Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:69]([O:71]C(C)(C)C)=[O:70])[CH2:20][O:21][C:22](=[O:68])[CH2:23][CH2:24][C:25]([O:27][CH2:28][C@H:29]3[O:36][C@H:33]([O:34][CH3:35])[C@H:32]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C@@H:31]([O:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[C@@H:30]3[OH:67])=[O:26])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>C(O)(C(F)(F)F)=O>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:69]([OH:71])=[O:70])[CH2:20][O:21][C:22](=[O:68])[CH2:23][CH2:24][C:25]([O:27][CH2:28][C@H:29]3[O:36][C@H:33]([O:34][CH3:35])[C@H:32]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C@@H:31]([O:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[C@@H:30]3[OH:67])=[O:26])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCCCCCCCCCO[C@H]1[C@@H](OC)O[C@H](COC(=O)CCC(=O)OC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)OC(C)(C)C)[C@@H](O)[C@@H]1OCCCCCCCCCCCCCC
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCO[C@H]1[C@@H](OC)O[C@H](COC(=O)CCC(=O)OC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)[C@@H](O)[C@@H]1OCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
Conjugate 23 (0.2 g, 0.17 mmol) was dissolved in TFA/wet CH2Cl2(1/5, v/v, 4 mL) and the resulting mixture was stirred for 2 h at rt. After that, the volatiles were evaporated under the reduced pressure, the residue was diluted with CH2Cl2 (5 mL) and neutralized with triethylamine (until pH ˜7). The volatiles were removed under the reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate/hexane 1/1, v/v) to obtain the title compound 24 (0.13 g, 0.14 mmol) as a white amorphous solid in 81% yield. Analytical data for 24: Rf=0.58 (methanol/ethyl acetate, 1.5/8.5, v/v); [α]D26+34.9° (c=1.0, CHCl3); 1H NMR (500 MHz, CDCl3/(CD3)2SO, 2/1, v/v): δ, 0.78 (t, 6H, 2×CH3), 1.45 (br. s, 40H, 20×CH2), 1.47 (m, 4H, 2×CH2), 2.5 (m, 4H, 2×CH2), 3.10 (dd, 1H, J2,3=9.4 Hz, H-2), 3.22-3.33 (m, 7H), 3.41-3.51 (m, 3H), 3.55 (m, 1H, H-5), 3.64 (t, 2H, J=6.7 Hz), 4.14-4.32 (m, 7H), 4.42 (d, 1H, J=9.5 Hz), 4.63 (d, 1H, J1,2=3.2 Hz, H-1), 6.52 (br. s, 1H, Ser-NH), 7.22-7.82 (m, 8H, aromatic) ppm; 13C NMR (125 MHz, CDCl3/(CD3)2SO, 2/1, v/v): δ, 13.6, 21.9, 25.4, 25.5, 28.6, 28.8, 28.9, 29.0, 29.5 (×2), 31.2, 39.0, 39.2, 39.3, 39.5, 39.7, 39.8 (×2), 39.9, 40.0, 40.1, 46.6, 54.3, 63.4, 65.6, 69.2, 69.4, 70.6, 72.7, 79.6, 80.7, 97.3, 119.4, 124.6, 124.8, 126.6, 127.1, 140.1, 143.4, 155.4, 171.3, 171.6, 178.3, 178.7 ppm; HR FAB MS [M+Na]+ calcd for C57H89NO13Na 1018.6232. found 1018.6182.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:12]([N:14]2[CH:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=3)=[O:20])[CH2:17][CH:16]=[N:15]2)=[O:13])[CH2:8][C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.Cl.[C:37]1([CH2:43][O:44][NH2:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(Cl)CCl.N1C2C(=NC=CC=2)N(O)N=1>ClCCl>[CH:1]1([CH2:6][C@H:7]([CH2:8][C:9](=[O:11])[NH:45][O:44][CH2:43][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:12]([N:14]2[C@H:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=3)=[O:20])[CH2:17][CH:16]=[N:15]2)=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NOCc1ccccc1
Reactant: O=C(O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)Nc1ccc(F)cn1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1ccc(F)cn1)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.2 %

Procedure:
To a solution of (3R)-3-(cyclopentylmethyl)-4-(5-{[(5-fluoro-2-pyridinyl)amino]carbonyl}-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (283 mg, 0.72 mmol) in dichloromethane (DCM) (10 mL) was added N-methylmorpholine (0.20 mL, 1.88 mmol), O-(phenylmethyl)hydroxylamine hydrochloride (173 mg, 1.08 mmol), EDC (167 mg, 0.87 mmol) and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (99 mg, 0.72 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 4 hours. The reaction mixture was then washed with water (5 mL) and NaHCO3 solution (5 mL×3), and concentrated to provide the crude product as a mixture of diastereomers. This mixture was purified by Gilson HPLC (Sunfire Column 19×50 mm, flowrate 25 mL/min, 10 min, 5-65% MeCN:H2O) to afford (5S)-1-((2R)-2-(cyclopentylmethyl)-4-oxo-4-{[(phenylmethyl)oxy]amino}butanoyl)-N-(5-fluoro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxamide (140 mg, 39% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1>CN(C=O)C.O>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]([CH2:18][CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:25][CH:26]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1cc2c(Cl)nccc2[nH]1
Reactant: FC(F)(F)Oc1ccc(OCCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2c(Cl)nccc2n1CCOc1ccc(OC(F)(F)F)cc1
Temperature: 60 °C
Yield: 71.4 %

Procedure:
To a solution of Methyl 4-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (350 mg, 1.662 mmole) in DMF (6 mL) was added NaH (60% dispersion in mineral oil, 86 mg, 2.160 mmole) portionwise at RT. After gas evolution had ceased a solution of 1-(2-bromoethoxy)-4-(trifluoromethoxy)benzene (616 mg, 2.160 mmole) in DMF (1 mL) was added. After the addition was complete the mixture was heated to 60° C. After 4 hr the mixture was cooled to RT. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with H2O and brine, dried (MgSO4), filtered, and concentrated. Flash column (Biotage-SNAP-25 g SiO2, 30% EtOAc/hexanes) gave the title compound (492 mg, 71%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.21 (d, J=6.0 Hz, 1 H); 7.45 (s, 1 H); 7.42 (d, J=6.0 Hz, 1 H); 7.07 (d, J=8.6 Hz, 2 H); 6.76-6.70 (m, 2 H); 4.93 (t, J=5.13 Hz, 2 H); 4.34 (t, J=5.0 Hz, 3 H); 3.95 (s, 3 H).
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:3]=1.[C:31](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[CH3:31][O:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:23])=[O:24])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(O)cc(S(=O)(=O)c4ccccc4)cc3c2C1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1cc(S(=O)(=O)c2ccccc2)cc2c3c(oc12)CCN(C(=O)OC(C)(C)C)C3
Temperature: 25 °C
Yield: 85.1 %

Procedure:
To a solution of the product of step A (470 mg, 1.06 mmol) in acetone (45 mL) under a nitrogen atmosphere was added potassium carbonate (1.34 g, 9.7 mmol) and dimethylsulfate (0.22 mL, 2.11 mmol). The reaction mixture was refluxed for 2 h, cooled to ambient temperature and filtered. The filtrate was concentrated in vacuo and the residue purified by column chromatography (SiO2, 8:2, hexanes/ethyl acetate) to provide tert-butyl 6-methoxy-8-phenylsulfonyl-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (400 mg, 82%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 7.96-7.94 (m, 2H), 7.71 (br s, 1H), 7.58-7.48 (m, 3H), 7.33 (s, 1H), 4.55 (s, 2H), 4.04 (s, 3H), 3.82 (br s, 2H), 2.87 (br s, 2H), 1.50 (s, 9H).
Reaction SMILES: Cl.[S:2]1[CH:6]=[C:5]([C:7](=[O:24])[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:12][CH2:11]2)[C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]1=2.[BH4-].[Na+].O>CO>[S:2]1[CH:6]=[C:5]([CH:7]([OH:24])[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:12][CH2:11]2)[C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]1=2
Reactant: COc1ccccc1N1CCN(CCC(=O)c2csc3ccccc23)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccccc1N1CCN(CCC(O)c2csc3ccccc23)CC1
Yield: 30 %

Procedure:
To 500 mg of 1-(benzo[b]thiophen-3-yl)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-1-one hydrochloride (1.20×10−3 moles) in 30 ml of MeOH a 0° C. was added NaBH4 for about 20 min until the reaction ceased to evolve. After two hours 50 ml of H2O were added to the medium, it was stirred for a few minutes and was extracted twice with 200 ml of AcOEt. The organic phase was washed three times with H2O, was dried with Na2SO4 and the solvent was removed. It was purified in silica column with AcOEt/hexane (1:1). The free base was thus obtained in form of a white solid. Yield: 30%. Two polymorphic forms of this product were obtained, the melting points of which were 108° C. and 120° C. respectively.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][NH:5][C:6]=1[CH3:7].Br[CH2:10][C:11]1([CH3:15])[CH2:14][O:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][N:5]([CH2:10][C:11]2([CH3:15])[CH2:14][O:13][CH2:12]2)[C:6]=1[CH3:7]
Reactant: Cc1n[nH]c(C)c1Br
Reactant: CC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nn(CC2(C)COC2)c(C)c1Br
Temperature: 70 °C
Yield: 49.5 %

Procedure:
To a 4 mL vial equipped with a magnetic stir bar were added 4-bromo-3,5-dimethyl-1H-pyrazole (150 mg, 0.857 mmol), 3-(bromomethyl)-3-methyloxetane (283 mg, 1.714 mmol), K2CO3 (355 mg, 2.57 mmol), and acetonitrile (2 mL). The contents of the vial were stirred to give a white suspension. The vial was heated in a sand bath to 70° C. for 24 hours, and the reaction mixture was subsequently partitioned between water (15 mL) and ethyl acetate (20 mL). The layers were separated and the aqueous layer was back-extracted with ethyl acetate (20 mL). The combined organic layers were concentrated and the residue was purified via flash chromatography (4 g column) eluting with a gradient of 0-70% EtOAc in heptanes. The pure fractions were combined and concentrated to give the title compound as a clear liquid (110 mg, 49.5%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[N:3]=1.[C-:34]#[N:35].[Na+].[I-].[K+]>CC(N(C)C)=O.O>[CH:11]1([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([C:34]#[N:35])=[N:3][C:4]=3[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: [C-]#N
Reactant: CN1CCN(CCCOc2ccccc2Nc2nc(Cl)nc3c2ncn3C2CCCC2)CC1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN1CCN(CCCOc2ccccc2Nc2nc(C#N)nc3c2ncn3C2CCCC2)CC1
Temperature: 160 °C
Reaction time: 24 h

Procedure:
(2-Chloro-9-cyclopentyl-purin-6-yl)-{2-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-amine (0.1 mmol), sodium cyanide (50 mg), potassium iodide (5 mg) are suspended in DMA (2 ml) and heated up to 160° C. and the mixture is stirred at this temperature for 24 hours. The mixture is diluted with water and extracted 3 times with ethyl acetate. The combined organic phases are washed with brine and the extract is dried over sodium sulfate and evaporated. The residue is dissolved in diethylether, filtered over powdered charcoal and cooled to 4° C. The solid material formed is filtered of and dried (vacuum). A white powder with mp. 136-138PC is obtained.
Reaction SMILES: Br[C:2]1[C:3]([Cl:20])=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:20][C:3]1[C:2]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH3:21])[CH:28]=2)=[CH:7][N:6]=[C:5]2[N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:4]=12
Reactant: COc1cccc(B(O)O)c1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Cl)c(Br)cnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cccc(-c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2Cl)c1
Temperature: 80 °C
Yield: 76.1 %

Procedure:
5-Bromo-4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyri dine (0.750 g, 2.01 mmol, see Example 6), 3-methoxyphenylboronic acid (0.321 g, 2.11 mmol), Pd(PPh3)4 (0.116 g, 0.100 mmol) and K2CO3 (4.20 mL, 3.02 mmol) were added to an Ar degassed solution of 2:1 toluene:EtOH (8 mL). The reaction was then heated to 80° C. overnight. The reaction was then poured into water and extracted with DCM. The organic fractions were dried, filtered, and concentrated to give the crude product. The crude product was purified (1:1 to 1:2 hexane:DCM) to give 4-chloro-5-(3-methoxyphenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.610 g, 75.8% yield).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.[CH3:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][C:42](Cl)=[O:43]>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19](=[O:20])[NH:18][C:15]2[CH:14]=[CH:13][C:12]([N:7]3[CH:6]=[N:5][C:4]4[C:8]3=[N:9][CH:10]=[N:11][C:3]=4[NH:2][C:42](=[O:43])[CH2:41][O:40][CH2:39][CH2:38][O:37][CH2:36][CH2:35][O:34][CH3:33])=[CH:17][CH:16]=2)=[CH:23][C:24]=1[C:29]([F:31])([F:32])[F:30]
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: COCCOCCOCC(=O)Cl
Agent: Cl
Product: COCCOCCOCC(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and 2-[2-(2-methoxyethoxy)ethoxy]acetyl chloride by using the same method as in Example 107.
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:15]([O:1][C:2]1[C:10]([O:11][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]([C:12]([O:14][CH2:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: O=C(O)c1ccc(C(=O)O)c(O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c1OCc1ccccc1
Temperature: 67 °C
Yield: 48 %

Procedure:
1 (101.798 g, 0.514 mol), benzyl chloride (258 mL, 2.242 mol), KI (25.304 g, 0.140 mol), K2CO3 (664.270 g, 4.806 mol), and 1.3 L DMF were combined in a 5-L 3-neck round-bottom flask, yielding a mixture of dark brown solution and undissolved solid. The flask was fitted with a reflux condenser and mechanical stirrer, and placed in a heating mantle. The reaction mixture was heated at 67° C. for 3 d and filtered. The dark brown, clear filtrate was rotovapped to ˜400 mL of opaque, brown, viscous oil, which was dissolved in ˜600 mL DCM. The opaque, brown solution was filtered and extracted with water (5×500 mL). A small amount of brine was used to break up emulsions. The organic layer was dried with MgSO4 and rotovapped to ˜250 mL of dark brown oil. This oil was purified by silica column chromatography (0-5% MeOH in DCM) to yield a hardened brown oil (48%).
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.[CH:10]([C:12]1[S:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:13]=1)=O>CCO>[OH:3][N:2]=[CH:10][C:12]1[S:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(C=O)s1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C=NO)s1
Temperature: 25 °C
Yield: 57.9 %

Procedure:
Hydroxylamine hydrochloride (420 mg, 6.1 mmol) and pyridine (0.5 mL) were added to a solution of methyl 5-formylthiophene-2-carboxylate (690 mg, 4.1 mmol) in EtOH (25 mL). The reaction mixture was refluxed for 3 h, cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in diethyl ether, the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to get product methyl 5-((hydroxyimino)methyl)thiophene-2-carboxylate (440 mg, yield 60%), which was carried through without any further purification. 1H NMR (400 MHz, DMSO-d6) δ 12.5 (s, 1H), 7.98 (s, 1H), 7.78 (d, J=4.1 Hz, 1H), 7.51 (d, J=4.1 Hz, 1H), 3.82 (s, 3H). MS (ESI) m/z: Calculated for C7H7NO3S: 185.01. found: 186.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10][C:11]1[N:15]=[CH:14][NH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][N:23]([CH3:27])[C:24](Cl)=[O:25]>CN(C)C=O>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[S:10][C:11]1[N:15]=[CH:14][N:13]([C:24](=[O:25])[N:23]([CH3:27])[CH3:22])[N:12]=1
Reactant: CN(C)C(=O)Cl
Reactant: Cc1cc(C)c(Sc2nc[nH]n2)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(Sc2ncn(C(=O)N(C)C)n2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-(2,4,6-trimethylphenyl)thio-1H-1,2,4-triazole (220 mg), anhydrous potassium carbonate (280 mg) and N,N-dimethylformamide (1 ml) was added N,N-dimethylcarbamoyl chloride (0.14 ml), and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate-water. The organic layer was washed with water, followed by saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to a silica-gel column chromatography with 10 to 15% (20% 2-propanol/ethyl acetate)/hexane to yield the title compound (276 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([S:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:6][N:5]2[CH:17]=1.Cl[C:19]([O:21][CH3:22])=[O:20].C(=O)(O)[O-].[Na+]>O>[CH3:22][O:21][C:19]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([S:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:6][N:5]2[CH:17]=1)=[O:20]
Reactant: Nc1cn2cc(Sc3ccccc3)ccc2n1
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)Nc1cn2cc(Sc3ccccc3)ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.200 G. of 2-amino 6-(phenylthio) imidazo [1,2-a] pyridine is suspended in 2.2 ml. of water and treated dropwise with 0.0140 gm. of methyl chloroformate. After stirring the reaction mixture for 30 minutes at room temperature, solid sodium bicarbonate (0.111 gm.) is added in small portions. The solids are collected by filtration washed with water and dried. After recrystallization from ethanol, the purified 2-methoxycarbonylamino-6-(phenylthio) imidazo [1,2-a] pyridine m.p. 247°-249° C. is obtained.
Reaction SMILES: Cl.Cl.[CH2:3]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH:14]([NH2:16])[CH3:15])[CH3:4].Cl[C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][NH:22]2.CCN(C(C)C)C(C)C>C(O)CCC>[CH2:3]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH:14]([NH:16][C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][NH:22]2)[CH3:15])[CH3:4]
Reactant: CCn1c(C(C)N)nc2ccccc21
Reactant: Clc1ncnc2[nH]cnc12
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(C(C)Nc2ncnc3[nH]cnc23)nc2ccccc21
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(1-ethyl-1H-1,3-benzodiazol-2-yl)ethan-1-amine dihydrochloride (346 mg, 1.32 mmol), 6-chloro-9H-purine (204 mg, 1.32 mmol) and DIPEA (904 μL, 5.28 mmol) in n-butanol (2.5 mL) was stirred in a sealed tube for 3 h at 120° C. After cooling to RT, the crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) and triturated with a mixture EtOAc/diethyl ether, filtered and further washed with additional diethyl ether affording racemic 107 as a pale pink solid (182 mg, 45%). LCMS: RT 2.18 min [M+H]+ 308.1. 1H NMR (CDCl3, 400 MHz): δ 8.51 (1H, s), 7.95 (1H, s), 7.76 (1H, d, J=7.17 Hz), 7.39-7.34 (1H, m), 7.31-7.15 (3H, m), 6.03 (1H, br), 4.51-4.39 (1H, m), 4.37-4.26 (1H, m), 1.97-1.80 (4H, m), 1.43 (3H, t, J=7.21 Hz)
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:49][NH:48]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:48]4[CH2:49][C:50]5[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=5)[CH2:47]4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: c1ccc2c(c1)CNC2
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2Cc3ccccc3C2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with 2,3-dihydro-1H-isoindole (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C44H50Cl2N5O3 [(M+H)+] 766.3285, observed 766.3286.
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].[C:6]1([S:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:6]1([S:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[S:1][CH2:2][C:3]([OH:5])=[O:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)CS
Reactant: O[C@@H]1CCCC[C@H]1Sc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CS[C@@H]1CCCC[C@H]1Sc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Mercaptoacetic acid (0.44 g, 0.0048 mole) was added to a cold solution of the compound of Example 6 (1.0 g, 0.0048 mole) in methylene chloride (5 ml) containing trifluoracetic acid (3.5 ml). The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated to an oil with a rotary evaporator. The residue was dissolved in diethyl ether (50 ml), washed three times with 20 ml of 5% sodium bicarbonate, followed by in hydrochloric acid (10 ml) and water (20 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to a colorless oil with a rotary evaporator. The product was purified by silica gel chromatography. The structure was supported by NMR, infrared spectroscopy and elemental analysis.