Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38]>CN(C)C=O.C(OCC)(=O)C>[CH2:40]([O:39][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][N:3]1[C:2](=[O:1])[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[N:5]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:4]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: O=C(CCCCCBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(CCCCCC(=O)OCc1ccccc1)CN2c1ccccc1
Temperature: 55 °C
Reaction time: 18 h
Yield: 12.4 %

Procedure:
To a solution of tert-butyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.4 g, 1.2 mmol) and potassium carbonate (0.25 g, 1.8 mmol) in N,N-dimethylformamide (5 mL), was added benzyl 6-bromohexanoate (0.34 g, 1.2 mmol). After stirring at 55° C. for 18 hours, the reaction mixture was diluted with ethyl acetate (25 mL), washed with dilute citric acid, water and brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to obtain the title compound (0.08 g, 12%); MS for C31H41N3O5 m/z 536.16 (M+H)+.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:12](=O)([O-])[O-:13].[K+].[K+]>O>[OH:13][CH2:12][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: NC(=O)c1ccccc1
Agent: C=O
Agent: [K+]
Solvent: O
Product: O=C(NCO)c1ccccc1
Temperature: 45 °C
Reaction time: 48 h

Procedure:
Benzamide (25 g, 206 mmol), formaldehyde (37% aqueous, 70 mL, 890 mmol), and potassium carbonate (700 mg, 5 mmol) were mixed in 36 mL of water. The mixture was heated at 45° C. long enough to dissolve the reagents and then cooled to room temperature. The reaction was allowed to proceed for 48 hours when 1H NMR indicated that the reaction was complete. The reaction was diluted with about 500 mL of water and crystals began to form and were allowed to continue to form for 18 hours. The crystals were collected by vacuum filtration, washed with water, and vacuum dried at 40° C. The filtrate was extracted with ethyl acetate and the organic layer was dried over sodium sulfate, filtered, and evaporated to give a white solid which was also vacuum dried at 40°C. The lots were combined for a total of 29.0 g of title compound. 93%. 1H NMR consistent with title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([NH:12][CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.Cl.C([OH:29])C>C(OCC)C>[ClH:1].[OH:29][C:2]1[C:11]2[C:6](=[C:7]([NH:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCO
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc3c(Cl)nccc23)CC1
Agent: Cl
Solvent: CCOCC
Product: Oc1nccc2c(NC3CCNCC3)cccc12
Temperature: 85 °C

Procedure:
Intermediate 84 (76.6 mg) was added with concentrated hydrochloric acid (1.5 ml) and stirred with heating at 85° C. for 7 hours. The reaction mixture was cooled to room temperature, and then the residue was added with ethanol (1 ml) and diethyl ether (2 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (55.5 mg) as white powdery solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[F:18])[C:12](Cl)=[O:13])(=[O:8])=[O:7].[C:19]1([O:25][CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[F:18][C:17]1[CH:16]=[CH:15][C:11]([C:12](=[O:13])[C:22]2[CH:23]=[CH:24][C:19]([O:25][CH3:26])=[CH:20][CH:21]=2)=[CH:10][C:9]=1[S:6]([Cl:5])(=[O:8])=[O:7]
Reactant: O=C(Cl)c1ccc(F)c(S(=O)(=O)Cl)c1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(F)c(S(=O)(=O)Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.1 %

Procedure:
To a suspension of aluminium chloride (2.1 g, 15.7 mmol) in methylene chloride (50 mL) is added 3-chlorosulfonyl-4-fluoro benzoyl chloride (10.5 mmol). The reaction mixture is stirred at room temperature for 10 minutes then anisole (1.36 g, 12.5 mmol) is added. After the mixture is stirred at room temperature for 16 h, the reaction is quenched with 6 N HCl, and extracted with methylene chloride three times. The combined organic layers are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (ethyl acetate/hexane: 1:9) followed by recrystallization (methylene chloride-hexane) provides 1.8 g (54% yield) of the title compound as a white solid. 1H NMR (CDCl3): δ 8.41 (m, 1H), 8.20 (m, 1H), 7.82 (d, J=15 Hz, 2H), 7.50 (t, 1H), 7.08 (d, J=15 Hz, 2H), 3.95 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:9]([N:11]1[CH2:15][CH2:14][C:13](=[N:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]1[CH3:25])=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:18]([O:17][N:16]=[CH:13][CH:12]1[CH2:25][CH2:14][CH2:15][N:11]1[C:9](=[O:10])[C@@H:8]([NH2:7])[CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC1C(=NOCc2ccccc2)CCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](C(=O)N1CCCC1C=NOCc1ccccc1)C1CCCCC1

Procedure:
The solution of {(S)-2-[benzyloxylimino-methyl-pyrrolidine-1-yl]-1-cyclohexyl-2-oxo-ethyl}-carbamic acid tert-butyl ester (1.76 g, 3.97 mmole) and TFA (10 ml) in dichloromethane (20 ml) is stirred for a hour. Solvent is removed under vacuum. The residue is carried to next step without further purification. M+H+=344.2
Reaction SMILES: C([N:8]1[CH2:27][CH2:26][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:16][C@@H:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH3:18])[C:10]=2[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.C(N(CC)C(C)C)(C)C>ClCCCl>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C@H:17]([NH:16][C:15]2[C:10]3[CH2:9][NH:8][CH2:27][CH2:26][C:11]=3[N:12]=[CH:13][N:14]=2)[CH3:18])=[CH:20][CH:21]=1
Reactant: C[C@@H](Nc1ncnc2c1CN(Cc1ccccc1)CC2)c1ccc(Cl)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C[C@@H](Nc1ncnc2c1CNCC2)c1ccc(Cl)cc1
Yield: 118.4 %

Procedure:
A 250 mL flask fitted with a condenser was charged with (R)-6-benzyl-N-(1-(4-chlorophenyl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (4.43 g, 11.7 mmol), 1,2-dichloroethane (50 mL), α-chloroethyl chloroformate (1.5 mL, 14 mmol) and finally N,N-diisopropylethylamine (2.4 mL, 14 mmol), and the resultant red-brown solution was placed in an oil bath at 60° C. Additional α-chloroethyl chloroformate (2.0 mL, 18.4 mmol, 1.6 eq) was added after 2.5 h. After 4 h the mixture was concentrated to a brown oil and the residue was dissolved in methanol (50 mL), and heated at reflux for 1 h. After cooling, the mixture was concentrated in vacuo, and the residue was partitioned between 4/1 ethyl acetate/CH2Cl2 (100 mL) and 0.5M aq. NaH2PO4 (100 mL). The organic layer was extracted with 1M citric acid (2×25 mL), and the combined aqueous layers were basified to pH>12 with 50% aqueous KOH (50 mL), and extracted with CH2Cl2 (250 mL, 50 mL). The combined CH2Cl2 extracts were dried (Na2SO4) and concentrated to give an orange solid foam (4.0 g), which was purified by basic alumina column (0-5% MeOH/CH2Cl2) to give a light yellow foam (1.48 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:50][C@H:51]1[C@@H:55]([OH:56])[CH2:54][N:53]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:52]1>CN(C=O)C>[C:60]([O:59][C:57]([N:53]1[CH2:54][C@H:55]([OH:56])[C@H:51]([NH:50][C:12]([C:11]2[CH:10]=[N:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[CH:16][CH:15]=2)=[O:14])[CH2:52]1)=[O:58])([CH3:63])([CH3:61])[CH3:62]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@@H](O)C1
Reactant: O=C(O)c1ccc(-c2cccc(F)c2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](O)[C@H](NC(=O)c2ccc(-c3cccc(F)c3)nc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
To a solution of 6-(3-fluorophenyl)nicotinic acid (391 mg, 1.8 mmol ) in DMF (10 mL) at 0° C. was added HATU (753 mg, 1.98 mmol) and DIPEA (0.47 mL, 2.07 mmol ). After 15 min, cis-tert-butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate was added and the reaction stirred at room temperature for 5 hrs. The solvent was removed in vacuo and the residue diluted with ethyl acetate and water. The layers were separated and the organic layer washed with brine, dried (MgSO4) and the solvent removed to give an oil, which after chromatography (silica, 65% ethyl acetate:hex) to give the desired product, cis-tert-butyl-3-({[6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)-4-hydroxypyrrolidine-1-carboxylate (420 mg, 58%). LC/MS (M+H)=401.9 observed, 402.18 expected.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH:6]1([N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)[CH2:8][CH2:7]1.[OH-].[Na+].CN([CH:19]=[O:20])C>>[CH:6]1([N:9]2[CH:13]=[CH:12][CH:11]=[C:10]2[CH:19]=[O:20])[CH2:8][CH2:7]1
Reactant: CN(C)C=O
Reactant: c1ccn(C2CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cccn1C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
POCl3 (44.5 ml) was added to a stirred solution of 1-cyclopropyl-1H-pyrrole (46.5 g) in DMF (37 ml) at 0° C., then the mixture was stirred at room temperature overnight. The mixture was poured into aqueous 5N NaOH (336 ml) at 0° C., and the mixture was made basic with an additional aqueous 5N NaOH. The mixture was extracted with CH2Cl2 and the organic extract was dried over Na2SO4, concentrated, and the residue was purified on silicagel column chromatography (hexane/EtOAc) to give intended compound as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:26]=[N:25][N:24]([CH:27]([CH3:29])[CH3:28])[C:16]=2[N:17]=[C:18]([NH:20]CC=C)[CH:19]=1)=[O:13].CS(O)(=O)=O>C(O)C.C(Cl)Cl.[Pd]>[NH2:20][C:18]1[CH:19]=[C:14]([C:12]([NH:11][CH2:10][C:3]2[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])=[O:13])[C:15]2[CH:26]=[N:25][N:24]([CH:27]([CH3:29])[CH3:28])[C:16]=2[N:17]=1
Reactant: C=CCNc1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C(C)C)c2n1
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(N)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C

Procedure:
A mixture of 10% Pd/C (0.200 g, 0.188 mmol) and N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(2-propen-1-ylamino)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.200 g, 0.507 mmol) was suspended in ethanol (10 mL) and stirred. Added next was methanesulfonic acid (0.033 mL, 0.507 mmol), and the stirring contents were heated at reflux for 2 h. After cooling to room temperature, the reaction mixture was diluted with DCM and filtered through Celite. The filter pad was washed with 10% MeOH/DCM. The filtrate was pre-adsorped onto silica gel, and the crude product purified by silica gel chromatography (dry loaded, eluent: gradient of 5-80% Dichloromethane/Chloroform containing 10% 2M Ammonia (in methanol)). The collected product was dried in vacuum oven at 45° C. overnight. The final product was collected as 0.065 g (36%). LCMS E-S (M+H)=355.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (d, J=6.82 Hz, 6 H), 2.12 (s, 3 H), 2.21 (s, 3 H), 4.31 (d, J=5.05 Hz, 2 H), 4.85-5.00 (m, 1 H), 5.89 (s, 1H), 6.49-6.68 (m, 3 H), 7.85 (s, 1 H), 8.46 (t, J=5.05 Hz, 1 H), 11.54 (br. s., 1 H).
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7][C:8]1[CH:9]=[C:10]2[C:19](=[CH:20][C:21]=1[CH3:22])[CH:18]=[CH:17][C:16]1[CH2:15][CH2:14][CH2:13][C:12](=[O:23])[C:11]2=1.[CH2:24](I)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH2:34].O>C1C=CC=CC=1>[CH3:7][C:8]1[CH:9]=[C:10]2[C:19](=[CH:20][C:21]=1[CH3:22])[CH:18]=[CH:17][C:16]1[CH2:15][CH2:14][CH:13]([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=[CH2:24])[C:12](=[O:23])[C:11]2=1.[CH3:7][C:8]1[CH:9]=[C:10]2[C:19](=[CH:20][C:21]=1[CH3:22])[CH:18]=[CH:17][C:16]1[CH2:15][CH2:14][CH2:13][C:12](=[O:23])[C:11]2=1
Reactant: C=CCCCCCCCCCI
Agent: CC(C)(C)[O-]
Agent: Cc1cc2ccc3c(c2cc1C)C(=O)CCC3
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: C=CCCCCCCCCCC1CCc2ccc3cc(C)c(C)cc3c2C1=O
Temperature: 60 °C
Yield: 39 %

Procedure:
t-BuOK (3.6 g, 0.032 mole) was dissolved in 250 ml of dry benzene at 40°-50° C. To the stirred solution was added 6,7-Dimethyl-4-oxo-1,2,3,4-tetrahydrophenanthrene (3.6 g, 0.016 mole) in 50 ml of dry benzene and then, 10-undecenyl iodide (4.58 g, 0.016 mole) at 30° C. under N2. The mixture was heated to 60° C. for 2.5 hr under N2. After cooling the reaction mixture to room temperature, water was added. The whole mixture was extracted twice with diethylether. The combined diethylether solution was dried over anhydrous MgSO4 and then concentrated. Flash column chromatography of the residue on silica gel afforded 6,7-Dimethyl-4-oxo-3-(10-undecenyl)-1,2,3,4-tetrahydrophenanthrene as a sticky brown solid (2.36 g, 0.0063 mole, 39% yield) as a desired product, and unreacted 6,7-Dimethyl-4-oxo-1,2,3,4-tetrahydrophenanthrene (1.70 g, 47% recovered). 1H NMR (CDCl3) δ 1.29-1.62 (m,14H), 1.86-2.08 (m,4H), 2.21-2.35 (m,2H), 2.40 (s,3H), 2.46 (s,3H), 2.52-2.63 (m,1H), 3.07-3.13 (m,2H), 4.90-5.04 (m,2H), 5.75-5.89 (m,1H), 7.17 (d, J=8.2 Hz,1H), 7.53 (s,1H), 7.77 (d, J=8.2 Hz,1H), 9.10 (s,1H), IR (KBr) cm-1 2920, 2850, 1669, 1600, exact (EI) mass. calcd. for C27H36O: 376.2766, Found: 376.2766.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14](Cl)=[O:15])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[O:17]1[CH2:21][CH2:20][C@H:19]([NH2:22])[CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:1][C:2]1[C:3]([C:14]([NH:22][C@H:19]2[CH2:20][CH2:21][O:17][CH2:18]2)=[O:15])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1noc(-c2ccc(Cl)cc2)c1Cl
Reactant: N[C@H]1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(N[C@H]1CCOC1)c1noc(-c2ccc(Cl)cc2)c1Cl
Reaction time: 48 h

Procedure:
A mixture of 4-chloro-5-(4-chlorophenyl)isoxazole-3-carbonyl chloride (24 mg, 0.087 mmol), (S)-tetrahydrofuran-3-amine (13 μL, 0.13 mmol), and potassium carbonate (36 mg, 0.261 mmol) in dichloromethane (1 mL) was stirred for 48 hours. The volatiles were removed in vacuo, and the residue was purified by silica gel chromatography, eluting with dichloromethane 5% methanol in dichloromethane to afford the title compound: (19.1 mg, 0.059 mmol). MS (ESI) m/z (M+H+): 327.2/329.2.
Reaction SMILES: FC1C(N2CCNCC2)=CC2NC=C3C(=O)N(C4C=CC=CC=4)N=C3C=2C=1.F[C:29]1[C:30]([F:49])=[CH:31][C:32]2[C:33]3[C:34]([C:39](=[O:48])[N:40]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:41]=3)=[CH:35][NH:36][C:37]=2[CH:38]=1.[CH3:50][CH:51]1[O:56][CH:55]([CH3:57])[CH2:54][NH:53][CH2:52]1>>[CH3:57][CH:55]1[O:56][CH:51]([CH3:50])[CH2:52][N:53]([C:29]2[C:30]([F:49])=[CH:31][C:32]3[C:33]4[C:34]([C:39](=[O:48])[N:40]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[N:41]=4)=[CH:35][NH:36][C:37]=3[CH:38]=2)[CH2:54]1
Reactant: O=c1c2c[nH]c3cc(F)c(F)cc3c-2nn1-c1ccccc1
Reactant: CC1CNCC(C)O1
Agent: O=c1c2c[nH]c3cc(N4CCNCC4)c(F)cc3c-2nn1-c1ccccc1
Product: CC1CN(c2cc3[nH]cc4c(=O)n(-c5ccccc5)nc-4c3cc2F)CC(C)O1

Procedure:
The title compound was prepared following the procedure described in the synthesis of 28a using 27a and 2,6-dimethylmorpholine. 1H-NMR (DMSO-d6) δ (ppm): 1.15 (6H, d, J=6.73 Hz), 2.40 (2H, brm), 3.41 (2H, d, J=10.99 Hz), 3.76 (2H, brm), 7.13 (1H, m), 7.26 (1H, d, J=7.69 Hz), 7.41 (2H, t, J=7.42 Hz), 7.83 (2H, d, J=12.91 Hz), 8.19 (2H, m), 8.66 (1H, s). m/z 393.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][C:12]([O:14]CC)=O.C1(C)C=CC=CC=1>C(OCC)(=O)C.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[F:8][C:7]1[C:2]2[NH:1][C:12](=[O:14])[CH2:11][CH2:10][NH:9][C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCNc1cccc(F)c1N
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1CCNc2cccc(F)c2N1
Temperature: 80 °C
Yield: 96.9 %

Procedure:
A disposable tube was charged with ethyl 3-(2-amino-3-fluorophenylamino)propanoate (800 mg, 3.54 mmol) and a stirbar. Toluene (10 mL) was added, followed by tetraisopropoxytitanium (523 μl, 1.768 mmol), and the solution was stirred at 80° C. 0.5 h. The solution was diluted with ethyl acetate, concentrated with celite, and purified by silica gel chromatography (eluting with hexanes/ethyl acetate) to yield 9-fluoro-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one as a white amorphous solid (0.618 g, 3.43 mmol, 97%).
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[H-].[Na+].[Cl:7][C:8]1[CH:13]=[N:12][CH:11]=[C:10](Cl)[N:9]=1>C1COCC1>[Cl:7][C:8]1[CH:13]=[N:12][CH:11]=[C:10]([O:4][CH:2]([CH3:3])[CH3:1])[N:9]=1
Reactant: CC(C)O
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Oc1cncc(Cl)n1
Reaction time: 0.25 h
Yield: 86.9 %

Procedure:
To a solution of 2-propanol (2.26 mL, 31.99 mmol) in dry THF (40 mL) was added 60% NaH (960 mg, 39.90 mmol) at 0° C. and the reaction was stirred for 15 min. To the mixture at 0° C. was added 2,6-dichloropyrazine (4 g, 26.66 mmol, Aldrich) and the reaction was stirred for 2 h at RT. The reaction was quenched with ice cold H2O (20 mL) and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified with silica gel column chromatography (eluent: 100% petroleum ether) to afford 2-chloro-6-isopropoxypyrazine (4.0 g, 86%) as an off brown liquid. MS (ESI, pos. ion) m/z: 173.0 (M+1); 1H NMR (400 MHz, CDCl3): δ 8.28 (s, 1H), 8.14 (s, 1H), 5.31-5.25 (m, 1H), 1.37-1.36 (m, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[N:13]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)=[C:5]([CH3:22])[N:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:3]1=[O:33].[B-](F)(F)(F)[F:35].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.Cl.C(OCC)(=O)C>C(#N)C>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[N:13]([C:14]3[CH:15]=[CH:16][C:17]([C:18]#[N:19])=[CH:20][CH:21]=3)[N:12]=[CH:11][C:10]=2[F:35])=[C:5]([CH3:22])[N:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)[C:3]1=[O:33]
Reactant: F[B-](F)(F)F
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1c(-c2c(F)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 22.9 %

Procedure:
To a solution of 4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 1) (1.0 g) in acetonitrile (20 ml) was added Selectfluor (trade mark) (1.2 g) and the resulting mixture was stirred at 80° C. for four hours. To the reaction mixture was added 10% hydrochloric acid followed by an addition of ethyl acetate (20 ml×2) such the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-fluoro-1H-pyrazol-1-yl)benzonitrile (238 mg). UPLC/MS 470 (M+H)/1.023 min. (measurement condition 9)
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([F:33])[CH:11]=1>>[F:33][C:12]1[CH:11]=[C:10]([N:7]2[C@H:3]([CH2:2][OH:1])[CH2:4][CH2:5][C:6]2=[O:8])[CH:15]=[CH:14][C:13]=1[C:16]([N:18]1[CH2:19][CH2:20][N:21]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=2)[CH2:22][CH2:23]1)=[O:17]
Reactant: O=C1CC[C@@H](CO)N1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@H]4CO)cc3F)CC2)nc1C

Procedure:
Using (S)-5-hydroxymethylpyrrolidin-2-one and (4-bromo-2-fluorophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (406 mg) described in Preparation Example 128 and by the reaction and treatment in the same manner as in Example 1, the title compound (171 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:16][C:15]3[CH2:14][C@H:13]([CH2:17][O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[NH:12][C:11](=[O:26])[C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.C1OCCOCCOCCOCCOCCOC1.C([O-])([O-])=O.[K+].[K+].[C:51]([CH2:55]OS(C(F)(F)F)(=O)=O)([F:54])([F:53])[F:52]>CN(C=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:16]([CH2:55][C:51]([F:54])([F:53])[F:52])[C:15]3[CH2:14][CH:13]([CH2:17][O:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:12][C:11](=[O:26])[C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-c2cc3c([nH]2)C[C@H](COCc2ccccc2)NC3=O)n1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nccc(-c2cc3c(n2CC(F)(F)F)CC(COCc2ccccc2)NC3=O)n1
Temperature: 50 °C
Yield: 70.6 %

Procedure:
To a stirred mixture of (R)-2-(2-amino-pyrimidin-4-yl)-6-benzyloxymethyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (73 mg, 0.21 mmol) in dry DMF (2 mL) were added 18-crown-6 ether (110.5 mg, 0.42 mmol), K2CO3 (115.5 mg, 0.84 mmol) and CF3CH2OSO2CF3 (0.21 mmol). The reaction mixture was heated at 50° C. for 7 hours, then treated with water and extracted with AcOEt. The organic phase was dried over anh. Na2SO4 and evaporated to yield a crude product that was purified by flash chromatography (eluant: DCM/MeOH 95:5) to provide 64 mg of the title product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.Cl.C(O[C:14](=N)[CH2:15][Cl:16])C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:14]([CH2:15][Cl:16])=[N:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: CCOC(=N)CCl
Agent: Cl
Product: ClCc1nc2cc(Br)ccc2[nH]1

Procedure:
Using the procedure for Step D in Example 1 (as described in J. Med. Chem., 1986, 29, 2280), the title compound was prepared from 4-bromo-benzene-1,2-diamine (200 mg, 1.07 mmol) and 2-chloroacetimidic acid ethyl ester hydrochloride salt (168 mg, 1.07 mmol) and was obtained as an off-white solid (240.3 mg, 92% yield). 1H NMR (400 MHz, CD3OD) δ (ppm): 7.75 (d, 1H, J=1.4 Hz), 7.47 (d, 1H, J=8.6 Hz), 7.74 (dd, 1H, J=8.6 Hz, J=1.3 Hz), 4.84 (s, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C18H20ClN3O2S: 247.50 (M+H), Found 247.0.