Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[N:4][CH:3]=1.[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C(Cl)(Cl)Cl>[O:20]([C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[N:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccccc1
Reactant: Clc1cncc(N2CCNCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: c1ccc(Oc2cncc(N3CCNCC3)n2)cc1
Temperature: 165 °C
Reaction time: 4.5 h

Procedure:
A mixture of the product obtained in example 13, step 2 (1.97 g, 9.92 mmol), phenol (2.43 g, 25.8 mmol), CuO (1.0 g, 12.6 mmol), and K2CO3 (1.43 g, 10.3 mmol) in dioxane (2 mL) was stirred for 4.5 h at 165° C. in a sealed pyrex tube. The reaction mixture was diluted with CHCl3 and filtered through a pad of Celite. The pad was washed with several portions of CHCl3/MeOH (95:5). Solvent removal in vacuo furnished a dark brown oil which was purified by column chromatography on silica gel (14×5 cm) using CHCl3/MeOH (95:5, followed by 90:10) as eluent. The brown oil (1.66 g) was subjected to repeated column chromatography, first on silica gel (18×4 cm) using CHCl3/MeOH (9:1) as eluent and finally on alumina (4×5 cm) using ether/MeOH (95:5) as eluent. This furnished 1.37 g (54%) of the title compound as a light beige oil. HRMS m/z calcd for C14H16N4O (M)+ 256.1324, found 256.1321. Anal. (C14H16N4O) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([N:9]=[C:10]=[O:11])([CH3:8])[CH3:7])=[CH:4][CH:3]=1.[C-]#N.[CH2:16]([NH:20][CH3:21])[CH:17]([CH3:19])[CH3:18]>>[CH2:16]([N:20]([CH3:21])[C:10]([NH:9][C:6]([CH3:8])([CH3:7])[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=1)=[O:11])[CH:17]([CH3:19])[CH3:18]
Reactant: CNCC(C)C
Reactant: CC(C)(N=C=O)c1ccc(Cl)cc1
Agent: [C-]#N
Product: CC(C)CN(C)C(=O)NC(C)(C)c1ccc(Cl)cc1
Yield: 92.2 %

Procedure:
3.9 g of p-chloro-α,α-dimethylbenzyl isocyanate, prepared from the corresponding cyanide in the same way as in Synthesis Example 1, was added to 1.9 g of N-i-butyl-N-methylamine. The precipitated crystals were separated by filtration and recrystallized from n-hexane to obtain 5.2 g of the title compound.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:31]=[CH:30][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[F:29])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:49][C:50]1[CH:55]=[CH:54][C:53]([O:56][CH2:57][CH:58]2[CH2:60][O:59]2)=[CH:52][CH:51]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[F:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([F:28])[C:22]=1[CH2:21][NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:60][C@H:58]([OH:59])[CH2:57][O:56][C:53]3[CH:54]=[CH:55][C:50]([OH:49])=[CH:51][CH:52]=3)=[CH:31][CH:30]=2)[CH2:13][CH2:14]1)=[O:19]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(NC2CCN(C(=O)NCc3c(F)cccc3F)CC2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=CO
Product: O=C(NCc1c(F)cccc1F)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 20.9 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(2,6-difluorobenzyl)-1-piperidinecarboxamide formate (0.50 g, 1.15 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.465 g, 1.15 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.192 g, 0.24 mmol).
Reaction SMILES: C([NH:4][C@:5]1([C:22](NC(C)(C)C)=[O:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH2:8][NH:7][CH2:6]1)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].[NH:36]1[CH:40]=[C:39]([CH:41]=O)[N:38]=[CH:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=[O:45])C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl.C(O)(=O)C>[NH:36]1[CH:40]=[C:39]([CH2:41][N:7]2[CH2:8][C@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[C@:5]([NH2:4])([C:22]([OH:23])=[O:45])[CH2:6]2)[N:38]=[CH:37]1
Reactant: O=Cc1c[nH]cn1
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: N[C@@]1(C(=O)O)CN(Cc2c[nH]cn2)C[C@@H]1CCCB(O)O
Reaction time: 2 h
Yield: 25.7 %

Procedure:
A stirred solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and imidazole-4-carboxaldehyde (110 mg, 0.7 mmol), stirred for 2 h, then treated with sodium triacetoxyborohydride (212 mg, 1.0 mmol) and glacial acetic acid (2 drops) and stirred for 16 h. Aqueous sodium carbonate (10%, 5 mL) was added and the mixture stirred for a few minutes and extracted with ethyl acetate (30 mL, then 2×10 mL). The combined organic solution was washed with water and saturate aqueous sodium chloride (20 mL each), dried (MgSO4), and concentrated. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-1-((1H-imidazol-4-yl)methyl)-3-amino-4-(3-boronopropyl)pyrrolidine-3-carboxylic acid (38 mg, 21%) as a pale yellow granular solid. NMR (D2O) 8.74 (s, 1 H), 7.71 (s, 1 H), 4.60-4.80 (m, 2 H), 3.96 (d, J=12.5 Hz, 1H), 3.80 (dd, J1=11 Hz, J2=8 Hz, 1 H), 3.71 (d, J=12.5 Hz, 1 H), 3.40 (t, J=11.5 Hz, 1 H), 2.50-2.65 (m, 1 H), 1.50-1.65 (m, 1 H), 1.15-1.35 (m, 3 H), 0.60-0.70 (m, 2 H). MS (m−H2O+1): 279.0; MS (m−2 H2O+1): 261.3.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]([CH3:14])([C:11]([OH:13])=[O:12])[CH3:10])=[C:6]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:4][CH:3]=1.[CH3:18]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].IC>O>[CH3:18][O:12][C:11](=[O:13])[C:9]([CH3:10])([CH3:14])[NH:8][C:7]1[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=1[N+:15]([O-:17])=[O:16]
Reactant: CN(C)C=O
Reactant: CC(C)(Nc1c(Cl)cccc1[N+](=O)[O-])C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COC(=O)C(C)(C)Nc1c(Cl)cccc1[N+](=O)[O-]
Reaction time: 16 h

Procedure:
A mixture of N-(6-chloro-2-nitrophenyl)-2-methylalanine (X, EXAMPLE 14, 11.4 g), DMF (130 ml), potassium carbonate (18.2 g) and iodomethane (13.8 ml) is stirred at 20°-25° for 16 hr, diluted with water, extracted several times with ether. The ether phases are combined and are washed with water and saline, dried over magnesium sulfate and concentrated to give the title compound, IR (mineral oil) 3369, 2990, 2951, 1738, 1598, 1534, 1492, 1451, 1386, 1337, 1277, 1188, 1145, 1103 and 749 cm-1 ; NMR (CDCl3) 7.97, 7.55, 6.94, 6.89, 3.78 and 1.53 δ; MS (m/z) 272 and 213.
Reaction SMILES: [OH:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[C:8]1([Mg]Cl)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl-].[NH4+]>ClCCl.O=[Mn]=O>[C:8]1([CH:3]2[CH2:4][O:5][CH2:6][CH2:7][N:2]2[OH:1])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: ON1CCOCC1
Agent: O=[Mn]=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: ON1CCOCC1c1ccccc1
Reaction time: 1 h
Yield: 10.2 %

Procedure:
Activated MnO2 (0.65 g, 7.41 mmol) was added to a solution of N-hydroxymorpholine (0.25 g, 2.47 mmol) in dichloromethane (15 mL) at 0° C. and the mixture was stirred for 1 h. The reaction mixture was filtered through a pad of Celite™ and Na2SO4. The filtrate was added dropwise to a solution of phenylmagnesium chloride (2.0 M in tetrahydrofuran, 2.47 mL, 4.94 mmol) at −10° C. The reaction mixture was stirred at 0° C. for 0.5 h and then saturated aqueous ammonium chloride solution (15 mL) and dichloromethane (15 mL) were added. The aqueous phase was separated and extracted with dichloromethane (2×20 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude product was subjected to flash chromatography on SiO2 eluting with 25% diethyl ether in hexanes to give the title compound (0.045 g, 11%) as a white crystalline solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@@H:17]([CH3:25])[C:18]([O:20]C(C)(C)C)=[O:19])[C:13]1=[O:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@@H:17]([CH3:25])[C:18]([OH:20])=[O:19])[C:13]1=[O:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](C(=O)O)N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.1 %

Procedure:
tert-Butyl (2S)-2-((3S)-3-{[(benzyloxy)carbonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (0.5 g) was dissolved in DCM (7 ml), and trifluoroacetic acid (4.7 ml) was added. The mixture was stirred at room temperature for 1.5 h and then concentrated under reduced pressure to give the title compound (0.423 g) as a colourless oil which after azeotroping with toluene, crystallised.
Reaction SMILES: F[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1.[Br:29]C1C=CC2SC(I)=NC=2C=1>>[Br:29][C:28]1[CH:2]=[CH:3][C:4]2[S:8][C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)=[N:6][C:5]=2[CH:27]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(F)cc2s1
Reactant: Brc1ccc2sc(I)nc2c1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2cc(Br)ccc2s1

Procedure:
Same procedure as 3-(6-fluorobenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine except using 5-bromo-2-iodo-1,3-benzothiazole in place of 2-chloro-6-fluorobenzothiazole to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.11-2.30 (m, 4H), 3.11 (q, J=11.0 Hz, 2H), 3.41 (d, J=12.8 Hz, 2H), 4.47-4.56 (m, 1H), 7.74 (dd, J=8.6, 2.0 Hz, 1H), 8.03-8.08 (m, 2H), 8.34 (br. s., 1H), 8.39 (s, 1H), 8.51 (d, J=1.4 Hz, 1H), 8.54 (d, J=2.2 Hz, 1H). MS (ES+): m/z=455.02/457.00 [MH+]. HPLC: tR=2.19 min (ZQ2, polar—5 min).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([N:8]1[CH2:10][CH2:9]1)=[O:7])([O-:3])=[O:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([OH:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C1C=CC=CC=1>CO>[ClH:15].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([OH:28])[CH2:23][CH2:24][N:25]([CH2:9][CH2:10][NH:8][C:6](=[O:7])[C:5]3[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=3[N+:1]([O-:3])=[O:2])[CH2:26][CH2:27]2)=[CH:18][CH:17]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: O=C(c1ccccc1[N+](=O)[O-])N1CC1
Solvent: CO
Solvent: c1ccccc1
Product: Cl
Product: O=C(NCCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1ccccc1[N+](=O)[O-]

Procedure:
A mixture of 7.6 parts of 1-(2-nitrobenzoyl)aziridine, 8.46 parts of 4-(4-chlorophenyl)-4-piperidinol, 43.2 parts of benzene and 6.4 parts of methanol is stirred and refluxed for 1.50 hours. The reaction mixture is cooled and the product is extracted with trichloromethane. The extract is washed three times with water, dried, filtered and evaporated. The residue is converted into the hydrochloride salt in 2-propanone. The salt is filtered off and crystallized from a mixture of ethanol and 2,2'-oxybispropane. The product is filtered off and dried, yielding 6parts of N-{2-[4-(4-chlorophenyl)-4- hydroxy-1-piperidinyl]ethyl}-2-nitrobenzamide hydrochloride; mp. 174.1° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12](N3C=CN=C3)[N:11]3[C:19](=[O:22])[NH:20][N:21]=[C:10]3[C:9]=2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:37][C:38]1[CH:39]=[CH:40][C:41]([C:44]([F:47])([F:46])[F:45])=[N:42][CH:43]=1.[OH2:48]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:48])[N:11]3[C:19](=[O:22])[N:20]([CH2:37][C:38]4[CH:43]=[N:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=4)[N:21]=[C:10]3[C:9]=2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1
Reactant: O
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(-n3ccnc3)n12
Reactant: FC(F)(F)c1ccc(CCl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1[nH]c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7,8-bis(4-chlorophenyl)-5-(1H-imidazol-1-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (60 mg, 0.14 mmol) in DMF (0.5 mL) at room temperature under argon was added K2CO3 (25 mg, 0.18 mmol), followed by 5-(chloromethyl)-2-(trifluoromethyl)pyridine (28 mg, 0.14 mmol). The reaction mixture was stirred at 50° C. in a pre-heated oil bath for 30 min. After the reaction mixture was cooled to room temperature, water (5 mL) and EtOAc (5 mL) were added. The layers were separated. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product thus obtained was purified by preparative reverse phase HPLC (without TFA) to obtain 22.5 mg of the title compound as a white solid. HPLC/MS: retention time=3.871 min, [M+H]30 =532.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([CH2:18][OH:19])[O:12]2)=[C:4](Cl)[N:3]=1.[CH:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1.CN(C)C>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([CH2:18][OH:19])[O:12]2)=[C:4]([NH:26][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[N:3]=1
Reactant: NC1CCCC1
Reactant: Nc1nc(Cl)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Agent: CN(C)C
Solvent: CCO
Product: Nc1nc(NC2CCCC2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To suspension of (4S,2R,3R,5R)-2-[2-amino-6-chloro-purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol in 15 mL of ethanol was added 0.4 g of cyclopentyl amine and 10 mmol of trimethyl amine. The mixture was stirred at 80° C. for 24 hours. The residue was purified using preparative thin layer chromatography (15:1 dichloromethane:methanol) to yield (4S,2R,3R,5R)-2-[2-amino-6-(cyclopentylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol, a compound of formula (8).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[C:20]([C:22]#[C:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=[C:18]([CH2:28]O)[CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].CS(Cl)(=O)=O.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>C(Cl)Cl.C(N(CC)CC)C.C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[C:20]([C:22]#[C:23][Si:24]([CH3:26])([CH3:27])[CH3:25])[CH:19]=[C:18]([CH2:28][N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: C1CCNC1
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(C#C[Si](C)(C)C)cc(CO)c1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(C#C[Si](C)(C)C)cc(CN2CCCC2)c1
Reaction time: 8 h

Procedure:
398 mg of the ethyl (RS)-(4-cyano-phenylamino)-(3-hydroxymethyl-5-trimethylsilanylethynyl-phenyl)-acetate described in Example 156.3 were dissolved in 6 ml of CH2Cl2 g and 0.41 ml of triethylamine followed by 0.1 ml of methanesulphonyl chloride were added dropwise at 0° C. The mixture was stirred overnight and an intermediate was then isolated by extraction. This was taken up in 5 ml of THF and stirred together with 0.41 ml of triethylamine and 0.32 ml of pyrrolidine. By repeat extraction there was obtained a crude product, which was purified by column chromatography (cyclohexan/ethyl acetate). There were obtained 130 mg of ethyl (RS)-(4-cyano-phenylamino)-(3-pyrrolidin-1-ylmethyl-5-trimethylsilanylethynyl-phenyl)-acetate as a light brown solid; MS: 460 ([M]+).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:13][C:14](=[O:31])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C@@H:25]([CH2:26][OH:27])[CH2:24][C:23]([CH3:29])([CH3:28])[C:22]1=[O:30])[CH3:12].C(N(CC)CC)C>ClCCl>[CH2:11]([O:13][C:14](=[O:31])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C@@H:25]([CH:26]=[O:27])[CH2:24][C:23]([CH3:28])([CH3:29])[C:22]1=[O:30])[CH3:12]
Reactant: CCOC(=O)CCCCCCN1C(=O)C(C)(C)C[C@@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)CCCCCCN1C(=O)C(C)(C)C[C@@H]1C=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
A solution of dimethylsulfoxide (0.93 mL, 12 mmol) in dichloromethane (40 mL) was cooled to −78° C. under nitrogen, and a solution of oxalyl chloride (0.820 mL, 9.4 mmol) in dichloromethane (3 mL) was added to it, over a 2 minute period. The reaction mixture was left stirring at −78° C. for 30 minutes. A solution of 7-((R)-5-hydroxymethyl-3,3-dimethyl-2-oxo-pyrrolidin-1-yl)-heptanoic acid ethyl ester (2.25 g, 7.5 mmol) in dichloromethane (20 mL) was added slowly. When the addition was complete, the reaction flask was stirred for 15 minutes at −78° C. Finally, triethylamine (2.1 mL, 15.0 mmol) was added slowly to the reaction flask; it was left to reach room temperature and stirred for an additional 15 minutes. It was then quenched by adding 20 mL of water and 20 mL of diethyl ether, and extracted with dichloromethane. The organic phase was dried over potassium carbonate and concentrated to dryness. The crude mixture was purified by chromatography on silica gel using hexane:ethyl acetate 2:1 as a solvent giving 1.5 g of 7-((R)-5-formyl-3,3-dimethyl-2-oxo-pyrrolidin-1-yl)-heptanoic acid ethyl ester.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=[C:10]([NH:15][C:16]([CH3:18])=[O:17])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[S:19]([OH:22])(=O)=[O:20])(=[O:3])[CH3:2].S1(CCCC1)(=O)=O.P(Cl)(Cl)([Cl:32])=O>>[C:1]([O:4][C:5]1[C:14]2[C:9](=[C:10]([NH:15][C:16]([CH3:18])=[O:17])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[S:19]([Cl:32])(=[O:22])=[O:20])(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)Nc1cccc2c(OC(C)=O)c(S(=O)(=O)O)ccc12
Solvent: O=S1(=O)CCCC1
Product: CC(=O)Nc1cccc2c(OC(C)=O)c(S(=O)(=O)Cl)ccc12
Temperature: 40 °C
Yield: 81 %

Procedure:
100 g of 1-acetoxy-5-acetaminonaphthalene-2-sulfonic acid was added to 500 ml of sulfolane, and 200 ml of phosphorus oxychloride was dropwise added thereto at 40° C. while stirring. After continuing stirring for about 1 hour, the reaction mixture was poured into 2 liters of ice-water, and the precipitated crystals were collected by filtration, washed with water until the filtrate did not show acidity, and air-dried as such for 24 hours to obtain 70 g (81% yield) of product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:3]=1.[N-:16]=[N+]=[N-].[Na+].O.[BH4-].[Na+]>CN(C=O)C.CO>[NH2:16][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(Cl)cc(C(F)(F)F)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N)cc(C(F)(F)F)n1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 4-chloro-6-trifluoromethylpyridine-2-carboxylate (2.44 g, 10.2 mmol) in aqueous DMF was added NaN3 (0.7 g, 10.8 mmol). The resulting mixture was heated at 70° C. for 18 hr, added to H2O and extracted (3×) with Et2O. The organic layer was concentrated to yield a white solid that was dissolved in 10 mL of MeOH. Excess NaBH4 was added and the reaction mixture stirred at RT for 0.5 hr. This material was added to H2O, extracted (3×) with Et2O. The extract was dried over MgSO4 and concentrated. The resulting residue was purified via flash column chromatography to give 0.95 of product as a white solid; mp 114° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C@@H:7]([C:12]([OH:14])=[O:13])[NH:8][CH2:9]2)=[CH:4][CH:3]=1.[ClH:15].[CH3:16]O>>[ClH:15].[CH3:16][O:13][C:12]([C@@H:7]1[CH2:6][C:5]2[C:10](=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)[CH2:9][NH:8]1)=[O:14]
Reactant: CO
Reactant: O=C(O)[C@@H]1Cc2ccc(O)cc2CN1
Agent: Cl
Product: COC(=O)[C@@H]1Cc2ccc(O)cc2CN1

Procedure:
To a suspension of (S)-7-hydroxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid dehydrate (109 mmol) in methanol (150 mL) was added hydrochloric acid (27 mL of 4M solution in dioxane.) at r.t and the reaction mixture was refluxed for 4 h. The mixture was concentrated, resuspended in 150 mL of MeOH and hydrochloric acid (27 mL of 4M solution in dioxane.) added. The mixture refluxed for 4 h and was concentrated under reduced pressure. The residue was triturated with ether, filtered and washed with ether to give (S)-7-hydroxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid methyl ester hydrochloride salt (25.1 g). 1H NMR (400 MHz, DMSO d6): 10.1 (m, 2H), 9.62 (s, 1H), 7.03 (d, 1H), 6.7 (m, 1H), 6.26 (d, 1H), 4.48 (m, 1H), 4.21 (s, 2H), 3.77 (s, 3H), 3.17-2.96 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>O>[Br:1][C:2]1[C:3](/[N:9]=[CH:12]/[N:13]([CH3:15])[CH3:14])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: Nc1ncc(Cl)cc1Br
Solvent: O
Product: CN(C)/C=N/c1ncc(Cl)cc1Br
Temperature: 100 °C
Reaction time: 1 h
Yield: 63483.8 %

Procedure:
A mixture of 3-bromo-5-chloropyridin-2-amine (10 g, 0.05 mol) and dimethoxy-N,N-dimethylmethanamine (7 g, 0.06 mmol) was stirred at 100° C. for 1 h. The mixture was poured into water and then extracted with Ethyl acetate (20 mL×4). The combined organic layer was concentrated under reduced pressure and the residue was purified with silica gel chromatography eluting with Ethyl acetate/PE (1:2) to afford 108a (10 g, 77%). LCMS: [M+H]+ 262.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:27][O:28][CH2:29][CH3:30])[N:21]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[C:17]=2[C:16]2[CH:15]=[CH:14][C:13]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][NH:43][C:44](=[O:67])[CH2:45][CH2:46][S:47]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:12][C:11]=2[N:10]=1.C([SiH](CC)CC)C>ClCCl>[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:27][O:28][CH2:29][CH3:30])[N:21]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[C:17]=2[C:16]2[CH:15]=[CH:14][C:13]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][NH:43][C:44](=[O:67])[CH2:45][CH2:46][SH:47])=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCCOCCOCCOCCNC(=O)CCSC(c4ccccc4)(c4ccccc4)c4ccccc4)ccc3c2n1CC(C)(C)O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(OCCOCCOCCOCCNC(=O)CCS)ccc3c2n1CC(C)(C)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
Trifluoroacetic acid (8 mL) was added to a 0° C. solution of N-(2-{2-[2-(2-{[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethoxy)ethoxy]ethoxy}ethyl)-3-(tritylthio)propanamide (1.38 g, 1.65 mmol) and triethylsilane (3.16 mL, 19.8 mmol) in dichloromethane (12 mL). The solution was stirred at 0° C. for 2 hours, then was concentrated under reduced pressure. The residue was concentrated under reduced pressure from toluene several times. The crude product was purified twice by HPFC on silica gel (gradient elution with 2-70% CMA in chloroform) to provide 0.55 g of N-(2-{2-[2-(2-{[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethoxy)ethoxy]ethoxy}ethyl)-3-mercaptopropanamide as a foam. MS (ESI) m/z 594 (M+H)+. Anal. Calcd for C28H43N5O7S: C, 56.64; H, 7.30; N, 11.80; S, 5.40. Found: C, 56.36; H, 7.52; N, 11.53; S, 5.34.