Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:15])=[N:12][NH:13][CH:14]=1.[CH:16](O)=[O:17]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH:15][CH:16]=[O:17])=[N:12][NH:13][CH:14]=1
Reactant: Nc1n[nH]cc1-c1nc2ccccc2s1
Reactant: O=CO
Product: O=CNc1n[nH]cc1-c1nc2ccccc2s1
Yield: 90 %

Procedure:
A solution of 4-benzothiazol-2-yl-1H-pyrazol-3-ylamine (1.1 g, 5.0 mmol) in 20 mL of formic acid was heated to 70° C. overnight. The formic acid was evaporated under reduced pressure and the resulting crude material was recrystallized from ethanol to yield 1.1 g (90%) of N-(4-benzothiazol-2-yl-1H-pyrazol-3-yl)-formamide.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([Cl:12])[N:3]=1.[CH2:13]([CH:15]([NH2:18])[CH2:16][CH3:17])[CH3:14]>C1COCC1>[Cl:12][C:4]1[N:3]=[C:2]([CH3:1])[N:7]=[C:6]([NH:18][CH:15]([CH2:16][CH3:17])[CH2:13][CH3:14])[C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: CCC(N)CC
Solvent: C1CCOC1
Product: CCC(CC)Nc1nc(C)nc(Cl)c1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 4 h
Yield: 35.9 %

Procedure:
A mixture of 2-methyl-5-nitro-4,6-dichloro-pyrimidine (208 mg, 1.00 mmol) and 1-ethyl-propyl-amine (87 mg, 1.03 mmol) in 2 ml of dry THF was stirred at -78° C. for 4 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give a green oil. The oil was purified through silica gel column chromatography using chloroform to 1:1 hexane/chloroform as eluent to give the title compound (93 mg, 35%). 1H NMR (CDCl3) δ7.50 (brs, 1H), 4.29 (m, 1H), 2.51 (s, 3H), 1.4-1.8 (m, 4H), 0.92 (t, 6H) ppm.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([CH2:10][NH2:11])[CH2:9][CH2:8][CH2:7]1.[CH:12]1[N:17]=[C:16](Cl)[C:15]2[N:19]=[CH:20][N:21]([C@@H:22]3[O:26][C@H:25]([CH2:27][OH:28])[C@@H:24]([OH:29])[C@H:23]3[OH:30])[C:14]=2[N:13]=1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([CH2:10][NH:11][C:16]2[C:15]3[N:19]=[CH:20][N:21]([C:14]=3[N:13]=[CH:12][N:17]=2)[C@@H:22]2[O:26][C@H:25]([CH2:27][OH:28])[C@@H:24]([OH:29])[C@H:23]2[OH:30])[CH2:9][CH2:8][CH2:7]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NCC1(c2cccs2)CCC1
Product: OC[C@H]1O[C@@H](n2cnc3c(NCC4(c5cccs5)CCC4)ncnc32)[C@H](O)[C@@H]1O
Yield: 76.2 %

Procedure:
The above amine (1.67 g, 10 mmol) is reacted with 6-chloropurine riboside (2.87 g, 10 mmol) as described in Example 1 and 7 is purified by column chromatography to give N6-(1-(thien-2-ylcyclobutyl)methyl)adenosine (3.18 g, 76%) as a colorless glass m.p. 84°-92° C. Found: C, 54.88; H, 5.69; N, 16.77; S, 7.55%. C19H23N5O4S calculated requires: C, 54.68; H, 5.52; N, 16.79; S, 7.67%.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]3[C:16](=[O:19])[CH2:17][CH2:18][C:14]=3[N:13]=[C:12]2[CH:20]([CH3:22])[CH3:21])=[CH:6][CH:5]=1>ClCCl.CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][N:11]2[C:15]3[CH:16]([OH:19])[CH2:17][CH2:18][C:14]=3[N:13]=[C:12]2[CH:20]([CH3:22])[CH3:21])=[CH:8][CH:9]=1
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(O)CC2
Reaction time: 3 h
Yield: 93.1 %

Procedure:
Sodium borohydride (76 mg) was added to a stirred solution of Intermediate 18 (290 mg) in dichloromethane (3 ml) and methanol (3 ml). The reaction mixture was stirred for 3 hours. The reaction mixture was concentrated under vacuum, partitioned between EtOAc (20 ml) and water (15 ml). The two phases were separated and the aqueous phase was extracted again with EtOAc (2×10 ml). The phases were separated, the organic extracts were combined, dried (hydrophobic frit) and concentrated under vacuum to give the title compound (272 mg). LC/MS MH+ 291, Rt 1.35 min (5 minute run).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:23]=[CH:22][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:10][CH:9]=2)[CH2:3]1.Br[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:25]([N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:9]=[CH:10][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:22][CH:23]=2)[CH2:3]1)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C3CCCNC3)cc2)nc1
Reactant: BrCCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc(C3CCCN(CCc4ccccc4)C3)cc2)nc1
Yield: 64.2 %

Procedure:
Combine 6-(4-piperidin-3-yl-phenoxy)-nicotinamide (compound of example 322) (0.0237 g, 0.0797 mmol), (2-bromoethyl)benzene (0.0108 mL, 0.0791 mmol), and potassium carbonate (0.0237 g, 0.171 mmol) in dimethylformamide (0.96 mL) and stir for 15 min. Then purify the reaction mixture by ion exchange chromatography (SCX resin, methanol→2 M ammonia in methanol) to provide 0.0204 g (64%) of the title compound as an off-white foam: high resolution mass spectrum (electrospray): m/z calc for C25H28N3O2 402.2182, found 402.2182; 1H NMR (methanol-d4): 8.66 (d, 1H, J=2.0 Hz), 8.28 (dd, 1H, J=2.9, 8.3 Hz), 7.37 (d, 2H, J=7.8 Hz), 7.33-7.27 (m, 2H), 7.27-7.18 (m, 3H), 7.12 (d, 2H, J=8.3 Hz), 7.01 (d, 1H, J=8.8 Hz), 3.15 (d, 2H, J=11.2 Hz), 2.97-2.85 (m, 3H), 2.73-2.65 (m, 2H), 2.19 (q, 2H, J=11.2 Hz), 2.03-1.74 (m, 3H), 1.59 (dq, 1H, J=4.4, 12.7 Hz).
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[CH:18]=[C:11]2[C:12]([O:14]C(=O)[NH:16][C:10]2=[CH:9][CH:8]=1)=O)(=[O:6])=[O:5])[CH3:2].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CC(C)=O.C(O)C>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:12](=[O:14])[C:11]2[C:10](=[CH:9][CH:8]=[C:7]([S:4](=[O:5])(=[O:6])[NH:3][CH2:1][CH3:2])[CH:18]=2)[NH2:16])[CH2:22][CH2:21]1
Reactant: CN1CCNCC1
Reactant: CCNS(=O)(=O)c1ccc2[nH]c(=O)oc(=O)c2c1
Solvent: CC(C)=O
Solvent: CCO
Product: CCNS(=O)(=O)c1ccc(N)c(C(=O)N2CCN(C)CC2)c1

Procedure:
In a manner analogous to that described in Example 1, the reaction of 5-(N-ethylsulfamoyl)-isatoic anhydride with 1-methylpiperazine yields 5-(N-ethylsulfamoyl)-anthranilic acid (4-methyl)-piperazide with a melting point of 175°-177° (from acetone/ethanol).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:33]2[C:29](=[O:39])[C:30]3[C:31](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:32]2=[O:34])[CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(Br)n1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cccc(Br)n1
Reaction time: 17 h
Yield: 60.2 %

Procedure:
A solution of (6-bromo-pyridin-2-yl)-methanol (3.37 g, 17.9 mmol) (H. Tsukube et al., J. Org. Chem., 1993, 58, 4389), triphenylphosphine (5.17 g, 19.7 mmol) and phtalimide (2.90 g, 19.7 mmol) in THF was cooled in an ice bath. A solution of diethylazodicarboxylate (3.43 g, 19.7 mmol) in THF (15 ml) was added slowly and the mixture was left to reach rt. Stirring was continued for 17 hr, then the solvent was distilled off and the residue chromatographed (SiO2 with hexane/AcOEt=4/1) to provide 3.42 g (66%) of the title compound as a colorless viscous oil. MS: m/e=316 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:26])[N:12]([C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][CH:25]=4)[NH:22][CH2:21][CH2:20]5)[CH2:13][CH2:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([C:39](O)=[O:40])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].CCN(CC)CC.F[P-](F)(F)(F)(F)F.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C>C(Cl)Cl>[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([C:39]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([N:12]4[CH2:13][CH2:14][C:15]5[N:16]=[C:8]([C:5]6[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=6)[S:9][C:10]=5[C:11]4=[O:26])=[CH:25][CH:24]=3)[CH2:20][CH2:21]2)=[O:40])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Reactant: O=C1c2sc(-c3ccc(Cl)cc3)nc2CCN1c1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCc3cc(N4CCc5nc(-c6ccc(Cl)cc6)sc5C4=O)ccc32)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
Dissolve 2-(4-chloro-phenyl)-5-(2,3-dihydro-1H-indol-5-yl)-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (163 mg, 0.43 mmol) in CH2Cl2 (4.0 mL) and add (±)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (140 mg, 0.65 mmol), Et3N (0.09 mL, 0.64 mmol), and [dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluoro phosphate (246 mg, 0.65 mmol). Stir the solution at room temperature for 2 h. Concentrate and purify by flash chromatography, using a 8% MeOH (2N NH3)/CHCl3 as eluent, to give the title compound (231 mg, 93%). 1H NMR (400 MHz, DMSO-d6): δ 8.10 (d, 1H, J=8.8 Hz), 8.05 (d, 2H, J=8.8 Hz), 7.62 (d, 2H, J=8.3 Hz), 7.29 (s, 1H), 7.19-7.15 (m, 1H), 4.22 (t, 2H, J=8.8 Hz), 4.07 (t, 2H, J=7.0 Hz), 3.54 (t, 1H, J=8.8 Hz), 3.47-3.36 (m, 3H), 3.29 (m, 1H), 3.26 (t, 2H, J=6.2 Hz), 3.18 (t, 2H, J=8.3 Hz), 2.16 (m, 1H), 2.01 (m, 1H), 1.41 (s, 9H).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][NH:6][N:5]=1.I[CH2:15][CH3:16]>O1CCCC1.[Cl-].[Na+].O>[CH2:15]([N:6]1[CH:7]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([I:3])=[N:5]1)[CH3:16]
Reactant: CCOC(=O)c1c[nH]nc1I
Reactant: CCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cn(CC)nc1I
Temperature: -45 °C
Reaction time: 4 h

Procedure:
A 500 mL flask was charged with the sodium hydride (0.584 g, 14.61 mmol) and tetrahydrofuran (100 mL). To the resulting suspension was added a solution of EXAMPLE 59A (3.11 g, 11.69 mmol) in tetrahydrofuran (50 mL) dropwise over about 20 minutes and the reaction was stirred for 4 hours under nitrogen. The reaction mixture was cooled to −45° C. and a solution of iodoethane (3.77 mL, 46.8 mmol) in tetrahydrofuran (20 ml) was added dropwise over 20 minutes. The reaction mixture was allowed to come to ambient temperature and stirring was continued for 42 hours. The reaction was diluted with brine (400 mL) and extracted with ether (400 ml, 2×200 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. The crude material was purified on the ISCO chromatography system on a silica gel cartridge (150 g) eluting with a 0, 10, 25, and 50% ethyl acetate/hexane step gradient to give the title compound. MS DCI+) m/e 295 (M+H)+.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[CH2:10]([O:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][C:29](OCC)=[O:30])=[C:20]([N+:34]([O-:36])=[O:35])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N#N.Cl>C1COCC1>[CH2:10]([O:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][CH2:29][OH:30])=[C:20]([N+:34]([O-:36])=[O:35])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)Cc1c([N+](=O)[O-])cc(OCc2ccccc2)c2ccccc12
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: N#N
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(OCc2ccccc2)c2ccccc2c1CCO
Reaction time: 0.25 h
Yield: 106.3 %

Procedure:
DIBAL-H (1.0 M, 3.84 mL, 3.84 mmol) was added to a solution of ethyl 2-[4-benzyloxy-2-nitronaphthalen-1-yl]acetate (0.35 g, 0.96 mmol) in THF (4 mL) slowly under N2 atmosphere at 0° C., and stirred for 15 min. The mixture was poured into chilled 1 N HCl (10 mL) slowly, and the mixture was extracted with AcOEt (50 mL). The organic layer was washed with 1 M HCl (10 mL), saturated aqueous NaHCO3 (10 mL) and saturated aqueous NaCl (10 mL), and then the organic layer was dried (Na2SO4) and evaporated to yield 2-[4-benzyloxy-2-nitronaphthalen-1-yl]ethanol (0.33 g, quant.) as a dark brown solid. Mp 82-90 ° C.; 1H NMR (CDCl3, 500 MHz) δ 8.43 (d, 8.5, 1H), 8.25 (d, 9.0, 1H), 7.71 (t, 7.0, 1H), 7.65 (t, 7.0, 1H), 7.54 (d, 8.0, 2H), 7.45 (t, 7.5, 2H), 7.40 (t, 7.0, 1H), 7.19 (s, 1H), 5.29 (s, 2H), 4.08 (t, 6.5, 2H), 3.49 (t, 6.5, 2H); EIMS m/z 323 (M+); IR (neat) νmax 3368, 2929, 1593, 1526, 1513, 1463, 1423, 1363, 1337, 1271, 1240, 1161, 1103, 1039, 829, 755, 697 cm−1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5](Cl)=[C:4]2[CH:9]=[N:10][CH:11]=[CH:12][C:3]=12.[CH3:13][C@H:14]1[CH2:19][NH:18][CH2:17][CH2:16][NH:15]1>CN1C(=O)CCC1.O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:18]2[CH2:17][CH2:16][NH:15][C@@H:14]([CH3:13])[CH2:19]2)=[C:4]2[CH:9]=[N:10][CH:11]=[CH:12][C:3]=12
Reactant: C[C@H]1CNCCN1
Reactant: Clc1nnc(Cl)c2cnccc12
Solvent: O
Solvent: CN1CCCC1=O
Product: C[C@H]1CN(c2nnc(Cl)c3ccncc23)CCN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1,4-dichloropyrido[3,4-d]pyridazine 3 (0.500 g, 2.50 mmol) in NMP (2.5 ml) was added (S)-2-methylpiperazine (0.300 g, 3.00 mmol). The reaction was stirred at 25° C. for 2 h. After one hour reaction contents were diluted with water (20×) and extracted with 10% MeOH in CH2Cl2 (3×25 mL). The combined organics were dried with Na2SO4 and concentrated in vacuo. Silica gel chromatography (gradient elution 0 to 5% MeOH in CH2Cl2) afforded (S)-1-chloro-4-(3-methylpiperazin-1-yl)pyrido[3,4-d]pyridazine 4 plus 10-15% substitution at the 4-position. 1H NMR (CDCl3) δ 9.48 (s, 1H), 9.03 (d, J=5.5 Hz, 1H), 7.94 (d, J=5.5 Hz, 1H) 3.96 (m, 2H), 3.11-3.88 (m, 5H), 2.93 (dd, J=12.8, 10.4, 1H). MS (calc'd) 263.1 (M+H, found) 264.1.
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:25](Cl)(=[O:28])[C:26]#[CH:27]>C1C=CC=CC=1>[CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([O:15][C:25](=[O:28])[C:26]#[CH:27])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: CN1CCC(O)N(c2nnc(C3CC3)s2)C1=O
Reactant: C#CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C#CC(=O)OC1CCN(C)C(=O)N1c1nnc(C2CC2)s1

Procedure:
Tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Propynoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-propynoyloxy-2(1H)-pyrimidinone as the residue.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH3:9][CH:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CS(O)(=O)=O>C1(C)C=CC=CC=1>[CH3:9][CH:10]([O:5][C:4](=[O:6])[CH2:3][CH2:2][C:1]([O:8][CH:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:9])=[O:7])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCC(C)O
Reactant: O=C(O)CCC(=O)O
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCC(C)OC(=O)CCC(=O)OC(C)CCCCCC

Procedure:
A mixture of succinic acid (Alfa-Aesar, 149.00 g, 1.26 mol), 2-octanol (Alfa-Aesar, 350.00 g, 2.69 mol), toluene (625 mL), and methanesulfonic acid (Alfa-Aesar, 2.00 g, 21 mmol) was heated to reflux for 6 hours. The water liberated was collected in a Dean Stark trap. The mixture was cooled, washed with saturated sodium bicarbonate (300 mL) and brine (100 mL), and dried over magnesium sulfate. The solvent was removed under vacuum to give a yellow oil that was used without further purification (426.39 g).
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[N:16][N:17]2[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:13][C:12]=1[O:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32])=[O:10].Cl.Cl.[CH3:35][O:36][C:37](=[O:45])[CH:38]([NH2:44])[CH2:39][CH2:40][N:41]([CH3:43])[CH3:42].C(N(CC)CC)C>ClCCl>[CH3:35][O:36][C:37](=[O:45])[C@@H:38]([NH:44][C:9]([C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[N:16][N:17]2[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:13][C:12]=1[O:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32])=[O:10])[CH2:39][CH2:40][N:41]([CH3:43])[CH3:42]
Reactant: COC(=O)C(N)CCN(C)C
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)ON3C(=O)CCC3=O)cc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCN(C)C)NC(=O)c1cc2c(cnn2CC(C)C)cc1Oc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid 2,5-dioxopyrrolidin-1-yl ester (32.0 g, 72.2 mmol) and 2-amino-4-dimethylaminobutyric acid methyl ester dihydrochloride (19.35 g, 83.0 mmol) in dichloromethane was added triethylamine (35 mL, 253 mmol) and the mixture stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and diluted with dichloromethane (400 mL). The solution was washed with saturated NH4Cl (2×200 mL), saturated NaHCO3 (2×200 mL) and brine (200 mL). The organics were dried over MgSO4 and concentrated under reduced pressure to afford the crude product.
Reaction SMILES: O1CCCC1.C[Si](C)(C)[C:8]([F:11])([F:10])[F:9].[O:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1.Cl>CCOC(C)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[F:9][C:8]([F:11])([F:10])[C:17]1([OH:20])[CH2:18][CH2:19][O:14][CH2:15][CH2:16]1
Reactant: O=C1CCOCC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC1(C(F)(F)F)CCOCC1
Temperature: 0 °C
Yield: 42.6 %

Procedure:
Tetrahydrofuran (110 mL) was added to a round bottom flask and placed under N2. trimethyl(trifluoromethyl)silane (4.13 mL, 28.0 mmol) was then added and stirred under N2 and then cooled to 0° C. Dihydro-2H-pyran-4(3H)-one (1.845 mL, 19.98 mmol) was then added via syringe and stirred for 5 minutes at 0° C. to ensure complete mixing. TBAF (0.200 mL, 0.200 mmol) was added dropwise slowly via syringe. The reaction was then allowed to warm up to RT for 30 min. The reaction was then cooled back down to 0° C. and added 1M HCl (50 mL) and then stirred at RT for overnight. The reaction was diluted with EtOAc and separated with brine. The organic layer was dried over MgSO4, filtered and evaporated to give the crude material which was crystallized from hexane to give the product 4-(trifluoromethyl)tetrahydro-2H-pyran-4-ol (1.45 g, 8.52 mmol, 42.7% yield) as white crystals. 1H NMR (400 MHz, CHLOROFORM-d) d 3.96-3.84 (m, 2H), 3.76 (td, J=12.1, 2.1 Hz, 2H), 2.08-1.90 (m, 3H), 1.65-1.48 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[CH:10]=[C:9]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[O:8][N:7]=1)([CH3:5])[CH3:4].[CH2:20]([CH:22]1[O:24][CH2:23]1)Br>>[CH:3]([C:6]1[CH:10]=[C:9]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:20][CH:22]2[O:24][CH2:23]2)[O:8][N:7]=1)([CH3:5])[CH3:4]
Reactant: CC(C)c1cc(C=Cc2ccccc2O)on1
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Product: CC(C)c1cc(C=Cc2ccccc2OCC2CO2)on1

Procedure:
This compound is prepared by the method described for Example VI, from 3.4 g of 55% strength sodium hydride (0.078 mole), 18 g (0.078 mole) of 3-isopropyl-5-(2-hydroxystyryl)-isoxazole and 10.8 g (0.078 mole) of epibromohydrin. 21.5 g (97% of theory) of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:29][O:30][CH2:31][CH3:32])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.B1([C:40]2[CH:45]=[CH:44][CH:43]=[N:42][CH:41]=2)OCCCO1>>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:29][O:30][CH2:31][CH3:32])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: c1cncc(B2OCCCO2)c1
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 85.4 %

Procedure:
tert-Butyl 4-[(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate (12.79 g, 24.67 mmol) and pyrdine-3-boronic acid 1,3-propanediol cyclic ester (4.42 g, 27.14 mmol) were coupled according to the method described in Examples 118–121. The work-up procedure described in Part F of Examples 125–135 was followed. The crude product was recrystallized twice from ethyl acetate to provide 10.89 g of tert-butyl 4-{[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidine-1-carboxylate as an off-white solid, mp 197–198° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:13])=[C:9](/[CH3:12])\[CH2:10][OH:11])=[CH:4][CH:3]=1.[CH2:14]([O:16][C@@H:17]([CH2:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:15]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[CH3:13])=[C:9](/[CH3:12])\[CH2:10][O:11][C:27]2[CH:26]=[CH:25][C:24]([CH2:23][C@H:17]([O:16][CH2:14][CH3:15])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:29][CH:28]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: C/C(CO)=C(\C)c1ccc(Br)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C(C)=C(/C)c2ccc(Br)cc2)cc1)OCC
Yield: 95.3 %

Procedure:
The title compound (0.91 g, 95% yield) was prepared from (Z)-3-(4-bromophenyl)-2-methyl -but-2-en-1-ol (0.50 g, 2.07 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.519 g, 2.18 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [CH:1]([CH:4]1[O:9][CH2:8][CH:7]([CH2:10]O)[CH2:6][O:5]1)([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:32]>>[CH:1]([CH:4]1[O:9][CH2:8][CH:7]([CH2:10][Cl:32])[CH2:6][O:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)C1OCC(CO)CO1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)C1OCC(CCl)CO1
Temperature: 70 °C

Procedure:
A solution of 217 g 2-isopropyl-5-hydroxymethyl-1,3-dioxane in 11 of carbon tetrachloride is added dropwise to a solution of 356 g triphenylphosphine in 1 l of carbon tetrachloride, heated to 70° C. The mixture is refluxed and after approx. 1 hour cooled down (ice-bath), filtrated and evaporated. The residue is repeatedly treated with diethylether and filtered. After evaporating the filtrate the residue is purified by distillation. The desired 2-isopropyl-5-chloromethyl-1,3-dioxane is obtained as a colorless liquid; b.p. 84°-94° C. mm Hg; cis-trans mixture; identification by NMR.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.ON1C2C=CC=CC=2N=N1.N=C=N.[Cl:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42][NH2:43])=[CH:40][CH:39]=1.C(=O)([O-])[O-]>ClCCl>[Cl:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42][NH:43][C:1]([C:4]23[CH2:9][CH2:8][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:6][CH2:5]2)[CH2:10][CH2:11]3)=[O:3])=[CH:40][CH:39]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Agent: N=C=N
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)NCc3ccc(Cl)cc3)(CC1)CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(2S,4S)-1-[[N-(4-Carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg), 1-hydroxybenzotriazole (28.0 mg), PS-carbodiimide (240 mg) and dichloromethane (4 mL) were mixed together and the mixture was stirred at room temperature for 15 minutes. 4-chlorobenzylamine (19.0 μL) was then added and the mixture was stirred at room temperature for further 24 hours. Subsequently, MP-carbonate (270 mg) was added and the mixture was stirred at room temperature for 5 hours and was left overnight. The insoluble material in the mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was then purified by a silica gel column (eluant:dichloromethane:methanol=10:1) to give (2S,4S)-1-[[N-[4-[N-(4-chlorophenylmethyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (29.1 mg).