Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([CH3:39])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([CH3:39])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(COc2nn(Cc3ccccc3)cc2C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 70.4 %

Procedure:
To a mixture of ethyl 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methylbenzyl)oxy]-1H-pyrazole-4-carboxylate (0.15 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was heated under reflux for 1 hr. The reaction mixture was neutralized by adding 1N hydrochloric acid and water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methylbenzyl)oxy]-1H-pyrazole-4-carboxylic acid as crystals (0.10 g, yield 71%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 176-177° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1Cl)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][Cl:16])[N:14]=1)=[O:8].Cl.ClCC1N=C(N)SC=1.[F:30]C1C=C(C=CC=1)CN=C=O>>[Cl:16][CH2:15][C:13]1[N:14]=[C:10]([NH:9][C:7]([NH:6][CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[C:2]([F:30])[CH:3]=2)=[O:8])[S:11][CH:12]=1
Reactant: O=C=NCc1cccc(F)c1
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CCl)cs1
Agent: Cl
Agent: Nc1nc(CCl)cs1
Product: O=C(NCc1cccc(F)c1)Nc1nc(CCl)cs1

Procedure:
Prepared by same procedure described for Intermediate 2 with 4-(chloromethyl)thiazol-2-amine hydrochloride and 3-fluorobenzyl isocyanate. 1H-NMR (ppm, DMSO-d6): 10.70 (bs, 1H), 7.36 (dd, 1H), 7.07 (m, 4H), 4.63 (s, 2H), 4.34 (d, 2H).
Reaction SMILES: [O-]CC.[Na+].[Na].[NH:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH:11]1([CH2:16]Br)[CH2:15][CH2:14][CH2:13][CH2:12]1>C(O)C>[CH:11]1([CH2:16][N:6]2[CH:10]=[CH:9][N:8]=[CH:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: BrCC1CCCC1
Reactant: c1c[nH]cn1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: c1cn(CC2CCCC2)cn1

Procedure:
A solution of sodium ethoxide was made by dissolving sodium (2.3 g, 0.1 mole) in absolute ethanol (100 ml). Imidazole (6.8 g, 0.1 mole) was then added. The mixture was heated under reflux and cyclopentylmethylbromide (16.3 g, 0.1 mole) was added dropwise. The reaction mixture was allowed to reflux for a further 16 hours after addition. The mixture was then left to cool.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]([C@@H:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][N:13]1[C:22](=[O:35])[C@@H:23]([NH:27]C(=O)OC(C)(C)C)[CH:24]([CH3:26])[CH3:25])=[O:11].[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C(Cl)Cl>[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[NH2:27][C@@H:23]([CH:24]([CH3:26])[CH3:25])[C:22]([N:13]1[C@H:12]([C:10]([NH:9][C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[O:11])[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)=[O:35]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1Cc2ccccc2C[C@H]1C(=O)Nc1c(F)cccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](N)C(=O)N1Cc2ccccc2C[C@H]1C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (S)-1-((S)-3-(2,6-difluorophenylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-1-oxobutan-2-ylcarbamate (0.11 g, 226 μmol, Eq: 1.00) in DCM (2 mL) was added TFA (2.96 g, 2 mL, 26.0 mmol, Eq: 115) and the resulting solution was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo and the residue azeotroped with n-heptanes to give (S)-2-((S)-2-amino-3-methylbutanoyl)-N-(2,6-difluorophenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide trifluoroacetate which was used without purification (0.11 g).
Reaction SMILES: [NH2:1][C@@H:2]1[C:16](=[O:17])[N:15]2[CH2:18][C@H:19]([O:21][C:22]3[C:31]([C:32]4[S:33][C:34]5[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=5[N:36]=4)=[N:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH2:20][C@H:14]2[C:13](=[O:41])[NH:12][C@:11]2([C:43]([NH:45][S:46]([CH:49]3[CH2:51][CH2:50]3)(=[O:48])=[O:47])=[O:44])[CH2:42][C@H:10]2[CH2:9][C:8]([F:53])([F:52])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.C(N(C(C)C)CC)(C)C.[CH3:64][C:65]1[O:69][N:68]=[C:67]([C:70](O)=[O:71])[CH:66]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[S:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=[C:32]1[C:31]1[C:22]([O:21][C@H:19]2[CH2:18][N:15]3[C:16](=[O:17])[C@@H:2]([NH:1][C:70]([C:67]4[CH:66]=[C:65]([CH3:64])[O:69][N:68]=4)=[O:71])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([F:52])([F:53])[CH2:9][C@@H:10]4[CH2:42][C@@:11]4([C:43](=[O:44])[NH:45][S:46]([CH:49]4[CH2:51][CH2:50]4)(=[O:48])=[O:47])[NH:12][C:13](=[O:41])[C@@H:14]3[CH2:20]2)=[N:23][C:24]2[C:29]([N:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: N[C@H]1CCCCCC(F)(F)C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccccc4nc3-c3nc4ccccc4s3)CN2C1=O
Reactant: Cc1cc(C(=O)O)no1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N[C@H]2CCCCCC(F)(F)C[C@@H]3C[C@@]3(C(=O)NS(=O)(=O)C3CC3)NC(=O)[C@@H]3C[C@@H](Oc4nc5ccccc5nc4-c4nc5ccccc5s4)CN3C2=O)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To (2R,6S,13aS,14aR,16aS)-6-amino-2-(3-(benzo [d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-12,12-difluoro-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide, Hydrochloric Acid (Example 14a, 16.1 mg, 0.020 mmol) was added DMF (200 μl) and diisopropylethylamine (25 μl, 0.14 mmol). To the yellow solution was added 5-methylisoxazole-3-carboxylic acid (3.85 mg, 0.030 mmol) followed by HATU (13.89 mg, 0.037 mmol). The reaction mixture was stirred at rt 2 h, cooled to 0° C. and neutralized with HCl (4 N in dioxane, 36 μl, diluted with EA). The solution was concentrated under reduced pressure and purified by prep-TLC (dichloromethane/EA=1/1, 2×) to provide the title compound N-((2R,6S,13aS,14aR,16aS)-2-(3-(benzo [d]thiazol-2-yl)quinoxalin-2- yloxy)-14a-(cyclopropylsulfonylcarbamoy1)-12,12-difluoro-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)-5-methylisoxazole-3-carboxamide (14.3 mg, 81% yield). MS (ESI): m/z=877.1 [M+H], 875.2 [M−H]. Example 14 provided an IC50 of between 0.1 and 0.5 nM in a 1a enzyme assay; an IC50 of between 0.1 and 0.5 nM in a 1b enzyme assay; a HLM stability value of <50 μl/min/mg; an EC50 of between 2.0 and 5.0 nM in a replicon cell line assay in a 1a-H77 background, and an EC50 of between 1.0 and 2.0 nM in a replicon cell line assay in a 1-con1 background.
Reaction SMILES: ClCl.[CH3:3][C:4]1[CH:12]=[C:11](Cl)[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]>B(O[O-])=O.[Na+]>[CH3:3][C:4]1[CH:12]=[C:11]([S:14]([CH3:10])(=[O:16])=[O:15])[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Cc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)O
Agent: ClCl
Agent: O=BO[O-]
Agent: [Na+]
Product: Cc1cc(S(C)(=O)=O)c(S(C)(=O)=O)cc1C(=O)O

Procedure:
in stage c) the chlorine substituent is converted into a second methylsulfonyl group by reacting 2-methyl-4-chloro-5-methylsulfonylbenzoic acid with sodium methylthiolate and then oxidizing the thioether with an oxidizing agent, in particular sodium perborate, to give the corresponding intermediate 2-methyl-4,5-di(methylsulfonyl)benzoic acid,
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:6]2[C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([NH:18][C:19]([C@H:21]([NH:24]C(=O)OC(C)(C)C)[CH2:22][CH3:23])=[O:20])=[CH:14][N:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:24][C@H:21]([CH2:22][CH3:23])[C:19]([NH:18][C:15]1[CH:14]=[N:13][C:12]([O:11][C:7]2[C:6]3[C:2]([CH3:1])([CH3:32])[CH2:3][O:4][C:5]=3[CH:10]=[CH:9][CH:8]=2)=[N:17][CH:16]=1)=[O:20]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cnc(Oc2cccc3c2C(C)(C)CO3)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](N)C(=O)Nc1cnc(Oc2cccc3c2C(C)(C)CO3)nc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 88.1 %

Procedure:
To a solution of 1,1-dimethylethyl {(1R)-1-[({2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}amino)carbonyl]propyl}carbamate (Intermediate 66, 4.4 mg) in dichloromethane (1 ml) cooled to 0° C. TFA (0.019 ml, 0.249 mmol) was added dropwise. The mixture reaction was stirred at 0° C. for 1.5 hours. The solvent and the TFA were evaporated. The mixture was diluted with dichloromethane (5 ml) and neutralized with an aqueous saturated solution of NaHCO3 (5 ml). The organic layer was separated, dried over sodium sulphate, filtered end evaporated to afford the title compound (3 mg) which was directly used in the next step
Reaction SMILES: [CH:1]12[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.Br[C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[N:21][CH:22]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N+:23]([C:20]1[N:21]=[CH:22][C:17]([N:3]2[CH2:4][CH:5]3[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:1]([CH2:7][CH2:6]3)[CH2:2]2)=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc([N+](=O)[O-])nc1)C2
Temperature: 140 °C

Procedure:
tert-Butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.4 g; 1.9 mmol), prepared as described in (J. Med. Chem., (1998) 41, 674), 5-bromo-2-nitropyridine (0.43 g; 2.27 mmol), prepared as described in (J. Am. Chem. Soc., (1945) 67, 668), and triethylamine (0.23 g; 2.27 mmol) in toluene (10 mL) were heated at reflux for 14 hours. After evaporation of the solvent, additional triethylamine (0.23 g) was added and the mixture further heated at 140° C. for 2 hours. The residue was purified on SiO2 (CH2Cl2:EtOAc 9:1) to provide the title compound.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>[Pd].C(O)C>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(-c2noc(-c3ccccc3)n2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc(-c2noc(-c3ccccc3)n2)cc1
Reaction time: 1 h

Procedure:
A suspension of 5.0 g. (0.02 mole) of 5-phenyl-3-(4-nitrophenyl)-1,2,4-oxadiazole, from part (a), in 200 ml. of 95% ethanol containing 0.5 g. of 5% Pd/C and 3ml. of concentrated HCl is hydrogenated on the Parr hydrogenator at 50 psi. over a period of 1 hour. The catalyst is removed by filtration followed by removal of the ethanol by distillation in vacuo to yield the 5-phenyl-3-(4-aminophenyl)-1,2,4-oxadiazole.
Reaction SMILES: C(ON=O)CC(C)C.[I:9][C:10]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([I:21])[C:11]=1N.Cl>CN(C=O)C>[I:9][C:10]1[CH:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[C:13]([I:21])[CH:11]=1
Reactant: Nc1c(I)cc(C(F)(F)F)cc1I
Agent: CC(C)CCON=O
Agent: Cl
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(I)cc(I)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of isopentylnitrite (365 mg, 3.12 mmol) in DMF (8 mL) at 65° C. was added 2,6-diiodo-4-(trifluoromethyl)aniline (685 mg, 1.66 mmol). The reaction was stirred overnight at rt then poured into 1 N HCl (10 mL) and extracted with methylene chloride. The organic layer was dried over sodium sulfate, filtered, concentrated and the residue was purified on silica (hexanes) to afford a pink solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][CH2:11][NH2:12]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:8][CH2:9][CH2:10][CH2:11][NH2:12]
Reactant: Brc1ccccn1
Reactant: NCCCN
Product: NCCCNc1ccccn1
Yield: 44.9 %

Procedure:
2-Bromopyridine (100 g; 0.633 mol) and 1,3-diaminopropane (234.5 g; 3.16 mol) were refluxed for 7 h. After the reaction was complete, the mixture was evaporated, and distillation of the remaining residue under oil pump vacuum afforded 43 g of the required product; ESI-MS [M+H+]=152.15.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:8][CH:7]=1)(=[NH:4])[CH2:2][CH3:3].Br[CH2:23][C:24]([C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1)=O>>[C:30]([C:29]1[CH:32]=[CH:33][C:26]([C:24]2[N:4]=[C:1]([CH2:2][CH3:3])[N:5]([C:6]3[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:8][CH:7]=3)[CH:23]=2)=[CH:27][CH:28]=1)#[N:31]
Reactant: CCC(=N)Nc1ccc(CCNC(=O)OC(C)(C)C)cc1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Product: CCc1nc(-c2ccc(C#N)cc2)cn1-c1ccc(CCNC(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 4 of Example 26 from tert-butyl 2-[4-(propanimidoylamino)phenyl]ethylcarbamate and 4-(bromoacetyl)benzonitrile: MS (ESI) m/z 417 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH:16]=[CH:15][N:14]=[C:13](Cl)[N:12]=1.C(OC([N:25]1[C:30]2([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:29][CH:28]([NH2:36])[CH2:27][CH2:26]1)=O)(C)(C)C>>[NH:25]1[C:30]2([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:29][CH:28]([NH:36][C:13]2[N:12]=[C:11]([C:7]3[C:6]4[C:10](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=4)[NH:9][CH:8]=3)[CH:16]=[CH:15][N:14]=2)[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC12CCCCC2
Reactant: Fc1cccc2c(-c3ccnc(Cl)n3)c[nH]c12
Product: Fc1cccc2c(-c3ccnc(NC4CCNC5(CCCCC5)C4)n3)c[nH]c12

Procedure:
The racemic title compound was prepared as described in Example 244, starting from 7-Fluoro-3-(2-chloro-pyrimidin-4-yl)-1H-indole and 4-amino-1-aza-spiro[5.5]undecane-1-carboxylic acid tert-butyl ester from step A.
Reaction SMILES: [Na].[C:2]([NH:10]O)(=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:13][C:14]([OH:16])=[O:15].Cl>C(O)C.O>[CH2:2]([NH:10][CH2:13][C:14]([OH:16])=[O:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)CCl
Reactant: O=C(NO)c1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: O=C(O)CNCc1ccccc1
Reaction time: 3 h

Procedure:
9.2 Grams (0.4 moles) of metallic sodium was dissolved in 300 ml of absolute ethanol. To the resulting solution, a solution of 27 g (0.2 moles) of benzhydroxamic acid in 600 ml of absolute ethanol was added dropwise 20°-25° C. with stirring for 3 hours. Subsequently, a solution of 9.5 g (0.1 mole) of chloroacetic acid in 100 ml of absolute ethanol was added dropwise and the resulting mixture wa stirred at 50° C. for 8 hours. After cooling the mixture, water was added and the mixture was neutralized with concentrated HCl. Ethanol was distilled off under vacuum and the pH of the residue was adjusted to 1 by addition of concentrated HCl. The precipitating crystal was recovered by filtration and dried to obtain benzamidooxyacetic acid in an amount of 8.2 g (yield, 42 mol %).
Reaction SMILES: [NH:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5](O)[C:4]=2[N:3]=[CH:2]1.P(Cl)(Cl)([Cl:17])=O.C(=O)(O)[O-].[Na+]>>[Cl:17][C:5]1[C:4]2[N:3]=[CH:2][NH:1][C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]=1
Reactant: Oc1nc2ccccc2c2[nH]cnc12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1nc2ccccc2c2[nH]cnc12

Procedure:
A mixture of 500 mg of 1H-imidazo[4,5-c]quinolin-4-ol and about 6 mL of phosphorous oxychloride was heated on a steam bath for about 16 hours, then poured over ice. The mixture was neutralized with saturated sodium bicarbonate solution, then the solid was separated by filtration. The solid was dissolved in dilute hydrochloric acid, the mixture was filtered and the filtrate was neutralized with concentrated ammonium hydroxide to reprecipitate the product. Filtration and drying was followed by recrystallization from methanol to provide crystals of 4-chloro-1H-imidazo[4,5-c]quinoline. Analysis: Calculated for C10H6N3 : %C, 59.0; %H, 3.0; %N, 20.6; Found: %C, 59.5; %H, 3.0; %N, 20.2.
Reaction SMILES: IC1C([N+]([O-])=O)=CC(Cl)=CN=1.C1([Mg]Cl)C=CC=CC=1.[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[O:25]>>[F:20][C:21]1[CH:22]=[C:23]([CH2:24][OH:25])[CH:26]=[CH:27][CH:28]=1
Reactant: O=Cc1cccc(F)c1
Agent: Cl[Mg]c1ccccc1
Agent: O=[N+]([O-])c1cc(Cl)cnc1I
Product: OCc1cccc(F)c1
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
A freshly oven dried 250 mL round-bottom flask was charged with 2-iodo-3-nitro-5-chloro-pyridine (1.41 g, 5.0 mmol). The resultant solution was cooled to −78° C. under N2 and PhMgCl (2 M, 3 mL, 6.0 mmol) added and then stirred at the same temperature for 30 min. 3-Fluorobenzaldehyde (1.24 g, 10 mmol) was added and the resulting mixture stirred at −78° C. for two hours and then at room temperature for 24 h. The reaction was quenched with NH4Cl (sat), extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was further purified through automated normal-phase chromatography to afford 5-chloro-3-nitropyridin-2-yl)(3-fluorophenyl)methanol (560 mg, 40%) which was used directly for the next step: 1H NMR (400 MHz, CDCl3) δ 8.85 (d, 1H), 8.37 (d, 1H), 7.23 (m, 1H), 7.06 (dd, 1H), 6.95 (dd, 1H), 6.43 (d, 2H), 4.99 (d, 1H); MS (ES) (M+−OH) expect 265.0. found 265.1.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4](Cl)[N:3]=1.[CH3:12][C@H:13]1[CH2:18][O:17][CH2:16][CH2:15][NH:14]1.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][C@@H:13]2[CH3:12])[N:3]=1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Reactant: C[C@H]1COCCN1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1COCCN1c1nc(Cl)nc2[nH]cnc12
Yield: 52.6 %

Procedure:
An ethanol (5 ml) solution of 2,6-dichloro-9H-purine (187 mg, 0.99 mmol), (S)-3-methyl-morpholine (100 mg, 0.99 mmol), and N,N-diisopropylethylamine (252 μl, 1.48 mmol) was heated to reflux for 15 hours. The reaction mixture was returned to room temperature and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (methylene chloride:methanol=98:2 to 97:3) to give the title compound (132 mg, 53%) as a solid.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:26])[CH3:23].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:20][CH:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][O:8][C:5]2[CH:6]=[N:7][C:2]([C:30]3[CH:31]=[CH:32][C:27]([C:25]([O:24][CH2:22][CH3:23])=[O:26])=[CH:28][CH:29]=3)=[CH:3][CH:4]=2)[CH2:11][CH2:12]1)=[O:17])[CH3:21]
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)C)CC3)cn2)cc1

Procedure:
1-Methylethyl-4-{[(6-{4-[(ethyloxy)carbonyl]phenyl}-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate was prepared as an off-white solid from 1-methylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 81, Step 1, 0.13 g, 0.67 mmol), {4-[(ethyloxy)carbonyl]phenyl}boronic acid (0.30 g, 0.84 mmol), 2M Na2CO3 (10 mL) and Pd(PPh3)4 (0.01 g, 0.01 mmol) in DME (10 mL) in a manner similar to Example 1, Step 1. 1H NMR (400 MHz, CDCl3): δ 8.39 (d, 1H, J=2.7 Hz), 8.11 (d, 2H, J=8.6 Hz), 7.98 (d, 2H, J=8.6 Hz), 7.72 (d, 1H, J=8.8 Hz), 7.31-7.26 (m, 1H), 4.94-4.87 (m, 1H), 4.38 (q, 2H, J=7.1 Hz), 4.28-4.16 (m, 2H), 3.89 (d, 2H, J=6.4 Hz), 2.82-2.72 (m, 2H), 2.06-1.94 (m, 1H), 1.87-1.80 (m, 4H), 1.39 (t, 3H, J=7.1 Hz), 1.23 (d, 6H, J=6.4 Hz); LRMS (ESI), m/z 427 (M+H).
Reaction SMILES: [CH3:1][CH:2]([C@@H:4]1[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:7][NH:6][CH2:5]1)[CH3:3].[C:17](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O>C(Cl)Cl>[CH3:17][N:6]1[CH2:7][CH2:8][N:9]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[C@@H:4]([CH:2]([CH3:1])[CH3:3])[CH2:5]1
Reactant: CC(C)[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)[C@H]1CN(C)CCN1C(=O)OC(C)(C)C
Yield: 102.7 %

Procedure:
Commercially-available (S)—N-1-Boc-2-isopropylpiperazine (2.0 g, 8.76 mmol), sodium triacetoxyborohydride (2.76 g, 13 mmol), and formaldehyde (37% in H2O, 1.06 mL, 13 mmol) were dissolved and stirred in CH2Cl2 (40 mL) overnight at room temperature. After this time, the reaction mixture was diluted with additional CH2Cl2 and washed with 1 N NaOH and brine. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to provide 1,1-dimethylethyl (2S)-4-methyl-2-(1-methylethyl)-1-piperazinecarboxylate (2.18 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:36])=[C:4]([CH:33]=[CH:34][CH:35]=1)[C:5]([N:7]1[CH2:12][C@@H:11]2[CH2:13][C@H:8]1[CH2:9][N:10]2[CH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([N:24](COC)[C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[N:23]=1)[C:18]([OH:20])=[O:19])=[O:6].O>FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:3]([F:36])=[C:4]([CH:33]=[CH:34][CH:35]=1)[C:5]([N:7]1[CH2:12][C@@H:11]2[CH2:13][C@H:8]1[CH2:9][N:10]2[CH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([NH:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[N:23]=1)[C:18]([OH:20])=[O:19])=[O:6]
Reactant: COCN(c1cc(C(=O)O)cc(CN2C[C@@H]3C[C@H]2CN3C(=O)c2cccc(Cl)c2F)n1)c1nccs1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)c1cc(CN2C[C@@H]3C[C@H]2CN3C(=O)c2cccc(Cl)c2F)nc(Nc2nccs2)c1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
33 mg of 2-(((1S,4S)-5-(3-chloro-2-fluorobenzoyl)-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl) -6-((methoxymethyl)(1,3-thiazol-2-yl)amino)isonicotinic acid was dissolved in 0.9 ml of trifluoroacetic acid and 0.1 ml of water followed by stirring 2 hours at 75° C. The reaction mixture was concentrated in vacuo to give the title compound. (15) Synthesis of 2-(((1S,4S)-5-(3-chloro-2-fluorobenzoyl)-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl)-N,N-dimethyl-6-(1,3-thiazol-2-ylamino)isonicotinamide trifluoroacetate