Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][CH2:16][CH:17]=[CH2:18]>CN(C=O)C>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([CH2:18][CH2:17][CH:16]=[CH2:15])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCC(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 72 h
Yield: 71 %

Procedure:
A mixture of sodium hydride (60% in mineral oil, 435 mg, 10.87 mmol, 1.1 eq) in DMF (20 mL) was treated dropwise with diethyl malonate (1.5 mL, 9.88 mmol, 1.0 eq). The reaction mixture was then cooled to 0° C. and 4-bromo-1-butene (1.0 mL, 9.88 mmol, 1 eq) was added dropwise. The reaction mixture was warmed to rt, stirred for 3 days and then partitioned between ether and water. The layers were separated, the aqueous layer was extracted with ether (2×50 mL) and the combined organic phases were washed with water (2×) and brine, dried over MgSO4 and concentrated. Column chromatography (SiO2, 5% ether/heptane) gave C8.1 (1.51 g, 71% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 5.77 (m, 1H), 5.00 (m, 2H), 4.13 (q, J=7.1 Hz, 4H), 3.43 (t, J=7.4 Hz, 1H), 2.02 (m, 2H), 1.84 (m, 2H), 1.17 (t, J=7.1 Hz, 6H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][CH:14]2[CH2:23][CH2:22][N:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:15]2)=[O:11])=[CH:2]1.[CH:24]1([CH2:27]Br)[CH2:26][CH2:25]1>>[CH:24]1([CH2:27][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]([O:12][CH2:13][CH:14]3[CH2:23][CH2:22][N:21]4[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20]4)[CH2:15]3)=[O:11])=[CH:2]2)[CH2:26][CH2:25]1
Reactant: O=C(OCC1CCN2CCCCC2C1)c1c[nH]c2ccccc12
Reactant: BrCC1CC1
Product: O=C(OCC1CCN2CCCCC2C1)c1cn(CC2CC2)c2ccccc12

Procedure:
eq-Quinolizidin-2-ylmethyl indole-3-carboxylate (E9b) was alkylated with cyclopropylmethyl bromide using the method in Example 18. The product was chromatographed on silica gel eluting initially with ether, then with ethyl acetate, to afford the title compound (E28) as a colourless oil. This was converted to its hydrochloride salt mp 167°-169° C. (acetone/ether).
Reaction SMILES: [I-:1].[Na+].CS(O[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])(=O)=O.O>CC(C)=O>[I:1][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14]
Reactant: CS(=O)(=O)OCCCCC(F)(F)C(F)(F)F
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: FC(F)(F)C(F)(F)CCCCI
Yield: 82.9 %

Procedure:
Sodium iodide (168 g, 1.12 mol) was added to a solution of 1-methanesulfonyloxy-5,5,6,6,6-pentafluorohexane (101 g, 373.77 mmol) in acetone (2000 ml), followed by heating under reflux for 12 hours. Water was added to the reaction mixture, which was then extracted twice with ether. The combined organic layers were washed with 1% aqueous sodium thiosulfate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: pentane) to give 1-iodo-5,5,6,6,6-pentafluorohexane (93.6 g, Yield 83%).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH:9]=1)(O)=[O:6]>>[ClH:3].[Cl:3][C:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH:9]=1)=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cn(-c2ccc3ccccc3n2)c2ccccc12
Product: Cl
Product: O=C(Cl)c1cn(-c2ccc3ccccc3n2)c2ccccc12

Procedure:
25 cm3 of thionyl chloride are added at 25° C. under an argon atmosphere to 0.93 g (2.86 mmol) of 3-carboxy-1-(quinol-2-yl)-1H-indole. After stirring at reflux for 3 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), successively triturated twice with 10 cm3 of dimethoxyethane and then concentrated to dryness under reduced pressure (2.7 kPa) to give 1 g of 3-chlorocarbonyl-1-(quinol-2-yl)-1H-indole hydrochloride in the form of a yellow solid which is used directly in the following step.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][CH:4]1[CH2:18][NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][NH:5]1.[Cl-:20].[Mn+2:21].[Cl-:22]>CO>[Cl:20][C:4]1([CH2:3][CH:2]([CH3:19])[CH3:1])[CH2:18][NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][N:5]1[Cl:22].[Mn+2:21]
Reactant: CC(C)CC1CNCCNCCNCCNCCN1
Reactant: [Cl-]
Agent: [Mn+2]
Solvent: CO
Product: CC(C)CC1(Cl)CNCCNCCNCCNCCN1Cl
Yield: 48 %

Procedure:
A solution of 2-(2-methylpropyl)-1,4,7,10,13-pentaazacyclopentadecane prepared as in Example 5D (0.66 g, 2.4 mmole) and anhydrous manganese(II) chloride (0.31 g, 2.4 mmole) in anhydrous methanol (40 ml) was refluxed under a dry nitrogen atmosphere overnight. The solution was filtered and the solvent removed in vacuo. The resulting yellow solid was recrystallized from THF-ethyl ether to give 0.46 g (48% yield) of the product as an off-white solid: FAB mass spectrum (NBA) m/z (relative intensity) 396 (M30, 1), 361/363 [(M-Cl)+ 84/26], 272 [(M-MnCl2 +H)30 100]. Anal. Calcd. for C14H33Cl2MnN5 : C, 42.33; H, 8.37; N, 17.63. Found: C, 41.90;H, 8.22; N, 17.30.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH2:28][C:29]2[NH:33][C:32]3[CH:34]=[CH:35][C:36]([C:38]#[N:39])=[CH:37][C:31]=3[N:30]=2)=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8](S(C1C=CC(C)=CC=1)(=O)=O)[CH:7]=[C:6]2[C:23]1[NH:27][N:26]=[CH:25][CH:24]=1)[CH3:2].[OH-].[K+]>CCO.C(Cl)Cl>[CH2:1]([C:3]1[C:4]([CH2:28][C:29]2[NH:33][C:32]3[CH:34]=[CH:35][C:36]([C:38]#[N:39])=[CH:37][C:31]=3[N:30]=2)=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[C:6]2[C:23]1[NH:27][N:26]=[CH:25][CH:24]=1)[CH3:2]
Reactant: CCc1cc(C)c2c(c(-c3ccn[nH]3)cn2S(=O)(=O)c2ccc(C)cc2)c1Cc1nc2cc(C#N)ccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CCc1cc(C)c2[nH]cc(-c3ccn[nH]3)c2c1Cc1nc2cc(C#N)ccc2[nH]1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-((5-ethyl-7-methyl-3-(1H-pyrazol-5-yl)-1-tosyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (63 mg, 0.118 mmol) and KOH (33.1 mg, 0.589 mmol) in EtOH (5 mL) was stirred at 100° C. for 0.5 h under microwave irradiation. The reaction mixture was diluted with CH2Cl2 and filtered through silica gel. The silica gel cake was washed with CH2Cl2/MeOH (c.a. 9/1). After concentration the resulting residue was purified by RP-HPLC (HC-A) to give the title compound. 1H NMR (TFA salt, 400 MHz, DMSO-d6) δ ppm 10.13 (br. s., 1H), 8.53 (s, 1H), 8.23 (d, J=8.60 Hz, 1H), 8.18 (br. d, J=8.60 Hz, 1H), 8.05 (s, 1H), 7.96 (d, J=2.78 Hz, 1H), 7.54 (s, 1H), 6.72 (br. s., 1H), 5.32 (br. s., 2H), 3.38 (q, J=7.60 Hz, 2H), 3.06 (s, 3H), 1.69 (t, J=7.58 Hz, 3H). HRMS calcd. for C23H20N6 (M+H)+ 381.1828. found 381.1828.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C@@H:20]([OH:32])[CH2:21][C@@H:22]([C:28]([OH:31])([CH3:30])[CH3:29])[C:23]([NH:25][CH2:26][CH3:27])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])(C)(C)C.[CH2:40]([C@H:47]([CH2:51][C:52]([N:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1)=[O:53])C(O)=O)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>>[CH2:40]([C@H:47]([CH2:51][C:52]([N:54]1[CH2:55][CH2:56][O:57][CH2:58][CH2:59]1)=[O:53])[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:33][CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1)[C@@H:20]([OH:32])[CH2:21][C@@H:22]([C:28]([OH:31])([CH3:30])[CH3:29])[C:23]([NH:25][CH2:26][CH3:27])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1
Reactant: CCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Product: CCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1)C(C)(C)O
Yield: 32 %

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 100 mg (0.176 mmoles) of (2S, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-ethylhexanamide [prepared as described in Example 14(a)], 50 mg (0.18 mmoles) of 2(R)-benzyl-3-(morpholinocarbonyl)propionic acid, 0.28 ml (2 mmoles) of triethylamine, and 0.029 ml (0.18 mmoles) of diethyl cyanophosphate were used, to obtain 41 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:15]=[CH:14][NH:13][N:12]=1.[F:16][C:17]([F:27])([F:26])[C:18](=O)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([C:17]([F:16])([F:26])[F:27])[NH:10][C:11]3=[N:12][NH:13][CH:14]=[C:15]23)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1ccc(Cl)cc1
Product: CCOC(=O)C1=C(C(F)(F)F)Nc2n[nH]cc2C1c1ccc(Cl)cc1

Procedure:
The title compound was prepared from 4-chlorobenzaldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.[CH3:12]CCCCC.C[Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: CCCCCC
Reactant: O=C(O)c1ccc(F)cc1O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(F)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A solution of 4-fluoro-2-hydroxybenzoic acid (9.8 g, 62.3 mmol) in benzene (100 mL) and MeOH (20 mL) was cooled in an ice bath and a 2 M hexane solution of (trimethyl-silyl)diazomethane (50 mL) was added dropwise. The reaction was stirred overnight at ambient temperature, diluted with benzene (348 mL) and MeOH (39 mL), and treated with more of the (trimethylsilyl)diazomethane solution (15 mL). The mixture was concentrated in vacuo to dryness to give the title compound (10.4 g, 98%) as a solid.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.[O:23]=[C:24](Cl)OC(Cl)(Cl)Cl.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[N:31]1([C:24]([N:17]2[CH2:16][CH2:15][C:12]3([C:11](=[O:20])[N:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)[CH2:19][CH2:18]2)=[O:23])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: C1COCCN1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Product: O=C(N1CCOCC1)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and morpholine. MS (ESI): 428.3 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH2:9])=[O:8].[CH:13]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.Cl>[OH-].[Na+]>[CH:13]1([C:19]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH2:9])=[O:8])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NC(=O)NCCC[C@H](N)C(=O)O
Reactant: O=C(Cl)C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)NCCC[C@H](NC(=O)C1CCCCC1)C(=O)O
Temperature: 25 °C
Yield: 77.5 %

Procedure:
L-Citrulline (35.2 g., 0.2 mole) was dissolved in 200 mL of 2 N sodium hydroxide. Cyclohexanoyl chloride (29 mL, 0.2 mole) was added dropwise to the mixture. The reaction mixture was maintained at about 25° C. for 1 hour. The mixture was then acidified to pH 2.6 with aqueous (4:1) hydrochloric acid. The precipitate which formed was separated by decantation. The solids were dissolved in 2 N sodium hydroxide to pH 6.5 and dried by lyophilization to furnish 44.2 g of N-cyclohexanoyl-(L)-citrulline. The product was a white solid.
Reaction SMILES: C(OC([N:8]([C:13]1[CH:14]=[C:15]([C:21]2[CH:22]=[C:23]3[C:29]([C:30]4[CH:31]=[N:32][N:33]([CH2:35][C:36]5[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=5)[CH:34]=4)=[CH:28][N:27](C(OC(C)(C)C)=O)[C:24]3=[N:25][CH:26]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C>Cl.CCOCC.CO>[CH3:20][O:19][C:18]1[CH:17]=[CH:16][C:15]([C:21]2[CH:22]=[C:23]3[C:29]([C:30]4[CH:31]=[N:32][N:33]([CH2:35][C:36]5[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=5)[CH:34]=4)=[CH:28][NH:27][C:24]3=[N:25][CH:26]=2)=[CH:14][C:13]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: COc1ccc(-c2cnc3c(c2)c(-c2cnn(Cc4cccnc4)c2)cn3C(=O)OC(C)(C)C)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COc1ccc(-c2cnc3[nH]cc(-c4cnn(Cc5cccnc5)c4)c3c2)cc1NS(C)(=O)=O
Yield: 12.5 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 5-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxyphenyl)-3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (60 mg, 0.219 mmol) was deprotected in HCl in ether/MeOH (1/3 ml) to afford 13 mg (29% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.78 (s, 2H), 8.53 (s, 2H), 8.42-8.37 (m, 2H), 8.02 (s, 1H), 8.00-7.94 (m, 1H), 7.77-7.76 (m, 2H), 7.62-7.59 (dd, 1H), 7.24-7.21 (d, 1H), 5.66 (s, 2H), 3.98 (s, 3H), 2.99 (s, 3H). MS: m/z=475.1 (M+1), HPLC: 97.36% in method A.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].COC([CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[N:13]([C:19]1[C:24]([NH2:25])=[CH:23][N:22]=[C:21]([Cl:26])[N:20]=1)[CH:14]1C[CH2:17][CH2:16][CH2:15]1)=O>C(O)(=O)C>[Cl:26][C:21]1[N:22]=[CH:23][C:24]2[NH:25][C:1](=[O:3])[CH:2]3[CH:14]([CH2:15][CH2:16][CH2:17]3)[N:13]([CH:9]3[CH2:10][CH2:11][CH2:12][CH2:8]3)[C:19]=2[N:20]=1
Reactant: CCO
Reactant: COC(=O)C1CCCC1N(c1nc(Cl)ncc1N)C1CCCC1
Solvent: CC(=O)O
Product: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)C2CCCC12

Procedure:
A mixture of 150 mL of ethanol, 3.0 mL of acetic acid and 2.85 g (0.0084 mole) of (rac)-2-[(5-amino-2-chloro-pyrimidin-4-yl)-cyclopentyl-amino]-cyclopentanecarboxylic acid methyl ester (V-68) from the previous step, combined with material from a separate experiment was heated at reflux overnight and then concentrated under reduced pressure to give 2.49 g of (rac)-6-chloro-4-cyclopentyl-2,3,3a,4,9,10a-hexahydro-1H-4,5,7,9-tetraaza-benzo[f]azulen-10-one (VI-68), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[O:12]1[CH2:17][CH2:16][N:15]([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([N:15]1[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1)[C:21]1[CH:26]=[N:25][C:24]([C:27]([F:29])([F:30])[F:28])=[N:23][CH:22]=1)=[O:6]
Reactant: NCC(c1cnc(C(F)(F)F)nc1)N1CCOCC1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)N1CCOCC1)c1ccc(Cl)cc1Cl

Procedure:
From 2,4-dichlorobenzoic acid and 2-morpholino-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[F:10].Cl[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[F:10][C:3]1[CH:4]=[C:5]([CH:6]=[O:7])[CH:8]=[CH:9][C:2]=1[O:1][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=Cc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Oc2ccc(C=O)cc2F)nc1
Yield: 72.7 %

Procedure:
Using a method similar to Example 365, step 1, using 4-hydroxy-3-fluoro-benzaldehyde (3.00 g, 21.4 mmol), 6-chloro nicotinonitrile (2.98 g, 21.5 mmol), and potassium carbonate (7.40 g, 53.5 mmol) in dimethylacetamide (100 mL) after 6 h at 100° C. provides 3.77 g (73%) of the title compound as a yellow solid (silica gel chromatography conditions: 19:1→1:4 hexanes:ethyl acetate): mass spectrum (electrospray): m/z=243.0 (M+1); 1H NMR (CDCl3): 10.00 (d, 1H, J=2.0 Hz), 8.42 (d, 1H, J=1.5 Hz), 8.01 (dd, 1H, J=2.0, 8.3 Hz), 7.80-7.72 (m, 2H), 7.43 (d, 1H, J=7.3 Hz), 7.19 (d, 1H, J=8.8 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH3:23])[CH:13]=2)[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:23][N:14]1[CH:13]=[C:12]([C:4]2[CH:3]=[C:2]([O:1][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:22]
Reactant: BrCc1ccccc1
Reactant: Cn1cc(-c2cc(O)cc(S(C)(=O)=O)c2)c2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(OCc3ccccc3)cc(S(C)(=O)=O)c2)c2ccccc2c1=O
Temperature: 80 °C
Yield: 37.6 %

Procedure:
A capped mixture of 4-(3-hydroxy-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one (25 mg, 0.076 mmol), benzyl bromide (20 mg, 0.12 mmol), and Cs2CO3 (50 mg, 0.15 mmol) in DMF (600 uL) was heated to 80° C. for 3 h. The mixture was filtered and the filter cake was washed with ACN (500 uL), the filtrate was purified by prep-HPLC to afford the title compound (12 mg, 38%) as a tan solid. LCMS (M+H)+=420.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:21]([NH:23][CH2:24][C:25]3[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=3[CH3:31])=[O:22])[C:12]3[CH:17]=[N:16][N:15]([CH:18]([CH3:20])[CH3:19])[C:13]=3[N:14]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:34][N:35](C=O)[CH3:36].CNC.O>CCOC(C)=O>[CH3:31][C:30]1[CH:29]=[C:28]([CH3:32])[NH:27][C:26](=[O:33])[C:25]=1[CH2:24][NH:23][C:21]([C:11]1[C:12]2[CH:17]=[N:16][N:15]([CH:18]([CH3:19])[CH3:20])[C:13]=2[N:14]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][N:35]([CH3:36])[CH3:34])[CH:4]=2)[CH:10]=1)=[O:22]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(CBr)c3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CN(C)C=O
Agent: CNC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(CN(C)C)c3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 8 h
Yield: 40 %

Procedure:
To a stirred solution of 6-(3-(bromomethyl)phenyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) in a DMF, dimethylamine (5 equiv.) was added at 0° C. & resulting reaction mixture stirred for overnight. After completion of reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the crude material which was purified by column chromatography to give pure final compounds (40% yield). LCMS: 473.20 (M+1)+; HPLC: 99.89% (@ 254 nm) (Rt; 5.325); 1H NMR (DMSO-d6, 400 MHz) δ 11.52 (s, 1H), 8.96 (bs, 1H), 8.35 (s, 1H), 8.13-8.10 (m, 3H), 7.50 (t, J=8.4 Hz, 1H), 7.43-7.41 (m, 1H), 5.89 (s, 1H), 5.34-5.31 (m, 1H), 4.41 (d, J=4 Hz, 2H), 3.50 (s, 2H), 2.23 (s, 3H), 2.19 (s, 6H), 2.12 (s, 3H), 1.54 (d, J=6.8 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][C:11]([OH:15])([C:13]#[CH:14])C.O1CCCC1>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C>[NH2:1][C:2]1[NH:3][C:4]([C:14]#[C:13][CH:11]([OH:15])[CH3:10])([CH3:9])[CH:5]=[CH:6][N:7]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(O)C#CC1(C)C=CN=C(N)N1

Procedure:
A mixture of 10.0 g of 2-amino-4-chloro-6-methylpyrimidine, 8.8 ml of 2-methyl-3-butyn-2-ol, 400 ml of tetrahydrofuran (THF), 0.06 g of copper (I) iodide, 0.5 g of bis(triphenylphosphine)palladium (II) chloride and 20.4 ml of triethylamine was heated overnight at reflux under a nitrogen atmosphere. The reaction mixture was allowed to cool. It was then partitioned between 200 ml of ethyl acetate and 100 ml of sodium bicarbonate. The organic layer was washed successively with 100 ml of water and 100 ml of brine. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was placed on a silica gel dry column and eluted with dichloromethane/ethyl acetate/THF (10:90:0.1). The product band was extracted with THF. The organic extract was concentrated. Trituration of the residue (butyl chloride) gave 4.44 g of the title compound as a solid, m.p. 155°; PMR (90 MHz, CDCl3) δ1.65(s, 6H, CH3), 2.3(s, CH3, 3H), 2.8(s, OH, 1H), 5.2(bs, 2H, NH2), 6.6(s, Het-H, 1H); IR(nujol) 2221(w, C≡C) cm-1.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][O:5][C:6]([C:8]1[O:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:10](=[O:11])[CH:9]=1)=[O:7].ClC(Cl)(Cl)C(O)=O>CCOCC>[CH3:16][C:13]1([CH3:15])[O:14][C@H:8]([C:6]([O:5][CH2:4][CH2:3][CH2:2][CH3:1])=[O:7])[CH2:9][C:10](=[O:11])[CH2:12]1
Reactant: CCCCOC(=O)C1=CC(=O)CC(C)(C)O1
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCCCOC(=O)[C@@H]1CC(=O)CC(C)(C)O1
Reaction time: 72 h
Yield: 87.9 %

Procedure:
A solution of Indalon (230 mg) and 2R,5R-5-butyl-methyl-2-(5-methylfuran-2-yl) imidazolidin-4-one (55 mg) in dry ether (4.6 mL) was stirred and cooled at ice bath temp (0-4° C.) as t-Butyl Hantzch ester (346 mg) and trichloroacetic acid (32 mg) were added sequentially. The resulted yellow solution was stirred at ice bath temp for 3 days, and monitored by TLC. The reaction mix was passed through a short pad of silica gel and eluted with ether (60 mL). Concentration of the ether and purified by flash chromatography (20% EtOAc in Hexane) gave 204 mg (88%) of the product as oil: 1H NMR (400 MHz, CDCl3) δ 4.46 (dd, 1H, J=4.0, 11.0 Hz), 4.19 (td, 2H, J=2.7, 6.7 Hz), 2.58 (dd, 1H, J=1.6, 14.0 Hz), 2.56 (d, 1H, J=13.2), 2.50 (s, H, J=13.2 Hz), 2.32 (dd, 1H, J=1.6, 14.0 Hz), 1.64 (m, 2H), 1.46 (s, 3H), 1.37 (m, 2H), 1.23 (s, 3H), 0.94 (t, 3H, J=7.4 Hz); 13C NMR (CDCl3, 100 MHz) ä 205.2, 170.1, 76.2, 70.0, 65.4, 52.9, 43.5, 30.5, 28.6, 28.0, 23.8, 19.0, 13.6.
Reaction SMILES: B1([O-])OO1.[OH2:5].[OH2:6].O.O.[Na+].C(O)(=O)C.[NH2:14][C:15]1[NH:19][N:18]=[CH:17][C:16]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]>O>[N+:14]([C:15]1[NH:19][N:18]=[CH:17][C:16]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])([O-:6])=[O:5]
Reactant: CCOC(=O)c1cn[nH]c1N
Reactant: O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Product: CCOC(=O)c1cn[nH]c1[N+](=O)[O-]
Temperature: 85 °C

Procedure:
A mixture of sodium perborate tetrahydrate (95%, 15.7 g, 96.9 mmol) and acetic acid (60 mL) was heated to 85° C. Ethyl 5-amino-1H-pyrazole-4-carboxylate (3.0 g, 19 mmol) was added, and the mixture was allowed to react at 85° C. for 18 hours. The reaction was then poured into water and extracted with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo; purification via silica gel chromatography (Gradient: 0% to 100% EtOAc in heptane) provided C1. Yield: 1.41 g, 7.62 mmol, 40%. LCMS m/z 184.0 (M−1). 1H NMR (400 MHz, CDCl3) δ 1.39 (t, J=7.2 Hz, 3H), 4.40 (q, J=7.1 Hz, 2H), 8.32 (s, 1H).