Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[C:26]3[N:25]=[C:23]([NH2:24])[NH:22][C:20](=[O:21])[C:19]=3[N:18]=[CH:17]2)[C@H:13]([OH:27])[C@@H:12]1[OH:28])([O:4][P:5]([OH:8])([OH:7])=[O:6])(=[O:3])[OH:2].[Na].S(OC)(O[CH3:34])(=O)=O.[OH-].[Na+]>O.C(O)(=O)C>[P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[C:26]3[N:25]=[C:23]([NH2:24])[NH:22][C:20](=[O:21])[C:19]=3[N:18]([CH3:34])[CH2:17]2)[C@H:13]([OH:27])[C@@H:12]1[OH:28])([O:4][P:5]([OH:7])([OH:8])=[O:6])(=[O:2])[OH:3]
Reactant: COS(=O)(=O)OC
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CN1CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c2nc(N)[nH]c(=O)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a clean, dry 2000 mL round bottom flask equipped with a stifling bar and under a stream of argon slowly dissolve dry and finely powdered guanosine 5′-diphosphate (1), (10.0 g, 20.5 mmol), either in free acid or sodium as a counter ion form, in 200 mL water, adjusting pH to 4.0 with glacial acetic acid. Dimethyl sulfate (20 mL, 119.04 mmol) was then added over a period of one hour with constant stirring at room temperature and the reaction continued for an additional hour during which time a decrease in pH was observed but pH was kept between pH 3.8 to 4.0 by drop-wise addition of 10 mM NaOH and methylation was monitored by analytical HPLC for progress. Methylation was determined to be 98% complete within 2 hr. After 2 hr, the reaction mixture was extracted with CHCl3(3×200 mL) to remove unreacted excess dimethyl sulfate.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24].O[N:28]=[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH3:38])[NH2:30].CCN(C(C)C)C(C)C>>[CH3:38][O:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:29]1[N:28]=[C:18]([C:17]2[CH:21]=[CH:22][C:14]([N:9]3[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]3[CH3:7])=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[O:20][N:30]=1
Reactant: COc1ccccc1C(N)=NO
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1noc(-c2ccc(N3CCCCC3C)c(C(F)(F)F)c2)n1

Procedure:
Oxalyl chloride (106 μL; 1.25 mmol; 3 eq.), Intermediate 24 (120 mg; 0.42 mmol; 1 eq.), Intermediate 1 (69 mg; 0.42 mmol, 1 eq.) and DIEA (93 μL; 1.25 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 80/20) followed by precipitation from n-pentane afforded the title compound as a white solid.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15]([OH:17])=O)[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]([OH:52])([CH3:51])[CH3:50])=[CH:45][CH:44]=1>CN(C=O)C.CS(C)=O>[CH3:2][N:1]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15]([NH:42][C:43]3[CH:44]=[CH:45][C:46]([C:49]([OH:52])([CH3:50])[CH3:51])=[CH:47][CH:48]=3)=[O:17])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4]
Reactant: CC(C)(O)c1ccc(N)cc1
Reactant: Cn1c(=O)c2c(ncn2CC(=O)O)n(C)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: Cn1c(=O)c2c(ncn2CC(=O)Nc2ccc(C(C)(C)O)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a 0° C. solution of acid 101 (0.32 g, 1.34 mmol) in DMF/DMSO (1:1, 20 mL) was added HATU (0.0.76 g, 2.01 mmol). The reaction was then stirred an additional 15 min at room temperature. The solution was cooled to 0° C. and amine 135 (0.30 g, 2.01 mmol) was added. The reaction was then stirred at rt overnight. The DMF was concentrated in vacuo and water was added to the reaction. The aqueous layer was extracted with EtOAc The ethyl acetate layer was then washed again with water and the organic layer was concentrated in vacuo. The product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes and EtOAc/MeOH to yield 402 as a pure light brown semi solid (0.086 g, 17.5%). MS (APCI): m/z 372.2 [M−H]+ Anal. Calcd. For C18H21N5O4.0.35 EtOAc: C, 57.93; H, 5.96; N, 17.41; Found C, 58.36; H, 6.14; N, 16.96.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].C(NC(C)C)(C)C.[C:28]([CH2:30][CH2:31][CH2:32][CH2:33][C:34]#[CH:35])#[N:29]>CN(C)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>[C:28]([CH2:30][CH2:31][CH2:32][CH2:33][C:34]#[C:35][C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])#[N:29]
Reactant: C#CCCCCC#N
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: N#CCCCCC#Cc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 50 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
Under argon, to a solution of 2-iodoadenosine (420 mg, 1.07 mmol) and bis(triphenylphosphine)palladium dichloride (75 mg, 10 mol %) dissolved in N,N-dimethylformamide (10 mL), diisopropylamine (0.18 mL, 1.28 mmol, 1.2 eq.) and 6-cyano-1-hexyne (137 mg, 1.28 mmol, 1.2 eq.) were added, and, under ice-cooling conditions, cuprous iodide (10 mg, 5 mol %) was added thereto, followed by stirring at 50° C. for 24 hours. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by dry packed silica gel column chromatography (ethyl acetate:methanol=10:1), to thereby yield a compound of the present invention as a pale yellow powder (yield: 217 mg, percent yield: 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][CH3:19])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([NH2:16])[CH3:15])=[CH:10][CH:9]=2)[CH:7]=1.C(N(CC)CC)C.[Cl:27][C:28]1[N:32]([CH3:33])[N:31]=[C:30]([CH3:34])[C:29]=1[S:35](Cl)(=[O:37])=[O:36]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][CH3:19])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]([NH:16][S:35]([C:29]3[C:30]([CH3:34])=[N:31][N:32]([CH3:33])[C:28]=3[Cl:27])(=[O:36])=[O:37])[CH3:15])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: CCOc1ccc(Cl)cc1-c1ccc(C(C)N)cc1
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccc(Cl)cc1-c1ccc([C@@H](C)NS(=O)(=O)c2c(C)nn(C)c2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
A suspension of 5-chloro-2-ethoxyphenylboronic acid (601 mg, 3.0 mmol), palladium (II) acetate (33 mg, 0.15 mmol) and (R)-1-(4-bromophenyl)ethylamine (295 mg, 1.5 mmol) in water (4 ml) was heated for 5 min at 200° C. in a Smithcreator microwave oven. The reaction mixture was diluted with dichloromethane and purified on a Strata™ 5 g/20 ml SCX column (eluted with 2M ammonia in methanol) to give (R)-1-(5′-chloro-2′-ethoxy-biphenyl-4-yl)-ethylamine (341 mg, 1.2 mmol, 82%). To a solution of 1-(5′-chloro-2′-ethoxy-biphenyl-4-yl)-ethylamine (30 mg, 0.1 mmol) in dichloromethane (0.75 ml) was added triethylamine (36 mg, 0.35 mmol) and 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride (30 mg, 0.13 mmol) in dichloromethane (0.5 ml). The reaction mixture was then agitated at room temperature for 16 h and quenched with acetic acid (200 μl). Purification by preparatory LCMS and removal of solvent under reduced pressure gave the title compound (21 mg, 0.04 mmol, 40%): 1H NMR (400 MHz, DMSO-d6): δ 8.25 (d, 1H), 7.32-7.37 (m, 3H), 7.21-7.24 (m, 3H), 7.10 (d, 1H), 4.35 (m, 1H), 4.05 (m, 2H), 2.20 (s, 3H), 1.26-1.35 (m, 6H) ppm; MS (ESI) m/z: value [M+H]+.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[NH:25]([C:27]1[N:34]=[C:33]([CH3:35])[CH:32]=[C:31]([CH3:36])[C:28]=1[C:29]#[N:30])N>>[CH3:23][S:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:25]([C:27]4[N:34]=[C:33]([CH3:35])[CH:32]=[C:31]([CH3:36])[C:28]=4[C:29]#[N:30])[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)(=[O:22])=[O:21]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Reactant: Cc1cc(C)c(C#N)c(NN)n1
Product: Cc1cc(C)c(C#N)c(-n2nccc2-c2nn(-c3cccc(S(C)(=O)=O)c3)ccc2=O)n1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and 2-hydrazino-4,6-dimethyl-nicotinonitrile according to example 43 gave the desired product. MS: M=447.0 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[Cl:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:13]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.ClC(Cl)C>ClCCl>[Cl:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:1][C:19]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:20]
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1cnc2ccccc2c1Cl
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: O=C(Nc1cnc2ccccc2c1Cl)C1CCCCC1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, a mixture of 3-amino-4-chloroquinoline (8.00 g, 1 eq), cyclohexanecarbonyl chloride (18.2 mL, 3 eq) and anhydrous dichloroethane (150 mL) was heated at 90° C. for 23 hours. The reaction mixture was diluted with dichloromethane, washed sequentially with saturated aqueous potassium carbonate, water, and brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was triturated with hexanes to provide a solid. The solid was combined with hexanes, stirred for 30 minutes, isolated by filtration, rinsed with hexanes, and then dried to provide 11.9 g of N-(4-chloroquinolin-3-yl)cyclohexanecarboxamide.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.[H-].[Na+].CS(O[CH2:21][CH2:22][N:23]1[CH2:28][CH:27]2[CH:25]([CH:26]2[NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24]1)(=O)=O.COC1C=C2C(C=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1>ClCCl.CO>[C:12]([C:9]1[CH:10]=[CH:11][C:5]2[O:4][CH2:3][C:2](=[O:1])[N:7]([CH2:21][CH2:22][N:23]3[CH2:24][CH:25]4[CH:27]([CH:26]4[NH:29][C:30](=[O:31])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:28]3)[C:6]=2[CH:8]=1)#[N:13]
Reactant: N#Cc1ccc2c(c1)NC(=O)CO2
Reactant: CC(C)(C)OC(=O)NC1C2CN(CCOS(C)(=O)=O)CC21
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1C2CN(CCN3C(=O)COc4ccc(C#N)cc43)CC21
Yield: 74 %

Procedure:
3-Oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Intermediate 60) (231 mg, 1.5 mmol) was deprotonated with sodium hydride and alkylated with 2-{6-[(tert-butoxycarbonyl)amino]-3-azabicyclo[3.1.0]hex-3-yl}ethyl methanesulfonate (Intermediate 95) (1.55 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/methanol (20:1) gave 442 mg (94%) product as a yellow gum.
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:20][C:21]1[CH:34]=[CH:33][C:24]([C:25]([NH:27][C:28]2[S:29][CH:30]=[CH:31][N:32]=2)=[O:26])=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1>>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:18]=[CH:19][C:2]([C:22]2[CH:23]=[C:24]([C:25](=[O:26])[NH:27][C:28]3[S:29][CH:30]=[CH:31][N:32]=3)[CH:33]=[CH:34][C:21]=2[CH3:20])=[N:3][CH:4]=1
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Product: COc1cccc(CNC(=O)c2ccc(-c3cc(C(=O)Nc4nccs4)ccc3C)nc2)c1

Procedure:
N-(3-Methoxybenzyl)-6-[2-methyl-5-(thiazol-2-ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate 3) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide (Intermediate 11) using General Method B. LCMS: retention time 3.20 min, MH 459. NMR: δH [2H6]-DMSO 12.71,(1H, b), 9.31,(1H, t), 9.17,(1H, d), 8.39,(1H, dd), 8.22,(1H, s), 8.07,(1H, d), 7.83,(1H, d), 7.57,(1H, d), 7.52,(1H, d), 7.29-7.25,(2H, m), 6.94,(2H, m), 6.84,(1H, d), 4.52,(2H, d), 3.75,(3H, s), 2.45,(3H, s).
Reaction SMILES: [CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[CH2:18][CH2:19]C(NC1SC=CN=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:28]=[N+:29]=[N-:30].[Na+].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N:28]([CH2:19][CH2:18][CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16](=[O:17])[N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CCC1c2ccccc2C(=O)N1Cc1ccccc1)Nc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCC1c2ccccc2C(=O)N1Cc1ccccc1

Procedure:
The product from Example 1, Part B (2.0 g, 7.5 mmol), sodium azide (731 mg, 11.25 mmol), and K2CO3 (3.1 g, 225 mmol) were stirred in 20 mL DMF at 50° C. for 16 h. The mixture was poured into water and washed with EtOAc. The organic phase was washed with water and brine, then dried (Na2SO4), filtered and evaporated. The title compound was purified by silica gel chromatography (2.04 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[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.[Cl:65][C:66]1[CH:67]=[C:68]([CH:70]=[CH:71][C:72]=1[C:73]1[NH:77][N:76]=[N:75][N:74]=1)[NH2:69]>C(Cl)Cl>[Cl:65][C:66]1[CH:67]=[C:68]([NH:69][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]2)=[O:30])[CH:70]=[CH:71][C:72]=1[C:73]1[NH:77][N:76]=[N:75][N:74]=1
Reactant: Nc1ccc(-c2nnn[nH]2)c(Cl)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(-c3nnn[nH]3)c(Cl)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA (0.150 mL, 0.855 mmol) and 3-chloro-4-(1H-tetrazol-5-yl) aniline (made below, 67 mg, 0.34 mmol). The mixture was stirred at rt for 1.5 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a reverse phase HPLC to give a white solid. 52 mg.
Reaction SMILES: [CH:1]1[C:2]2[CH:22]=[CH:21][C:20]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH:13]=[CH:12][C:11]=3[C:3]=2[O:4][C:5]=1[C:6](OCC)=[O:7].[BH4-].[Li+].C1COCC1.Cl>O>[CH:1]1[C:2]2[CH:22]=[CH:21][C:20]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH:13]=[CH:12][C:11]=3[C:3]=2[O:4][C:5]=1[CH2:6][OH:7]
Reactant: CCOC(=O)c1cc2ccc3c4ccccc4ccc3c2o1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc2ccc3c4ccccc4ccc3c2o1
Yield: 90.3 %

Procedure:
To a RB flask equipped with magnetic stirring bar, reflux condenser, N2 inlet tube with bubbler was added ethyl phenanthro(1,2-b]furan-2-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc., 7.9 g, 27.2 mmol), lithium borohydride (Aldrich, 0.65 g, 30 mmol) and dry THF (400 mL). The mixture was stirred at reflux for 6 h and then poured into H2O (1 L). The reaction mixture was acidified with 1 N HCl and the resulting white solid was filtered, washed with additional H2O (1500 mL) then dissolved in CH2Cl2 (500 mL), dried (Na2SO4), filtered, concentrated to 200 mL and diluted to 500 mL with hexane. The resulting material was filtered, washed with hexane (100 mL) and placed in a vacuum oven overnight. A total of 6.1 g (90.1%) of phenanthro[1,2-b]furan-2-methanol, mp 125°-126° was obtained (C,H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:24])[N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23])[CH2:16][CH2:17][C:12]=3[C:11]([C:25]([F:28])([F:27])[F:26])=[N:10]2)=[CH:5][CH:4]=1.Cl.[NH2:30][OH:31].C(N(CC)CC)C>C(O)C>[OH:31][NH:30][C:22](=[NH:23])[CH2:21][CH2:20][CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][C:12]2[C:11]([C:25]([F:28])([F:26])[F:27])=[N:10][N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:13]=2[C:14]1=[O:24]
Reactant: NO
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCCCC#N)CC3)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCCCC(=N)NO)CC3)cc1
Yield: 414.8 %

Procedure:
5-[1-(4-Methoxy-phenyl)-7-oxo-3-trifluoromethyl-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-pentanenitrile (0.100 g, 0.255 mmol), hydroxylamine hydrochloride (0.027 g, 0.382 mmol), and triethylamine (0.071 mL, 0.510 mmol) were dissolved in ethanol (10 mL). The reaction was refluxed overnight, concentrated, and purified by reverse HPLC and freeze-drying to afford the title compound (0.45 g, 42%): 1H NMR (CHCl3) δ 7.61 (bs, 0.5 H), 7.38 (d, j=8.5 Hz, 2H), 6.94 (d, j=8.8 Hz, 2H), 6.72 (bs, 0.5H), 3.82 (s, 3H), 3.68 (t, j=6.4 Hz, 2H), 3.48 (s, 2H), 3.01 (t, j=6.4 Hz, 2H), 3.35 (s, 3H), 1.56 (bs, 4H) ppm; Mass Spec 426.3(M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:28](B(O)O)=[CH:27][CH:26]=[N:25]2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[C:28]([C:2]3[CH:3]=[CH:4][C:5]4[N:9]=[CH:8][N:7]([C:10]5[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=5)[C:6]=4[CH:16]=3)=[CH:27][CH:26]=[N:25]2)=[CH:22][CH:23]=1
Reactant: OB(O)c1ccnn1-c1ccc(Cl)cc1
Reactant: Brc1ccc2ncn(-c3ccncc3)c2c1
Product: Clc1ccc(-n2nccc2-c2ccc3ncn(-c4ccncc4)c3c2)cc1

Procedure:
The title compound, white solid (50 mg, 37%), MS (ISP) m/z=372.4 [(M+H)+], mp 203° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-pyridin-4-yl-1H-benzoimidazole (intermediate L) (100 mg, 365 μmol) and 1-(4-chloro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate D) (97.4 mg, 438 μmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:5]([O:7][CH3:8])=[O:6].C(O)(=O)C.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C.[O-2].[Mn+4].[O-2]>[CH:15]([N:14]1[C:12](=[O:13])[C:11]2[C:2](=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=2)[N:1]=[C:22]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:17])[CH3:16]
Reactant: COC(=O)c1ccc(C(=O)NC(C)C)c(N)c1
Reactant: O=Cc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1ccc2c(=O)n(C(C)C)c(-c3ccccc3)nc2c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-amino-4-[(isopropylamino)carbonyl]benzoate (15 mg, 0.07 mmol) in ethanol (1.5 mL) was added acetic acid (32 μL, 0.56 mmol) and benzaldehyde (19.4 μL, 0.19 mmol). The reaction mixture was heated to 110° C. and stirred overnight. The mixture was then concentrated to dryness and taken up in chloroform (1 mL). To this solution was added manganese (IV) oxide (28 mg, 0.32 mmol) and the reaction mixture was heated to 110° C. and stirred for 2 d. The reaction mixture was then filtered through Celite, rinsed with chloroform and concentrated to dryness to afford methyl 3-isopropyl-4-oxo-2-phenyl-3,4-dihydroquinazoline-7-carboxylate. LC-MS: (FA) ES+ 323.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:15]2[CH:23]=[CH:22][C:18]3=[N:19][O:20][N:21]=[C:17]3[CH:16]=2)O1.[NH2:25][C:26]1[C:31]([F:32])=[C:30](Cl)[N:29]=[C:28]([C:34]([O:36][CH3:37])=[O:35])[C:27]=1[Cl:38].C(#N)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>[NH2:25][C:26]1[C:31]([F:32])=[C:30]([C:15]2[CH:23]=[CH:22][C:18]3=[N:19][O:20][N:21]=[C:17]3[CH:16]=2)[N:29]=[C:28]([C:34]([O:36][CH3:37])=[O:35])[C:27]=1[Cl:38]
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1Cl
Reactant: CC1(C)OB(c2ccc3nonc3c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1nc(-c2ccc3nonc3c2)c(F)c(N)c1Cl
Temperature: 85 °C
Reaction time: 4 h
Yield: 57.3 %

Procedure:
Bis(triphenylphosphine)palladium(II) chloride (110 mg, 0.16 mmol) and sodium carbonate (210 mg, 2.0 mmol) were sequentially added to a stirred mixture of ˜60% 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole (900 mg, 2.2 mmol) and methyl 4-amino-3,6-dichloro-5-fluoropicolinate (480 mg, 2.0 mmol, 1.0 equiv) in a 1:1 mixture of water:acetonitrile (6.8 mL) at 23° C. The resulting brown mixture was heated to 85° C. and stirred for 4 h. The cooled reaction mixture was diluted with water (150 mL) and extracted with dichloromethane (3×80 mL). The combined organic layers were dried (magnesium sulfate), gravity filtered, and concentrated by rotary evaporation. The residue was purified by reverse phase column chromatography (5% acetonitrile to 100% acetonitrile gradient) to afford the title compound as a tan powder (370 mg, 57% yield).
Reaction SMILES: [CH3:1][CH2:2][O:3]CC.Br[C:7]([CH3:13])([CH3:12])[C:8]([O:10][CH3:11])=[O:9].C(OC(=O)C)(=O)C.Cl>[Zn].C1C=CC=CC=1>[CH3:12][C:7]([CH3:13])([C:2](=[O:3])[CH3:1])[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOCC
Reactant: COC(=O)C(C)(C)Br
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: COC(=O)C(C)(C)C(C)=O

Procedure:
To a mixture of 20.86 g of 20 mesh zinc metal, 165 ml of 120:210 by volumes ether:benzene and 0.05 g of mercuric chloride was added a few drops of a solution of 26.64 g of methyl alpha-bromoisobutyrate and 18.72 g of acetic anhydride followed by brief heating with a heat gun to initiate the reaction. The remaining solution was added slowly at reflux. After addition was complete, the mixture was refluxed for 21/2 hrs, cooled, poured over 12 ml concentrated HCl mixed with ice, and extracted with ether. The combined extract was washed with water, dried (MgSO4) and stripped to give 23.15 g of a yellow oil. Distillation yielded 15.41 g of the desired product as a colorless oil, b.p. 32° C. (1 mm Hg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C@@H:9]([OH:12])[CH2:10][OH:11].C(N(CC)CC)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.Cl>ClCCCl>[S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)([O:11][CH2:10][C@H:9]1[O:12][CH2:8]1)(=[O:28])=[O:27]
Reactant: OC[C@H](O)CCl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reaction time: 26 h
Yield: 70.3 %

Procedure:
To a suspension of 37.5 g of potassium carbonate (0.27 mol) and 250 ml of 1,2-dichloroethane, was added dropwise at 24-28° C. 20 g of (S)-3-chloro-1,2-propanediol (0.18 mol) (optical purity: 98.9% ee). After finishing the addition, the solution was stirred for 26 hours and cooled. To the reaction solution were added dropwise under stirring at 5-10° C. 20.1 g of triethylamine (0.2 mol) and 0.4 g of N,N-dimethylaminopyridine (0.0033 mol) and 34.5 g of p-toluenesulfonyl chloride (0.18 ml) in order. After finishing the addition the mixture was stirred for 3 hours and the resulting salt was dissolved by adding 150 ml of 3% hydrochloric acid. The organic layer was washed with 150 ml of 1% hydrochloric acid and 150 ml of water. The excess solvent was removed under vacuo. The chemical purity and optical purity at that time were 93.7%, 96.6% ee respectively. The residue was recrystallized from isopropyl alcohol/hexane=1/1 (V/V) to give 28.9 g of (S)-glycidyl tosylate (yield 70%). Chemical purity: 98.3%, optical purity: 97.5% ee