Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3][CH:2]=1.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][C:38]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[NH:40][CH:39]=2)[CH2:32][CH2:31]1>C1COCC1>[NH:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:38]([CH2:37][CH2:36][N:33]2[CH2:32][CH2:31][CH:30]([NH:29][C:11]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=[CH:2][CH:3]=3)=[O:13])[CH2:35][CH2:34]2)=[CH:39]1
Reactant: O=C(O)c1ccnc2ccccc12
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(CCc2c[nH]c3ccccc23)CC1)c1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
A suspension of quinoline-4-carboxylic acid (0.87 g, 5.03 mmol) and triethylamine (0.6 g, 5.94 mmol) in dry THF (10 cm3) was stirred at -20° C. while a solution of isobutylchloroformate (0.65 g, 5.01 mmol) was added dropwise. The mixture was allowed to warm to room temperature over 31/2 hours then was cooled to -20° C. again and a solution of 3-[2-(4-amino-1-piperidyl)ethyl]indole (1.2 g, 4.94 mmol) in dry THF (20 cm3) was added dropwise. The mixture was stirred at room temperature overnight then the solvent was evaporated and the residue triturated with water and aqueous potassium carbonate to give 1.39 g of crude title compound.
Reaction SMILES: C(OC([N:11]1[CH2:14][C@H:13]([C:15]([OH:17])=[O:16])[C@@H:12]1[C:18]([OH:20])=[O:19])=O)C1C=CC=CC=1.[H][H]>[Pd].CO>[NH:11]1[CH2:14][C@H:13]([C:15]([OH:17])=[O:16])[C@@H:12]1[C:18]([OH:20])=[O:19]
Reactant: [H][H]
Reactant: O=C(O)[C@H]1CN(C(=O)OCc2ccccc2)[C@H]1C(=O)O
Agent: [Pd]
Solvent: CO
Product: O=C(O)[C@H]1CN[C@H]1C(=O)O

Procedure:
cis-N-(Benzyloxycarbonyl)azetidine-2,3-dicarboxylic acid, 10% Pd/C and methanol are hydrogenated under 3 atm of hydrogen in a Parr shaker for 4 hours. The catalyst is filtered off and thoroughly washed. The solution is evaporated to dryness and dried in vacuo to arrive at cis-azetidine-2,3-dicarboxylic acid.
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][C:20]([SH:22])=[N:19][N:18]=3)=[CH:13][C:12]=12.Br[CH2:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[C:28]#[N:29]>>[N:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][C:20]([S:22][CH2:24][C:25]4[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=4)[C:28]#[N:29])=[N:19][N:18]=3)=[CH:13][C:12]=12
Reactant: N#Cc1cccc(CBr)c1
Reactant: Sc1nnc(-c2ccn3ncnc3c2)o1
Solvent: CCN(CC)CC
Product: N#Cc1cccc(CSc2nnc(-c3ccn4ncnc4c3)o2)c1
Yield: 20 %

Procedure:
In the same manner as in Example 1 and using 5-(1,2,4-triazolo[1,5-a]pyridin-7-yl)-1,3,4-oxadiazole-2-thiol triethylamine salt instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-(bromomethyl)benzonitrile instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 20%) was obtained as colorless crystals.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:22][CH:4]1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=2)=[CH:9][CH:8]=1.[CH3:23]I.O>CN(C)C=O>[O:3]1[CH2:22][CH:4]1[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]([CH3:23])[CH:15]=[C:16]([C:18]([F:20])([F:19])[F:21])[N:17]=2)=[CH:11][CH:12]=1
Reactant: CI
Reactant: FC(F)(F)c1c[nH]c(-c2ccc(OCC3CO3)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(C(F)(F)F)nc1-c1ccc(OCC2CO2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 g of sodium hydride dispersion (55% in oil) are added, while cooling in an ice bath, to a solution of 12 g of 2-[4-(2,3-epoxypropoxy)-phenyl]-4-(trifluoromethyl)-imidazole (J. med. Chem. 20, 1024 (1977)) in 90 ml of dimethylformamide and the yellow suspension is stirred for 11/2 hours at room temperature. After the addition of 8 ml of methyl iodide, stirring is continued for a further 12 hours at room temperature, the reaction mixture is subsequently poured into water and extracted several times with ethyl acetate. After separating off the organic phase and removing the solvent, the residue is dissolved in chloroform and filtered over silica gel. The filtrate is again concentrated by evaporation and the residue is recrystallized from ether/hexane, yielding 2-[4-(2,3-epoxypropoxy)-phenyl]-1-methyl-4-(trifluoromethyl)-imidazole having a melting point of 65°-68°.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:24]2[S:28][C:27]([CH:29]3[CH2:34][CH2:33][CH:32]([C:35]([O:37]CC)=[O:36])[CH2:31][CH2:30]3)=[N:26][CH:25]=2)[CH:10]=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:12]=1)=[O:5])[CH3:2].[Li+].[OH-].Cl>O1CCCC1.CO>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:24]2[S:28][C:27]([CH:29]3[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=[O:36])[CH2:31][CH2:30]3)=[N:26][CH:25]=2)[CH:10]=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3CCC(C(=O)OCC)CC3)s2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3CCC(C(=O)O)CC3)s2)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a solution of ethyl 4-[5-(3-[(ethylcarbamoyl)amino]-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate (2.030 g, 3.70 mmol) in tetrahydrofuran (13.45 mL) and methanol (5.045 mL) was added aqueous 1N LiOH (11.10 mL, 11.10 mmol). The resulting solution was stirred 2 h at room temperature and 2 h at 50° C. The reaction was cooled to ambient temperature and was then quenched with HCl (11.10 mL, 11.10 mmol) and then diluted with aqueous 25% NH4OAc (to pH=7). The mixture was extracted with 2-Me-THF. The combined organic fractions were washed with brine, dried (Na2SO4), and filtered. The solvent was evaporated under reduced pressure and the resultant residue was purified by column chromatography on silica gel (Combiflash, 0-100% ethanol in dichloromethane) to give a brown oil-solid. The residue was triturated in hot ethyl acetate. Diethyl ether was added and the product was isolated by filtration. The solid was dried to give 4-[5-(3-[(ethylcarbamoyl)amino]-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (396 mg, 0.741 mmol, 20.02% yield) as a mixture of the syn and anti diastereoisomers. MS APCI: [M+H]+ m/z 535.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4](O[C@H](C2C=CC(Cl)=CC=2N2C=CC(C)=N2)C(F)(F)F)[N:3]=1.[Br:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([Br:47])[C:42]=1[CH:48]([OH:53])[C:49]([F:52])([F:51])[F:50]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:53][CH:48]([C:42]2[C:41]([Br:40])=[CH:46][CH:45]=[CH:44][C:43]=2[Br:47])[C:49]([F:50])([F:51])[F:52])[N:3]=1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Reactant: OC(c1c(Br)cccc1Br)C(F)(F)F
Product: Nc1nc(OC(c2c(Br)cccc2Br)C(F)(F)F)cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)n1

Procedure:
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with 1-(2,6-dibromophenyl)-2,2,2-trifluoroethanol.
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4][C:5]12[CH2:12][CH2:11][C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([CH2:9][CH2:10]1)[CH2:7][CH2:6]2.[Cr](Cl)([O-])(=O)=[O:20].[NH+]1C=CC=CC=1>C(Cl)Cl>[C:13]1([C:8]23[CH2:7][CH2:6][C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:20])([CH2:12][CH2:11]2)[CH2:10][CH2:9]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[Cr](=O)([O-])Cl
Reactant: COC=CC12CCC(c3ccccc3)(CC1)CC2
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)CC12CCC(c3ccccc3)(CC1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
To a stirred solution of 4-[2-methoxyethenyl]-1-phenylbicyclo[2.2.2]octane (Intermediate 7; 12.6 g, 51.99 mmol) in DCM (200 mL) was added pyridinium chlorochromate (33.6 g, 155.97 mmol) in portions and the reaction mixture was allowed to stir at ambient temperature for 2 hrs. Further pyridinium chlorochromate (12 g, 55.99 mmol) was added and stirring was continued for a further 1 hr. The mixture was filtered and the filtrate was concentrated under reduced pressure, ether (200 mL) was added and the organic phase was washed with water (200 mL). Water (200 mL) and ether (2×200 mL) were added to the filtered solid and the mixture was filtered through a pad of celite. The organic extracts were combined, dried (MgSO4) and concentrated to leave a brown gum. This was purified on a 330 g Crawford silica cartridge, loading the sample in DCM and eluting with 5-10-20% EtOAc-isohexane to provide the title compound as a cream solid (7.89 g, 30.53 mmol, 59%); 1H NMR (CDCl3) δ 1.63-1.71 (6H, m), 1.83-1.93 (6H, m), 2.17 (2H, s), 3.67 (3H, s), 7.14-7.19 (1H, m), 7.29-7.32 (4H, m); GC-MS EI m/e M+ 258.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:7][CH2:8][C:9](Cl)=[O:10].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Cl:7][CH2:8][C:9]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:10]
Reactant: c1ccccc1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCl)c1ccccc1

Procedure:
Benzene (0.5 mL), chloroacetyl chloride (120 mg), and aluminium chloride (180 mg) were reacted in dichloromethane (1.5 mL) at from −40° C. to room temperature for 2 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (11 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:23])[CH2:4][C@@:5]23[CH2:18][CH2:17][N:16](C)[C@@H:13]([C@@H:14]2[CH:15]=1)[CH2:12][C:11]1[CH:10]=[CH:9][C:8]([O:20][CH3:21])=[C:7]([OH:22])[C:6]3=1.Cl.[H][H]>C(O)C.[Pd]>[OH:22][C:7]1[C:6]2[C@:5]34[CH2:18][CH2:17][NH:16][C@@H:13]([C@@H:14]3[CH2:15][C@H:2]([CH3:1])[C:3](=[O:23])[CH2:4]4)[CH2:12][C:11]=2[CH:10]=[CH:9][C:8]=1[O:20][CH3:21]
Reactant: [H][H]
Reactant: COc1ccc2c(c1O)[C@]13CCN(C)[C@H](C2)[C@@H]1C=C(C)C(=O)C3
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc2c(c1O)[C@]13CCN[C@H](C2)[C@@H]1C[C@H](C)C(=O)C3
Yield: 68.3 %

Procedure:
To a solution of 14 (22.0 g, 70 mmole) in 95% ethanol (200 ml) was added concentrated HCl (12 ml) and 10% palladium on activated carbon (2.0 g). The mixture was hydrogenated at an initial pressure of 50 psi until the uptake of hydrogen ceased. The mixture was filtered from the catalyst and the filtrate evaporated to a small volume. The residue was dissolved in water, the solution made basic with concentrated NH4OH and extracted with three portions of chloroform. The chloroform extracts were washed with dilute NH4OH, dried and evaporated to a thick syrup which crystallized on the addition of ethyl acetate. The crystals were collected and dried to give 14.4 g (65%) of 16a as white needles, mp 163°-165°. Recrystallization from acetone gave analytically pure 16a as the hemi-acetone solvate, 166°-167° NMR: δ 6.55, s, 2H (aromatic); 6.40, broad, 1H (hydroxyl H); 4.22, d, 1H (H-5α, J=13 Hz); 3.77 (CH3O--); 2.38 (CH3N); 0.87, d, 3H (7α-CH3, J=6.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(Cl)c1
Temperature: 105 °C
Reaction time: 0.25 h

Procedure:
1.76 g (10.0 mmol) 3-chloro-4-fluoro-1-nitro-benzene are combined with 2.614 ml (30 mmol) morpholine in 5 ml DMF and heated to 105° C. with stirring for 15 min. The reaction mixture is poured into ice water, the resulting precipitate is suction filtered, washed with water and dried at 50° C. in the drying cupboard.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:5][C:6]=1[CH2:7]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:38]N1C(=O)CCC1=O>C1COCC1>[Br:38][CH2:7][C:6]1[S:5][C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CBr
Reaction time: 0.75 h
Yield: 83.9 %

Procedure:
Cool (10° C.) a solution of [4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol (Example 2, 753 mg, 3 mmol) in THF (12 mL) add triphenylphosphine (864 mg, 3.3 mmol) followed by freshly recrystallized N-bromosuccinimide (587 mg, 3.3 mmol). On complete addition, remove the cold bath and stir continuously for 45 min. Concentrate the resulting mixture under vacuum and purify the residue by flash chromatography (elute with 10% ethyl acetate/10% dichloromethane in heptane) to give the title compound as an orange solid (846 mg).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]([CH3:18])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)(=O)=O.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.CN1C(=O)CCC1>O>[CH3:18][N:8]([CH2:7][CH2:6][N:23]1[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1
Reactant: CN1CCNCC1
Reactant: CN(CCOS(C)(=O)=O)c1cccc([N+](=O)[O-])c1
Solvent: CN1CCCC1=O
Solvent: O
Product: CN1CCN(CCN(C)c2cccc([N+](=O)[O-])c2)CC1

Procedure:
A mixture of 2-[methyl(3-nitrophenyl)amino]ethyl methanesulfonate (Preparation Example 472) (1.0 g), 1-methylpiperazine (1.61 mL) and NMP (5 mL) was reacted at 130° C. for 30 minutes using a microwave reaction system. The reaction liquid was diluted with water, extracted with a mixed solvent of chloroform and methanol (10:1), and then washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; chloroform:methanol:saturated aqueous ammonia=10:1:0.1) to give N-methyl-N-[2-(4-methylpiperazin-1-yl)ethyl]-3-nitroaniline (890 mg) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([O:10][CH2:11][CH3:12])[C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[C-:16]#[N:17].[Na+]>CN(C)C=O.O>[C:16]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([O:10][CH2:11][CH3:12])[C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1)#[N:17]
Reactant: [C-]#N
Reactant: CCOC1Oc2ccc(Br)cc2C1(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC1Oc2ccc(C#N)cc2C1(C)C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
5-Bromo-2,3-dihydro-3,3-dimethyl-2-ethoxybenzofuran (4.7 g, 0.017 mole) was heated under reflux with cuprous cyanide (2.7 g, 0.03 mole) in dimethyl formamide (10 ml) as in example 2 for 3 hours. A warm solution of sodium cyanide (5 g) in water (20 ml) was added with stirring and stirring was continued for 1 hour at ambient temperature. The solution was diluted with water and extracted with ether. The extracts were washed with water, dried over magnesium sulphate and run down yielding 3.6 g crude product. Purification was accomplished by silica gel chromatography in 1:4 ether/petroleum ether (b.p. 40°-60° C.). The yield of pure title product was 2.9 g (79%).
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C([O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>>[Cl:9][C:8]1[C:2]([Cl:1])=[C:3]2[C:5]([C:13]([OH:12])=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:20]=[N:4]2)=[CH:6][CH:7]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cccc(Cl)c1Cl
Product: CCOC(=O)c1cnc2c(Cl)c(Cl)ccc2c1O
Temperature: 60 °C
Yield: 87.7 %

Procedure:
2,3-Dichloroaniline (7.83 g) and diethyl ethoxymethylenemalonate (9.76 g) are heated at 130° C. for 1.5 hours. The reaction is cooled to 60° C. and the solution poured into hexanes. The intermediate enamine is collected and dried. The solid is added to 70 mL diphenyl ether and heated to 250° C. for 1.5 hours with removal of ethanol with a Dean-Stark trap. The reaction is cooled to room temperature. The product is collected by filtration, washed thoroughly with hexanes, and dried to yield 11.32 g of ethyl 7,8-dichloro-4-hydroxyquinoline-3-carboxylate. A mixture of this ester (0.48 g) and 4-chlorobenzylamine (1.0 mL) are heated at 180° C. for 1 hour. The reaction is cooled to room temperature and diethyl ether is added. The resulting solid is filtered, washed twice with diethyl ether, and dried. The solid is adsorbed onto silica and purified by Biotage Flash 40S chromatography (eluent 2% MeOH:CH2Cl2). The product-containing fractions are evaporated to give a white solid (0.12 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[NH:13][C:12]([N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][CH2:17]2)=[N:11][C:10]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].CCN(CC)CC>C1COCC1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([S:30]([CH3:29])(=[O:32])=[O:31])[C:12]([N:16]2[CH2:17][CH2:18][CH:19]([CH2:22][O:23][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:20][CH2:21]2)=[N:11][C:10]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1nc(N2CCC(CO)CC2)[nH]c(=O)c1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(N2CCC(COS(C)(=O)=O)CC2)n(S(C)(=O)=O)c(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.2 %

Procedure:
To a solution of ethyl 5-(benzyloxy)-2-(4-(hydroxymethyl)piperidin-1-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.814 g, 2.1 mmol) in THF (20 mL) was added methanesulfonyl chloride (0.327 mL, 4.20 mmol) followed by Et3N (0.732 mL, 5.25 mmol). The resulting mixture was stirred at room temperature for 2.5 h (white solids precipitated out over the reaction time). The mixture was diluted with ethyl acetate (50 mL) and washed with water followed by brine. The organic phase was dried (Na2SO4), filtered and concentrated to give the title compound as an amber oil (1.1320 g, 99% yield). 1H NMR (500 MHz, CDCl3) δ: 7.44 (2H, d, J=7.32 Hz), 7.39-7.32 (3H, m), 4.98 (2H, s), 4.67-4.64 (2H, m), 4.35 (2H, q, J=7.1 Hz), 4.09 (2H, d, J=6.4 Hz), 3.46 (3H, s), 3.02 (3H, s), 2.91 (2H, td, J=12.9, 2.4 Hz), 2.08-2.00 (1H, m), 1.86-1.84 (2H, m), 1.35-1.28 (5H, m). LCMS (M+H) calcd for C22H30N3O9S2: 544.14; found: 544.30.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2[C@H:15]1[C@@H:19]2[O:20][C:21]([CH3:24])([CH3:23])[O:22][C@@H:18]2[C@@H:17]([C:25](O)=[O:26])[O:16]1>C(Cl)(Cl)Cl>[Cl:5][C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2[C@H:15]1[C@@H:19]2[O:20][C:21]([CH3:24])([CH3:23])[O:22][C@H:18]2[C@@H:17]([C:25]([NH:10][CH2:15][CH:19]([OH:20])[CH3:18])=[O:26])[O:16]1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](C(=O)O)O[C@H]2n1cnc2c(Cl)ncnc21
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(O)CNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@@H]2OC(C)(C)O[C@H]21
Temperature: 20 °C
Reaction time: 18 h
Yield: 113.6 %

Procedure:
Thionyl chloride (4.3 ml) was added to a stirred solution of (3aS,4S,6R,6aR)-6-(6-chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxole4-carboxylic acid (10.0 g), in chloroform (100 ml). The mixture was heated at reflux temperature under nitrogen for 60 min. After cooling to 20° C. the solvent was removed in vacuo and the residue azeotroped with toluene (2×50 ml). A suspension of the residue in chloroform (50 ml) was added dropwise at an equal rate with a solution of 1-amino-2-propanol (2.3 ml) and diisopropylethylamine (5.1 ml) in chloroform (50 ml) over 10 min to chloroform (50 ml) at 0° C. The mixture was stirred at 20° C. for 18 hours. Phosphate buffer (pH 6.5, 100 ml) was added and the phases separated. The aqueous phase was extracted with chloroform (50 ml). The combined chloroform layers were dried with sodium sulphate and the solvent removed in vacuo to give the title compound as a white foam (6.63 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:7]1([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)[CH2:6][CH:5]2[CH2:16][C:17]([OH:19])=[O:18].Cl[C:21]([O:23][CH:24]1[CH:31]2[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:33][CH:25]1[CH2:26]3)[CH2:30]2)=[O:22]>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:7]1([CH2:8][CH2:9][N:10]([C:21]([O:23][CH:24]3[CH:25]4[CH2:33][CH:29]5[CH2:28][CH:27]([CH2:32][CH:31]3[CH2:30]5)[CH2:26]4)=[O:22])[CH2:11][CH2:12]1)[CH2:6][CH:5]2[CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Reactant: Cc1ccc2c(c1)C(CC(=O)O)CC21CCNCC1
Product: Cc1ccc2c(c1)C(CC(=O)O)CC21CCN(C(=O)OC2C3CC4CC(C3)CC2C4)CC1

Procedure:
The title compound was prepared from 2-(5-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid and 2-adamantyl chloroformate following a procedure analogous to that described in Example 57. LC-MS Method 1 tR=2.24 min, m/z=0.438; 1H NMR (CDCl3) δ=7.06 (m, 2H), 7.00 (s, 1H), 4.88 (s, 1H), 4.19 (t, 2H), 3.61 (m, 1H), 3.03 (m, 3H), 2.64 (dd, 1H), 2.48 (dd, 1H), 2.34 (s, 3H).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:11][C:10]2[C:12]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8][CH2:7][CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=1[C:12]1[C:10]2[O:11][C@@H:5]([CH2:4][NH2:1])[CH2:6][CH2:7][CH2:8][C:9]=2[CH:15]=[CH:14][CH:13]=1
Reactant: [N-]=[N+]=NC[C@H]1CCCc2cccc(-c3c(Cl)cccc3Cl)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC[C@H]1CCCc2cccc(-c3c(Cl)cccc3Cl)c2O1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.6 %

Procedure:
To a solution of (2R)-2-azidomethyl-9-(2,6-dichloro-phenyl)-2,3,4,5-tetrahydro-benzo[b]oxepine (0.24 g, 0.689 mmol) in tetrahydrofuran (10 mL) and water (1 mL) was added polymer-bound triphenylphosphine (˜3 mmol/g, 0.69 g, 2.068 mmol) and the reaction mixture stirred at room temperature for 20 hours. The brown suspension was then filtered through celite, the filter cake washed with ethyl acetate (50 mL) and the combined filtrates concentrated under reduced pressure to afford a yellow syrup. Purification by flash chromatography using a solvent gradient of 0 to 5% ammonia saturated methanol solution in dichloromethane gave 179 mg (80%) of {[(2R)-9-(2,6-dichlorophenyl)-2,3,4,5-tetrahydro-1-benzoxepin-2-yl]methyl}amine as a colorless syrup. The product was dissolved in 2-propanol (1 mL) and diethyl ether (3 mL), a solution of hydrogen chloride (1.0 M in diethyl ether, 0.55 mL, 0.55 mmol) was added followed by hexane (4 mL). The resulting white precipitate was filtered to afford 182 mg (73%) of {[(2R)-9-(2.6-dichlorophenyl)-2,3.4,5-tetrahydro-1-benzoxepin-2-yl]methyl}amine hydrochloride as a white solid. MS (ESI) m/z 322 ([M+H]+).
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([OH:12])=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(Cl)(=O)C([Cl:16])=O.CN(C=O)C>C(Cl)Cl>[N:1]1[CH:2]=[C:3]([C:10]([Cl:16])=[O:12])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C(O)c1cnc2ccccn12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of imidazo[1,2-a]pyridine-3-carboxylic acid (5.270 g, 32.5 mmol) in DCM (200 ml) was treated with oxalyl chloride (3.13 ml, 35.8 mmol) followed by the addition of DMF (0.252 ml, 3.25 mmol). The reaction mixture was stirred at RT overnight. The solvent was removed in vacuo to afford the title compound as a hydrochloride salt;