Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH2:9]Br)=[CH:7][N:6]=[C:5]([Cl:11])[CH:4]=1.[CH3:12][Si:13]([CH3:29])([CH3:28])[CH2:14][CH2:15][O:16][CH2:17][N:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH2:20][C:19]1=[O:27].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:11][C:5]1[N:6]=[CH:7][C:8]2[CH2:9][C:20]3([CH2:2][C:3]=2[CH:4]=1)[C:21]1[C:22](=[N:23][CH:24]=[CH:25][CH:26]=1)[N:18]([CH2:17][O:16][CH2:15][CH2:14][Si:13]([CH3:28])([CH3:12])[CH3:29])[C:19]3=[O:27]
Reactant: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Reactant: Clc1cc(CBr)c(CBr)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCN1C(=O)C2(Cc3cnc(Cl)cc3C2)c2cccnc21
Reaction time: 21 h

Procedure:
To a solution of 4,5-bis(bromomethyl)-2-chloropyridine from Step D (254 mg, 0.85 mmol) and 1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (226 mg, 0.86 mmol, described in Intermediate 4) in DMF (8 mL) was added cesium carbonate (455 mg, 1.40 mmol). After 21 h, the reaction mixture was poured into H2O (60 mL) and extracted with EtOAc (2×60 mL). The organic layer was washed with brine (40 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=402 (M+1).
Reaction SMILES: COC[O:4][CH2:5][C@@H:6]1[CH2:10][N:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:19][CH2:18][C:17](=[O:20])[NH:16][C:15]=3[CH:21]=2)[C:8](=[O:22])[CH2:7]1.O1CCCC1.Cl.ClCCl>CO>[OH:4][CH2:5][C@@H:6]1[CH2:10][N:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:19][CH2:18][C:17](=[O:20])[NH:16][C:15]=3[CH:21]=2)[C:8](=[O:22])[CH2:7]1
Reactant: COCOC[C@H]1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: O=C1COc2ccc(N3C[C@@H](CO)CC3=O)cc2N1
Temperature: 60 °C
Reaction time: 18 h
Yield: 89.4 %

Procedure:
To a solution of 6-{(4S)-4-[(methoxymethoxy)methyl]-2-oxopyrrolidin-1-yl}-2H-1,4-benzoxazin-3(4H)-one (1.49 g, 4.86 mmol) in methanol (10 ml)/tetrahydrofuran (10 ml) was added 4N Hydrochloric acid (2 ml) at room temperature and the mixture was heated to 60° C. and stirred for 18 hours. The reaction solution was poured into a mixture of dichloromethane and a saturated sodium hydrogen carbonate aqueous solution and the resultant was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. A mixed solvent of dichloromethane/methanol (10:1) was added to the obtained solid to prepare a slurry and the solid was collected by filtration to yield 1.14 g (90%) of the title compound in the form of a light yellow solid.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]#[CH:14])(OC(C)(C)C)=O.[CH2:15]([O:17][C:18]([C:20]1[C:24]([CH3:25])=[C:23](/[CH:26]=[C:27]2\[C:28](=[O:38])[NH:29][C:30]3[C:35]\2=[C:34](I)[C:33]([F:37])=[CH:32][CH:31]=3)[NH:22][CH:21]=1)=[O:19])[CH3:16]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH2:15]([O:17][C:18]([C:20]1[C:24]([CH3:25])=[C:23](/[CH:26]=[C:27]2\[C:28](=[O:38])[NH:29][C:30]3[C:35]\2=[C:34]([C:14]#[C:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[C:33]([F:37])=[CH:32][CH:31]=3)[NH:22][CH:21]=1)=[O:19])[CH3:16]
Reactant: CCOC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1C
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(C#C[C@@H]4CCCN4)c32)c1C
Reaction time: 2 h

Procedure:
Using Method C above, (S)-N-Boc-2-Ethynyl-pyrrolidine (106 mg, 0.55 mmol) (Example 87B) was coupled with (Z)-5-(5-fluoro-4-iodo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (80 mg, 0.18 mmol) (Example 116B) using (Ph3P)4Pd (21 mg, 0.02 mmol) and a catalylic amount of CuI in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated and the residue was chromatographed on a silica gel column with a 0-40% EtOAc in hexanes gradient. The resulting intermediate was dissolved in 5 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.5 mL of H2O at 0° C. and stirred for 2 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with ammonium hydroxide. The organic layer was dried over Na2SO4 and concentrated. (S)-(Z)-5-[[5-Fluoro-2-oxo-4-[(pyrrolidin-2-yl)ethynyl]-1,2-dihydro-indol-3-ylidene]methyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester was obtained after silica gel column chromatography with a 0-100% EtOAc in hexanes-30% THF in EtOAc gradient and precipitation out of THF with excess of hexanes. (Yield 21 mg, 28%).
Reaction SMILES: [N:1]([C:4]1[C:13]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[C:5]=1[F:30])=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][C:4]1[C:13]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[C:5]=1[F:30]
Reactant: COC(=O)c1cc(SCc2ccccc2)c(N=[N+]=[N-])c(F)c1Nc1ccccc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(SCc2ccccc2)c(N)c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 100.4 %

Procedure:
To a solution of methyl 4-azido-5-(benzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate (10.38 g, 24.36 mmol) in MeOH (100 mL) was added and 10% palladium on carbon (1.55 g) under nitrogen atmosphere. Then the nitrogen atmosphere was completely changed to hydrogen atmosphere. The mixture was stirred for 6 h at ambient temperature. After the insoluble matter was filtered off, the solvent was evaporated in vacuo to give the desired product (9.79 g, 100% yield). 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 7.69 (s, 1H), 7.19-7.17 (m, 3H), 7.15-6.83 (m, 6H), 4.54 (s, 2H), 3.79 (s, 2H), 3.75 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:6]([CH2:18]O)=[CH:5]2.O=S(Cl)[Cl:22]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:6]([CH2:18][Cl:22])=[CH:5]2
Reactant: O=S(Cl)Cl
Reactant: CS(=O)(=O)CCn1c(CO)cc2cc(Cl)cc(F)c21
Solvent: ClCCl
Product: CS(=O)(=O)CCn1c(CCl)cc2cc(Cl)cc(F)c21

Procedure:
A solution of {5-chloro-7-fluoro-1-[2-(methylsulfonyl)ethyl]-1H-indol-2-yl}methanol (130 mg, 0.43 mmol) in 40 mL of DCM was stirred with SOCl2 (254 mg, 2.13 mmol) at RT and the reaction was monitored by LC/MS. After all starting materials were consumed, the mixture was concentrated in vacuo to afford the crude 5-chloro-2-(chloromethyl)-7-fluoro-1-[2-(methylsulfonyl)ethyl]-1H-indole, which was used for next step directly.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.Cl[Si:10]([CH2:13][Cl:14])([CH3:12])[CH3:11].C([Li])CCC>O1CCCC1.CCCCCC.CCOCC.[Cl-].[Li+]>[Cl:14][CH2:13][Si:10]([C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1)([CH3:12])[CH3:11]
Reactant: Clc1ccc(Br)cc1
Reactant: C[Si](C)(Cl)CCl
Agent: [Cl-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(CCl)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 54.7 %

Procedure:
A solution of 9.6 g (0.050 mol) of 4-bromochlorobenzene and 6.6 ml (7.2 g, 0.050 mol) of chlorochloromethyldimethylsilane in 75 ml of tetrahydrofuran was stirred at -78° under nitrogen while 31 ml (0.050 mol) of 1.6 molar n-butyllithium in hexane was added dropwise. The resulting clear solution was allowed to warm to room temperature, diluted with ether until no more lithium chloride precipitated, and filtered. Evaporation of the filtrate left 10.6 g of a light yellow liquid, which was distilled to give 6.0 g (55%) of the title compound as a colorless liquid: bp 54°-58° C. (0.05 mm); ir (neat) 2910, 1560, 1470, 1370, 1250, 1080, 1010, 840, 805, 790, 740 cm-1 ; nmr (CDCl3) 0.4 (6H, s), 2.9 (2H, s), 7.1-7.6 (4H, q).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:15][C:16]1[C:17]([C:21]2[N:22]([CH2:38][CH3:39])[C:23]3[C:28]([C:29]4[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=4)[CH:32]=O)=[CH:27][N:26]=[CH:25][C:24]=3[N:37]=2)=[N:18][O:19][N:20]=1>>[NH2:15][C:16]1[C:17]([C:21]2[N:22]([CH2:38][CH3:39])[C:23]3[C:28]([C:29]4[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=4)[CH2:32][NH:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:27][N:26]=[CH:25][C:24]=3[N:37]=2)=[N:18][O:19][N:20]=1
Reactant: CCn1c(-c2nonc2N)nc2cncc(-c3cccc(C=O)c3)c21
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: CCn1c(-c2nonc2N)nc2cncc(-c3cccc(CNC4CCNCC4)c3)c21

Procedure:
The title compound was prepared from 4-amino-piperidine-1-carboxylic acid tert-butyl ester and the product of Example 153 Step 1 using the method of Example 149, followed by the method described in Example 21. MS (ES+) m/e 419 [M+H]+.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]#[N:13])[C:8]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[C:27]1([CH2:33][C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)(Cl)Cl>[CH:1]1([N:6]2[C:10]([NH:11][C:34]([CH2:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:35])=[C:9]([C:12]#[N:13])[C:8]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: N#Cc1c(Cc2ccccc2)nn(C2CCCC2)c1N
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: N#Cc1c(Cc2ccccc2)nn(C2CCCC2)c1NC(=O)Cc1ccccc1
Reaction time: 3 h
Yield: 33.3 %

Procedure:
To a stirred solution of 1-cyclopentyl-3-phenylmethyl-5-amino-1H-pyrazole-4-carbonitrile (2.3 g, 8.6 mmol), CHCl3 (50 ml) and pyridine (20 ml) in an ice bath was added a solution of phenylacetyl chloride (2.3 ml, 17.2 mmol) in CHCl3 (10 ml) over a period of 20 minutes. The reaction mixture was stirred in an ice bath for 3 hours, then at room temperature for 2 hours. The solvent was removed in vacuo, the residue was partitioned between CHCl3 (100 ml) and water (50 ml) , and the organic layer was separated. Concentration of the organic layer afforded a gummy solid which was recrystallized from isopropanol to afford 1.1 g (88%) of 1-cyclopentyl-3-phenylmethyl-4-cyano-5-(phenylmethylcarbonylamino)-1H-pyrazole, as white needles, m.p. 166-168° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([Cl:11])[N:3]=1.[H-].[Na+].I[CH:15]([CH3:17])[CH3:16].O>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:15]([CH3:17])[CH3:16])=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To 2,6-dichloro-9H-purine (a) (998 g, 5.28 mol) dissolved in anhydrous DMF (5.0 L) was added sodium hydride (60% dispersion, 254 g, 6.35 mol) with stirring at 10° C. over 1 hr. 2-iodopropane (1595 g) was added and the mixture was stirred at rt for 24 hr. Water (5.0 L) was added, and the resulting solid precipitate was collected and washed with water (500 ml) and heptane (2×2.5 L). The crude solid was crystallized from isopropyl acetate (2.1 L) to provide the title compound as a solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH:11]([CH3:17])[C:12]([O:14]CC)=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.Cl>[OH-].[Na+]>[CH:1]1[C:10]2[C:5](=[C:6]([CH:11]([CH3:17])[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CCOC(=O)C(C)c1cccc2cnccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)O)c1cccc2cnccc12
Temperature: 25 °C

Procedure:
Ethyl 2-(5-isoquinolinyl)propanoate (1.00 g, 4.36 mmol) was heated at 85° C. in NaOH (25%, 20 mL) for 1 hour. The mixture was allowed to cool to room temperature, acidified to around pH 1 with HCl, and concentrated to a dry residue. The solid was extracted with CHCl3:isopropyl alcohol (3:1, 50 mL×4). The extracts were combined, filtered, and the filtrate concentrated under reduced pressure to provide the title compound. MS (ESI+) m/z 202 (M+H)+; MS (ESI−) m/z 200 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.42 (d, J 7.1, 3H), 4.01 (q, J 7.1, 1H), 7.58 (t, J 8.1, 1H), 7.63 (d, J 7.5, 1H), 7.86 (d, J 8.1, 1H), 8.19 (d, J 6.8, 1H), 8.43 (d, J 6.8, 1H), 9.22 (s, 1H); Anal. Calcd for C12H10NO2Na+0.9H2O: C, 60.20; H, 4.97; N, 5.85. Found: C, 60.45; H, 5.26; N, 5.46.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:31]=[CH:32]/[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39](=[O:47])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C@@:22]([OH:30])([CH2:26][CH2:27][O:28][CH3:29])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16]C)=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[Li+].[OH-]>CO>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:31]=[CH:32]/[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39](=[O:47])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C@@:22]([OH:30])([CH2:26][CH2:27][O:28][CH3:29])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCOC)C(=O)O)C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCOC)C(=O)O)C(=O)O)cc1
Temperature: 25 °C
Yield: 48.8 %

Procedure:
To a mixture of No. 5233427, (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-2-(2-methoxy-ethyl)-12-oxo-nonadec-4-enoic acid (30 mg, 0.042 mmol) and methanol (4.0 mL) was added an aqueous solution (400 μL) of 2 M LiOH, and the mixture was stirred at room temperature. After confirming the consumption of the starting materials by LCMS, 1 M hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine and dried over anhydrous sodium sulfate. The filtrate was then concentrated under reduced pressure. The resulting residue was purified by preparative HPLC and then freeze-dried to obtain the title compound (13.2 mg, 49%, white solid).
Reaction SMILES: [CH:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([CH:16]=1)[C@@H]1O[C@H](CO)[C@@H](O)C1)=[O:2]>COS(C)(=O)=O.[O-2].[O-2].[Mn+4]>[CH:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[NH:7][CH:16]=1)=[O:2]
Reactant: O=Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: [Mn+4]
Agent: COS(C)(=O)=O
Agent: [O-2]
Product: O=Cc1c[nH]c(=O)[nH]c1=O

Procedure:
5-formyl-2′-deoxyuridine prepared according to Mertes and Shipchandler, J. Heterocyclic Chem. 1, 751 (1970). 5-hydroxymethyluricil (1 mmol) dissolved in 20 ml dimethylsulfonate was heated at 100° C. with manganese dioxide (2.5 mmol) for 15 minutes. The solvent was evaporated at reduced pressure. The residue was taken up in hot ethanol and recrystallized from ethanol to yield 5-formyluracil, 5-formyluracil (0.10 g) was silylated and dissolved in dry acetonitrile (2.5 ml). 2-deoxy-3,5-di-0-p-toluyl-D-ribofuranosyl chloride (Bhat, Syn. Proc. in Nucleic Acid Chem., Vol. 1, p. 521 (1968) (0.22 g) and molecular sieves (0.2 g) were added, and the mixture stirred at 25° C. for 40 hours under anhydrous conditions. The mixture was filtered and evaporated. The resulting oil was treated with anhydrous ethanol (2 ml) and chromatographed on silica gel to obtain the partially pure anomer which was recrystallized from ethanol (M.P. 195°–196° C.) The toluyl groups were removed by reaction of the product in methanol benzene with sodium methoxide. The mixture was neutralized with Dowex 50 (H+). 5-formyl-2′-deoxyuridine was recrystallized from ethanol M.P. 175°–176° C.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Br[C:11]1[C:16]([Br:17])=[N:15][CH:14]=[CH:13][N:12]=1>C1COCC1>[Br:17][C:16]1[CH:11]=[N:12][C:13]([N:7]2[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5][CH2:6]2)=[CH:14][N:15]=1
Reactant: CN1CCNCC1
Reactant: Brc1nccnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(c2cnc(Br)cn2)CC1

Procedure:
To sodium hydride (0.20 g) taken in dry THF (15 ml), N-methyl piperazine (0.93 ml) was added under nitrogen at 0° C. 2,3-Dibromopyrazine (2 g) taken in 15 ml dry THF was added to the above mixture at 0° C. The reaction mixture was allowed to reflux for overnight and quenched with water (5 ml). The organic layer was removed under vacuum. The resulting crude mass was purified by column chromatography to afford 2-bromo-5-(4-methylpiperazin-1-yl)pyrazine as pure product.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[C:3]([O:5][CH3:6])=[O:4].[F:16][C:17]([F:28])([F:27])[C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=O.CCN(C(C)C)C(C)C.C([BH3-])#N.[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl.CO.C(OCC)(=O)C.Cl[Ti](Cl)(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[C@@H:2]([NH:1][CH:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:17]([F:16])([F:28])[F:27])[CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: COC(=O)[C@@H](N)CCSc1ccccn1
Reactant: O=C(c1ccc(F)cc1)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCSc1ccccn1)NC(c1ccc(F)cc1)C(F)(F)F
Reaction time: 0.75 h

Procedure:
Methyl 2(S)-amino-4-(pyridin-2-ylsulfanyl)butyrate (0.610 g, 2.33 mmol), 2,2,2,4′-tetrafluoroacetophenone (0.393 g, 2.05 mmol), and DIPEA (1.24 g, 9.63 mmol) were combined in CH2Cl2 (10 mL). TiCl4 (1.90 mmol in CH2Cl2) was added dropwise over a 5 min period. The resulting dark solution was stirred for 3 h at which time sodium cyanoborohydride (6.35 mmol) in methanol (5 mL) was added in one portion, and the brown solution stirred for an additional 45 min. The reaction mixture was diluted with ethyl acetate, poured onto a bed of MgSO4 and filtered. Concentration and purification by flash chromatography (50% ethyl acetate/hexanes) afforded 4-(pyridin-2-ylsulfanyl)-2(S)-[2,2,2-trifluoro-1-(4-fluorophenyl)ethylamino]-butyric acid methyl ester as a mixture of diastereomers.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24](O)=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2].[N:35]1(C(N2C=CN=C2)=O)C=CN=[CH:36]1.CN>CN(C=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([NH:35][CH3:36])=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)O)ccn34)c12
Agent: CN
Solvent: CN(C)C=O
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)NC)ccn34)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
To 3-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl) imidazo[1,2-a]pyridine-7-carboxylic acid (26 mg, 0.057 mmol; prepared as in Example 28, step A) in DMF (2 mL) was added di(1H-imidazol-1-yl)methanone (14 mg, 0.086 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. Methanamine (286 μL, 0.57 mmol) was added to the reaction mixture. The reaction vial was sealed and the mixture was heated at 70° C. for 2 hours. The mixture was cooled to ambient temperature. The DMF was removed under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH 10:1) to provide the final product (13 mg). MS (ES+APCI) m/z=468 (M+H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[C@@H:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].ClC(OCC(C)C)=O.C(N(CC)CC)C.[C:40]([NH:43][CH2:44]CO)(=[O:42])[CH3:41]>O1CCCC1.C(OCC)(=O)C>[C:40]([NH:43][CH2:44][CH2:23][O:22][C:20]([C:5]1[C@H:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]([C:8]([OH:10])=[O:9])=[C:2]([CH3:1])[NH:3][C:4]=1[CH3:24])=[O:21])(=[O:42])[CH3:41]
Reactant: CC(=O)NCCO
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)[C@@H]1c1cccc([N+](=O)[O-])c1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)NCCOC(=O)C1=C(C)NC(C)=C(C(=O)O)[C@H]1c1cccc([N+](=O)[O-])c1
Reaction time: 0.17 h

Procedure:
The authentic (R)-form of the title compound was prepared as follows. That is, 5 mg of (S)-(+)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-3-pyridinecarboxylic acid prepared according to the method described by Shibanuma et al. (Chem. Pharm. Bull., 28(9), 2809-2812 (1980)) was dissolved in 0.5 ml of tetrahydrofuran. Then 2 μl of isobutyl chloroformate was added to the solution. After stirring for 10 minutes, 6 μl of triethylamine and 30 μl of N-acetyl-ethanolamine were added to the mixture followed by stirring for further 2 hours. After 5 ml of ethyl acetate was added to the reaction mixture, the mixture was washed with water and the resulting organic layer was dried over anhydrous sodium sulfate. The solvent was then distilled off. The residue thus obtained was purified on a preparative silica gel TLC (developing system, toluene-acetone; 1:1) to obtain 3 mg of the authentic (R)-form. The thus obtained authentic (R)-form compound showed the same residence time (14.0 minutes; moving phase 2.5% isopropanol/0.01M phosphate buffer (pH 7.1), flow rate: 0.8 ml/min) as that of the title compound obtained above on the column for optical resolution described above. With respect to the (S)-form, the residence time was 8.4 minutes under the same conditions.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O)[CH3:8]>>[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1)[CH3:8]
Reactant: CCOc1ccccc1B(O)O
Reactant: Ic1cccs1
Product: CCOc1ccccc1-c1cccs1

Procedure:
2-Iodothiophene and 2-ethoxyphenylboronic acid were treated in a manner similar to Reference Example 26-(2) to give 2-(2-ethoxyphenyl)thiophene as a pale yellow solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][NH:17][C:18]4[CH:23]=[CH:22][N:21]=[CH:20][C:19]=4[NH2:24])=[N:14][N:15]=3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:25]([O-])=O.[Na+]>CC(O)=O.O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][N:17]4[C:18]5[CH:23]=[CH:22][N:21]=[CH:20][C:19]=5[N:24]=[N:25]4)=[N:14][N:15]=3)[N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cnccc1NCc1nnc2ccc(-c3ccccc3)nn12
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: c1ccc(-c2ccc3nnc(Cn4nnc5cnccc54)n3n2)cc1
Reaction time: 1 h

Procedure:
To a solution of N4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)pyridine-3,4-diamine (0.0640 g, 0.202 mmol) in HOAc (5 mL) was added sodium nitrite (0.0153 g, 0.222 mmol) in water (2 mL). Stirred for 1 h. Concentrated. Took up in DMSO and purified on RPHPLC. Took fractions containing product and made basic with 91 sodium carbonate and removed volatiles in vacuo. Product crashed out and was isolated by filtration. MS m/z=329.2[M+1]+. Calc'd for C17H12N8: 328.3.