[CH2:62][CH2:61]4)(=[O:65])=[O:64])=[O:46])[CH:16]([CH2:17]3)[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)O)NC(=O)C3CC(Oc4cc(-c5ccccc5)nc(OC)n4)CN3C2=O)cc1
Reactant: NS(=O)(=O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)NS(=O)(=O)C3CC3)NC(=O)C3CC(Oc4cc(-c5ccccc5)nc(OC)n4)CN3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 2d (200 mg, 0.305 mmol) was dissolved in DCM (10 ml). EDAC (70 mg, 0.366 mmol) was added and the reaction mixture was stirred at RT for 30 min. Cyclopropanesulfonic amide (41 mg, 0.336 mmol) and DBU (96 μl, 0.641 mmol) were added and the reaction was stirred at RT for 72 h. 5% Citric acid was added and the organic layer was separated and washed with brine, dried, filtered and evaporated. This material was used directly in the following step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[C:13]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][O:7][C:5]([C:4]1[CH:3]=[C:2]([CH:11]=[CH:10][CH:9]=1)[O:1][C:13]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16])=[O:6]
Reactant: COC(=O)c1cccc(O)c1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(Oc2ccc([N+](=O)[O-])cc2C(=O)OC)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a solution of 35.3 g of methyl 3-hydroxybenzoate and 50.0 g of methyl 2-chloro-5-nitrobenzoate, dissolved in 400 ml of N,N-dimethylformamide, was added 48.1 g of anhydrous potassium carbonate. The mixture was stirred for 3 hours at 80° C. Water was added to the reaction mixture and the whole was extracted with ethyl acetate. The organic layer was washed with saturated brine, and was dried over anhydrous magnesium sulfate. The crude product obtained by removal of the solvent under reduced pressure was purified by recrystallization from methanol to yield 75.4 g of methyl 2-(3-methoxycarbonylphenoxy)-5-nitrobenzoate (melting point: 97-99° C.) (Reaction Scheme (27) described below).
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].[OH:41][CH:42]([C@@H:66]1[CH2:70][C@H:69]([SH:71])[CH2:68][N:67]1[C:72]([O:74][CH2:75][C:76]1[CH:81]=[CH:80][C:79]([N+:82]([O-:84])=[O:83])=[CH:78][CH:77]=1)=[O:73])[CH2:43][C:44]([N:46]1[CH2:50][CH2:49][C@@H:48]([N:51]([CH3:65])[C:52]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=2)=[O:53])[CH2:47]1)=[O:45]>>[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:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])=[C:8]([S:71][C@@H:69]3[CH2:68][N:67]([C:72]([O:74][CH2:75][C:76]4[CH:77]=[CH:78][C:79]([N+:82]([O-:84])=[O:83])=[CH:80][CH:81]=4)=[O:73])[C@H:66]([CH:42]([OH:41])[CH2:43][C:44]([N:46]4[CH2:50][CH2:49][C@H:48]([N:51]([CH3:65])[C:52]([O:54][CH2:55][C:56]5[CH:57]=[CH:58][C:59]([N+:62]([O-:64])=[O:63])=[CH:60][CH:61]=5)=[O:53])[CH2:47]4)=[O:45])[CH2:70]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CN(C(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1CCN(C(=O)CC(O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
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
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(O)CC(=O)N4CC[C@H](N(C)C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 71.7 %

Procedure:
By using 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(diphenylphosphoryloxy)-1-carbapen-2-em-3-carboxylate (819 mg) and (2S,4S)-2-[1-hydroxy-2-[(3R)-3-(N-methyl-N-4-nitrobenzyloxycarbonylamino)pyrrolidin-1-ylcarbonyl]ethyl]-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (830 mg), reaction and purification were carried out in a similar manner to that described in Example 40-(1), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(2S,4S)-2-[1-hydroxy-2-[(3S)-3-(N-methyl-N-4-nitrobenzyloxycarbonylamino)pyrrolidin-1-ylcarbonyl]ethyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-methyl-1-carbapen-2-em-3-carboxylate (919 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:16][C:17]2([OH:21])[CH2:20][CH2:19][CH2:18]2)[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6](Cl)[C:5]=2[N:15]=1.[NH3:22]>CO>[NH2:1][C:2]1[N:3]([CH2:16][C:17]2([OH:21])[CH2:20][CH2:19][CH2:18]2)[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:22])[C:5]=2[N:15]=1
Reactant: N
Reactant: Nc1nc2c(Cl)nc3ccccc3c2n1CC1(O)CCC1
Solvent: CO
Product: Nc1nc2ccccc2c2c1nc(N)n2CC1(O)CCC1
Temperature: 150 °C

Procedure:
1-[(2-Amino-4-chloro-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanol (1.14 g, 3.77 mmol) and ammonia (15 mL of a 7 N solution in methanol) were added to a pressure vessel, which was sealed and heated at 150° C. for five days. Additional ammonia in methanol (50 mL) was added after two days. When the reaction was complete, the volatiles were removed under reduced pressure, and the residue was triturated sequentially with methanol and saturated aqueous sodium bicarbonate and isolated by filtration. The resulting yellow solid was purified by automated flash chromatography on silica gel (40+M cartridge, eluting with 0% to 75% CMA in chloroform) followed by recrystallization from methanol. The crystals were dried overnight in a vacuum oven at 90° C. to provide 0.240 g of 1-[(2,4-diamino-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanol as pale yellow crystals, mp 295° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2([C:16](OC)=[O:17])[CH2:12][CH2:11][CH:10]([CH:13]([F:15])[F:14])[CH2:9][CH2:8]2)=[C:4](I)[CH:3]=1.N#N.C([Mg]Cl)(C)C.[Cl-].[Li+]>C1COCC1>[Br:1][C:2]1[CH:21]=[C:20]2[C:5]([CH2:6][C:7]3([CH2:8][CH2:9][CH:10]([CH:13]([F:15])[F:14])[CH2:11][CH2:12]3)[C:16]2=[O:17])=[CH:4][CH:3]=1
Reactant: COC(=O)C1(Cc2ccc(Br)cc2I)CCC(C(F)F)CC1
Agent: CC(C)[Mg]Cl
Agent: N#N
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=C1c2cc(Br)ccc2CC12CCC(C(F)F)CC2
Temperature: -20 °C
Reaction time: 0.67 h
Yield: 36.2 %

Procedure:
Methyl 1-(4-bromo-2-iodobenzyl)-4-(difluoromethyl)cyclohexanecarboxylate (Intermediate 90, 2.3 g, 4.72 mmol) was dissolved in THF (30 mL). The atmosphere was exchanged to N2 (g), and the solution was cooled to −20° C. Isopropylmagnesium chloride—lithium chloride (1.3M in THF, 4.00 mL, 5.19 mmol) was added dropwise over one h. The reaction mixture was stirred at −20° C. for 40 min. The reaction mixture was removed from the cooling bath, and left to warm up to r.t., while stirred for 1.5 h. The reaction was stirred at r.t. overnight and then heated at 40° C. for 3 h. The reaction was cooled to r.t. and quenched with sat. NH4Cl. The resulting mixture was stirred overnight. The organic layer was collected and dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (0-10% EtOAc in heptane) followed by preparative chromatography to give the title compound (0.562 g, 24% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 1.46-1.65 (m, 4H), 1.75-1.96 (m, 5H), 2.93 (s, 2H), 6.00 (dt, 1H), 7.51 (d, 1H), 7.73 (d, 1H), 7.83 (dd, 1H).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([NH2:39])[CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]3[O:27][N:39]=[C:31]([CH2:32][N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[N:30]=3)[CH2:10]2)=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: NC(CN1CCOCC1)=NO
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(CN3CCOCC3)no2)C1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 35 mg (0.22 mmol, 1.1 eq.) of N′-hydroxy-2-morpholin-4-ylethanimidamide were reacted according to the General Method 1. Yield: 28 mg (26% of theory)
Reaction SMILES: ClC1C=CC(F)=C[N+]=1[O-].[Cl:10][C:11]1[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([F:20])=[CH:13][N+:12]=1[O-]>>[NH2:17][C:15]1[C:14]([F:20])=[CH:13][N:12]=[C:11]([Cl:10])[CH:16]=1
Reactant: O=[N+]([O-])c1cc(Cl)[n+]([O-])cc1F
Agent: [O-][n+]1cc(F)ccc1Cl
Product: Nc1cc(Cl)ncc1F

Procedure:
2-Chloro-5-fluoropyridine (9), a highly volatile substance, was synthesized from thermolysis of 2-chloro-5-pyridinediazonium tetrafluoroborate (8). Hand, E. S.; Baker, D. C. Synthesis 1989, 905-908. The isolation of 9 by the literature procedure was very complicated, in that it included repeated extractions, repeated distillations, treatment with sulfuric acid and sodium hydroxide, and steam distillation. In our hands, the reported yield of 70% was difficult to obtain after these operations. To improve upon these complicated procedures, following the thermolysis of compound 8, the reaction mixture was directly treated with 50% hydrogen peroxide and trifluoroacetic acid to give 2-chloro-5-fluoropyridine-N-oxide (10), which was easily isolated, with a total yield of 73%. Nitration of 10, followed by catalytic hydrogenation of the resulting 2-chloro-5-fluoro-4-nitropyridine-1-oxide (11) removed the N-oxide function, as well as reduced the nitro group to give the desired 4-amino-2-chloro-5-fluoropyridine (12). N-Oxidation of commercially available 2,5-dichloropyridine (13), followed by nitration and reduction yielded 4-amino-2,5-dichloropyridine (16).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]=[CH:14][C:15]1[C:16]([NH:23][CH2:24][CH3:25])=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1C[CH2:35][CH2:34][CH2:33]1>>[CH:24]1([NH:23][C:16]2[C:15]([CH2:14][NH:13][C:3]3[C:4]([F:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=3[F:1])=[CH:20][N:19]=[C:18]([S:21][CH3:22])[N:17]=2)[CH2:35][CH2:34][CH2:33][CH2:25]1
Reactant: CCNc1nc(SC)ncc1C=Nc1c(F)c(OC)cc(OC)c1F
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1cc(OC)c(F)c(NCc2cnc(SC)nc2NC2CCCC2)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A solution of 25.30 g (assume 0.0523 mol) of (5-[(2,6-difluoro-3,5-dimethoxy-phenylimino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl)-ethyl-amine in 425 mL of anhydrous tetrahydrofuran was cooled to 0° C. using an ice/acetone bath. The cooled mixture was treated dropwise via syringe with 78.50 mL (0.0785 mol) 1 M solution of lithium aluminum hydride in tetrahydrofuran which resulted initially with vigorous bubbling. The resulting mixture continued to stir at 0° C. for 1 hour under nitrogen atmosphere. The ice bath was removed and the reaction mixture was allowed to warm up to room temperature and continued stirring at room temperature overnight. The reaction mixture was cooled to 0° C. using an ice/acetone bath and quenched by the slow addition of 78.50 mL of water, 78.50 mL of 15% sodium hydroxide and 157 mL of water. The salts were filtered over a bed of Celite and removed the tetrahydrofuran in vacuo. The residue was redissolved in dichloromethane and filtered again. The layers were separated and dried the organic layer over sodium sulfate, filtered and evaporated. The crude product was purified using medium-pressure chromatography eluting with a gradient of 2:1 to 1:1 hexanes/ethyl acetate to give 16.34 g (76%) of title compound. MS (APCI) (m+1)/z 411.1.
Reaction SMILES: [CH2:1]([NH:9][C:10]([C:12]1([CH2:25][CH2:26][CH2:27][CH2:28]Br)[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:30]1([C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:1]([NH:9][C:10]([C:12]1([CH2:25][CH2:26][CH2:27][CH2:28][N:33]2[CH2:34][CH2:35][N:30]([C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:37]=3)[CH2:31][CH2:32]2)[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(NCCc1ccccc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Product: O=C(NCCc1ccccc1)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(phenethyl)-amide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[C:3](=[O:18])[CH2:4][C:5](=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24].Cl.CN>CO>[C:3]([C:4]1[C:5](=[O:17])[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=2)=[CH:24][N:23]([CH3:25])[CH:22]=1)(=[O:18])[CH:2]([CH3:19])[CH3:1]
Reactant: COC(OC)N(C)C
Reactant: CC(C)C(=O)CC(=O)Cc1cccc(C(F)(F)F)c1
Agent: CN
Agent: Cl
Solvent: CO
Product: CC(C)C(=O)c1cn(C)cc(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
A 0.6 g. portion of impure 5-methyl-1-(3-trifluoromethylphenyl)-2,4-hexanedione was reacted overnight at reflux temperature with N,N-dimethylformamide dimethyl acetal as described in the examples above to obtain 0.8 g. of a dark oil. The oil was dissolved in methanol and reacted with 2 g. of methylamine hydrochloride under reflux for 4 hours. The reaction mixture was evaporated under vacuum to obtain a yellow solid, which was purified as described in Example 10 to obtain 0.09 g. of the desired product, m.p. 104°-105°, showing the following peaks in nmr analysis in DMSOd6 : δ7.6-8.3 (m, 6H, aromatic): 3.7-4.2 (m, 1H, COCH); 3.8 (s, 3H, N--CH3); 1.0-1.2 (d, 6H, CH(CH3)2).
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[C:12]([CH3:13])=[C:11](F)[C:10]([N+:15]([O-:17])=[O:16])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].Cl>C1COCC1>[Cl:3][C:4]1[C:12]([CH3:13])=[C:11]([NH:2][CH3:1])[C:10]([N+:15]([O-:17])=[O:16])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CN
Reactant: Cc1c(F)c([N+](=O)[O-])cc(C(=O)O)c1Cl
Agent: Cl
Solvent: C1CCOC1
Product: CNc1c([N+](=O)[O-])cc(C(=O)O)c(Cl)c1C
Temperature: 25 °C

Procedure:
A mixture of methylamine (2M THF solution, 8.56 mL, 17 mmol), 2-chloro-3-methyl-4-fluoro-5-nitro-benzoic acid (1.00 g, 4.2 mmol) and 20 mL THF is stirred over the weekend at rt. Then the mixture is acidified with 4M aq HCl and concentrated and the residue is washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:15]1[CH:14]=[CH:13][N:12]=[CH:17][CH:16]=1)[C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[N:25][CH:26]=1)=[O:6]
Reactant: NCC(c1ccncc1)c1ccc(C(F)(F)F)nc1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(c1ccncc1)c1ccc(C(F)(F)F)nc1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(pyridin-4-yl)-2-(2-(trifluoromethyl)pyridin-5-yl)ethanamine. LCMS (MH+): m/z=440.0, tR (minutes, Method F)=2.43
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[O:28]([CH2:35][CH2:36][CH2:37][NH2:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>O1CCCC1.[Cl-].[Na+].O>[O:28]([CH2:35][CH2:36][CH2:37][NH:38][C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCCCOc1ccccc1
Reactant: Cc1ccc(CCC(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(CCC(=O)NCCCOc2ccccc2)cc1
Reaction time: 1 h
Yield: 60.6 %

Procedure:
A solution of 4-methylbenzenepropanoic acid (2.0 g, 12.2 mmol) and triethylamine (4.3 mL, 3.1 g, 30.9 mmol) in 80 mL of tetrahydrofuran is cooled in ice and treated dropwise with isobutyl chloroformate (1.7 mL, 1.8 g, 13.1 mmol). The mixture is stirred for 1 hour, and a solution of 3-phenoxy-1-propanamine (1.9 g, 12.6 mmol) in 10 mL of tetrahydrofuran is added slowly. The mixture is stirred at room temperature for 18 hours, then added to 400 mL of brine. The mixture is acidified with 4.0 N hydrochloric acid and extracted with ethyl acetate. The combined organic layers are washed with brine, dried (anhydrous sodium sulfate), and evaporated. Recrystallization of the residue gives 2.2 g (61%) of the amide intermediate product, mp 101-102° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25]C(=O)OC(C)(C)C)[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:18][CH2:17][O:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[ClH:33]>C(O)(C(F)(F)F)=O.CO.C(Cl)Cl.CCOCC>[ClH:33].[NH2:25][C@@H:21]1[CH2:22][CH2:23][CH2:24][N:19]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12]([CH:14]4[CH2:18][CH2:17][O:16][CH2:15]4)=[O:13])[C:4]=23)[CH2:20]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CCOC4)c23)C1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CCOC4)c23)C1
Yield: 37 %

Procedure:
A solution of tert-butyl(3R)-1-(5-bromo-3-(tetrahydrofuran-3-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (57 mg, 0.11 mmol) in neat TFA (5 mL) was stirred at room temperature for 30 minutes and concentrated in vacuo. The oily residue was dissolved in a few drops of CH2Cl2 and treated with 2M HCl in Et2O (3 mL). The solid formed was filtered, washed with additional Et2O and purified by C-18 reverse phase column chromatography (Biotage C-18, 12M+) on Biotage SP4 unit eluting with 5%-60% CH3CN/water gradient. The product isolated was dissolved in few drops of 10% MeOH/CH2Cl2 and treated with 2M HCl in Et2O (4 mL). The precipitate formed was filtered, washed with additional Et2O (2×2 mL) followed by CH3CN (1 mL) and dried to provide N-(4-((R)-3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydrofuran-3-carboxamide hydrochloride (20 mg, 37% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.84 (s, 1H), 9.49 (s, 1H), 8.24 (br s, 4H), 7.57 (s, 1H), 3.84-3.71 (m, 4H), 3.44-3.36 (m, 3H), 3.28-3.21 (m, 2H), 3.11-3.06 (m, 1H), 2.17-2.08 (m, 3H), 1.87-1.80 (m, 1H), 1.76-1.65 (m, 1H), 1.53-1.43 (m, LCMS (APCI+) m/z 408, 410 (M+H)+, Retention time=1.99 minutes (Method 2).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O)[C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:4][CH:3]=1.[NH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30]>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20]([NH:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:22])[C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)CCCN
Reactant: Cc1cccc(C)c1N(CCCC(=O)O)C(=O)c1ccc(Cl)cc1
Product: COC(=O)CCCNC(=O)CCCN(C(=O)c1ccc(Cl)cc1)c1c(C)cccc1C

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyric acid and methyl 4-aminobutyrate and suitable processing produces methyl N-[N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyryl]-4-aminobutyrate (oil), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyryl]-4-aminobutyric acid (M.P. 141° to 142°).