Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][N:9]([C:12]3[N:34]=[CH:33][CH:32]=[CH:31][C:13]=3[C:14]([NH:16][CH:17]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[CH:18]([OH:22])[C:19]([OH:21])=O)=[O:15])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:36][O:37][NH2:38]>>[F:30][C:26]1[CH:25]=[C:24]([CH2:23][CH:17]([NH:16][C:14](=[O:15])[C:13]2[CH:31]=[CH:32][CH:33]=[N:34][C:12]=2[N:9]2[CH:10]=[CH:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8]2)[CH:18]([OH:22])[C:19]([NH:38][O:37][CH3:36])=[O:21])[CH:29]=[CH:28][CH:27]=1
Reactant: O=C(NC(Cc1cccc(F)c1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccccc2)n1
Reactant: CON
Agent: Cl
Product: CONC(=O)C(O)C(Cc1cccc(F)c1)NC(=O)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 3-(2-(3-phenyl-1H-pyrazol-1-yl)nicotinamido)-2-hydroxy-4-(3-fluorophenyl)-butanoic acid with O-methylhydroxylamine hydrochloride. ESI-MS [M+H]+: 490.2
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Cl:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:15](=[O:16])[CH2:14][CH2:13][CH2:12][Cl:11])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=C(Cl)CCCCl
Reactant: COc1cccc(Cl)c1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)CCCCl)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2,3-Dichloroanisole (120 gm, 0.65 mole) and 4-chlorobutyryl chloride (100 gm, 0.709 mole) were dissolved in methylene chloride (425 ml) and aluminum chloride (98.8 g, 0.741) added portionwise with stirring over 30 minutes. The temperature rose to 32° C. and hydrogen chloride was evolved. After stirring for 3 hours, the mixture was poured into ice containing concentrated hydrochloric acid (80 ml). The layers were separated and the aqueous layer extracted with methylene chloride.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.N[NH:18][C:19]([NH2:21])=[S:20].[OH-].[NH4+]>O>[NH2:21][C:19]1[S:20][C:13]([C:12]2[CH:15]=[CH:16][C:9]([Cl:8])=[CH:10][CH:11]=2)=[N:14][N:18]=1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: NNC(N)=S
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1nnc(-c2ccc(Cl)cc2)s1
Temperature: 0 °C
Reaction time: 16 h
Yield: 35.6 %

Procedure:
To 125 ml of stirred trifluoroacetic acid at room temperature was added 4-chlorobenzonitrile (50.0 g, 0.365 mole), followed by the slow addition of thiosemicarbazide (35.0 g, 0.386 mole). Upon complete addition, the reaction mixture was heated under reflux for 60 hours. The cooled reaction mixture was poured into a mixture of 150 ml of ice and 150 ml of water, then made basic by addition of 150 ml of concentrated ammonium hydroxide. After standing for 16 hours, a crystalline solid was isolated from the mixture by filtration. The solid was recrystallized from 900 ml of ethanol to give 2-amino-5-(4-chlorophenyl)-1,3,4-thiadiazole (27.5 g, mp 227°-229° C.).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C@@H:37](O)[CH3:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][C@@H:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[C:30]([F:29])([F:40])[F:41])[CH3:38])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Reactant: C[C@H](O)c1ccccc1C(F)(F)F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O[C@H](C)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Under a nitrogen atmosphere, 4.45 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate and 3.02 g of (1S)-1-[2-(trifluoromethyl)phenyl]ethanol are dissolved in 140 ml anhydrous dichloromethane. 7.07 g triphenylphosphine (polymer bound, ˜3 mmol/g) and 4.88 g of di-tert-butyl azodicarboxylate are added. The reaction mixture is stirred at room temperature for 90 minutes and then filtered. The filter cake is washed with 10 ml dichloromethane and 10 ml methanol. The filtrate is concentrated to dryness under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.O>CN(C)C=O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([C:13]2[NH:12][CH:16]=[CH:15][N:14]=2)[N:3]=1
Reactant: c1c[nH]cn1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(-c2ncc[nH]2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
In 80 ml of N,N-dimethylformamide were dissolved 4.00 g of 2-amino-6-chloro-3-nitropyridine and 15.69 g of imidazole, and the solution was stirred at 120° C. overnight. After spontaneous cooling to room temperature, 100 ml of water was added and the resulting crystals were collected by filtration. The crystals were rinsed with a small amount of water and dried under reduced pressure to provide 3.76 g of 2-amino-6-imidazolyl-3-nitropyridine. Physicochemical properties:
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[Cl:10][C:11]1[C:12]([N+:26]([O-:28])=[O:27])=[C:13](OC)[C:14]([N+:21]([O-:23])=[O:22])=[C:15]([Cl:20])[C:16]=1[N+:17]([O-:19])=[O:18]>C1(C)C=CC=CC=1>[Cl:10][C:11]1[C:12]([N+:26]([O-:28])=[O:27])=[C:13]([Cl:3])[C:14]([N+:21]([O-:23])=[O:22])=[C:15]([Cl:20])[C:16]=1[N+:17]([O-:19])=[O:18]
Reactant: COc1c([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c(Cl)c1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(Cl)c([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1Cl
Temperature: 95 °C
Yield: 9.5 %

Procedure:
Thionyl chloride (0.20 ml, 0.027 mol) and dimethylformamide (0.15 ml, 0.022 mol) were added to a solution of 5 (0.624 g, 0.020 mol) in toluene (2 ml) at 50° C. The mixture was stirred and heated to 95° C. over a period of 15 min. and maintained at that temperature for another hour. The pale yellow solution was washed with water, dried over magnesium sulfate, treated with activated carbon, filtered, and evaporated to give a cream-colored solid (0.600 g, 95% yield). The melting point of the material so obtained was 194-195° C. (195-196° C. after recrystallization from acetic acid).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[S:9]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)([OH:12])(=[O:11])=[O:10].[CH3:20][NH:21]CCCCC=C>>[S:9]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)([OH:12])(=[O:11])=[O:10].[CH3:20][NH:21][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH:7][CH3:8]
Reactant: C=CCCCCNC
Reactant: C=CCCCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC=CCCCCNC

Procedure:
Compound 32b was synthesized from 7-bromo-heptene as a white solid in quantitative yield, following the procedure as described for compound 32a.
Reaction SMILES: C(N)C1C=CC=CC=1.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[C:19]([NH2:28])=[N:20][C:21]([NH2:27])=[N:22]3)[CH2:11][CH2:10]1.[CH3:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1.[ClH:38].O1CCOCC1>>[ClH:38].[CH3:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[C:19]([NH2:28])=[N:20][C:21]([NH2:27])=[N:22]4)[CH2:11][CH2:10]2)=[CH:32][CH:31]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Agent: Cl
Solvent: NCc1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc(CN2CCC(COc3cccc4nc(N)nc(N)c34)CC2)cc1
Yield: 90 %

Procedure:
The benzylamine was obtained by reacting 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (75 mg; 0.27 mmol) and 4-methylbenzyl bromide (60 mg; 0.32 mmol) via Method BB to a solid, which was stirred in the presence of 4M HCl in dioxane (4 eq). Solids were filtered and rinsed once with ether to give title compound. (101 mg; 90% yield). 1HNMR (400 MHz, DMSO-d6) δ 12.8 (s, 1H), 11.0 (s, 1H), 8.82 (s, 1H), 8.23 (s, 1H), 7.69 (m, 2H), 7.5 (d, J=8.0 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H), 4.91 (br s, 2H), 4.17 (m, 4H), 3.36 (br d, J=11.6 Hz, 2H), 2.85 (m, 2H), 2.33 (s, 3H), 2.2 (m, 1H), 1.79 (m, 4H). MS m/z (ESI) 378 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=O.C(Cl)(Cl)Cl.N=C=N.[CH3:17][O:18][C:19]1[CH:49]=[CH:48][C:22]([C:23]([NH:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][C:31]=2[NH:32][C:33](=[O:47])[C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=2[O:42][CH2:43][CH2:44][CH2:45][NH2:46])=[O:24])=[CH:21][CH:20]=1>CC=C(C)C>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([NH:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][C:31]=2[NH:32][C:33](=[O:47])[C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=2[O:42][CH2:43][CH2:44][CH2:45][NH:46][C:7]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=2)=[O:9])=[O:24])=[CH:48][CH:49]=1
Reactant: COc1ccc(C(=O)Nc2cnccc2NC(=O)c2ccc(OC)cc2OCCCN)cc1
Reactant: Cn1cccc1C(=O)O
Agent: CC=C(C)C
Agent: N=C=N
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)Nc2cnccc2NC(=O)c2ccc(OC)cc2OCCCNC(=O)c2cccn2C)cc1
Reaction time: 8 h
Yield: 13.5 %

Procedure:
1-Methyl-2-pyrrolecarboxylic acid (57.6 mg, 460 μmol) was dissolved in amylene stabilized chloroform (8 mL). Resin-supported carbodiimide (1.1 g, 0.85 mm ol/g, 920 μmol) was added. To the resin-acid slurry was added N3-(4-methoxybenzoyl)-N4-[4-methoxy-2-(3-aminopropoxy)benzoyl]-3,4-pyridinediamine (106 mg crude, 230 μmol) in amylene stabilized chloroform (5 mL). The vial was capped and the reaction was agitated overnight on an orbital platform shaker. The slurry was filtered. The filtrate was concentrated and then purified by semipreparative HPLC as described in Example 2-F to provide N3-(4-methoxybenzoyl)-N4-[4-methoxy-2-[3-(1-methylpyrrol-2-ylcarbonyl)aminopropoxy]benzoyl]-3,4-pyridinediamine (17.3 mg, 27%) as ivory needles.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:17][CH:18]1[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:36]([CH3:38])[CH3:37])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:28])[C:22]2C=[CH:40][CH:41]=[CH:42][C:21]=2N(C2C=CC=CC=2)[C:19]1=O)=O)(C)(C)C.[H-].[Na+].CI.[CH3:54][N:55]([CH:57]=[O:58])[CH3:56]>>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:17][C:18]1([CH3:19])[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:36]([CH3:38])[CH3:37])[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:28])[C:22]2[CH:21]=[CH:42][CH:41]=[CH:40][C:54]=2[N:55]([C:56]2[CH:18]=[CH:17][CH:9]=[CH:10][CH:11]=2)[C:57]1=[O:58]
Reactant: CN(C)C=O
Reactant: CC(C)N(C(=O)CN1C(=O)C(Cc2cc3ccccc3n2C(=O)OC(C)(C)C)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CC(C)N(C(=O)CN1C(=O)C(C)(Cc2cc3ccccc3[nH]2)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a stirring solution of 190 mg (0.28 mmol) of 2-[3-(N-tert-butoxycarbonyl-indol-2-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-phenyl acetamide, prepared as in Intermediate 37, in 4 mL of DMF at 0° C. is added 17 mg (0.43 mmol, 1.5 equiv) of sodium hydride (60% dispersion in mineral oil). The resulting solution is stirred 5 min, then 26 μL (0.43 mmol, 1.5 equiv) of methyl iodide is added. The reaction mixture is stirred 2 h at RT and then heated to 50° C. for 3 h, then quenched with 1 mL H2O. The reaction mixture is diluted with 40 mL EtOAc and washed with 40 mL H2O. The organic layer is dried (MgSO4) and the solvents removed in vacuo. The crude material is then dissolved in 3 mL of dichloromethane, 1 mL of TFA is added, and the reaction mixture is stirred 3 h at RT. The volatiles are removed in vacuo and the resulting crude oil purified via reverse phase MPLC using a C-18 column and 75% acetonitrile/25% H2O with 0.1% TFA as eluent followed by lyophilization afforded 15 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ9.22 (s, 0.33H), 7.68-7.00 (m, 17H), 6.84 (m, 1H), 6.28 (s, 0.33H), 6.16 (s, 0.66H), 5.26 (m, 0.66H), 5.10 (m, 0.33H), 4.72 (d, 0.66H, J=16.3), 4.45 (d, 0.33H, J=16.6), 4.02 (m, 0.33H), 3.82 (d, 0.66H, J=16.3), 3.70 (m, 0.33H), 3.45 (d, 0.33H), 3.15 (d, 0.66H, J=14.9), 2.62 (d, 0.66H, J=14.9), 1.42 (s, 2H), 1.26 (m, 7H); low resolution MS (FAB)m/e 571 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[CH2:32]([O:35][CH2:36][CH2:37][NH2:38])[CH2:33][CH3:34]>>[CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:38][CH2:37][CH2:36][O:35][CH2:32][CH2:33][CH3:34])=[O:25])[C:6]1=[O:29]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Reactant: CCCOCCN
Product: CCCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and [2-(propyloxy)ethyl]amine employing methods similar to those described in Example 245 and was purified by reverse phase preparative BPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.63 (1H, br), 8.21 (1H, br s), 7.30 (1H, br s), 7.28 (2H, dd, J˜9, 5.6 Hz), 7.11 (2H, t, J˜9 Hz), 4.95 (2H, s), 4.01 (2H, s), 3.43-3.30 (6H, m), 3.08 (3H, s), 2.79 (3H, s), 1.50 (2H, m, J=7 Hz), 0.85 (3H, t, J=7 Hz); HRMS calcd for C25H29FN4O5+H+: 485.2200. Found: 485.2190.
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:18])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([OH:16])[CH:11]=[C:10]([OH:17])[CH:9]=2)[CH2:2][CH2:3][CH3:4].[O:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]Cl)[CH2:21][CH2:20]1>C(O)C>[CH2:1]([C:5]1[C:6](=[O:18])[O:7][C:8]2[C:13]([C:14]=1[O:15][CH2:26][CH2:25][N:22]1[CH2:23][CH2:24][O:19][CH2:20][CH2:21]1)=[C:12]([O:16][CH2:26][CH2:25][N:22]1[CH2:23][CH2:24][O:19][CH2:20][CH2:21]1)[CH:11]=[C:10]([O:17][CH2:26][CH2:25][N:22]1[CH2:23][CH2:24][O:19][CH2:20][CH2:21]1)[CH:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: ClCCN1CCOCC1
Reactant: CCCCc1c(O)c2c(O)cc(O)cc2oc1=O
Solvent: CCO
Product: CCCCc1c(OCCN2CCOCC2)c2c(OCCN3CCOCC3)cc(OCCN3CCOCC3)cc2oc1=O
Yield: 45 %

Procedure:
7.5 g. (0.03 mol) of 3-butyl-4,5,7-trihydroxy-coumarin are treated with 17.5 g. (0.117 mol) of 2-morpholino-1-chlorethane, as in Example 1. A beige-coloured solid is obtained. M.P. 131° C. (ethanol). Weight 7.7 g.; yield 45% (theoretical yield 17.7 g.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8](COCC[Si](C)(C)C)COCC[Si](C)(C)C)[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:4]2[N:3]=1.[NH:38]1[CH2:44][CH2:43][C:42](=[O:45])[NH:41][CH2:40][CH2:39]1.C(N(C(C)C)C(C)C)C>CN1C(=O)CCC1>[NH2:8][C:6]1[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:4]2[N:3]=[C:2]([N:38]2[CH2:44][CH2:43][C:42](=[O:45])[NH:41][CH2:40][CH2:39]2)[CH:7]=1
Reactant: O=C1CCNCCN1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3cnc4ccccc4c3)cnn12
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCNC(=O)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 185 °C
Yield: 96.2 %

Procedure:
A mixture of 5-chloro-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)-pyrazolo-[1,5-a]pyrimidin-7-amine (50 mg, 0.09 mmoL), 1,4-diazepan-5-one (36 mg, 0.32 mmoL), EtN(iPr)2 (110 uL, 0.63 mmoL) in NMP (0.8 mL) was heated at 185° C. under microwave condition for 45 min. Purification by prep-LC afforded titled compound (32.3 mg, 85%) as its formic acid salt. LCMS tR=2.49 Min. Mass calculated for, M+ 373.1, observed LC/MS m/z 374.1 (M+H).
Reaction SMILES: [ClH:1].[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[NH2:11].Cl.[N:13]1([C:18](=N)[NH2:19])C=CC=N1.C(N(C(C)C)CC)(C)C>C(#N)C>[ClH:1].[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[NH:11][C:18]([NH2:19])=[NH:13]
Reactant: NC1Cc2ccccc2C1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N=C(N)NC1Cc2ccccc2C1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
Stir a solution of 2,3-dihydro-1H-inden-2-amine hydrochloride (197 g; 1.08 equiv; 1.16 moles), 1H-pyrazole-1-carboximidamide hydrochloride (158 g; 1.00 equiv; 1.08 moles) and diisopropylethylamine (400 g; 2.87 equiv; 3.09 moles; 539.74 mL) in acetonitrile (2 L) at 62° C. for 2 hours, during which time a white solid precipitates. Cool the mixture to 25° C., then filter and wash with 300 mL acetonitrile and 300 mL methyltert-butyl ether. Dry the product in air at 25° C. for 1 h to afford the title compound (200 g, 87%) as a white solid: MS (m/z): 176 (M+1).
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:5][N:4]([C:6]2[CH:7]=[CH:8][C:9]([C:16]([OH:18])=O)=[N:10][C:11]=2[O:12][CH2:13][CH2:14][F:15])[CH2:3]1.Cl.[F:21][C:22]1([F:30])[CH2:26][NH:25][C@H:24]([C:27]([NH2:29])=[O:28])[CH2:23]1>>[F:19][C:2]1([F:1])[CH2:3][N:4]([C:6]2[CH:7]=[CH:8][C:9]([C:16]([N:25]3[CH2:26][C:22]([F:30])([F:21])[CH2:23][C@H:24]3[C:27]([NH2:29])=[O:28])=[O:18])=[N:10][C:11]=2[O:12][CH2:13][CH2:14][F:15])[CH2:5]1
Reactant: NC(=O)[C@@H]1CC(F)(F)CN1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCCF)n1
Agent: Cl
Product: NC(=O)[C@@H]1CC(F)(F)CN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCCF)n1
Yield: 43.3 %

Procedure:
In analogy to the procedure described in Example 127 e), 5-(3,3-difluoroazetidin-1-yl)-6-(2-fluoroethoxyl)pyridine-2-carboxylic acid (Example 147 c, 25 mg, 90.5 μmol) was reacted with (S)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (CAN 426844-51-1, 20.3 mg, 109 μmol) to obtain the title compound (16 mg, 43%) as off-white solid, MS (ESI): m/e=409.1304 [MH+].
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:9]=O)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].O>CN(C=O)C>[CH3:8][C:5]1[N:4]=[C:3]2[CH:9]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:1][C:2]2=[CH:7][CH:6]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(O)c(C=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2nc(C)ccc2o1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 233.7 %

Procedure:
To a solution of 3-hydroxy-6-methylpyridine-2-carbaldehyde (4.92 mmol, 35.9 mmol) in DMF (70 mL) were added potassium carbonate (9.93 g, 71.8 mmol) and ethyl bromoacetate (5.97 mL, 53.9 mmol), and the mixture was stirred at 100° C. for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1 to 3:2) to give the title compound (2.36 g, yield 32%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Br:30][C:31]1[S:35][C:34]([C:36](O)=[O:37])=[CH:33][CH:32]=1>>[Br:30][C:31]1[S:35][C:34]([C:36]([NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=[CH:10]3)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)=[O:37])=[CH:33][CH:32]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: O=C(O)c1ccc(Br)s1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2ccc(Br)s2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 70 mg, 0.18 mmol) and 5-bromothiophene-2-carboxylic acid (44.4 mg, 0.21 mmol)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH3:30])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1)=[O:16].C(=O)([O-])O.[Na+].[N+:36]([O-])([OH:38])=[O:37]>>[O:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH3:30])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1)=[O:16])[N+:36]([O-:38])=[O:37]
Reactant: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCO)cn2)CC1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Product: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCO[N+](=O)[O-])cn2)CC1
Temperature: -25 °C
Reaction time: 0.67 h

Procedure:
To 30 ml of fuming nitric acid cooled to -30° C. was gradually added 7.9 g of N-(12-hydroxydodecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide over 30 minutes and the mixture was stirred at -30 to -20° C. for 40 minutes. The reaction solution was poured into ice, neutralized with sodium hydrogen carbonate and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and distilled under reduced pressure. The residue thus obtained was chromatographed over a silica gel column and recystallized from methanol-water to afford the title compound as a crystal.
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7](CN3C(=O)C4=CC=CC=C4C3=O)[O:6][N:5]=2)[CH2:3][CH2:2]1.[CH3:21][NH:22]N>ClCCCl>[NH2:22][CH2:21][N:8]1[CH2:7][O:6][N:5]=[C:4]1[CH:1]1[CH2:2][CH2:3]1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nc(C2CC2)no1
Reactant: CNN
Solvent: ClCCCl
Product: NCN1CON=C1C1CC1

Procedure:
N-[(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)methyl]phthalimide (104 g, 387 mmol) was dissolved in 1,2-dichloroethane (500 mL), N-methylhydrazine (22.4 mL, 426 mmol) was added and the solution was refluxed for 5 h. The suspension was cooled in ice, the precipitate (2-methyl-2,3-dihydro-phthalazine-1,4-dione) was filtered off and washed with 1,2-dichloroethane (100 mL). The filtrate was evaporated and the residue distilled at 70° C./0.4 mbar (bath-T 100-150° C). Yield: 39.3 g (73%). m/z 139 (M).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:8]([Br:22])[S:7][CH:6]=1)=[O:4].Cl.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]Cl)[CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[C:9]([N:10]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:30][C:26]2[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=2)=[C:8]([Br:22])[S:7][CH:6]=1)=[O:4]
Reactant: ClCc1cccnc1
Reactant: COC(=O)c1csc(Br)c1NS(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1csc(Br)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.8 %

Procedure:
To a solution of 4.80 g (11.82 mmol) of the product of Example 17 dissolved in 5.0 mL of DMF was added 2.04 g (12.41 mmol) of 3-picolyl chloride hydrochloride and 4.89 g (35.46 mmol) of potassium carbonate. The reaction mixture was then stirred at room temperature for 18 h, diluted with water and extracted with ether. The oragnics were then extracted with 6N HCl solution and the aqueous acid layer was then basified with 6N NaOH solution and then extracted with ether. The resulting ether layer was dried over sodium sulfate, filtered and concentrated in vacuo to provide 4.16 g (71%) of the desired product as a tan solid. Electrospray Mass Spec: 498 (M+H).