Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[S:14][CH:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=2)=O)=[C:8]([CH3:21])[C:7]([O:22][CH3:23])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1N=C(C2C=C(O)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[CH:18]([C:16]1[N:17]=[C:13]([C:11]2[CH:2]=[C:1]([OH:3])[C:4]3[C:9](=[C:8]([CH3:21])[C:7]([O:22][CH3:23])=[CH:6][CH:5]=3)[N:10]=2)[S:14][CH:15]=1)([CH3:20])[CH3:19]
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1C
Agent: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1C
Yield: 60 %

Procedure:
Compound 43b was synthesized from compound 42b as a yellow solid in 60% yield, according to the procedure as described for compound 43a.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][OH:20])[O:13]2)=[C:5]([NH:21][CH2:22][CH:23]2[C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:29]3[C:24]2=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:4]=1.[CH:36]([N:39]([CH:50]([CH3:52])[CH3:51])[CH2:40][CH2:41][NH:42][C:43](N1C=CN=C1)=[O:44])([CH3:38])[CH3:37]>>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][OH:20])[O:13][C@H:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([CH2:2][NH:1][C:43]([NH:42][CH2:41][CH2:40][N:39]([CH:50]([CH3:52])[CH3:51])[CH:36]([CH3:37])[CH3:38])=[O:44])=[N:4][C:5]=2[NH:21][CH2:22][CH:23]1[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2
Reactant: CC(C)N(CCNC(=O)n1ccnc1)C(C)C
Reactant: NCc1nc(NCC2c3ccccc3-c3ccccc32)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Product: CC(C)N(CCNC(=O)NCc1nc(NCC2c3ccccc3-c3ccccc32)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)C(C)C

Procedure:
The title compound was prepared from (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(9H-fluoren-9-ylmethyl)amino]-9H-purin-9-yl}-5-(hydroxymethyl)tetrahydro-3,4-furandiol (Preparation 13) and N-[2-(diisopropylamino)ethyl]-1H-imidazole-1-carboxamide (Preparation 27) in a similar procedure to Example 3.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH2:5][C@@:6]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4].Cl[C:38]1[N:43]=[N:42][C:41]([C:44]([O:46]C)=O)=[CH:40][CH:39]=1.[CH:48]1([NH2:51])[CH2:50][CH2:49]1>>[C:3]([C:2]([CH3:36])([CH3:1])[CH2:5][C@@:6]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18]([C:38]3[N:43]=[N:42][C:41]([C:44]([NH:51][CH:48]4[CH2:50][CH2:49]4)=[O:46])=[CH:40][CH:39]=3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)#[N:4]
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(Cl)nn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(C(=O)NC3CC3)nn2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrile and methyl 6-chloropyridazine-3-carboxylate following procedures analogous to those described in Example 8 using cyclopropylamine in Step 2. LC-MS Method 2 tR=1.17 min, m/z=524.3; 1H NMR (CDCl3) 0.71 (m, 2H), 0.94 (m, 2H), 1.34 (s, 3H), 1.48 (s, 3H), 1.59 (m, 3H), 2.18 (m, 2H), 2.36 (m, 1H), 2.53 (m, 2H), 2.94 (m, 1H), 3.02 (m, 1H), 5.72 (m, 1H), 7.03 (m, 2H), 7.39 (m, 5H), 7.84 (m, 2H), 7.93 (m, 1H), 7.25 (m, 1H), 8.34 (m, 1H)
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][C@H:6]([CH2:8][OH:9])[CH:5]=[CH:4]1.C(N(CC)CC)C.[C:17](Cl)(=[O:21])[CH2:18][CH2:19][CH3:20].O>C(Cl)Cl>[C:17]([NH:2][C@@H:3]1[CH2:7][C@H:6]([CH2:8][OH:9])[CH:5]=[CH:4]1)(=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: N[C@H]1C=C[C@@H](CO)C1
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCC(=O)N[C@H]1C=C[C@@H](CO)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
34.7 g of (1R,4S)-1-amino-4-hydroxymethyl-2-cyclopentene hydrochloride and 2 g of 4-N,N-dimethylaminopyridine were dissolved in 600 ml of methylene chloride. The solution was cooled to 0° C. Then 52 g of triethylamine were added dropwise (5 min). The mixture was stirred for a further 30 min. A solution of 35.2 g of butyryl chloride in 60 ml of methylene chloride was metered into the mixture at 0° C. over the course of 1 h. The mixture was stirred for a further 1.5 h at between 0 and 20° C., and then 600 ml of water were added. After phase separation, the aqueous phase was extracted with 600 ml of methylene chloride. The combined organic phases were washed 3 times with 500 ml of 10% strength KaOU each time, and then completely evaporated. The dried solid was dissolved in 120 ml of methanol. The solution was mixed with 5 g of K2CO3 and stirred for a further 2 h at room temperature. The inorganic salts were filtered off and washed with 20 ml of methanol. The filtrate was neutralized with 2N HCl. The suspension was filtered and the filter cake was washed with 20 ml of methanol. The filtrate was completely evaporated. The solid residue was dried and crystallized in 150 ml of toluene. 28.5 g of title compound were obtained. The yield was 67%.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[O:29][CH3:30])/[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O-:25])=[O:24])=[C:15]([C@@H:18]4[CH2:22][CH2:21][CH2:20][O:19]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].Br[CH2:33]/[C:34](=[CH:40]\[CH3:41])/[C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN1CCCC1=O.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[O:29][CH3:30])/[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O:25][CH2:33]/[C:34](/[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:40]/[CH3:41])=[O:24])=[C:15]([C@@H:18]4[CH2:22][CH2:21][CH2:20][O:19]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C/C=C(\CBr)C(=O)OCC
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C([C@@H]3CCCO3)CS[C@H]12)c1csc(N)n1
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C/C=C(/COC(=O)C1=C([C@@H]2CCCO2)CS[C@@H]2[C@H](NC(=O)/C(=N\OC)c3csc(N)n3)C(=O)N12)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-[(S)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate, (0.35 g) in 1-methyl-2-pyrrolidinone (4 ml) was treated with a solution of ethyl (Z)-2-bromomethylbut-2-enoate, (0.16 g) in 1-methyl-2-pyrrolidinone (1 ml) and stirred at ambient temperature overnight. The solution was diluted with ethyl acetate and washed with water (3×), brine and then dried. After removal of solvent in vacuo, the residue was purified by flash chromatography on silica gel, eluting with 70, 90% ethyl acetate-hexane and then ethyl acetate. The title compound was obtained as a pale yellow foam (0.368 g, 86%); νmax (CH2Cl2) 3480, 3389, 3320, 1781, 1726, 1682, 1606 and 1532 cm -1 ; δH (CDCl3) 1.30 (4H, t, J 7.1 Hz, overlapping M), 1.66 (1H, m), 1.97 (3H, d, J 7.3 Hz), 2.35 (1H, m), 3.33 and 3.64 (2H, ABq, J 18.7 Hz), 3.88 (2H, m), 4.08 (3H, s), 4.22 (2H, q, J 7.1 Hz), 4.93 (1H, m), 5.05 (3H, m), 5.80 (2H, br s, exch.), 5.99 (1H, dd, J 4.8, 9.0 Hz, collapses to d, J 4.8 Hz on exch.), 6.83 (1H, s), 7.21 (1H, q, J 7.3 Hz) and 7.73 (1H, d, J 9.0 Hz, exch.). [Mass spectrum: +ve ion (thioglycerol) MH+ (580)].
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]([CH3:27])([CH3:26])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:24])([CH3:23])[C:18]([O:20]CC)=[O:19])C.[OH-].[K+]>C(O)C.O>[CH3:23][C:17]([CH3:24])([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11](=[O:25])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:27])([CH3:26])[C:4]([OH:28])=[O:3])[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)C(C)(C)CCCCCC(=O)CCCCCC(C)(C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(CCCCCC(=O)CCCCCC(C)(C)C(=O)O)C(=O)O
Yield: 56.8 %

Procedure:
According to the procedure given for 210f, 209g (8.54 g, 21.4 mmol) was saponified with KOH (85%, 4.53 g, 68.6 mmol) in ethanol (13 mL) and water (5 mL) at reflux for 4 h. The solid product obtained after usual workup was recrystallized from Et2O/hexanes (50 mL/50 mL), affording 210g (4.16 g, 57%) as colorless needles. Mp 82-83° C. 1H NMR (CDCl3): δ 11.53 (br., 2H), 2.39 (t, 4H, J=7.3), 1.60-1.50 (m, 8H), 1.30-1.20 (m, 8H), 1.18 (s, 12H). 13C NMR (CDCl3): δ 211.7, 185.0, 42.8, 42.3, 40.4, 29.7, 25.1, 24.8, 23.8. HRMS (LSIMS, gly): Calcd for C19H35O5 (MH+): 343.2484, found: 343.2444. HPLC: 92.6% pure. Anal. (C19H34O5) C, H.
Reaction SMILES: CNC(C1SC=C(C)C=1NC1C(Cl)=CN=C(NC2C=CC3CNCC(=O)N(CC)C=3C=2)N=1)=O.[CH3:34][NH:35][C:36]([C:38]1[S:39][CH:40]=[C:41](C)[C:42]=1[NH:43][C:44]1[C:49]([Cl:50])=[CH:48][N:47]=[C:46]([NH:51][C:52]2[CH:53]=[CH:54][C:55]3[CH2:61][N:60]([CH2:62][CH3:63])[CH2:59][C:58](=[O:64])[N:57]([CH2:65][CH3:66])[C:56]=3[CH:67]=2)[N:45]=1)=[O:37]>>[CH3:34][NH:35][C:36]([C:38]1[S:39][CH:40]=[CH:41][C:42]=1[NH:43][C:44]1[C:49]([Cl:50])=[CH:48][N:47]=[C:46]([NH:51][C:52]2[CH:53]=[CH:54][C:55]3[CH2:61][N:60]([CH2:62][CH3:63])[CH2:59][C:58](=[O:64])[N:57]([CH2:65][CH3:66])[C:56]=3[CH:67]=2)[N:45]=1)=[O:37]
Reactant: CCN1CC(=O)N(CC)c2cc(Nc3ncc(Cl)c(Nc4c(C)csc4C(=O)NC)n3)ccc2C1
Agent: CCN1C(=O)CNCc2ccc(Nc3ncc(Cl)c(Nc4c(C)csc4C(=O)NC)n3)cc21
Product: CCN1CC(=O)N(CC)c2cc(Nc3ncc(Cl)c(Nc4ccsc4C(=O)NC)n3)ccc2C1

Procedure:
Following a procedure analogous to Example 1856b, 3-[5-chloro-2-(1-ethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-4-methyl-thiophene-2-carboxylic acid methylamide was converted to 3-[5-chloro-2-(1,4-diethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-4-methyl-thiophene-2-carboxylicacid methylamide: 1H NMR (300 MHz, CD3OD) δ 8.12 (s, 1H), 7.62 (s, 1H), 7.3 (dd, 1H), 7.24 (s, 1H), 7.17 (d, 1H), 3.78 (q, 2H), 3.63 (s, 2H), 3.19 (s, 2H), 2.85 (s, 3H), 2.76 (q, 2H), 2.05 (s, 3H), 1.21 (t, 3H), 1.07 (t, 3H); MS (m/e): 514.5 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:46][C:47]1[CH:52]=[CH:51][C:50]([Br:53])=[CH:49][N:48]=1.N1C=CC=CC=1>C(Cl)Cl.O>[Br:53][C:50]1[CH:51]=[CH:52][C:47]([NH:46][C:35](=[O:37])[C@@H:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[CH2:33][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)=[N:48][CH:49]=1
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc(Br)cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccc(Br)cn1)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 96.5 %

Procedure:
A solution of triphenylphosphine (411 mg, 1.57 mmol) in methylene chloride (15 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (316 mg, 1.78 mmol). The reaction mixture was stirred at 0° C. until it was completely dissolved and became light purple in color. The reaction mixture was then treated with 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionic acid (prepared as in Example 54A, 300 mg, 1.05 mmol). The reaction mixture was stirred at 0° C. for 20 min and then warmed to 25° C. where it was stirred for 30 min. After such time, the reaction mixture was treated with 2-amino-5-bromopyridine (271 mg, 1.57 mmol) and pyridine (0.15 mL, 1.88 mmol). The resulting reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (10 mL) and extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 90/10 hexanes/ethyl acetate) afforded N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionamide (448 mg, 97%) as a white solid: mp 107.3–109.9° C.; [α]23589=−66.7° (c=0.084, chloroform); EI-HRMS m/e calcd for Cl9H19BrCl2N2O (M+) 440.0058, found 440.0056.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[CH:25]([C:27]1[CH:32]=[CH:31]C(B(O)O)=[CH:29][CH:28]=1)=[O:26].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:12]3[CH2:17][CH2:16][CH:15]([N:18]4[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:1]3[CH:31]=[CH:32][C:27]([CH:25]=[O:26])=[CH:28][CH:29]=3)[C:10]=12
Reactant: Cc1nn([C@H]2CC[C@@H](N3CCN(C)CC3)CC2)c2ncnc(N)c12
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN1CCN(C2CCC(n3nc(-c4ccc(C=O)cc4)c4c(N)ncnc43)CC2)CC1
Yield: 54.3 %

Procedure:
cis-3-Methyl-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3.0 g, 6.80 mmol), 4-formylphenylboronic acid (1.22 g, 8.16 mmol), palladium tetrakistriphenyphosphine (0.47 g, 0.41 mmol) and sodium carbonate (1.73 g, 16.31 mmol) were mixed with ethylene glycol dimethyl ether (70 mL) and water (35 mL). The reaction mixture was heated at reflux overnight under nitrogen. Organic solvent was removed under reduced pressure and the aqueous layer was filtered and washed with water. After drying on the lyophilizer, the residue was purified by flash column chromatography using dichloromethane/methanol (90:10 to 70:30) as mobile phase to give 4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}benzaldehyde (1.55 g, 54%). 1H NMR (DMSO-d6) δ 1.60 (m, 2H), 1.72 (m, 2H). 2.07 (m, 2H), 2.15 (s, 3H), 2.22-2.46 (m, 1H), 4.83 (m, 1H), 7.88 (d, J=8.13 Hz, 2H), 8.07 (d, J=8.10 Hz, 2H), 8.21 (s, 1H), 10.11 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+=420.2, Rt=0.70 min.
Reaction SMILES: C(O[C:4]1[C:5]([NH:11][C@@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][C:23]([F:26])([F:25])[F:24])[CH:20]=3)[O:15][C:14]([CH3:28])([CH3:27])[C@H:13]2[OH:29])=[N:6][S:7](=[O:10])(=[O:9])[N:8]=1)C.[CH3:30][NH:31][CH3:32]>>[CH3:28][C:14]1([CH3:27])[C@@H:13]([OH:29])[C@H:12]([NH:11][C:5]2[C:4]([N:31]([CH3:32])[CH3:30])=[N:8][S:7](=[O:10])(=[O:9])[N:6]=2)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][C:23]([F:24])([F:25])[F:26])[CH:20]=2)[O:15]1
Reactant: CNC
Reactant: CCOC1=NS(=O)(=O)N=C1N[C@@H]1c2cc(OC(F)(F)F)ccc2OC(C)(C)[C@H]1O
Product: CN(C)C1=NS(=O)(=O)N=C1N[C@@H]1c2cc(OC(F)(F)F)ccc2OC(C)(C)[C@H]1O

Procedure:
In a method similar to Example 3, the product of Example 1, Step 2 (0.250 g, 0.572) was converted to the title compound with dimethylamine gas to give, after recrystallization from diethyl ether/hexane, 0.19 g (76%) of product as a white solid: mp 135°-140° C.; 1H NMR (DMSO-D6): δ 8.09 (br s, 1H), 7.23 (br s, 1H), 7.10 (d, 1H), 6.82 (d, 1H), 5.84 (br s, 1H), 4.77 (m, 1H), 3.75 (m, 1H), 3.35 (s, 3H), 2.53 (s, 3H), 1.38 (s, 3H), 1.19 (s, 3H); IR (KBr): 3400, 1600 cm-1 ; MS (m/z) 437 (MH+, 100%), 419 (65), 245 (35) 177 (70); [α]D25 = -85.4 (THF).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27](O)=[O:28])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:31]=[C:32]([NH2:37])[CH2:33][CH2:34][O:35][CH3:36]>>[CH3:36][O:35][CH2:34][CH2:33][C:32]1[N:37]=[C:27]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]3)=[O:10])[CH2:12]2)[O:28][N:31]=1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Reactant: COCCC(N)=NO
Product: COCCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCC(C#N)CC3)C2)n1
Yield: 23.3 %

Procedure:
250 mg (0.611 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 100A) and 106 mg (0.672 mmol, 75% pure) of N′-hydroxy-3-methoxypropanimidamide (Example 64A) were reacted according to the General Method 1. Enantiomer separation of the racemate according to Method 16D gave 77.0 mg of the title compound from Example 277 and 70.0 mg of the title compound from Example 278 (47% of theory).
Reaction SMILES: [CH2:1]([OH:7])[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([O:7][CH2:1][CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1)(=[O:18])=[O:17]
Reactant: OCC1CCCO1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCCO1
Temperature: 0 °C
Reaction time: 14 h
Yield: 91.8 %

Procedure:
Tetrahydrofurfuryl alcohol (2.01 g, 19.7 mmol, 1.0 eq.) was dissolved in dichloromethane (100 mL) under an argon atmosphere, cooled to 0° C. and treated sequentially with triethylamine (3.02 mL, 21.7 mmol, 1.1 eq) and methanesulfonyl chloride (1.60 mL, 20.7 mmol, 1.05 eq.). The ice bath was removed and stirring continued for 14 h before the mixture was poured into a separatory funnel containing water. The phases were separated and the organic layer was washed with water (4×), dried on MgSO4, filtered and concentrated in vacuo to yield 3.26 g [92%] of tetrahydrofurfuryl methanesulfonate as a crude pale yellow oil, used in the subsequent displacement step without purification.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][N:22]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][N:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][N:22]=2)[CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Reactant: N#Cc1ccc(Cl)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC1(NC(=O)OCc2ccccc2)CCN(c2ccc(C#N)cn2)CC1
Yield: 73.3 %

Procedure:
A solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester hydrochloride salt (198 mg, 0.697 mmol), 2-chloro-5-cyanopyridine (90 mg, 0.65 mmol) and diisopropylethylamine (400 μL) in dioxane (2 mL) in a sealed tube was heated to 170° C. under microwave conditions for 20 minutes. The reaction mixture was cooled, concentrated and then purified by chromatography (silica gel, eluting with 10% hexane/ethyl acetate to 60% ethyl acetate/hexane) to provide the titled compound (167 mg) as a white foam. MS (CI) m/z 380 (M+1)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.45 (s, 1H), 7.80 (dd, 1H), 7.37 (m, 5H), 7.18 (s, 1H), 6.93 (d, 1H), 5.00 (s, 2H), 4.00-3.95 (m, 2H), 3.35-3.26 (m, 2H), 2.19-2.07 (m, 2H), 1.49-1.43 (m, 2H), 1.27 (s, 3H).
Reaction SMILES: C[Al](C)C.[CH3:5][CH:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:20]=[CH:19][C:18]([C:21]([O:23]C)=O)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[CH3:7].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH2:35][CH2:36][C:37]2[CH:38]=[C:39]([NH2:42])[NH:40][N:41]=2)[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1>C1(C)C=CC=CC=1>[CH3:34][O:33][C:31]1[CH:30]=[C:29]([CH2:35][CH2:36][C:37]2[CH:38]=[C:39]([NH:42][C:21]([C:18]3[CH:19]=[N:20][C:15]([N:11]4[CH2:12][CH2:13][CH2:14][N:8]([CH:6]([CH3:5])[CH3:7])[CH2:9][CH2:10]4)=[N:16][CH:17]=3)=[O:23])[NH:40][N:41]=2)[CH:28]=[C:27]([O:26][CH3:25])[CH:32]=1
Reactant: COC(=O)c1cnc(N2CCCN(C(C)C)CC2)nc1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCCN(C(C)C)CC4)nc3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 17.3 %

Procedure:
Trimethylaluminium (1.19 ml, 2.38 mmol) was added dropwise to a stirred suspension of methyl 2-(4-propan-2-yl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate (265 mg, 0.95 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (235 mg, 0.95 mmol) in toluene (4.76 ml) at 25° C. The resulting solution was stirred at 60° C. for 18 h. The cooled reaction mixture was quenched into methanol (50 mL) and treated with HCl (2M aqueous solution, to pH7 or lower) and purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure product. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (81 mg, 17%) as a cream solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Br:16])=[N:7][N:8]([CH:13]([CH3:15])[CH3:14])[C:9]2=[O:12])=[CH:4][CH:3]=1.[Cl:17][CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>CN(C=O)C>[Br:16][C:6]1[C:5]2[C:10](=[CH:11][C:2]([NH:1][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][Cl:17])=[CH:3][CH:4]=2)[C:9](=[O:12])[N:8]([CH:13]([CH3:14])[CH3:15])[N:7]=1
Reactant: CC(C)n1nc(Br)c2ccc(N)cc2c1=O
Reactant: O=C(Cl)CCCCl
Solvent: CN(C)C=O
Product: CC(C)n1nc(Br)c2ccc(NC(=O)CCCCl)cc2c1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.1 %

Procedure:
To a solution of 7-amino-2-isopropyl-4-bromo-2H-phthalazin-1-one (0.5 g, 1.8 mmol) in DMF (8 ml), was added TEA (0.28 ml, 1.98 mmol). After 5 min, 4-chlorobutyryl chloride (0.22 ml, 2.0 mmol) was added and the solution was stirred at RT for 2 hours. After this time LC-MS indicated the complete consumption of starting material and the mixture was diluted with DCM (30 ml) and washed with HCl (1M, 20 ml). The organic layer was separated, dried (MgSO4) and concentrated under vacuum. The residue was subjected to flash column chromatography (elution: 60% heptane, 40% EtOAc) to give N-(1-bromo-3-isopropyl-4-oxo-3,4-dihydro-phthalazin-6-yl)-4-chloro-butyramide (0.46 g, 67% yield) as a white solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[NH2:21][C:22]1[S:23][CH:24]=[C:25]([CH:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:31]([F:41])[CH:30]=2)[CH3:28])[N:26]=1.[CH3:42][N:43]=[C:44]=[S:45]>O1CCCC1>[CH3:42][NH:43][C:44]([NH:21][C:22]1[S:23][CH:24]=[C:25]([CH:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[C:31]([F:41])[CH:30]=2)[CH3:28])[N:26]=1)=[S:45]
Reactant: CN=C=S
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(N)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CNC(=S)Nc1nc(C(C)c2ccc(-c3ccccc3)c(F)c2)cs1
Reaction time: 0.33 h
Yield: 37.3 %

Procedure:
To lithium diisopropylamide in tetrahydrofuran prepared with diisopropylamine (0.187 g, 1.85 mmol) and n-butyllithium (1.9 mmol) was added 2-amino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (0.50 g, 1.68 mmol) in tetrahydrofuran at -70° C. After the mixture was stirred for 20 min, methylisothiocyanate (0.131 g, 1.8 mmol) in tetrahydrofuran was added to the mixture. After the mixture was stirred at room temperature for 3.5 h, the mixture was evaporated under reduced pressure to a residue, which was extracted with chloroform. The extracts were washed with water, dried over, and evaporated under reduced pressure to a residue, which was chromatographed and recrystallized to afford N-methyl-N'-(4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazol-2-yl)thiourea (0.233 g, 35% yield) as crystalline material: mp 180.5°-181.0° C.