Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)CCl.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[O:24]=[C:25]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=1)[CH2:26][CH2:27][C:28]([OH:30])=O.[CH3:43][CH:44]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[NH:46][CH2:45]1>C(Cl)Cl.CCCCCC>[CH3:43][CH:44]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[N:46]([C:28](=[O:30])[CH2:27][CH2:26][C:25]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=2)=[O:24])[CH2:45]1
Reactant: O=C(O)CCC(=O)NCc1cccc(C(F)(F)F)c1
Reactant: CC1CNC(c2ccccc2)c2ccccc21
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: CC1CN(C(=O)CCC(=O)NCc2cccc(C(F)(F)F)c2)C(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72 %

Procedure:
384 mg (2.0 mmol) of EDC, 306 μl (1.8 mmol) of DIPEA and 135 mg (1.0 mmol) of HOBt were added to a solution of 275 mg (1.0 mmol) of 4-oxo-4-(3-(trifluoromethyl)benzylamino)butyric acid (intermediate VVV01) in DCM (13 ml) and the mixture was stirred for 5 min at RT. Then 268 mg (1.2 mmol) of 4-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline were added and the mixture was stirred for a further 2 h at RT. It was then diluted with DCM and washed successively with a 10% aqueous hydrochloric acid, a saturated aqueous Na2CO3 solution, a saturated aqueous NH4Cl solution and brine. The organic phase was dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 7:3) of the residue produced 346 mg (0.72 mmol, 72%) of 4-(4-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)phenyl]methyl]butyric acid amide. MS: m/z 481.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=2[F:22])[CH:9]=[CH:8][N:7]=1)=[O:4].[Cl-].[NH4+].C(OCC)(=O)C.O1CCCC1.C(OCC)C.CCCCCC>C(O)C.O.[Fe]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:10]2[CH:9]=[CH:8][N:7]=[C:6]([NH:5][C:3]([N:2]([CH3:23])[CH3:1])=[O:4])[CH:11]=2)=[C:14]([F:22])[CH:15]=1
Reactant: CN(C)C(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C)C(=O)Nc1cc(Oc2ccc(N)cc2F)ccn1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
2-[(Dimethylamino)carbonylamino]-4-(2-fluoro-4-nitrophenoxy)pyridine (218 mg) was dissolved in ethanol (20 ml)-water (5 ml) to dissolve, and then electrolytic iron powder (250 mg) and ammonium chloride (500 mg) were added thereto, followed by heating under reflux for 1 hr. The reaction mixture was cooled down to room temperature, and then ethyl acetate-tetrahydrofuran (1:1) was added thereto, followed by stirring. An insoluble portion was filtered through celite, and washed with ethyl acetate and water. The organic layer of the filtrate was separated, washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, to which thus diethyl ether-hexane was then added to suspend. Crystals was filtered off and dried under aeration to provide the titled compound (180 mg, 91%) as pale yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH2:7][N:8]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([O-])=O.O.[Cl-].[NH4+]>[Fe].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH2:7][N:8]([C:17](=[O:22])[C:18]([F:19])([F:20])[F:21])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)CN(Cc1cccc([N+](=O)[O-])c1)C(=O)C(F)(F)F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)CN(Cc1cccc(N)c1)C(=O)C(F)(F)F
Temperature: 100 °C
Yield: 95.3 %

Procedure:
To a mixture of tert-butyl N-(3-nitrobenzyl)-N-(trifluoroacetyl)glycinate (4.30 g), iron (13.2 g), water (41.8 mL), and ethanol (83.5 mL) was added ammonium chloride (2.54 g) at room temperature, followed by heating and refluxing at 100° C. for 1 hour. After leaving to be cooled, the reaction suspension was filtered through Celite and the filtrate was concentrated under reduced pressure. To the residue was added water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain tert-butyl N-(3-aminobenzyl)-N-(trifluoroacetyl)glycinate (3.76 g).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([OH:31])[CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Br:32][C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1>>[Br:32][C:33]1[CH:38]=[CH:37][C:36]([O:31][CH:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][CH2:2][CH2:3]3)[CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=3)[CH2:17][CH2:18]2)=[CH:35][CH:34]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc4c(c3)CCC4)CC2)c1
Reactant: Oc1ccc(Br)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(Br)cc3)c3ccc4c(c3)CCC4)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(2,3-dihydro-1H-inden-5-yl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-bromophenol: ESMS m/e: 577.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N+:3]=1[O-:9].[N+:10]([O-])([OH:12])=[O:11].[OH-].[Na+]>S(=O)(=O)(O)O>[N+:10]([C:6]1[CH:5]=[C:4]([Br:8])[N+:3]([O-:9])=[C:2]([Br:1])[CH:7]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: [O-][n+]1c(Br)cccc1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cc(Br)[n+]([O-])c(Br)c1
Temperature: 90 °C
Yield: 16 %

Procedure:
2,6-dibromopyridine-N-oxide (6.28 g) was dissolved in concentrated sulphuric acid (20 ml) with stirring. A mixture of concentrated sulphuric acid (20 ml) and concentrated nitric acid (10 ml) was then continuously added dropwise. The solution was then heated at 90° C. for 3 hours with stirring, poured onto ice and then basified with sodium hydroxide. The solution was then continuously extracted with ether, and recrystallised from ethanol to give pale yellow leaflets of 4-nitro-2,6-dibromopyridine-N-oxide (1.2 g, 16%), m.p. 222° C.-224° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Brc1ccc2nccc(N3CCOCC3)c2c1
Temperature: 25 °C
Yield: 58.2 %

Procedure:
6-Bromo-4-chloroquinoline (1.0 G, 4.1 mmol), morpholine (0.468 g, 5.3 mmol) and K2CO3 (1.0 G, 7.2 mmol) in NMP (5 mL) were heated at 100° C. for 12 h. The reaction mixture was cooled to room temperature, diluted with water (20 mL) and the product was extracted into EtOAc/hexanes (140 mL/60 mL). The organic layer was washed with water (75 mL) and brine (20 mL) successively, dried over MgSO4 and filtered. The filtrate was concentrated and purified by flash column chromatography (Combiflash® companion System® with RediSep® silica gel column 40 g and 30-70% EtOAC/hexanes as an eluting solvent]. The product fractions were concentrated to provide 4-(6-bromoquinolin-4-yl)morpholine (700 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.73 (d, J=5.0 Hz, 1H), 8.13 (d, J=2.2 Hz, 1H), 7.90 (d, J=8.9 Hz, 1H), 7.81 (dd, J=9.0, 2.2 Hz, 1H), 7.06 (d, J=5.0 Hz, 1H), 3.87-3.84 (m, 4H), 3.18-3.02 (m, 4H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])=[O:2].[CH2:24](O)[CH2:25][OH:26]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:2]1[CH2:24][CH2:25][O:26][CH:1]1[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][N:10]1[C:11](=[O:20])[C:12]2=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]2[C:14]1=[O:15]
Reactant: O=Cc1cccc(OCCCN2C(=O)c3ccccc3C2=O)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCCOc1cccc(C2OCCO2)c1
Yield: 112.6 %

Procedure:
To a solution of N-[3-(3-formylphenoxy)propyl]phthalimide (92.8 g, 0.3 mole), ethylene glycol (44 mL, 0.8 mole) in benzene (1.5 L) was added 3 g of p-toluenesulfonic acid and the mixture was refluxed under a Dean-Stark trap for 14 hours. The cooled mixture was extracted with 100 mL of saturated aqueous sodium bicarbonate and then with 200 mL of saturated aqueous sodium chloride. The organic phase was dried and evaporated under reduced pressure to give 119.4 g of the title compound which crystallized on standing.
Reaction SMILES: [NH2:1][C:2]1[C:21]([Br:22])=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>>[Br:22][C:21]1[C:2]([N:1]2[CH2:24][CH2:25][CH2:26][C:27]2=[O:28])=[CH:3][C:4]2[O:8][C:7]([C:9]3[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=3)=[C:6]([C:16]([NH:18][CH3:19])=[O:17])[C:5]=2[CH:20]=1
Reactant: O=C(Cl)CCCCl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(Br)cc12
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N3CCCC3=O)c(Br)cc12

Procedure:
A solution of 5-bromo-2-(4-fluorophenyl)-6-(2-oxopyrrolidin-1-yl)benzofuran-3-carboxylic acid (280 mg, 0.67 mmol), HOBT (150 mg, 1.11 mmol) and EDCI (280 mg, 1.47 mmol) in dry DMF (2 mL) was allowed to stir at room temperature for 1 hour. Then Et3N (0.2 mL) and CH3NH2 (HCl salt, 100 mg, 1.48 mmol) was added to the mixture, and the reaction was allowed to stir for about 15 hours. After being concentrated in vacuo, water was added and the mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried and concentrated in vacuo and the resulting resulting residue was purified using column chromatography (eluted with petroleum ether:EtOAc=1:1) to provide 5-bromo-2-(4-fluorophenyl-N-methyl-6-(2-oxopyrrolidin-1-yl)benzofuran-3-carboxamide (220 mg, yield: 73%), which was also prepared from 6-amino-5-bromo-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide and 4-chlorobutanoyl chloride using the method described in step 1 above. 1H-NMR (CDCl3, 400 MHz) δ 7.94 (s, 1H), 7.82˜7.86 (m, 2H), 7.32 (s, 1H), 7.09˜7.14 (m, 2H), 6.29 (s, 1H), 3.75˜3.78 (m, 2H), 2.97 (d, J=4.8 Hz, 3H), 2.56˜2.60 (m, 2H), 2.24˜2.26 (m, 2H). MS (M+H)+: 431/433.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][N:6](C(OC(C)(C)C)=O)[C@@H:5]([CH2:15][CH2:16][N:17]2[C:22]3[CH:23]=[C:24]([C:27]#[N:28])[CH:25]=[CH:26][C:21]=3[O:20][CH2:19][C:18]2=[O:29])[CH2:4][CH2:3]1.N[C@H]1CN(C(OC(C)(C)C)=O)[C@H](CCN2C3C=C(C#N)C=CC=3OCC2=O)CC1.[Si](O[C@@H]1CN(C(OC(C)(C)C)=O)[C@H](C(OCC)=O)CC1)(C(C)(C)C)(C)C.[Si](O[C@H]1CN(C(OC(C)(C)C)=O)[C@@H](C(OCC)=O)CC1)(C(C)(C)C)(C)C.[O:111]1[C:120]2[CH:119]=[C:118]([CH:121]=O)[N:117]=[CH:116][C:115]=2[O:114][CH2:113][CH2:112]1>>[O:111]1[C:120]2[CH:119]=[C:118]([CH2:121][NH:1][C@H:2]3[CH2:7][NH:6][C@H:5]([CH2:15][CH2:16][N:17]4[C:22]5[CH:23]=[C:24]([C:27]#[N:28])[CH:25]=[CH:26][C:21]=5[O:20][CH2:19][C:18]4=[O:29])[CH2:4][CH2:3]3)[N:117]=[CH:116][C:115]=2[O:114][CH2:113][CH2:112]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)CC[C@@H]1CCN1C(=O)COc2ccc(C#N)cc21
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: CC(C)(C)OC(=O)N1C[C@H](N)CC[C@H]1CCN1C(=O)COc2ccc(C#N)cc21
Agent: CCOC(=O)[C@@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: CCOC(=O)[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Product: N#Cc1ccc2c(c1)N(CC[C@@H]1CC[C@@H](NCc3cc4c(cn3)OCCO4)CN1)C(=O)CO2

Procedure:
The product was obtained following the procedure described for Example 105, except, the enantiomer of Intermediate 183, tert-butyl (2S,5R)-5-amino-2-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidine-1-carboxylate (prepared by the exact route as Intermediate 183, but starting from 1-tert-butyl 2-ethyl (2S,5S)-5-{[tert-butyl(dimethyl)silyl]oxy}piperidine-1,2-dicarboxylate, the enantiomer of Intermediate 191) was reacted with 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde to yield the named compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O.CO.CCCCCC>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([C:35](=[O:36])[NH:1][C:2]2[CH:3]=[C:4]3[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]4=[C:7]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:8][C:9]([CH:10]=2)=[C:5]34)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc3c4c(c(-c5ccccc5)[nH]c4c2)C=NNC3=O)CC1
Yield: 70 %

Procedure:
Preparation of example 29 from the title compound of Example 7 (hydrochloride) (22 mg, 0.07 mmol), piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (19 mg, 0.084 mmol), triethylamine (0.015 mL, 0.105 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (32 mg, 0.084 mmol) in CH2Cl2 (0.3 mL) and N,N-dimethylformamide (0.3 mL) was carried out analogously to Example 11. Silica gel chromatography (8:5:2 CH2Cl2:hexane:methanol), also in an analogous manner, afforded the title compound (24 mg, 0.049 mmol) as a yellow powder in 70% yield.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[CH:15][C:16](O)=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.[CH3:49][O:50][C:51](=[O:58])[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][NH2:57]>[Cl-].[Na+].O.CN(C=O)C>[CH3:49][O:50][C:51](=[O:58])[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][NH:57][C:16](=[O:17])[CH:15]=[C:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: COC(=O)CCCCCN
Reactant: O=C(O)C=C1c2ccccc2Oc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCCCCNC(=O)C=C1c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.8 %

Procedure:
2-(9H-xanthen-9-ylidene)acetic acid (238 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxybenzo-triazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 6-aminocaproic acid methyl ester hydrochloride (219 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (321 mg, 88% yield) as a white solid. LC-MS (m/z) 366 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6](Cl)[CH:5]=1.[Br-].[CH:15]1([Zn+])[CH2:19][CH2:18][CH2:17][CH2:16]1>C1COCC1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:5]=1
Reactant: COC(=O)c1cc(Cl)nc(OC)c1
Reactant: [Zn+]C1CCCC1
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC)nc(C2CCCC2)c1
Temperature: 85 °C

Procedure:
Under argon, Pd(dppf) (2.00 g, 2.4 mmol) is added to a solution of 2-chloro-6-methoxy-isonicotinic acid methyl ester (32.0 g, 0.159 mol) in THF (100 mL). A 0.5 M solution of cyclopentylzincbromide in THF (330 mL) is added via dropping funnel. Upon complete addition, the mixture is heated to 85° C. for 3 h before it is cooled to rt. The reaction mixture is concentrated, diluted with 1 N aq. HCl (275 mL) and extracted with TBME (275 mL). The org. extract is washed with 1 N aq. HCl (275 mL), filtered over Celite and washed with water (275 mL). The org. extract is concentrated and dried to give crude 2-cyclopentyl-6-methoxy-isonicotinic acid methyl ester (34.8 g) as a brown oil. This material is dissolved in ethanol (180 mL), water (45 mL) and 32% aq. NaOH solution (45 mL). The mixture is stirred at 90° C. for 30 min before it is cooled to rt. The ethanol is evaporated and the remaining solution is diluted with water (150 mL) and extracted with DCM (200 mL). The aq. phase is acidified by adding 32% aq. HCl (45 mL) and then extracted twice with DCM (2×100 mL). The org. extracts are combined and concentrated. The crude product is purified by crystallisation from hot acetonitrile (174 mL). The crystalline material is collected and dried at 50° C. under HV. From the mother liquor a second crop of crystalline material can be obtained. The two crops are combined to give 2-cyclopentyl-6-methoxy-isonicotinic acid (24.1 g) as a pale grey crystalline powder; LC-MS: tR=0.93 min, [M+1]+=222.02; 1H NMR (CDCl3): δ1.68-1.77 (m, 2H), 1.81-1.90 (m, 4H), 2.03-2.12 (m, 2H), 3.15-3.25 (m, 1H), 3.99 (s, 3H), 7.18 (d, J=1.0 Hz, 1H), 7.35 (d, J=0.8 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](F)[C:3]=1[Cl:10].[CH3:11][O-:12].[Na+]>CO>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:12][CH3:11])[C:3]=1[Cl:10]
Reactant: C[O-]
Reactant: Fc1cc(Cl)cc(Br)c1Cl
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)cc(Br)c1Cl
Temperature: 25 °C
Yield: 97.7 %

Procedure:
1-Bromo-2,5-dichloro-3-fluorobenzene (40 g, 0.16 mol) and sodium methoxide (44.3 g, 0.82 mol) were stirred in methanol (500 ml) at the reflux temperature for 16 hours. The reaction was cooled to ambient temperature then quenched with water (500 ml). The mixture was extracted with diethyl ether (3×300 ml), dried (Na2SO4) and evaporated to afford the product as a white solid (40 g)
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:46]=2[N:47]=[CH:48][N:49]=1)[C@@H:15]1[O:45][C@H:19]([CH2:20][O:21]C(C2C=CC=CC=2)(C2C=CC(OC)=CC=2)C2C=CC(OC)=CC=2)[C@@H:17]([OH:18])[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:50](O[C@@H]1[C@@H](CO)O[C@@H](N2C3N=C(NC(=O)C(C)C)NC(=O)C=3N=C2)C1)([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51]>>[Si:50]([O:18][C@@H:17]1[C@@H:19]([CH2:20][OH:21])[O:45][C@@H:15]([N:14]2[C:46]3[N:47]=[CH:48][N:49]=[C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:11]=3[N:12]=[CH:13]2)[CH2:16]1)([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51]
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)O2)c(=O)[nH]1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1CO

Procedure:
This compound was prepared from N6 -benzoyl-5'-O-(4,4'-dimethoxytrityl)-2'-deoxyadenosine by the same procedure used for the preparation of 3'-O-t-butyldimethylsilyl-N2 -isobutyryl-2'-deoxyguanosine.
Reaction SMILES: [OH-].[K+].C(O)C.C[O:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][C:18]3[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:12][CH:11]=1)=[O:9].Cl>O>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][C:18]3[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:12][CH:11]=1)([OH:9])=[O:7]
Reactant: CCCCCCCCc1ccc2nc(-c3ccc(C(=O)OC)cc3)sc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCc1ccc2nc(-c3ccc(C(=O)O)cc3)sc2c1
Temperature: 65 °C
Yield: 95.7 %

Procedure:
To 0.76 g (11.5 mM) of 85%-potassium hydroxide, 50 ml of ethanol was added, followed by stirring at 65° C. and dissolving. To the resultant solution, 1.80 g (4.72 mM) of 2-(p-methoxycarbonylphenyl)-6-octylbenzothiazole was added, followed by stirring for 20 minutes at 65° C. After the reaction, the reaction mixture was poured into water and 1.5 ml of concentrated hydrochloric acid was added thereto to precipitate a crystal. The crystal was recovered by filtration and sufficiently washed with water, followed by drying to obtain 1.66 g of 2-(p-carboxyphenyl)-6-octylbenzothiazole (Yield: 95.7%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:20][CH2:19][CH2:18][C@@H:17]4[C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([O:28][CH2:29][CH:30]5[CH2:34][O:33]C(C)(C)[O:31]5)[CH:22]=4)=[N:12][C:11]=23)=[O:6])[CH2:3][CH2:2]1>O1CCOCC1.Cl.CCN(C(C)C)C(C)C>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:20][CH2:19][CH2:18][C@@H:17]4[C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([O:28][CH2:29][CH:30]([OH:31])[CH2:34][OH:33])[CH:22]=4)=[N:12][C:11]=23)=[O:6])[CH2:3][CH2:2]1
Reactant: CC1(C)OCC(COc2cc(F)cc([C@H]3CCCN3c3ccn4ncc(C(=O)NC5CC5)c4n3)c2)O1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cc(OCC(O)CO)c3)nc12
Reaction time: 0.03 h
Yield: 82.8 %

Procedure:
A solution of N-cyclopropyl-5-((2R)-2-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Example 206, 30 mg, 0.061 mmol) in dioxane (0.5 mL) was charged with two drops of 6N HCl and shaken for two minutes. DIEA (5 drops) was added and the mixture directly purified by reverse phase column chromatography (0-50% acetonitrile/water) to afford N-cyclopropyl-5-((2R)-2-(3-(2,3-dihydroxypropoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (23 mg, 83% yield) as a clear film. MS (apci) m/z=456.1 (M+H).
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:10]([O:19][CH2:20][C:21]([O:23]C)=[O:22])=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[K+].[Br-]>>[CH2:1]([C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[C:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cc(-c2ccccc2)c(OCC(=O)OC)c(-c2ccccc2)c1
Agent: [Br-]
Agent: [K+]
Product: CCCCCCc1cc(-c2ccccc2)c(OCC(=O)O)c(-c2ccccc2)c1

Procedure:
The title compound was prepared as a white solid (0.559 g, 67%) from (5′-Hexyl-[1,1′;3′,1″]terphenyl-2′-yloxy)acetic acid, methyl ester (0.870 g, 2.161 mmol) using a procedure similar to step 4 of example 165; mp 87-89° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.82-0.86 (m, 3H), 1.22-1.37 (m, 6H), 1.56-1.64 (m, 2H), 2.61 (t, J=7.5 Hz, 2H), 3.71 (s, 2H), 7.16 (s, 2H), 7.32-7.37 (m, 2H), 7.39-7.44 (m, 4H), 7.54-7.59 (m, 4H), 12.47 (broad s, 1H); IR (KBr) 3450, 2920, 1725, 1420, 1210 cm−1; mass spectrum [EI], m/z 388 M+; Anal. Calcd. for C26H2803: C, 80.38; H, 7.26; N, 0.00, Found: C, 79.99; H, 7.24; N, 0.13.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:14]([F:17])([F:16])[F:15])=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-])=O.[Sn](Cl)Cl>Cl>[F:17][C:14]([F:15])([F:16])[C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)c2cccnc12
Agent: Cl
Agent: Cl[Sn]Cl
Product: Nc1ccc(C(F)(F)F)c2cccnc12
Yield: 85.5 %

Procedure:
In a similar fashion using route 1 general procedure 4, 8-nitro-5-(trifluoromethyl)quinoline (Intermediate 33) (820 mg, 3.39 mmol), tin (II) chloride (1.93 g, 10.2 mmol) and 6 N HCl (10 drops) gave the title compound (615 mg, 85%) which was used in the next step without purification.