Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[N:14]=[C:13]([N:15]2[C:19]3[CH:20]=[C:21]([Br:24])[CH:22]=[CH:23][C:18]=3[N:17]=[C:16]2[O:25][CH:26]2[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]2)[CH:12]=[CH:11][N:10]=1.C(N(CC)CC)C>ClCCl>[NH:28]1[CH2:27][CH:26]([O:25][C:16]2[N:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH2:8])[N:14]=3)[C:19]3[CH:20]=[C:21]([Br:24])[CH:22]=[CH:23][C:18]=3[N:17]=2)[CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2nc3ccc(Br)cc3n2-c2ccnc(N)n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1nccc(-n2c(OC3CNC3)nc3ccc(Br)cc32)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 1130 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added dropwise into a solution of tert-butyl 3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]azetidine-1-carboxylate (250 mg, 0.49 mmol, 90%) in dichloromethane (2 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 hr. Triethylamine was then added to adjust the pH of the solution to 8. The mixture was concentrated under vacuum to give 2 g (88%) of 4-[2-(azetidin-3-yloxy)-6-bromo-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine as dark red oil: LC-MS: m/z=+361 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([O:7][CH:8]([CH3:10])[CH3:9])[C:3]=1[C:11]#[N:12].[CH3:13][N:14]=[C:15]=[O:16].C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC>O1CCCC1>[CH3:13][NH:14][C:15]([NH:1][C:2]1[S:6][N:5]=[C:4]([O:7][CH:8]([CH3:10])[CH3:9])[C:3]=1[C:11]#[N:12])=[O:16]
Reactant: CN=C=O
Reactant: CC(C)Oc1nsc(N)c1C#N
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C1CCOC1
Product: CNC(=O)Nc1snc(OC(C)C)c1C#N
Yield: 74.9 %

Procedure:
In the manner of Example V D, a mixture of 11 g of 5-amino-4-cyano-3-isopropoxyisothiazole and 6.8 g of methyl isocyanate in 50 ml of dry tetrahydrofuran containing 2 ml of dibutyltin diacetate were allowed to react under reflux overnight. Volatile materials were removed under reduced pressure and the residue was recrystallized from ethyl acetate to yield 10.8 g of 1-methyl-3-(4-cyano-3-isopropoxy-5-isothiazolyl)urea, mp 238° (decomposes.) The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]([CH3:8])[C:6]=1[CH3:7].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24].N>O.CC(O)C.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[CH3:16][O:17][C:18]1[C:19](=[O:24])[CH:20]=[CH:21]/[C:22](=[N:1]\[C:2]2[C:3](=[O:15])[N:4]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:5]([CH3:8])[C:6]=2[CH3:7])/[CH:23]=1
Reactant: COc1ccccc1O
Reactant: Cc1c(N)c(=O)n(-c2ccccc2)n1C
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: N
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: COC1=C/C(=N/c2c(C)n(C)n(-c3ccccc3)c2=O)C=CC1=O

Procedure:
10 mmol of 4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one was dissolved in 30 ml of water. This solution was admixed with 10 mmol of 2-methoxyphenol in solution in 30 ml of 2-propanol, 3 ml of 20% aqueous ammonia and 22 mmol of potassium ferricyanide at a temperature ranging from 5 to 10° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]([O:17]CC)=[O:16])=[CH:9]2.O[Li].O.C(O)C>C1COCC1.O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]([OH:17])=[O:16])=[CH:9]2
Reactant: CCOC(=O)c1cc2cc(OCCOC)ccc2[nH]1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COCCOc1ccc2[nH]c(C(=O)O)cc2c1
Reaction time: 16 h
Yield: 97.3 %

Procedure:
Ethyl 5-(2-methoxyethoxy)-1H-indole-2-carboxylate (2.0 g, 7.4 mmol) in THF (20 ml) was treated with a solution of LiOH•H2O (0.62 g, 14.8 mmol) in water (10 ml). Ethanol was added until a homogenous solution formed and stirring was continued for 16 h. The reaction mixture was diluted with water (50 ml) and the organic solvents were removed in vacuo. The pH was adjusted to 4 with 1M aqueous HCl and the aqueous solution was extracted with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated in vacuo to provide 5-(2-methoxyethoxy)-1H-indole-2-carboxylic acid (1.7 g, 7.2 mmol) as a white solid. The crude acid was directly used without further purification.
Reaction SMILES: [C:1]([CH:3]1[CH2:7][CH2:6][CH2:5][NH:4]1)#[N:2].[O:8]([CH2:15][CH2:16][CH2:17]Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:1]([CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:17][CH2:16][CH2:15][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:2]
Reactant: N#CC1CCCN1
Reactant: BrCCCOc1ccccc1
Product: N#CC1CCCN1CCCOc1ccccc1

Procedure:
Following the procedure of Preparation 9, the title compound is prepared from 2-cyanopyrrolidine [Helv. Chim. Acta 50(8), 2520-2531 (1967)] and 3-phenoxypropyl bromide.
Reaction SMILES: O[CH:2]1[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][C:3]1([C:12]([OH:14])=[O:13])[CH2:4]3)[CH2:8]2.[OH:15]C1C2CC3(C(O)=O)CC(CC1C3)C2>>[OH:15][C:9]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][C:3]([C:12]([OH:14])=[O:13])([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)C12CC3CC(C1)C(O)C(C3)C2
Reactant: O=C(O)C12CC3CC(CC(C3)C1O)C2
Product: O=C(O)C12CC3CC(CC(O)(C3)C1)C2

Procedure:
2-Hydroxyadamantane-1-carboxylic acid and 4-hydroxy adamantane-1-carboxylic acid: J. Org. Chem., 38, 3447 (1973).
Reaction SMILES: [F:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([O:13]C)=[O:12])=[CH2:3].[Li+].[OH-].O>O.C1COCC1>[F:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12])=[CH2:3]
Reactant: C=C(F)c1ccccc1CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=C(F)c1ccccc1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A suspension of methyl 2-(2-(1-fluorovinyl)phenyl)acetate (334, 770.8 mg, 4.015 mmol) (Hakamoto T.; Kobavashi T. J. Org. Chem. 2003, 68, 6354-6359) and LiOH×H2O (185 mg, 4.41 mmol) in H2O/THF (1:1, 11 mL) was stirred overnight at room temperature. The THF was evaporated off under reduced pressure; the aqueous residue was diluted with water, washed with EtOAc, acidified to pH˜3 by addition of 1N HCl and extracted with DCM. The organic extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure affording 335 (557.2 mg, 77% yield) as a white solid. LCMS: (M−1) 187.1 (100%).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[O:6]1[CH2:19][CH:7]1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1.C([O-])=O.[NH4+]>C1COCC1.[Pd]>[CH2:1]([NH:5][CH2:19][CH:7]([OH:6])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN
Reactant: O=[N+]([O-])c1ccc(OCC2CO2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)CNCC(O)COc1ccc(N)cc1
Yield: 100 %

Procedure:
Isobutylamine (5.1 ml, 51.2 mmol) was added to a solution of 4-(2,3-epoxypropoxy) nitrobenzene (obtained as described in Synthetic Communications, 1994, 24, 833; 1.0 g, 5.12 mmol) in THF (1 ml). The solution was heated under reflux for 3 hours and then volatile material was removed by evaporation. The residue was dissolved in methanol (5 ml) and 10% palladium on carbon (0.50 g) and ammonium formate (3.23 g, 51.2 mmol) were added. The mixture was heated under reflux for 3 hours and then filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to give the product as dark brown oil (1.22 g, 100%), which was used without further purification. MS (MH+): 238.9.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:17][NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([N:18]([CH3:17])[CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CNCCc1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Product: CN(CCc1ccc([N+](=O)[O-])cc1)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 52.5 %

Procedure:
2.4 g (10.9 mmol) of 1-(4-nitrophenyl)-4-piperidone and 2.0 g (10.9 mmol) of N-methyl-N-(2-(4-nitrophenyl)ethyl)amine were reacted in a similar manner to Example 1. 2.2 g of 1-(4-nitrophenyl)-4-(N-methyl-N-(2-(4-nitrophenyl)ethyl)amino)piperidine were obtained. Melting point 97°-98° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.[C:12]1([C:18](=O)[CH2:19][C:20](=O)[CH3:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:19][C:20]([CH3:21])=[N:11]2)=[CH:6][CH:5]=1
Reactant: COc1ccc(NN)cc1
Reactant: CC(=O)CC(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(-n2nc(C)cc2-c2ccccc2)cc1
Yield: 53 %

Procedure:
A mixture of 8.7 parts of (4-methoxyphenyl)hydrazine hydrochloride, 8.1 parts of 1-phenyl-1,3-butanedione, 7 parts of potassium carbonate and 160 parts of ethanol is stirred and refluxed for 20 hours. The reaction mixture is cooled and poured onto water. The product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed with water, dried filtered and evaporated. The residue is crystallized twice from petroleumether. The product is filtered off and dried, yielding 7 parts (53%) of 1-(4-methoxyphenyl)-3-methyl-5-phenyl-1H-pyrazole; mp. 110° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[NH:28][CH:29]=[CH:30][C:23]=34)=[C:17]([F:31])[CH:16]=2)[N:3]=1.CN(C(ON1N=N[C:42]2[CH:43]=[CH:44][CH:45]=[N:46][C:41]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NC(C)C)(C)C.N1CCCCC1>CN(C=O)C>[F:31][C:17]1[CH:16]=[C:15]([NH:14][C:4]2[CH:5]=[C:6]([CH2:8][CH2:9][CH2:10][C:11](=[O:13])[N:46]3[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]3)[N:7]=[C:2]([NH2:1])[N:3]=2)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1nc(CCCC(=O)O)cc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)n1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: Nc1nc(CCCC(=O)N2CCCCC2)cc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
70 mg (0.17 mmol) of 4-(2-amino-6-{[3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]amino}pyrimidin-4-yl)butyric acid (from example 130) are dissolved in 2.0 ml of DMF, 60 mg (0.16 mmol) of HATU, 23 mg (0.17 mmol) of 1-hydroxy-1H-azobenzotriazole hydrate, 43 mg (0.33 mmol) of diisopropylamine and 28 mg (0.33 mmol) of piperidine are added and the mixture is stirred at RT for 20 hours. Volatile components are removed under reduced pressure and the product is purified by preparative HPLC. The resulting product is purified further by thick-layer chromatography (1 mm silica gel coating, mobile phase: DCM:methanol=9:1).
Reaction SMILES: [CH3:1][C:2]([C:4]([CH3:6])=[CH2:5])=[CH2:3].[CH3:7][O:8][C:9](=[O:16])[C:10]#[C:11][C:12]([O:14][CH3:15])=[O:13]>C1C=CC=CC=1>[CH3:7][O:8][C:9]([C:10]1[CH2:5][C:4]([CH3:6])=[C:2]([CH3:3])[CH2:1][C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[O:16]
Reactant: C=C(C)C(=C)C
Reactant: COC(=O)C#CC(=O)OC
Solvent: c1ccccc1
Product: COC(=O)C1=C(C(=O)OC)CC(C)=C(C)C1

Procedure:
2,3-Dimethyl-buta-1,3-diene (2.0 g, 24.3 mmol) and but-2-ynedioic acid dimethyl ester in benzene (14 mL) were heated to reflux for 16 h. The resulting mixture was cooled and evaporated in vacuo to yield a solid, which was purified via flash column chromatography (EtOAc/heptane 9:1) to yield 4,5-dimethyl-cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester as a white solid.
Reaction SMILES: C([O:3][C:4]([C@@:6]1([NH:11][C:12]([C@@H:14]2[CH2:18][C@@H:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:16][C@H:15]2[C:38](=[O:59])[NH:39][C@H:40]([C:45](=[O:58])[NH:46][C@@H:47]([CH:52]2[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]2)[C:48](=[O:51])[NH:49][CH3:50])[C:41]([CH3:44])([CH3:43])[CH3:42])=[O:13])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])C.[Li+].[OH-].Cl>C1COCC1.CO.O>[CH:52]1([C@H:47]([NH:46][C:45]([C@@H:40]([NH:39][C:38]([C@@H:15]2[CH2:16][C@H:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:21]=3)[CH2:18][C@H:14]2[C:12]([NH:11][C@:6]2([C:4]([OH:5])=[O:3])[CH2:8][C@H:7]2[CH:9]=[CH2:10])=[O:13])=[O:59])[C:41]([CH3:43])([CH3:42])[CH3:44])=[O:58])[C:48](=[O:51])[NH:49][CH3:50])[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)NC)C1CCCCC1)C(C)(C)C)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)NC)C1CCCCC1)C(C)(C)C)C(=O)O
Reaction time: 48 h
Yield: 66.5 %

Procedure:
To a solution of compound 39 (20 mg, 0.025 mmol) in THF/MeOH/water 2:1:1 (2 mL) at 0° C. was added 1M LiOH (175 uL, 0.175 mmol) and the solution was allowed to attain room temperature and was stirred for 48 h. The solution was acidified to pH 3 with 1M HCl and was then evaporated and coevaporated with toluene. The crude product was purified by HPLC (MeOH/water 6:4+0.5% TFA followed by MeOH/water 4:1+0.2% TFA) to give compound 40 (13 mg, 67%) as a colorless solid.
Reaction SMILES: [N:1]1([CH2:8][C:9]([C:11]2[CH:22]=[CH:21][C:14]([O:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:13][CH:12]=2)=[O:10])[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].Cl.[Cl:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>O.O1CCOCC1>[ClH:24].[N:28]1[CH:29]=[CH:30][C:25]([N:4]2[CH2:5][CH2:6][N:1]([CH2:8][C:9]([C:11]3[CH:22]=[CH:21][C:14]([O:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][CH:12]=3)=[O:10])[C:2](=[O:7])[CH2:3]2)=[CH:26][CH:27]=1
Reactant: COC(=O)COc1ccc(C(=O)CN2CCNCC2=O)cc1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2=O)cc1
Yield: 40.7 %

Procedure:
A solution of methyl 4-[2-(piperazin-2-one-1-yl)acetyl]phenoxyacetate (0.347 g), 4-chloropyridine hydrochloride (0.19 g) and triethylamine (0.178 g) in water (8 ml) and dioxan (1 ml) was heated on a steam bath for 2 hours and then evaporated to dryness. The residue was triturated with water (2 ml) and filtered. The solid thus obtained was recrystallised from water to give the title compound (0.187 g), m.p. 275°-277° C.; NMR(d6DMSO δ8.33(2H,d), 8.0(2H,d), 7.21(2H,d), 7.1(2H,d), 4.97(2H,s), 4.81(2H,s), 3.94(2H,m), 3.59(2H,m); m/e 370(M+H)+ ; calculated for C19H20N3O5Cl. 0.75 H2O: C, 54.4; H, 5.0; N, 10.0. Found: C, 54.5; H, 5.3; N, 9.5%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[CH:12]=[C:13]([C@:17]2([CH3:37])[CH2:22][CH2:21][N:20]([CH2:23][C@@H:24]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:25]([O:27][CH3:28])=[O:26])[CH2:19][C@@H:18]2[CH3:36])[CH:14]=[CH:15][CH:16]=1)(=O)C.O>CO>[OH:10][C:11]1[CH:12]=[C:13]([C@:17]2([CH3:37])[CH2:22][CH2:21][N:20]([CH2:23][C@@H:24]([CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:25]([O:27][CH3:28])=[O:26])[CH2:19][C@@H:18]2[CH3:36])[CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)CN1CC[C@@](C)(c2cccc(OC(C)=O)c2)[C@@H](C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)CN1CC[C@@](C)(c2cccc(O)c2)[C@@H](C)C1
Reaction time: 2 h
Yield: 52.4 %

Procedure:
Potassium carbonate (0.156 g, 0.001 mol, 3 eq) was added to a solution of 5b (0.160 g, 0.0003 mol, 1 eq) in methanol (15 mL). The suspension was stirred under nitrogen for 2 h. Water (50 mL) was added and the suspension was extracted with ethyl acetate (100 mL). The organic solution was washed with brine (50 mL), separated and dried over sodium sulfate. Evaporation of the solvent afforded the methyl ester 6b as a solid (0.060 g, 41% yield). Rf 0.30 (hexane/EtOAc=8:2). 1H NMR δ (CDCl3) 0.73 (d, 3H), 1.26 (s, 3H), 1.51 (d, 1H), 1.94 (m, 1H), 2.20-2.35 (m, 2H), 2.40-2.50 (m, 2H), 2.55-2.70 (m, 2H), 2.80-3.00 (m, 3H), 3.58 (s, 3H), 6.60 (d, 1H), 6.75 (s, 1H), 6.85 (d, 1H), 7.10-7.30 (m, 7H).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C:13]1[CH:21]=[CH:20][C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=1)=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[BrH:22].Br.CCN(C(C)C)C(C)C.[N:33]1([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35](O)=[O:36]>CN(C=O)C>[N:33]1([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35]([NH:1][C@H:2]([C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([N+:17]([O-:19])=[O:18])=[CH:20][CH:21]=1)=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])=[O:36].[BrH:22]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: N=C(N)NCCC[C@H](N)C(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N)C(=O)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 70 %

Procedure:
1 g (2.19 mmol) of H-L-Arg-pNA.2HBr is dissolved in 10 ml of DMF, and 0.854 ml (6.57 mmol) of DIEA is then added. In another vessel, a solution of 4.71 mg (2.19 mmol) of Boc-L-Pro-OH in 50 ml of DMF is neutralized with 0.285 ml of DIEA. The two solutions are mixed and 970 mg of Bop are then added while the resulting mixture is kept at RT, with stirring, the pH being kept at between 7.0 and 8.0 throughout the reaction by the addition of small portions of DIEA. After one hour, the reaction is complete and the reaction mixture is evaporated to dryness under vacuum; the evaporation residue is taken up with an AcOEt/MeOH mixture and extracted with a 0.5 M aqueous solution of NaHCO3. The organic phase is dried over sodium sulfate, concentrated and precipitated in ether (MeOMe or EtOEt) to give 877 mg (yield: 70%) of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:34]([OH:36])[CH3:35].ClCCl>O.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:35][CH2:34][OH:36])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Reactant: CC(O)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCO)c2ccc(C#CCO)cc2c1=O
Temperature: 100 °C

Procedure:
To a flask containing N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 4 (0.37 g) is added potassium carbonate (2.75 g) and bromoethanol (0.71 mL). The flask is tightly capped and heated to 100° C. After 4 hours the reaction is cooled to room temperature and partioned between dichloromethane containing methanol and water. The organic layer is washed with two additional portions of water, brine, dried and concentrated under reduced pressure. The residue is adsorbed onto silica and chromatographed on silica eluting with 2% to 10% methanol in dichloromethane to afford 0.09 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([N:5]1[C:9]2[C:10]([F:24])=[CH:11][C:12]([N:14]3[CH2:18][C@H:17]([C:19]([O:21]C)=O)[O:16][C:15]3=[O:23])=[CH:13][C:8]=2[O:7][C:6]1=[O:25])[CH3:4]>CO>[CH2:3]([N:5]1[C:9]2[C:10]([F:24])=[CH:11][C:12]([N:14]3[CH2:18][C@H:17]([C:19]([NH:2][CH3:1])=[O:21])[O:16][C:15]3=[O:23])=[CH:13][C:8]=2[O:7][C:6]1=[O:25])[CH3:4]
Reactant: CN
Reactant: CCn1c(=O)oc2cc(N3C[C@H](C(=O)OC)OC3=O)cc(F)c21
Solvent: CO
Product: CCn1c(=O)oc2cc(N3C[C@H](C(=O)NC)OC3=O)cc(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A solution of methylamine in methanol (2M, 5 ml) is added to solid methyl (5R)-3-(3-ethyl-4-fluoro-2-oxo-2,3-dihydro-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxylate (EXAMPLE 87, Step 4, 0.250 g, 0.771 mmol) and the suspension stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and the residue purified by PTLC (10% methanol/dichloromethane) to give product as a white solid (0.10 g, 40%); MS for C14H14FN3O5 m/z 324 (M+H)+; 1H NMR (DMSO-d6, 300 Mhz) δ 8.40 (m, 1H), 7.51 (d, 1H), 7.44 (dd, 1H), 5.07 (dd, 1H), 4.27 (t, 1H), 4.02 (dd, 1H), 3.85 (q, 2H), 2.65 (d, 3H), 1.28 (t, 3H).
Reaction SMILES: C(O)C.[CH3:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:36])[C:12]=2[C:14]2[N:15]=[C:16]([O:34]C)[C:17]3[CH2:23][N:22]([C:24]4[CH:29]=[C:28]([CH:30]([CH3:32])[CH3:31])[CH:27]=[CH:26][C:25]=4[CH3:33])[CH2:21][CH2:20][C:18]=3[N:19]=2)[NH:7][N:6]=1.Cl>ClCCl.C(=O)(O)[O-].[Na+]>[CH3:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:36])[C:12]=2[C:14]2[N:15]=[C:16]([OH:34])[C:17]3[CH2:23][N:22]([C:24]4[CH:29]=[C:28]([CH:30]([CH3:31])[CH3:32])[CH:27]=[CH:26][C:25]=4[CH3:33])[CH2:21][CH2:20][C:18]=3[N:19]=2)[NH:7][N:6]=1
Reactant: COc1nc(-c2c(C)ccc3[nH]nc(C)c23)nc2c1CN(c1cc(C(C)C)ccc1C)CC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: Cc1ccc(C(C)C)cc1N1CCc2nc(-c3c(C)ccc4[nH]nc(C)c34)nc(O)c2C1
Temperature: 85 °C

Procedure:
Ethanol (12 mL) was added to 2-(3,5-dimethyl-1H-indazol-4-yl)-6-(5-isopropyl-2-methylphenyl)-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (2.07 g, 3.47 mmol), followed by 12 N aqueous hydrochloric acid (12 mL). The mixture was then heated at 85° C. for 18 h. The mixture was cooled to room temperature, diluted with dichloromethane and slowly neutralized with saturated aqueous sodium bicarbonate. The resulting layers were separated and the aqueous layers were extracted with dichloromethane. The organic layers were combined. The combined organics were dried and concentrated. The residue was purified by FCC (0-100% EtOAc/heptane) to provide 2-(3,5-dimethyl-1H-indazol-4-yl)-6-(5-isopropyl-2-methylphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ol. MS (ESI+) m/z 428.3 (M+H)+.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[N:11]=[C:10](Cl)[CH:9]=[C:8]([CH2:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:7]=1>CO.C(#N)C>[Cl:5][C:6]1[N:11]=[C:10]([NH:4][CH:1]2[CH2:3][CH2:2]2)[CH:9]=[C:8]([CH2:13][O:14][CH2:15][C:16]([F:19])([F:17])[F:18])[N:7]=1
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Reactant: NC1CC1
Solvent: CC#N
Solvent: CO
Product: FC(F)(F)COCc1cc(NC2CC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
A solution of cyclopropanamine (68 mg, 1.20 mmol) in MeOH (2 mL) was added dropwise to an ice-cold solution of 2,4-dichloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (104 mg, 0.40 mmol) in acetonitrile (2 mL). The mixture was stirred at rt overnight. The mixture was purified by preparative HPLC yielding to give the title compound (64 mg, 57%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:9])[CH3:8])(=[O:3])[CH3:2].[N:10]([O:12]CCC(C)C)=O.[ClH:18]>C(O)(=O)C>[C:1]([O:4][CH2:5][CH:6]([N:10]=[O:12])[C:7]([Cl:18])([CH3:9])[CH3:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC=C(C)C
Reactant: Cl
Reactant: CC(C)CCON=O
Solvent: CC(=O)O
Product: CC(=O)OCC(N=O)C(C)(C)Cl
Temperature: 0 °C

Procedure:
3,3-Dimethylallyl acetate (25 ml.), iso-amyl nitrite (45 ml.) and glacial acetic acid (65 ml.) were cooled in an ice-salt mixture. An ice-cold mixture of concentrated hydrochloric acid (20 ml.) and glacial acetic acid (20 ml.) was added gradually with stirring. The solution became green and towards the end of the addition a white solid precipitated. The solid was collected by filtration and dried (13 g.) Recrystallisation from CCl4 -- 40°/60° petrol gave the title compound as colourless needles (10 g.) m.p. 117°-119°.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:10](O)(=O)CC=CCCC.C(O)(=O)CCC=CCC.C(O)(=O)CCCCC=C.C(O)(=O)C=CCCC>>[C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:10]
Reactant: CCCCC=CC(=O)O
Reactant: CCCC=CCC(=O)O
Agent: C=CCCCCC(=O)O
Agent: CCC=CCCC(=O)O
Agent: CCCC=CC(=O)O
Product: C=CCCCCCC(=O)O

Procedure:
2-heptenoic acid; 3-heptenoic acid; 4-heptenoic acid; 5-hetpenoic acid; 6-heptenoic acid; 2-hexenoic acid;