Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]([CH2:26][C:27]4[C:32]([F:33])=[CH:31][C:30]([F:34])=[CH:29][C:28]=4[F:35])[N:15]=[C:16]4[C:21]=3[CH:20]=[CH:19][CH:18]=[C:17]4[C:22]([F:25])([F:24])[F:23])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(C(C)C)CC)(C)C.C1COCC1>C(OCC)(=O)C.O>[C:36]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:14]([CH2:26][C:27]4[C:28]([F:35])=[CH:29][C:30]([F:34])=[CH:31][C:32]=4[F:33])[N:15]=[C:16]4[C:21]=3[CH:20]=[CH:19][CH:18]=[C:17]4[C:22]([F:23])([F:24])[F:25])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Fc1cc(F)c(Cn2nc3c(C(F)(F)F)cccc3c2-c2ccc(N3CCNCC3)cc2)c(F)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccc1)N1CCN(c2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3c(F)cc(F)cc3F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
Combined in a vial were 3-(4-piperazin-1-ylphenyl)-2-(2,4,6-trifluorobenzyl)-7-(trifluoromethyl)-2H-indazole (0.10 g, 0.2 mmol), benzoyl chloride (0.030 g, 0.22 mmol), and diisopropylethylamine (0.2 mL) and THF (2 mL), which were stirred overnight at room temperature. Then the reaction mixture was diluted with ethyl acetate and water, and the organics washed with water and brine, then dried over magnesium sulfate. The crude product was purified by flash chromatography (silica 60, 5% EtOAc/CH2Cl2) to provide the title compound (0.06 g, 50%).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[N:6]=[CH:5][N:4]=1.C(N(CCC)CCC)CC.[CH:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>N1C=CC=CC=1>[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:30]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:31])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1ccc2ncnc(N)c2c1
Agent: CCCN(CCC)CCC
Agent: Cl
Solvent: c1ccncc1
Product: Nc1ncnc2ccc(NC(=O)C3CCCCC3)cc12
Reaction time: 1 h
Yield: 56.1 %

Procedure:
A mixture of 4,6-diaminoquinazoline hydrochloride (12 g) and tripropylamine (31.7 g) in dry pyridine (120 ml) was stirred in an ice-bath for 1 hour. Cyclohexanecarbonyl chloride (12.1 g) was added dropwise during 4 hours and 20 minutes to the mixture at 70° C. The mixture was stirred for additional 1 hour at 5° C. Crushed ice was added to the reaction mixture. The mixture was stirred for 1 hour and concentrated under reduced pressure. After addition of water, the mixture was adjusted to pH 8 with sodium hydrogen carbonate to give precipitates which were separated by filtration, washed with water and dried. The precipitates were dissolved in a mixture of chloroform and methanol under heating. Insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure to give crystalline 4-amino-6-cyclohexanecarboxamidoquinazoline (9.25 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([CH3:19])=[C:13]([NH:15][C:16]([NH2:18])=[S:17])[CH:14]=2)[CH:4]=1.[ClH:20].[C:21](OCC)(=O)[CH3:22]>CN(C)C=O.O1CCOCC1.ICC>[ClH:20].[ClH:20].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([CH3:19])=[C:13]([NH:15][C:16](=[NH:18])[S:17][CH2:21][CH3:22])[CH:14]=2)[CH:4]=1
Reactant: COc1ccnc(-c2ccc(C)c(NC(N)=S)c2)c1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CCI
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCSC(=N)Nc1cc(-c2cc(OC)ccn2)ccc1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of N-(5-(4-methoxypyridin-2-yl)-2-methylphenyl)-thiourea (0.15 g) in N,N-dimethylformamide (3 ml) were added a solution of hydrogen chloride in 1,4-dioxane (4N, 0.274 ml) and iodoethane (0.22 ml), and the mixture was stirred at ambient temperature for 5 hours. Ethyl acetate (100 ml) was added to the mixture, and the mixture was cooled. The precipitate was collected by filtration. The precipitate was dissolved in water, and to the solution was added a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and to the solution was added a solution of hydrogen chloride in 1,4-dioxane (4N, 0.5 ml). The precipitate was collected by filtration and dried under reduced pressure to give N-(5-(4-methoxypyridin-2-yl)-2-methylphenyl)-S-ethylisothiourea dihydrochloride (168 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH:8]2[CH2:11][CH2:10][CH2:9]2)[C:6](=[O:12])[NH:5][C:4](=[O:13])[C:3]=1[N:14]=O>CN(C=O)C.O=[Pt]=O>[CH:8]1([N:7]2[C:2]([NH2:1])=[C:3]([NH2:14])[C:4](=[O:13])[NH:5][C:6]2=[O:12])[CH2:9][CH2:10][CH2:11]1
Reactant: Nc1c(N=O)c(=O)[nH]c(=O)n1C1CCC1
Agent: O=[Pt]=O
Solvent: CN(C)C=O
Product: Nc1c(N)n(C2CCC2)c(=O)[nH]c1=O

Procedure:
6.9 g of 6-amino-1-cyclobutyl-5-nitroso-2,4-(1H,3H)-pyrimidinedione (IX) was catalytically hydrogenated in 250 ml of DMF and in the presence of 0.1 g PtO2 for 2 hours and at room temperature and at a pressure of 200 kPa. The catalyst and the crystals were filtered off and washed with ethanol. Yield 3.5 g (54%) (X).
Reaction SMILES: [C:1]([O:6][C@@H:7]([C:9]1[N:14]=[C:13](Cl)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[N:23]1([C:29]2[O:30][C:31]3[C:36]([N:37]=2)=[CH:35][CH:34]=[CH:33][N:32]=3)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(O)(C)C>[C:1]([O:6][C@@H:7]([C:9]1[N:14]=[C:13]([N:26]2[CH2:25][CH2:24][N:23]([C:29]3[O:30][C:31]4[C:36]([N:37]=3)=[CH:35][CH:34]=[CH:33][N:32]=4)[CH2:28][CH2:27]2)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: c1cnc2oc(N3CCNCC3)nc2c1
Reactant: CCCC(=O)O[C@H](C)c1nccc(Cl)n1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCCC(=O)O[C@H](C)c1nccc(N2CCN(c3nc4cccnc4o3)CC2)n1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 6.8 g, 29.9 mmol) and triethylamine (12.5 mL, 89.6 mmol) in isopropanol (100 mL) was added 2-(1-piperazinyl)oxazolo[5,4-b]pyridine (prepared according to the method of Example 9, Step A, 6.1 g, 29.9 mmol). This mixture was stirred at reflux overnight, cooled to room temperature, and evaporated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (1.5→2% methanol/chloroform) to give 11.1 g (94%) of the title compound of Example 9, Step B as a yellow oil which solidified upon standing. 1H NMR (CDCl3, 250 MHz) δ8.28 (d, 1H), 7.97 (dd, 1H), 7.60 (dd, 1H), 7.25 (dd, 1H), 6.44 (d, 1H), 5.70 (q, 1H), 3.85 (app s, 8H), 2.42 (t, 2H), 1.78-1.61 (c, 2H), 1.60 (d, 3H), 0.98 (t, 3H); MS (APCI) 397 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[N:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[CH3:17][C:18]([S@:21]([NH:23][CH:14]([C:4]1[N:5]=[N:6][C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[C:2]([CH3:1])[CH:3]=1)[CH3:15])=[O:22])([CH3:20])[CH3:19]
Reactant: CC(=O)c1cc(C)c(OCC(F)(F)F)nn1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)nnc1OCC(F)(F)F
Yield: 56 %

Procedure:
The title compound is prepared in 56% yield (402 mg, brown oil) from 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethanone (500 mg, 2.14 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (388 mg, 3.20 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [CH2:1]([CH:3]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[C:4]([OH:6])=[O:5])[CH3:2].[CH:13]([N-]C(C)C)(C)C.[Li+].C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C.CI>C(Cl)Cl>[CH2:1]([C:3]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)([CH3:13])[C:4]([OH:6])=[O:5])[CH3:2]
Reactant: CCC(C(=O)O)c1cccnc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCC(C)(C(=O)O)c1cccnc1
Yield: 30 %

Procedure:
To ethyl 3-pyridylacetic acid (10.86 grams) (65.7 mmoles) was added a 2.0 M solution of lithium diisopropylamide in THF/heptane/ethyl benzene (32.87 ml.) (65.8 mmoles) at −30° C. The semi-solid mixture was agitated and sonicated for 1 hour. The mixture was allowed to remain at 25° C. for 1 hour, whereupon methyl iodide (4.09 ml.) (65.7 mmoles) was added. After 1 hour at 25° C. the mixture was taken up in CH2Cl2 and washed with saturated aqueous sodium bicarbonate and water. The CH2Cl2 was dried (magnesium sulphate), filtered and evaporated to dryness. The residue was chromatographed on silica gel using 10% EtOAc in hexane as the eluant to give the title compound (Yield: 3.48 grams, 30%, MH+ 180).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]([CH2:11][OH:12])[CH2:7][C:6]=2[CH:5]=[C:4]([CH:13]([CH3:15])[CH3:14])[CH:3]=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:12][CH2:11][CH:8]2[CH2:7][C:6]3[CH:5]=[C:4]([CH:13]([CH3:15])[CH3:14])[CH:3]=[C:2]([Br:1])[C:10]=3[O:9]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: CC(C)c1cc(Br)c2c(c1)CC(CO)O2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C(C)C)cc(Br)c3O2)cc1
Yield: 97.1 %

Procedure:
To a solution of 4-isopropylphenol (13.38 g, 98.0 mmol) with N-bromosuccinimide (17.5 g, 98 mmol) generally according to the procedure described for Example 305 afforded 13.78 g (65%) of 2-bromo-4-isopropylphenol. Treatment of 2-bromo-4-isopropylphenol (13.74 g, 41.0 mmol) with potassium carbonate (22.0 g, 160 mmol) and allyl bromide (9.23 g, 76.8 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-bromo-4-isopropylphenol. Treatment of 2-allyl-6-bromo-4-isopropylphenol (6.85 g, 27.0 mmol) with 3-chloroperoxybenzoic acid (7.72 g, 27.0 mmol, 77%) followed by potassium carbonate (9.3 g, 67.5.0 mmol) generally according to the procedure described for Intermediate 9 afforded 1.12 g, (17%) of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methanol (1.12 g, 4.6 mmol) with p-toluenesulfonyl chloride (1.32 g, 6.9 mmol) generally according to the procedure described for Intermediate 10 gave 1.90 g (97%) of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.4 g, 0.94 mmol) and 2-methylphenylboronic acid (0.38 g, 2.82 mmol) generally according to the procedure described for Intermediate 35 afforded 0.19 g, (46%) of (5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.141 g, 2.17 mmol) generally according to the procedure described for Intermediate 98 afforded 0.11 g (83%) of (±)-2-(azidomethyl)-5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.188 g, 0.716 mmol) according to the procedure described in Example 154 afforded 0.055 g (48%) of (±)-[(5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine as a white solid, hydrochloride salt. mp 221-222° C. (dec).
Reaction SMILES: [O:1]=[C:2]1[CH:7](C(OCC2C=CC=CC=2)=O)[CH2:6][C:5](=[O:18])[NH:4][CH:3]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[H][H]>[Pd].C(OCC)(=O)C>[C:20]1([CH2:19][CH:3]2[NH:4][C:5](=[O:18])[CH2:6][CH2:7][C:2]2=[O:1])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: [H][H]
Reactant: O=C1CC(C(=O)OCc2ccccc2)C(=O)C(Cc2ccccc2)N1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1CCC(=O)C(Cc2ccccc2)N1

Procedure:
A stirred suspension of (±)-3,6-dioxo-2-(phenylmethyl)-4-piperidinecarboxylic acid, phenylmethyl ester, 1.59 g (0.0047 mole) and 0.2 g of 20% palladium on carbon in 200 ml of ethyl acetate was exposed to hydrogen gas for 15 minutes, the suspension was purged with nitrogen gas, filtered, and the solvent evaporated in vacuo and the residue chromatographed using 100 g of silica gel and eluting with 200 ml of dichloromethane-methanol (98:2) and 200 ml of dichloromethane-methanol (97:3) to give (±)-6-(phenylmethyl)-2,5-piperidinedione, 0.8 g; mp 140°-141°.
Reaction SMILES: CCN(CC)CC.[F:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([C:18](=[O:22])[C:19](Cl)=[O:20])=[CH:12][NH:13]2.OC(C(F)(F)F)=O.[C:30]1([C:36]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[NH:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[F:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([C:18](=[O:22])[C:19]([N:41]1[CH2:42][CH2:43][N:38]([C:36](=[NH:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:39][CH2:40]1)=[O:20])=[CH:12][NH:13]2
Reactant: N=C(c1ccccc1)N1CCNCC1
Reactant: O=C(Cl)C(=O)c1c[nH]c2cccc(F)c12
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N=C(c1ccccc1)N1CCN(C(=O)C(=O)c2c[nH]c3cccc(F)c23)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Et3N (2 ml) was added into a solution of 2-(4-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride (1.56 g) and phenyl(piperazin-1-yl)methanimine TFA salt (1.98 g) in THF (20 ml) and reaction was stirred at room temperature for 17 hours before quenched with saturated aqueous NaHCO3 solution (50 ml). The aqueous layer was extracted with ethyl acetate (3×50 ml). The organic phase combined and dried over anhydrous MgSO4. Concentration in vacuo provided a crude product, which was purified by silica gel column chromatography to afford 1-(4-fluoro-1H-indol-3-yl)-2-(4-(imino(phenyl)methyl)piperazin-1-yl)ethane-1,2-dione.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=[O:18])[C:8]3[C:13]4[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=4[S:11][C:9]=3[S:10][C:4]=2[CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1>[CH3:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=[O:18])[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)Sc1sc3c(c1C(=O)N2)CCCC3
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)Sc1sc3ccccc3c1C(=O)N2

Procedure:
In the same manner as in Example 77 and using 1,2,3,4-tetrahydro-8-methyl-[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one, dichlorodicyano-p-benzoquinone and benzene, 8-methyl-[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one is obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[N:21]=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=1>>[Br:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[N:21]=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(Br)nn1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Br
Product: Cc1ccc(-c2cc(C)c(Br)c(C)c2)nn1

Procedure:
The title compound is prepared from 2-bromo-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 3-bromo-6-methyl-pyridazine following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 9): tR=1.11 min; Mass spectrum (ESI+): m/z=277/279 (Br) [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.[CH2:12]([CH:16]1[CH2:20][O:19][C:18](=[O:21])[CH2:17]1)[CH2:13][CH2:14][CH3:15]>C1(C)C=CC=CC=1>[C:2]1([NH:1][C:18](=[O:21])[CH2:17][CH:16]([CH2:20][OH:19])[CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CCCCC1COC(=O)C1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCCCC(CO)CC(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 70.1 %

Procedure:
To a solution of aniline (0.36 mL, 4.0 mmol) in toluene (10 mL) was added trimethylaluminum in toluene (2M, 2.5 mL, 5 mmol). After 20 min, a solution of (+/−)-4-butyldihydrofuran-2-one (0.4 g, 4 mmol) in toluene (1 mL) was added and the reaction mixture was refluxed for 3 h. The reaction was cooled to 0° C. and carefully quenched with 1 M HCl (15 mL), and then extracted with dichloromethane (3×15 mL). The combined extractions were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, ethyl acetate/hexanes 3:2) to afford 3-hydroxymethylheptanoic acid phenylamide as a white solid (0.66 g, 70%). MS(ES) m/e 236 [M+H]+.
Reaction SMILES: CC(C)[O-].[Li+:5].[CH:6](=[N:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[OH:9]>C(#N)C>[C:15]1([N:14]=[CH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[O-:9])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1.[Li+:5]
Reactant: Oc1ccccc1C=Nc1ccccc1
Agent: CC(C)[O-]
Agent: [Li+]
Solvent: CC#N
Product: [O-]c1ccccc1C=Nc1ccccc1
Reaction time: 8 h
Yield: 459.2 %

Procedure:
Lithium isopropoxide (300 mL, 20.7 g, 66.03 mmol) was added slowly to a solution of N-salicylideneaniline (61.83 g, 66.03 mmol) in dried acetonitrile (200 mL) under nitrogen atmosphere. A pale yellow precipitate was formed and was left stirring overnight. It was filtered off, washed thoroughly with acetonitrile and dried in vacuum oven for 8 hours at 80° C. Giving 61.6 g of product (97% yield). Sublimation (260° C., 10−6 Torr.) yielded an analytical sample (25.1 g from 29.2 g).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[N:25]([CH2:26][CH2:27][C:28]#[N:29])[N:24]=[N:23][N:22]=2)[CH:16]=1)[C:10]#[N:11])=O)(C)(C)C>C(O)=O>[NH2:8][C@H:9]([CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[N:25]([CH2:26][CH2:27][C:28]#[N:29])[N:24]=[N:23][N:22]=2)[CH:16]=1)[C:10]#[N:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](C#N)COCc1cccc(-c2nnnn2CCC#N)c1
Solvent: O=CO
Product: N#CCCn1nnnc1-c1cccc(COC[C@@H](N)C#N)c1

Procedure:
A solution of (S)-2-t-butoxycarbonylamino-3-{3-[1-(2-cyanoethyl)-5-tetrazolyl]-benzyloxy}-propionitrile (3.49 g, 8.8 mmol) in formic acid (22 mL) is stirred at room temp. for 6 h., after which time the formic acid is evaporated at 25° C. The residue is then dissolved in water (50 mL), basified with sat'd aqueous NaHCO3, and extracted with ethyl acetate (3×150 mL). The combined organic layers are then washed with water (50 mL), brine (50 mL), dried (MgSO4) and evaporated to yield (S)-2-amino-3-{3-[1-(2-cyanoethyl)-5-tetrazolyl]-benzyloxy}-propionitrile, as a light yellow oil, which is utilized without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:14]3[N:15]=[C:16]([Cl:26])[CH:17]=[C:18]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:13]3=[N:12][C:11]=2[CH3:27])=[O:9])=[C:4]([F:28])[CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[N:14]3[N:15]=[C:16]([Cl:26])[CH:17]=[C:18]([CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[C:13]3=[N:12][C:11]=2[CH3:27])[OH:9])=[C:4]([F:28])[CH:3]=1
Reactant: Cc1nc2c(CN3CCOCC3)cc(Cl)nn2c1C(=O)c1ccc(Cl)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc2c(CN3CCOCC3)cc(Cl)nn2c1C(O)c1ccc(Cl)cc1F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 94.1 %

Procedure:
Combine (4-chloro-2-fluorophenyl)(6-chloro-2-methyl-8-(morpholinomethyl)imidazo[1,2-b]pyridazin-3-yl)methanone (0.43 g, 1.0 mmol) and methanol (15 mL) in a round bottom flask. Place under nitrogen and cool to 0° C. Add sodium borohydride (58 mg, 1.5 equiv.) in one portion. Stir for 5 min at this temperature then remove cooling bath and let warm to RT. After 15 min, quench the reaction with water then extract with EA. Wash the organics with water followed by aqueous saturated sodium chloride. Dry the organics over anhydrous magnesium sulfate. Filter and concentrate in vacuo to give the title compound (0.4 g, 93%). LCMS (4 min)=425.0, 427.0, M+1.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[C:7]1[N:11]2[CH:12]=[C:13]([O:16][C@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@@H:20]([NH2:27])[CH2:19][CH2:18]3)[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1.ClC(Cl)(Cl)C[O:31][C:32](=O)[NH:33][C:34]1[N:35]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[N:36]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:39]([C:37]1[CH:38]=[C:34]([NH:33][C:32]([NH:27][C@@H:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([C@H:3]5[CH2:4][CH2:5][CH2:6][N:2]5[CH3:1])=[N:8][N:9]=4)[CH:12]=3)[CH2:18][CH2:19]2)=[O:31])[N:35]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[N:36]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CN1CCC[C@@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@H]5CCCN5C)n4c3)c3ccccc32)cc1

Procedure:
A solution of Intermediate 60b (123 mg, 0.339 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 140 mg, 0.346 mmol) in 1,4-dioxane (4 mL) and DIPEA (91 μL, 0.52 mmol) was stirred at 93° C. for 3.25 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-20% MeOH in DCM, to give the impure product. Further purification by HPLC (C18 X-select column, 25-70% MeCN in H2O, 0.1% formic acid) gave the title compound as a white powder after freeze-drying (118 mg, 56%). LCMS (Method 5): Rt 3.67 min, m/z 619.2 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.80-2.27 (11H, m), 2.31-2.40 (4H, m), 3.11-3.18 (1H, m), 3.98 (1H, t, J 8.2), 4.78-4.86 (1H, m), 5.42 (1H, t, J 4.3), 6.32 (1H, s), 7.09 (1H, d, J 8.5), 7.26-7.42 (9H, m), 7.75 (1H, dd, J 9.7, 1.0), 8.03 (1H, s), 8.28 (1H, d, J 1.0).
Reaction SMILES: Cl.C1([C@@H]([NH:10][C@@H:11]([CH3:24])[CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:16]=[CH:17][CH:18]=2)C)C=CC=CC=1.C([O-])=O.[NH4+]>CCO.[OH-].[Pd+2].[OH-]>[CH3:23][O:22][C:20](=[O:21])[CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][C@@H:11]([NH2:10])[CH3:24])[CH:14]=1
Reactant: COC(=O)Cc1cccc(C[C@H](C)N[C@@H](C)c2ccccc2)c1
Agent: [Pd+2]
Agent: Cl
Agent: O=C[O-]
Solvent: CCO
Product: COC(=O)Cc1cccc(C[C@H](C)N)c1
Yield: 58.6 %

Procedure:
A stirred solution of methyl {3-[(S)-2-((S)-1-phenylethylamino)propyl]-phenyl}acetate hydrochloride salt (1.12 g, 3.60 mmol), ammonium formate (1.16 g, 257 mmol), and palladium hydroxide (0.30 g, 2.1 mmol) in EtOH (40 mL) was heated at 75° C. for 1 h. The reaction mixture was filtered through Celite and the filter cake was washed with EtOAc (2×50 mL). The filtrate was concentrated under reduced pressure and the residue was dissolved in DCM (50 mL) and 20% aqueous ammonia solution (50 mL). The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (437 mg, 58% yield) as a colorless oil.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[NH:10][C:9](=[O:11])[C:8]2([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[N:7]=1)(=[O:3])[CH3:2].C(Cl)Cl.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[O:11]=[C:9]1[C:8]2([CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[N:7]=[C:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])[NH:10]1.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]
Reactant: CC(=O)NCC1=NC2(CCN(C(=O)OC(C)(C)C)CC2)C(=O)N1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)NCC1=NC2(CCNCC2)C(=O)N1
Reaction time: 0.5 h

Procedure:
For deprotection, 2A (1.0 equivalent) was dissolved in CH2Cl2 at 0° C., and slowly treated with a 1.6:1 solution of CH2Cl2/TFA (2:1 final ratio, 0.15 M). The reaction was completed in 30 minutes at 0° C. as determined by LCMS analysis. The volatiles were removed under reduced pressure to yield N-((4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-2-yl)methyl)acetamide (2B) as TFA salts which were used without further purification. ESI-MS: m/z 225.1 (M+H)+.