Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][N:5]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][N:14]=[CH:15][C:8]=2[N:7]([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[CH3:26])[N:19]([CH3:27])[CH:18]=2)[C:6]1=[O:28].[OH-].[Li+].Cl.O>O1CCOCC1>[CH3:27][N:19]1[C:20]2[C:25](=[C:24]([CH3:26])[CH:23]=[CH:22][CH:21]=2)[C:17]([CH2:16][N:7]2[C:8]3[CH:15]=[N:14][CH:13]=[CH:12][C:9]=3[C:10](=[O:11])[N:5]([CH2:4][C:3]([OH:29])=[O:2])[C:6]2=[O:28])=[CH:18]1
Reactant: COC(=O)Cn1c(=O)c2ccncc2n(Cc2cn(C)c3cccc(C)c23)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc2c1c(Cn1c(=O)n(CC(=O)O)c(=O)c3ccncc31)cn2C
Reaction time: 5 h
Yield: 66.7 %

Procedure:
To a solution of 70 mg of [1-(1,4-dimethyl-1H-indol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-pyrido[3,4-d]pyrimidin-3-yl]-acetic acid methyl ester in 1,4-dioxane (2.0 mL) is added lithium hydroxide solution (11 mg of lithium hydroxide monohydrate in 0.5 mL of water) at room temperature. The solution is stirred at the same temperature for 5 h. Then 1.0 mL of 1.0 M hydrochloric acid is added along with 50 mL of water. The mixture is extracted with ethyl acetate (3×50 mL) and the organic layers are combined, dried over magnesium sulfate and concentrated to give crude product. The crude product is rinsed with methanol (3.0 mL) and dichloromethane (5.0 mL) and the remaining light yellow solid is dried to give 45 mg (67%) of [1-(1,4-dimethyl-1H-indol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-pyrido[3,4-d]pyrimidin-3-yl]-acetic acid; LCMS (ESMS): m/z 379.16 (M+H+).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:13][C:14]1([CH3:21])[C:18]([CH3:20])([CH3:19])[O:17][BH:16][O:15]1>O1CCOCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:2]([B:16]2[O:17][C:18]([CH3:20])([CH3:19])[C:14]([CH3:21])([CH3:13])[O:15]2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC1(C)OBOC1(C)C
Reactant: COC(=O)c1c(C)cccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C)cccc1B1OC(C)(C)C(C)(C)O1
Temperature: 165 °C
Reaction time: 0.17 h
Yield: 26.2 %

Procedure:
To a degassed mixture of methyl 2-iodo-6-methylbenzoate (220 mg, 0.9 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.16 mL, 1.1 mmol), TEA (0.4 mL, 2.7 mmol) in 2 mL dioxane was added Pd(PPh3)2Cl2 (20 mg, 0.03 mmol). The mixture was stirred at 165° C. for 10 min in a microwave oven. The mixture was diluted with EtOAc, washed with sat. NH4C1, H2O and brine, dried over (Na2SO4), filtered and concentrated. The crude product was purified by HPLC to afford 65 mg (35%) of Intermediate 296.1.
Reaction SMILES: O.C([C@@](C(O)=O)(O)[C@@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.[O:28]=[C:29]([N:43]1[CH2:48][CH2:47][N:46]2[C:49]([C:52]([F:55])([F:54])[F:53])=[N:50][N:51]=[C:45]2[CH2:44]1)[CH2:30][CH:31]([NH2:42])[CH2:32][C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1[F:41]>CCO>[O:28]=[C:29]([N:43]1[CH2:48][CH2:47][N:46]2[C:49]([C:52]([F:55])([F:54])[F:53])=[N:50][N:51]=[C:45]2[CH2:44]1)[CH2:30][C@@H:31]([NH2:42])[CH2:32][C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1[F:41]
Reactant: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: O=C(O)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)O)C(=O)c1ccccc1
Solvent: O
Solvent: CCO
Product: N[C@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 62.5 °C
Reaction time: 1 h
Yield: 20.9 %

Procedure:
In a 50 mL three neck flask EtOH (5 mL) and Dibenzoyl-L-tartaric acid monohydrate (1.84 g) were taken. It was heated to 60-65° C. 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (2.0 g, % purity-93.8%) dissolved in EtOH (6 mL) was added into reaction mixture at 60-65° C. It was stirred for 1 h at 60-65° C. Solid salt was precipitated. It was gradually cooled to room temperature over a period of 2-3 h. The salt was filtered and washed with cold EtOH. An enantiomerically enriched desired Dibenzoyl-L-tartaric acid salt of mixture of (2R) and (2S)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine was obtained (Wt.-0.8 g, yield-20.9%, Purity by HPLC-99.6%, % Chiral purity by HPLC of R-isomer 78%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:13][C:14]1([F:29])[CH2:19][CH2:18][C:17]([CH2:27][NH2:28])([C:20]2[CH:21]=[N:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[F:29][C:14]1([F:13])[CH2:15][CH2:16][C:17]([CH2:27][NH:28][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:2]=2[F:1])([C:20]2[CH:21]=[N:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:18][CH2:19]1
Reactant: COc1ccc(F)c(C(=O)O)c1
Reactant: NCC1(c2ccc(F)nc2)CCC(F)(F)CC1
Product: COc1ccc(F)c(C(=O)NCC2(c3ccc(F)nc3)CCC(F)(F)CC2)c1

Procedure:
From 2-fluoro-5-methoxybenzoic acid and C-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=397.1, tR (minutes, Method D)=0.71
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.C([Li])CCC.[CH2:17]([O:24][C@@H:25]1[CH2:31][CH2:30][C@@H:29]2[C@@H:27]([O:28]2)[CH2:26]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+]>C1COCC1>[CH2:17]([O:24][C@H:25]1[CH2:26][C@H:27]([OH:28])[C@@H:29]([C:11]2[N:7]([CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[N:8]=[CH:9][CH:10]=2)[CH2:30][CH2:31]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(CO[C@@H]2CC[C@H]3O[C@H]3C2)cc1
Reactant: COCCOCn1cccn1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCn1nccc1[C@H]1CC[C@@H](OCc2ccccc2)C[C@@H]1O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 49.8 %

Procedure:
To a solution of the 1-[(2-methoxyethoxy)methyl]-1H-pyrazole (3.13 g, 20.1 mmol) prepared in Example 155a in THF (30 mL), butyl lithium (2.69 M solution in hexane; 7.46 mL, 20.1 mmol) and a boron trifluoride-diethyl ether complex (6.30 mL, 50.1 mmol) were added in that order at −78° C. The reaction solution was stirred at −78° C. for 10 minutes. Then, (1S*,3R*,6R*)-3-(benzyloxy)-7-oxabicyclo[4.1.0]heptane (J. Chem. Soc. Perkin Trans. 1 1997, 657; 3.41 g, 16.7 mmol) was added thereto, and the mixture was stirred at −78° C. for 5 hours. To the reaction solution, an aqueous sodium hydrogencarbonate solution (100 mL) was added, followed by extraction three times with ethyl acetate (100 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (ethyl acetate) to yield the title compound (3.00 g, 55%) as a mixture (3.00 g, 55%) with (1S*,2R*,4S*)-4-(benzyloxy)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35]>[I-].[K+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])[CH2:14][CH2:15]2)[OH:9])=[CH:4][CH:3]=1
Reactant: COc1ccccc1OCCCCl
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: [I-]
Agent: [K+]
Product: COc1ccccc1OCCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 66 %

Procedure:
Following the procedure of Example 1, [α,α-bis(p-fluorophenyl)]-4-piperidinemethanol and 1-chloro-3-(2-methoxyphenoxy)propane were reacted using in addition potassium iodide catalyst to give the title compound in 66% yield, (recrystallizing from isopropyl alcohol), m.p. 127°-218° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][C:3]=1[F:10].Cl.[CH2:12]([O:14][C:15](=[O:18])[CH2:16][NH2:17])[CH3:13].C(=O)([O-])O.[Na+]>>[CH2:12]([O:14][C:15]([C:16]1[NH:17][C:2]2[C:3]([F:10])=[CH:4][N:5]=[CH:6][C:7]=2[C:8]=1[NH2:9])=[O:18])[CH3:13]
Reactant: CCOC(=O)CN
Reactant: N#Cc1cncc(F)c1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1[nH]c2c(F)cncc2c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.8 %

Procedure:
A mixture of 4-chloro-5-fluoro-nicotinonitrile (3.5 g, 22.4 mmol), glycine ethyl ester hydrochloride (9.4 g, 67.1 mmol) and sodium hydrogencarbonate (11.3 g, 134.2 mmol) in IMS (60 mL) was stirred at reflux for 18 hours. The reaction was then cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was separated and washed with water and brine, dried over sodium sulphate, filtered and concentrated to give a solid which was triturated in diethyl ether. The mixture was aged at room temperature for 18 hours and the precipitate was filtered off and dried under vacuum at 60° C. to give the title compound as a beige solid (2.29 g, 46%). LCMS (method B): RT=1.50 min, M+H+=224.
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:14])[CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20].O>CS(C)=O>[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH:20][C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1nc2cc(C)ccc2nc1Cl
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CNc2nc3ccc(C)cc3nc2OC)c(OC)c1
Temperature: 60 °C
Reaction time: 45 h
Yield: 90.4 %

Procedure:
To 2-chloro-3-methoxy-6-methylquinoxaline (3.05 g, 14.6 mmol) dissolved in dimethylsulfoxide (40 ml), 2,4-dimethoxybenzylamine (9.77 g, 58.4 mmol) was added at room temperature. The mixture was stirred at 60° C. for 45 hours and then water was added thereto. The product was extracted with ethyl acetate and the organic layer was washed with water and dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (13:1) mixture and concentration gave 4.48 g of the titled compound (yield, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]([N:17]2[CH2:22][C@H:21]([CH3:23])[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:19][C@H:18]2[CH3:32])=[O:16])=[C:6]([CH2:8][CH2:9][C:10]([OH:12])=O)[CH:7]=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][S:46]([NH2:49])(=[O:48])=[O:47].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]([N:17]2[CH2:22][C@H:21]([CH3:23])[N:20]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH2:19][C@H:18]2[CH3:32])=[O:16])=[C:6]([CH2:8][CH2:9][C:10]([NH:49][S:46]([CH3:45])(=[O:48])=[O:47])=[O:12])[CH:7]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CCC(=O)O
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CCC(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.3 %

Procedure:
To a solution of 3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-propionic acid (0.20 g, 0.40 mmol) was added 4-dimethylaminopyridine (0.075 g, 0.60 mmol), (3-(dimethylamino)propyl)ethyl carbodiimide hydrochloride (0.12 g, 0.60 mmol), methanesulfonamide (0.045 g, 0.48 mmol) and triethylamine (0.12 mL, 0.84 mmol). The reaction was stirred at ambient temperature for 18 hours. The reaction mixture was then diluted with dichloromethane and washed with 10% aqueous acetic acid. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel to give the title compound (0.10 g, LRMS: 540.2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:6]=[CH:5][C:4]=1[CH:17]=[CH:18][C:19](=[O:24])[CH2:20][C:21](=[O:23])[CH3:22].[B]=O.[NH:27]1[C:31]2[CH:32]=[CH:33][C:34]([CH:36]=O)=[CH:35][C:30]=2[N:29]=[N:28]1.B(OC(C)C)(OC(C)C)OC(C)C.N1CCCCC1.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.[Cl-].[Na+].O>[NH:27]1[C:31]2[CH:32]=[CH:33][C:34](/[CH:36]=[CH:22]/[C:21](=[O:23])[CH2:20][C:19](=[O:24])/[CH:18]=[CH:17]/[C:4]3[CH:5]=[CH:6][C:7]([O:9][CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=4)=[CH:8][C:3]=3[O:2][CH3:1])=[CH:35][C:30]=2[N:29]=[N:28]1
Reactant: O=Cc1ccc2[nH]nnc2c1
Reactant: COc1cc(OCc2ccccn2)ccc1C=CC(=O)CC(C)=O
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: COc1cc(OCc2ccccn2)ccc1/C=C/C(=O)CC(=O)/C=C/c1ccc2[nH]nnc2c1
Temperature: 70 °C
Yield: 9.5 %

Procedure:
In a 20 mL reaction vessel were placed 44.3 mg (136 μmol) of 6-[2-methoxy-4-(2-pyridylmethoxy)phenyl]hex-5-ene-2,4-dione and 13.2 mg (0.190 mmol) of boron oxide and they were dissolved in 0.88 mL of ethyl acetate. To the mixture under stirring at 70° C., 20 mg (0.14 mmol) of 1H-benzotriazole-5-carboxaldehyde and 62 μL (0.27 mmol) of triisopropyl borate were sequentially added. After the mixture was stirred at the same temperature for 1 hour, a solution of 2.7 μL (27 μmol) of piperidine in ethyl acetate (0.135 mL) was added and the mixture was further stirred for 1 hour. To the reaction mixture was added a 1:1 solution (0.4 mL) of 1 N hydrochloric acid and saturated brine at room temperature and the mixture was stirred for 5 minutes to 1 hour (further, the mixture was neutralized with a saturated sodium bicarbonate aqueous solution as needed). The resulting organic phase was directly subjected to purification by silica gel column chromatography (hexane/ethyl acetate or methylene chloride/methanol) to give 5.9 mg (10% yield) of the title compound as an orange powder.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C@@H:4]1[CH2:9][CH2:8][N:7]([C@@H](C2C=CC=CC=2)C)[C@H:6]([CH3:18])[CH2:5]1>[Pd].CO>[ClH:1].[CH3:2][O:3][C@@H:4]1[CH2:9][CH2:8][NH:7][C@H:6]([CH3:18])[CH2:5]1
Reactant: CO[C@@H]1CCN([C@H](C)c2ccccc2)[C@H](C)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CO[C@@H]1CCN[C@H](C)C1
Reaction time: 1 h

Procedure:
Palladium on carbon (5%) (857 mg, 0.403 mmol) and HCl (concentrated) (734 μL, 24.3 mmol) were added to (2R,4R)-4-methoxy-2-methyl-1-((R)-1-phenylethyl)piperidine (1.88 g, 8.05 mmol) in MeOH (80 mL). Hydrogen was bubbled through the reaciton mixture for 15 min. After 1 h, the reaction mixture was filtered through Celite®. The filtrate was washed with a solution of DCM/MeOH (4:1) and concentrated in vacuo to give the title compound. 1H NMR (400 MHz, MeOD) δ ppm 3.40-3.51 (m, 2 H), 3.38 (s, 3 H), 3.19-3.28 (m, 1 H), 3.01 (td, J=13.5, 2.7 Hz, 1 H), 2.19-2.36 (m, 2 H), 1.48 (tdd, J=13.7, 10.7, 4.5 Hz, 1 H), 1.35 (d, J=6.6 Hz, 3 H), 1.25-1.33 (m, 1 H); [α]25D+15.03 (c 1.0, MeOH).
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][NH:5][CH2:4][CH:3]1[OH:7].[OH-].[Na+].[C:11](Cl)(=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl.O>[OH:7][CH:3]1[CH2:4][N:5]([C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:20])[CH2:6][C:2]1([CH3:8])[CH3:1]
Reactant: CC1(C)CNCC1O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC1(C)CN(C(=O)OCc2ccccc2)CC1O
Reaction time: 18 h
Yield: 72.9 %

Procedure:
A solution of 4,4-dimethylpyrrolidin-3-ol (2.58 g, 22.4 mmol) in dichloromethane (90 mL), was added 1N sodium hydroxide (90 mL, 90 mmol), then benzyl carbonochloridate (4.16 mL, 24.6 mmol) at rt. The mixture was vigorously stirred for 18 h. The reaction was diluted with dichloromethane and water. The organic phase was separated, dried and concentrated. The crude was purified by silica gel chromatography, eluting with 20-50% ethyl acetate in hexanes to afford benzyl 4-hydroxy-3,3-dimethylpyrrolidine-1-carboxylate (4.07 g, 73% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.52-7.28 (m, 5H), 5.14 (s, 2H), 3.97-3.80 (m, 1H), 3.74 (td, J=11.3, 5.2 Hz, 1H), 3.49 (d, J=5.5 Hz, 1H), 3.43-3.18 (m, 2H), 1.74 (br. s., 1H), 1.09 (d, J=3.3 Hz, 3H), 1.03 (d, J=4.6 Hz, 3H). MS (ES+) m/z: 250.1 (M+H); LC retention time: 2.84 min (analytical HPLC Method I).
Reaction SMILES: N[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]([NH:18][CH3:19])=[O:17])[CH:13]=[CH:14][CH:15]=2)[C:5]([C:20]#[N:21])=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:3]=1[C:28]#[N:29].[ClH:30].N([O-])=O.[Na+].[OH-].[Na+]>O>[Cl:30][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]([NH:18][CH3:19])=[O:17])[CH:13]=[CH:14][CH:15]=2)[C:5]([C:20]#[N:21])=[C:4]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:3]=1[C:28]#[N:29]
Reactant: CNC(=O)c1cccc(CSc2nc(N)c(C#N)c(-c3ccccc3)c2C#N)c1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CNC(=O)c1cccc(CSc2nc(Cl)c(C#N)c(-c3ccccc3)c2C#N)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1.72 g (4.3 mmol) of 3-{[(6-amino-3,5-dicyano-4-phenylpyridin-2-yl)sulfanyl]methyl}-N-methylbenzenecarboxamide Example 9 were dissolved in ice-cooled conc. hydrochloric acid. 0.89 g (12.89 mmol) of sodium nitrite was added, and the mixture was then stirred at 0° C. for 1 h and at RT overnight. After 1 h, a precipitate had already formed. With cooling, 100 ml of water were added to the reaction mixture, and the pH was adjusted carefully to pH 7 using conc. aqueous sodium hydroxide solution. The precipitate was filtered off.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.O[CH2:11][N:12]1[CH:17]=[C:16]([Cl:18])[CH:15]([Cl:19])[C:14](=O)[NH:13]1.C([O-])(O)=O.[Na+]>O.C(Cl)Cl>[Cl:18][C:16]1[C:15]([Cl:19])=[CH:14][NH:13][N:12]([CH2:11][Cl:3])[CH:17]=1
Reactant: O=C1NN(CO)C=C(Cl)C1Cl
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: ClCN1C=C(Cl)C(Cl)=CN1
Temperature: 0 °C

Procedure:
4,5-dichloripyridazine-3(2H)-one (60 g, 364 mmol) and distilled water 350 mL) were stirred at room temperature for 10 minutes. A formaldehyde solution (36%, 70 mL) were added and refluxed for 1.5 hours. The resulting material was cooled down to 5-10° C., and the produced precipitate was filtered, washed with cold water (0-5° C., 200 mL), and dried in the air to obtain N-hydroxymethyl-4,5-dichloropyridazine-3(2H)-one. A methylene chloride solution (50 mL) of thionyl chloride (357 mmol) and dimethyl formamide (360 mmol) was slowly added to a mixture of the N-hydroxymethyl-4,5-dichloropyridazine-3(2H)-one and methylene chloride (550 mL) and methylene chloride (550 mL) at room temperature for 30 minutes with stirring. The mixture was stirred at room temperature for 2 hours. After the mixture was cooled down to 0° C., water (200 mL) was slowly added. The solution was neutralized to pH 6.7-7.4 by using NaHCO3 saturated solution. An organic layer was separated and dried on anhydrous magnesium sulfate. The organic solution was evaporated to concentrated under reduced pressure. The residue was washed with n-hexane (100 mL) to obtain 4,5-dichloro-2-chloromethylpyridazine)-3(2H)-one (71.2 g, 92%). White crystal (diethyl ether/n-hexane=1:5, v/v). mp 69-70° C. TLC (CH2Cl2) Rf=0.65. IR (KBr) 3046, 2984, 1670, 1292, 1122, 964 cm-1; 1H NMR (CDCl3): δ 5.83 (s, 2H), 7.88 ppm (s, 1H); 13C NMR (CDCl3) δ 58.40, 134.87, 137.23, 137.34, 155.58 ppm. Elemental analysis calcd. for C5H3Cl3N2O: C, 28.13; H, 1.42; N, 13.12. Found: C, 28.10; H, 1.41; N, 13.09.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[C:16]1[CH:17]=[N:18][CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1>>[CH3:23][O:22][C:20]1[CH:21]=[C:16]([N:5]2[CH2:6][C@@H:1]3[CH2:7][C@H:4]2[CH2:3][N:2]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:17]=[N:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: COc1cncc(Br)c1
Product: COc1cncc(N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)c1

Procedure:
tert-Butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), and the product from Example 43A were coupled according to the procedure described in Example 1A to provide the title compound. MS (DCI/NH3) m/z 306 (M+H)+.
Reaction SMILES: CC1(C)[O:7][C:6](=[O:8])[C:5](=[CH:9][NH:10][C:11]2[NH:15][N:14]=[CH:13][C:12]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:4](=O)[O:3]1.C(N(CC)CC)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(O)C>C(Cl)Cl>[CH2:19]([O:18][C:16]([C:12]1[CH:13]=[N:14][N:15]2[C:4]([OH:3])=[C:5]([C:6]([OH:7])=[O:8])[CH:9]=[N:10][C:11]=12)=[O:17])[CH3:20]
Reactant: CCOC(=O)c1cn[nH]c1NC=C1C(=O)OC(C)(C)OC1=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cnn2c(O)c(C(=O)O)cnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
Ethyl 5-[(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-ylidene)methylamino]1H-pyrazole-4-carboxylate (14.9 g, 45.6 mmol) obtained in step 1 was suspended in methylene chloride (227 mL), and triethylamine (25 mL, 182 mmol) was added. Trimethylsilyl trifluoromethanesulfonate (33.2 mL, 182 mmol) was added dropwise over about 10 min under ice-cooling while maintaining the reaction inside temperature at not more than 10° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was cooled to 0° C., and ethanol (75 mL) was added dropwise over 10 min. After the completion of the dropwise addition, the mixture was stirred at room temperature for 10 hr. The precipitated crystals were collected by filtration, washed with cold ethanol (50 mL), and dried under reduced pressure at 40° C. overnight to give the title compound (10.5 g, 91%).