Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:25]=[N:26][C:27]([O:30]CC5C=CC=CC=5)=[CH:28][CH:29]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCCl.C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[CH:28][C:27](=[O:30])[NH:26][CH:25]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(NC1CC1)c1cn(-c2cccc(-c3ccc(OCc4ccccc4)nc3)c2)c2ncccc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CC1)c1cn(-c2cccc(-c3ccc(=O)[nH]c3)c2)c2ncccc2c1=O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of N-cyclopropyl-1-[3-(6-benzyloxypyridin-3-yl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Example 42 in 1,2-dichloroethane (25 ml/mmol) was added trifluoroacetic acid (1.5 ml/mmol) and the resulting mixture was stirred at 60° C. for 18 hours. More trifluoroacetic acid was added (0.75 ml/mmol) and heating was continued for a further 24 hours. The cooled mixture was diluted with methylene chloride and saturated aqueous sodium bicarbonate was added, resulting in precipitation of a solid which was filtered. From the filtrate the organic phase was collected and evaporated to a solid which was combined with the previous filtered solid. This mixture was chromatographed on silica gel eluting with 10% methanol in methylene chloride to afford the title compound as a white fluffy solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[OH2:18].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]([NH:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:10]([OH:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O
Reactant: C1=CCN(Cc2ccccc2)C1
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: OC1CN(Cc2ccccc2)CC1NCc1ccccc1
Yield: 74 %

Procedure:
To a solution of 15.9 g (0.1 mol) of 1-benzyl-3-pyrroline, 12.0 g (0.12 mol) of 98% sulfuric acid, 15.0 g of water, and 60.0 g of acetone in a quartz round flask reactor, 45.6 g (0.20 mol) of (NH4)2S2O8 (ammonium peroxydisulfate produced by Mitsubishi Gas Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 5 days at room temperature with irradiation by 500 W Xe lamps (UXL-500D xenon lamp produced by Ushio). After evaporation of acetone under reduced pressure, continuously 32.1 g (0.3 mol) of benzylamine (produced by Katayama Chemical Industry Co., Ltd.) was added to the reaction mixture and stirred for 5 hours at 100° C. After completion, excess benzylamine was removed by distillation under reduced pressure, and extracted with toluene and water. After the solvent was evaporated under reduced pressure, 20.9 g of 1-benzyl-4-benzylamino-3-pyrrolidinol (yield 74.0%) was obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6]1.C1(C)C=CC=CC=1.[Cl:22][C:23]1[N:28]=[C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[N:25][CH:24]=1>C(N(CC)CC)C>[ClH:1].[Cl:22][C:23]1[N:28]=[C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH2:2][CH2:3][CH2:4][N:5]3[C:13](=[O:14])[N:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]4=[N:6]3)[CH2:33][CH2:34]2)[CH:26]=[N:25][CH:24]=1
Reactant: Clc1cncc(N2CCNCC2)n1
Reactant: O=c1n(CCCCl)nc2ccccn12
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cl
Product: O=c1n(CCCN2CCN(c3cncc(Cl)n3)CC2)nc2ccccn12

Procedure:
To a solution of 3.2 g. (15.1 mmole) of 2-(3-chloropropyl)-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one in 25 ml. toluene is added 2.4 g. (12.1 mmole) of 6-chloro-2-(1-piperazinyl)pyrazine and 2.1 ml. triethylamine. The mixture is refluxed 3 days under N2, cooled, and filtered to give 1.85 g. of the crude base of the title compound. The crude base is chromatographed on silica gel to give the pure base on elution with 1-2% methanol-chloroform. This material is dissolved in absolute ethanol and the solution treated with anhydrous hydrogen chloride to give tan crystals of title compound, m.p. 243°-245°, dec.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH:17]=[CH2:18])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C(OC(=O)N[C@H]1C[CH:43]=[CH:42][C@@H:41]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:40](C)[C:39]1=O)(C)(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:39][N:40]([CH:41]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH:42]=[CH2:43])[C:13]([C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:16][CH:17]=[CH2:18])=[O:15]
Reactant: C=CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CC=C[C@H]1c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=CC[C@H](NC(=O)OCc1ccccc1)C(=O)N(C)C(C=C)c1ccccc1
Temperature: -20 °C
Reaction time: 8 h
Yield: 150.5 %

Procedure:
To a solution of (2S)-2-{[(benzyloxy)carbonyl]amino}pent-4-enoic acid (2a) (1.7 g) in DCM (8 mL) at −20° C. under N2 was added a mixture of EDAC.HCl (1.56 g) and DMAP (18 mg) in DCM (12 mL) portionwise. Methyl(1-phenylprop-2-en-1-yl)amine (1d) (1.0 g) in DCM (5 mL) was then added dropwise to the reaction mixture. The reaction mixture was stirred for 1 h at −20° C. and overnight at RT, then diluted with DCM (100 mL) and washed with 0.2 N HCl, saturated NaHCO3, brine, dried (Na2SO4), filtered, and evaporated. The crude product was purified via flash chromatography (20% EtOAc/hexanes) to give the desired product as a viscous oil (1.8 g, 70%). 1H NMR (300 MHz, CDCl3) δ 2.41-2.47 (m, 1H), 2.52-2.57 (m, 1H), 2.66-2.82 (m, 3H-diastereomer/rotamer mixture), 4.77 (m, 1H), 5.11-5.17 (m, 4H), 5.22-5.41 (m, 2H), 5.68-5.82 (m, 2H), 6.08 (m, 1H), 6.39-6.41 (m, 1H), 7.26-7.35 (m, 10H). MS APCI, m/z=379 (M+1). LC/MS 2.99 min., Method A.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:12][C:13]1[CH:20]=[C:19]([CH2:21]O)[C:18]([CH2:23][CH2:24][OH:25])=[CH:17][C:14]=1[C:15]#[N:16].ClC1C(CCO)=C(CO)C=CC=1C#N.O>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:20]=[C:19]2[C:18]([CH2:23][CH2:24][O:25][CH2:21]2)=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: N#Cc1cc(CCO)c(CO)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#Cc1ccc(CO)c(CCO)c1Cl
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1cc2c(cc1Cl)COCC2
Temperature: 25 °C
Yield: 76.5 %

Procedure:
p-Toluene sulfonic acid (0.76 g, 5.4 mmol) was added to a solution of a mixture (0.57 g, 2.7 mmol) of 2-chloro-5-(2-hydroxyethyl)-4-hydroxymethylbenzonitrile and 2-chloro-3-(2-hydroxyethyl)-4-hydroxymethylbenzonitrile in toluene (10 mL). The mixture was stirred while heating under reflux overnight. The reaction solution was cooled to room temperature, and water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude product. The resulting crude product was purified by silica gel column chromatography using n-hexane-ethyl acetate (mixing ratio=2:1), and dried under reduced pressure to give a 1:0.1 mixture (0.4 g, 79%) of the title compound and 5-chloroisochromane-6-carbonitrile.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1>[Br-:1].[Si:6]([O:5][CH2:4][CH2:3][CH2:2][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Solvent: c1ccccc1
Product: CC(C)(C)[Si](C)(C)OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 85 °C

Procedure:
To a solution of 1-bromo-3-[(tert-butyldimethylsilyl)oxy]propane (2.18 g, 8.56 mmol) in anhydrous benzene (1.6 mL) was added triphenylphosphine (2.64 g, 10.2 mmol) under argon with stirring. The mixture was heated at 85° C. for 18 hours and cooled to room temperature. The liquid was decanted and the solid residue was grounded with spatula, filtered, and washed several times with ether. Colorless crystals of phosphonium salt B (3.7 g) were purified by silica column chromatography. Pure salt B (3.04 g, 69%) was eluted with chloroform/methanol (96:4). B: 1H NMR (500 MHz, CDCl3) δ0.039 (6H, s, 2×SiCH3), 0.857 (9H, s, Si-t-Bu), 1.93 (2H, m, CH2—CH2—CH2), 3.86-3.94 (4H, br m, CH2—CH2—O and P—CH2), 7.70, 7.79 and 7.85 (6H, 3H and 6H, each m, Ar—H).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[S:27]1[CH:31]=[CH:30][C:29]([C:32](O)=O)=[CH:28]1>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:32]([C:29]3[CH:30]=[CH:31][S:27][CH:28]=3)[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: O=C(O)c1ccsc1
Product: CON=C1C[C@@H](c2noc(-c3ccsc3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and 3-thiophenecarboxylic acid, the title compound was obtained in 64% purity by HPLC. MS(ESI+): m/z=445.2.
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]3[CH:13]=[C:14]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[CH:16][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.Cl.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([NH:37]N)[CH:32]=2)=[CH:27][C:26]=1[CH3:39].CC1C=C(B(O)O)C=CC=1[F:47].ClC1C(F)=C(C=CC=1)N>>[F:47][C:32]1[C:31]([C:28]2[CH:29]=[CH:30][C:25]([F:24])=[C:26]([CH3:39])[CH:27]=2)=[CH:36][CH:35]=[C:34]2[C:33]=1[NH:37][C:2]1[C:3]3[CH:4]=[CH:5][C:6]([C:12]4[CH:13]=[C:14]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[CH:16][CH:17]=4)=[CH:7][C:8]=3[CH2:9][CH2:10][C:11]2=1
Reactant: Cc1cc(B(O)O)ccc1F
Reactant: CS(=O)(=O)Nc1cccc(-c2ccc3c(c2)CCCC3=O)c1
Reactant: Cc1cc(-c2cccc(NN)c2)ccc1F
Agent: Cl
Agent: Nc1cccc(Cl)c1F
Product: Cc1cc(-c2ccc3c4c([nH]c3c2F)-c2ccc(-c3cccc(NS(C)(=O)=O)c3)cc2CC4)ccc1F

Procedure:
The title material is prepared by reacting N-[3-(5-Oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)-phenyl]-methanesulfonamide and (4′-Fluoro-3′-methyl-biphenyl-3-yl)-hydrazine hydrochloride (prepared as in example 70, steps 1 and 2 except using 3-methyl-4-fluorophenylboronic acid and 3-chloro-2-fluoroaniline as the coupling partners) in an analogous manner to example 1, step 3 except that purification is accomplished by reverse phase UV triggered HPLC: 1H NMR (400 MHz, d6-DMSO) δ 12.66 (s, 1H), 9.88 (s, 1H), 8.82 (d, J=8.7 Hz, 1H), 8.31 (m, 1H), 8.29 (d, J=8.6 Hz, 1H), 8.08 (d, J=8.2 Hz, 1H), 7.94 (m, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.66 (m, 1H), 7.61 (m, 2H), 7.48 (m, 1H), 7.30 (m, 2H), 3.09 (m, 2H), 3.04 (s, 3H), 2.97 (m, 2H), 2.08 (s, 3H); LC/MS calculated for [M+H]+ C30H25F2N2O2S: 515.6, found: 515.0.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:24]([CH2:37][CH:38]([CH3:40])[CH3:39])[S:25]([C:28]1[CH:36]=[CH:35][C:31]2[N:32]=[CH:33][S:34][C:30]=2[CH:29]=1)(=[O:27])=[O:26])[C:11]1[S:12][C:13]([CH2:16][NH:17]S(C(C)(C)C)=O)=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.[ClH:41].O1CCOCC1>CO>[ClH:41].[NH2:17][CH2:16][C:13]1[S:12][C:11]([C@H:10]([N:24]([CH2:37][CH:38]([CH3:40])[CH3:39])[S:25]([C:28]2[CH:36]=[CH:35][C:31]3[N:32]=[CH:33][S:34][C:30]=3[CH:29]=2)(=[O:27])=[O:26])[CH2:9][OH:8])=[CH:15][CH:14]=1
Reactant: CC(C)CN([C@H](CO[Si](C)(C)C(C)(C)C)c1ccc(CNS(=O)C(C)(C)C)s1)S(=O)(=O)c1ccc2ncsc2c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)CN([C@H](CO)c1ccc(CN)s1)S(=O)(=O)c1ccc2ncsc2c1
Reaction time: 5 h

Procedure:
To a solution of N-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(5-{[(tert-butylsulfinyl)amino]methyl}thiophen-2-yl)ethyl]-N-(2-methylpropyl)-1,3-benzothiazole-6-sulfonamide (1.12 g, 1.74 mmol) in MeOH (8.7 mL) was added 4 N HCl in dioxane (5.0 mL, 20 mmol) and the reaction mixture was stirred for 5 hours. The reaction was concentrated under reduced pressure and concentrated from heptanes. The product was use as such in the next step.
Reaction SMILES: [C:1]([C:4]1[CH:37]=[CH:36][C:7]([O:8][CH2:9][CH:10]([N:12](CC2C=CC=CC=2)[CH2:13][CH:14]([OH:28])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=2)[CH3:11])=[CH:6][C:5]=1[OH:38])(=[O:3])[NH2:2]>CO.[Pd]>[C:1]([C:4]1[CH:37]=[CH:36][C:7]([O:8][CH2:9][CH:10]([NH:12][CH2:13][CH:14]([OH:28])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])=[CH:19][CH:18]=2)[CH3:11])=[CH:6][C:5]=1[OH:38])(=[O:3])[NH2:2]
Reactant: CC(COc1ccc(C(N)=O)c(O)c1)N(Cc1ccccc1)CC(O)COc1ccc(NS(C)(=O)=O)cc1
Agent: [Pd]
Solvent: CO
Product: CC(COc1ccc(C(N)=O)c(O)c1)NCC(O)COc1ccc(NS(C)(=O)=O)cc1

Procedure:
A solution of 20.0 g of crude 1-[N-[2-(4-carbamoyl-3-hydroxy-phenoxy)-1-methyl-ethyl]-benzylamino]-3-(4-methane-sulfonylamino-phenoxy)-2-propanol in 250 ml of methanol is hydrogenated, after the addition of 2.5 g of Pd/C catalyst (5%), under normal conditions until debenzylation is completed (DC control), for which an addition of a further 1.0 g of catalyst is required. The catalyst is filtered off; the filtrate is concentrated by evaporation, and the oil remaining behind is dissolved in a small amount of hot isopropanol. On cooling is obtained crystalline 1-[2-(4-carbamoyl-3-hydroxy-phenoxy)-1-methyl-ethylamino]-3-(4-methanesulfonylamino-phenoxy)-2-propanol, m.p. 147°-150° (diastereoisomeric mixture).
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[C:4]([OH:10])(=[O:9])[CH2:5][C:6]([OH:8])=O.[CH2:11]([K])[CH3:12].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH:26]1([CH:32]2[CH2:37][CH:36](C(O)=O)[CH2:35][CH2:34][N:33]2[C:41]([O:43][CH3:44])=[O:42])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C1COCC1>[CH:26]1([C@H:32]2[CH2:37][C@H:36]([C:6](=[O:8])[CH2:5][C:4]([O:10][CH2:11][CH3:12])=[O:9])[CH2:35][CH2:34][N:33]2[C:41]([O:43][CH3:44])=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: O=C(O)CC(=O)O
Reactant: CC[K]
Reactant: COC(=O)N1CCC(C(=O)O)CC1C1CCCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](C2CCCCC2)C1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 8.5 %

Procedure:
A suspension of magnesium chloride (2.085 g, 21.89 mmol) and ethyl potassium malonate (3.73 g, 21.89 mmol) in dry THF (80 mL) was stirred under nitrogen atmosphere at 50° C. for 2.5 h (flask 1). In another flask di(1H-imidazol-1-yl)methanone (2.96 g, 18.24 mmol) was added portionwise to a solution of 2-cyclohexyl-1-(methoxycarbonyl)piperidine-4-carboxylic acid (3.28 g, 12.16 mmol) (reference compound 35) in dry THF (20 mL) at 0° C. and put under nitrogen atmosphere. The ice bath was removed and the solution was stirred for 2 h at room temperature (flask 2). Then the contents of flask 1 was added to flask 2 and the resulting mixture was stirred overnight (20 h). The reaction mixture was concentrated and the residue was taken up in EtOAc and H2O. The aqueous phase was extracted once with EtOAc and the combined organic phase was washed with water, 10% Na2CO3 and then dried over Na2SO4. The organic phase was washed with 0.1 M NaOH and dried again and evaporated to give a yellow oil. The compound was purified further via Biotage, 2 runs, SNAP 340 g KP-SIL, linear gradient heptanes/ethyl acetate 9:1 to 1:1 over 7CV. Trans-methyl 2-cyclohexyl-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (349 mg, 6.9%) and cis-methyl 2-cyclohexyl-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.501, 49%) were isolated. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 0.90-1.29 (m, 5H), 1.26 (t, 3H), 1.37-2.05 (m, 10H), 2.57-2.70 (m, 1H), 2.85-3.02 (m, 1H), 3.48 (s, 2H), 3.67 (s, 3H), 3.71-3.84 (m, 1H), 3.86-3.99 (m, 1H), 4.18 (q, 2H). MS m/z 340 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 0.80-1.30 (m, 5H), 1.26 (t, 3H), 1.33-1.90 (m, 9H), 1.96-2.12 (m, 1H), 2.69-2.86 (m, 2H), 3.46 (s, 2H), 3.67 (s, 3H), 3.84-4.33 (m, 2H), 4.21 (q, 2H). MS m/z 340 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([O:18]C)=[O:17])=[C:13]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[N:5]2[N:6]=[C:7]3[C:12]([CH:11]=[CH:10][CH:9]=[CH:8]3)=[C:4]2[N:3]=1.[OH-].[Na+]>CO.C(O)C>[CH3:1][C:2]1[C:14]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([OH:18])=[O:17])=[C:13]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[N:5]2[N:6]=[C:7]3[C:12]([CH:11]=[CH:10][CH:9]=[CH:8]3)=[C:4]2[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc2c3ccccc3nn2c1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2c3ccccc3nn2c1-c1ccc(C)cc1
Temperature: 60 °C
Yield: 29.9 %

Procedure:
To a solution of methyl 2-(2-methyl-4-p-tolylpyrimido[1,2-b]indazol-3-yl)pentanoate (0.264 g; 0.68 mmol) in a mixture methanol-ethanol (2:1) (21 mL) was added a 5% sodium hydroxide solution (16.3 mL; 20.4 mmol) and the reaction mixture was heated to 60° C. for 18 h. The organic volatiles were removed under reduced pressure and the remaining basic solution was acidified till pH 2 with a 1N hydrochloric acid solution and the aqueous layer was extracted with ethyl acetate. The organics were combined, dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (1-20%) in dichloromethane and by preparative HPLC (method 2) furnished 0.076 g (30%) of 2-(2-methyl-4-p-tolylpyrimido[1,2-b]indazol-3-yl)pentanoic acid as a white solid. ESI/APCI(+): 374 (M+H). ESI/APCI(−): 372 (M−H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16]1[CH:26]=[CH:25][C:19]([CH:20]=[CH:21][C:22](O)=O)=[CH:18][CH:17]=1>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:22](/[CH:21]=[CH:20]/[C:19]3[CH:25]=[CH:26][C:16]([F:15])=[CH:17][CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: O=C(O)C=Cc1ccc(F)cc1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(F)cc3)nc2n(CC)c1=O
Yield: 48.3 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.31 g (13.9 mmol) of 4-fluorocinnamic acid. Then, the resultant crude crystals were recrystallized from tetrahydrofuran/water to give 2.00 g (yield 51%) of Compound 149 as colorless columns.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH:11]2[CH2:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[I-].[Na+].[C:30]([O:33][CH2:34][C@@H:35]([CH3:38])[CH2:36]Br)(=[O:32])[CH3:31]>CN(C)C=O>[C:1]([C:5]1[N:6]=[C:7]([N:15]2[CH2:20][CH2:19][N:18]([CH2:36][C@H:35]([CH3:38])[CH2:34][O:33][C:30](=[O:32])[CH3:31])[CH2:17][CH2:16]2)[CH:8]=[C:9]([CH:11]2[CH2:12][CH2:13][CH2:14]2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC[C@@H](C)CBr
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCNCC2)n1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@@H](C)CN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Temperature: 95 °C
Reaction time: 5 h
Yield: 102.9 %

Procedure:
3.87 g of 2-tert-butyl-4-cyclobutyl-6-piperazin-1-yl-pyrimidine (14.1 mmol) were stirred in 30 ml of dimethylformamide at room temperature. 3.18 g of triethylamine (63.1 mmol), 0.235 g of sodium iodide (1.57 mmol), 2.96 g of (R)-(−)-1-acetoxy-3-bromo-2-methyl-propane (15.2 mmol) were added and the reaction mixture was stirred for 5 h at 95° C. The dimethylformamide was evaporated under reduced pressure. The residue was partitioned between 100 ml of dichloromethane and 100 ml of water. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure to give a brownish oil (5.64 g).
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][CH2:4][C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2.[OH-].[Na+]>CO.O>[ClH:3].[C:5]12([CH2:4][NH:1][NH2:2])[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2
Reactant: ClCC12CC3CC(CC(C3)C1)C2
Reactant: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cl
Product: NNCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 38.4 %

Procedure:
4.0 g (120 mmol) of anhydrous hydrazine and 2.3 g (12 mmol) of 1-chloromethyladamantane were introduced into a sealable tube under nitrogen atmosphere. The tube was sealed and heated at 150° for 16 hours. After cooling to room temperature the contents were suspended in methanol, treated with a solution 0.5 g of sodium hydroxide in 1.5 ml of water, and the volatiles removed in vacuo. The resulting solid was extracted with ether and the solution dried with magnesium sulfate and treated with hydrogen chloride to give 1 g of the title compound (38% yield).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:9])[CH2:4][O:5][CH2:6][CH2:7][OH:8].[CH2:10](Br)[C:11]#[CH:12].C(OCC)(=O)C>C1COCC1>[CH2:12]([O:9][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8])[C:11]#[CH:10]
Reactant: OCCOCCO
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#CCOCCOCCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil) (23 mmol) in dry THF (20 mL) at 0° C. under nitrogen was added a THF solution (100 mL) of diethylene glycol (110 mmol) over 0.5 h. The resultant reaction mixture was allowed to stir at room temperature for 1 h. This was followed by the addition of propargyl bromide (21 mmol). The reaction mixture was then heated under reflux for 8 h. Following this, the reaction was cooled, concentrated in vacuo and diluted with water (30 mL). The mixture was then extracted with ethyl acetate (3×50 mL). The organics were combined, dried over sodium sulfate and the concentrated under vacuum to furnish a crude residue. This was subjected to column chromatography using hexanes and ethyl acetate to afford 22 as a clear oil. Yield 2.1 g (71%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-:8].O[CH2:10][P+:11]([CH2:16]O)([CH2:14]O)[CH2:12]O>C(O)C>[Cl-:8].[NH:1]([CH2:10][P+:11]([CH2:16][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH2:14][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:12][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[P+](CO)(CO)CO
Reactant: Nc1ccccc1
Agent: [Cl-]
Solvent: CCO
Product: c1ccc(NC[P+](CNc2ccccc2)(CNc2ccccc2)CNc2ccccc2)cc1
Reaction time: 2 h
Yield: 92.7 %

Procedure:
Aniline (7.70 g) was added to a solution of 3.83 g of tetrakis(hydroxymethyl)phosphonium chloride (THPC) in 75 ml of ethanol. There was a mild exotherm, followed immediately by the separation of solids. The mixture was stirred for 2 hours and then filtered, giving 9.15 g (93.0 percent yield) of tetrakis(anilinomethyl)phosphonium chloride, m.p. 129°-130°, as a white crystalline solid that yellowed rapidly on exposure to light. No further solids separated from the filtrate in the next 5 hours. The filtrate and washings, stripped under vacuum, left 1.15 g of a yellow oil containing the remainder of the product and the unreacted aniline.