Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][NH:41][C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)[CH2:34][CH2:33]1>C1COCC1>[CH3:31][N:32]1[CH2:33][CH2:34][N:35]([CH2:38][CH2:39][CH2:40][NH:41][C:42]2[CH:43]=[CH:44][C:45]([NH:48][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:30])=[CH:46][CH:47]=2)[CH2:36][CH2:37]1
Reactant: CN1CCN(CCCNc2ccc(N)cc2)CC1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(NCCCN4CCN(C)CC4)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 51 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 100 mg, 0.249 mmol) and THF (2.5 mL). To the resulting solution was added N-[3-(4-Methyl-piperazin-1-yl)-propyl]-benzene-1,4-diamine (prepared below, 86.2 mg, 0.347 mmol), and the mixture was stirred for 24 h at 65° C. The reaction mixture was cooled to room temperature and then diluted with Hexanes (˜40 mL). The black precipitate that formed was removed by filtration and the filtrate was concentrated in vacuo. The crude residue was dissolved in EtOAc (˜5 mL) and triturated with Hexane (˜50 mL) to give a yellow precipitate. The precipitate was filtered and washed with 0° C. i-prOH (˜5 mL) yielding 51% (0.0802 g, 0.127 mmol) of the title compound.
Reaction SMILES: [I:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6]([CH2:9][CH2:10][NH2:11])=[CH:7][O:8][C:4]=2[CH:3]=1.CO.[CH3:16][C:17]([CH3:19])=O>>[I:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6]3[CH2:9][CH2:10][NH:11][C:17]([CH3:19])([CH3:16])[C:7]=3[O:8][C:4]=2[CH:3]=1
Reactant: CC(C)=O
Reactant: NCCc1coc2cc(I)ccc12
Solvent: CO
Product: CC1(C)NCCc2c1oc1cc(I)ccc21
Temperature: 25 °C

Procedure:
To a solution of 2-(6-iodo-benzofuran-3-yl)-ethylamine (4.20 g, 14.63 mmol) in methanol (60.0 mL, 1.48 mol) was added acetone (1.63 mL) and the reaction mixture was stirred at rt. After 2 days the solvent was evaporated. The residue was dissolved in a mixture of TFA (7.0 mL) and DCE (70.0 mL) and heated to reflux. After 20 h the reaction mixture was cooled down and basified with 5M aq. NaOH. The layers were separated and the aqueous phase extracted with DCM. The combined organic layers was dried (Na2SO4) and the solvent was evaporated. The residue was purified on a silica gel column eluting with DCM-MeOH—NH4OH to afford 7-iodo-1,1-dimethyl-1,2,3,4-tetrahydro-benzo[4,5]furo[2,3-c]pyridine as an off-white solid. mp 97-98° C.; MS m/z 328 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:10])=[CH:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].N1C=CC=CC=1.[CH3:17][OH:18]>>[CH3:17][O:18][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH:3]=[C:2]([F:10])[F:1]
Reactant: O=C(Cl)CCCC=C(F)F
Reactant: CO
Solvent: c1ccncc1
Product: COC(=O)CCCC=C(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
42.1 g of 6,6-difluorohex-5-enoic acid chloride are added slowly at 10° to 17.6 g of pyridine in 200 ml of methanol. The mixture is then stirred at room temperature for 5 hours. The excess methanol is evaporated off in a rotary evaporator and the residue is taken up in tert-butyl methyl ether and washed with water. The organic phase is dried over sodium sulfate and concentrated to dryness by evaporation. The residue is distilled at 60 mbar. The title compound is obtained in the form of a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)=[O:4].C([N:16](CC)CC)C.ClC(OCC)=O.[OH-].[NH4+]>O1CCCC1.O>[C:11]([C@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7]1)(=[O:13])[NH2:16]
Reactant: CCN(CC)CC
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Agent: CCOC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H]1CC[C@H](C(N)=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a cooled (−10° C.) solution of trans-4-(methoxycarbonyl)cyclohexane-1-carboxylic acid (1.01 g, 5.43 mmol) in tetrahydrofuran (25 mL) was sequentially added triethylamine (1.50 mL, 10.9 mmol) and ethyl chloroformate (0.60 mL, 6.2 mmol) under a nitrogen atmosphere and the reaction mixture stirred at room temperature for 3 h. The reaction was then cooled to −10° C., ammonium hydroxide (5.0 mL, 33 mmol) was added and the reaction mixture warmed to room temperature and stirred overnight whereupon the mixture was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried and concentrated to give the title compound (0.84 g, 84%) as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:12]=[C:13]([C:16]#[N:17])[S:14][CH:15]=2)[N:9]=[C:8]([C:18]([F:21])([F:20])[F:19])[CH:7]=1.[NH:22]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:23]([C:25](ON1C(=O)CCC1=O)=[O:26])[CH3:24].C(N(CC)CC)C>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:12]=[C:13]([CH2:16][NH:17][C:25](=[O:26])[C@@H:23]([NH:22][C:35](=[O:36])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH3:24])[S:14][CH:15]=2)[N:9]=[C:8]([C:18]([F:20])([F:21])[F:19])[CH:7]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: N#Cc1cc(-n2nc(C(F)(F)F)cc2-c2ccco2)cs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1cc(-n2nc(C(F)(F)F)cc2-c2ccco2)cs1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 50.6 %

Procedure:
To a solution of compound 14 (0.907 g, 2.93 mmol) at 0 degrees in THF (3 mL) and under nitrogen was slowly added 1M borane tetrahydrofuran complex (11.73 mL, 11.73 mmol). The yellow solution was then stirred for 50 minutes at room temperature. It was cooled to 0 degrees and then slowly quenched with methanol (approx. 4 mL). After 10 minutes of stirring at room temperature the reaction solution was concentrated under reduced pressure to a yellow, gummy solid and dried under a high vacuum pump. The crude amine 5 was then dissolved in DCM (15 mL) at zero degrees and to this was added BOC-Ala-OSu (0.839 g, 2.93 mmol) followed by triethylamine (0.898 mL, 6.45 mmol). The reaction was stirred at zero degrees for 1 hour and at room temperature for 16 hours. The solvent was then removed under reduced pressure and the residue partitioned between ethyl acetate and saturated NH4Cl. The layers were separated and the ethyl acetate phase washed further with saturated NH4Cl and then brine, dried over Na2SO4, filtered and concentrated. The residue was absorbed onto silica gel and then purified by silica gel chromatography using a 40M Biotage column with a gradient of 20 to 60% ethyl acetate and hexanes to give compound 6 (0.718 g, 51%) as a white crusty solid. LRMS (ESI): calc. 484.1; found 385.1 (MH-Boc)+, 507.2 (MNa)+.
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8]([NH2:17])([C:14]([OH:16])=[O:15])[CH2:9]2)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:25](=O)([O:41]N1C(=O)CCC1=O)[O:26][CH2:27][CH:28]1[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2>C(#N)C.O>[C:25]([CH:9]1[C:10]2[C:5](=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:7][C:8]1([NH2:17])[C:14]([OH:16])=[O:15])([O:26][CH2:27][CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:35]2[C:40]1=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:41]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: CC(C)c1cccc2c1CCC(N)(C(=O)O)C2
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)c1cccc2c1CCC(N)(C(=O)O)C2C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 42.7 %

Procedure:
A mixture of racemic 5-isopropyl-2-aminotetraline-2-carboxylic acid (250 mg, 1.07 mmole), triethylamine (1.2 ml, 8.61 mmole), 9-fluorenylmethyl succinimidyl carbonate (Fmoc-OSu, 2.70 g, 8.00 mmole) in acetonitrile (30 ml) and water (30 ml) was stirred at room temperature for 2 days. The reaction mixture was concentrated in vacuo to remove most of the acetonitrile, acidified to pH 3 with 10% aqueous citric acid solution, and the white emulsion was extracted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. Filtration and concentration gave a crude oil which was purified by column chromatography (eluted with 2→5→8% methanol/methylene chloride) to give racemic Fmoc-5-isopropyl-2-aminotetraline-2-carboxylic acid (208 mg, 43% yield) as an off-white foam. HRMS (FAB): C29H30NO4 (M+H) calc. 456.2175; observed: 456.2184.
Reaction SMILES: N1C=CC=CN=1.C([O:14][C:15]1[N:16]=[N:17][C:18]([C:29]#[C:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)=[CH:19][C:20]=1[O:21]CC1C=CC=CC=1)C1C=CC=CC=1>C(OCC)(=O)C>[Cl:37][C:33]1[CH:32]=[C:31]([CH2:30][CH2:29][C:18]2[CH:19]=[C:20]([OH:21])[C:15](=[O:14])[NH:16][N:17]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: Clc1cccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Solvent: CCOC(C)=O
Solvent: c1ccnnc1
Product: O=c1[nH]nc(CCc2cccc(Cl)c2)cc1O
Yield: 32 %

Procedure:
Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(3-chloromethyl)phenyl)ethynyl]pyridazine (Intermediate 24) except that the reaction was carried out in ethyl acetate. The crude material was purified by reverse phase chromatography (50 g C18) cartridge eluting with 5-100% acetonitrile/water with acidic modifier and the appropriate fractions combined to give an orange solid. This was recrystallised from ethyl acetate to give a white solid (yield=32%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([N+:15]([O-:17])=[O:16])=[CH:5][C:6]1[C:14]2[C:10](=[N:11][O:12][N:13]=2)[CH:9]=[CH:8][CH:7]=1.[Na].[CH:20]([O:23][C:24](=[O:29])[CH2:25][C:26]([CH3:28])=[O:27])([CH3:22])[CH3:21].Cl>O1CCOCC1.CCOCC>[CH3:1][O:2][C:3](=[O:18])[CH:4]([N+:15]([O-:17])=[O:16])[CH:5]([C:6]1[C:14]2[C:10](=[N:11][O:12][N:13]=2)[CH:9]=[CH:8][CH:7]=1)[CH:25]([C:24]([O:23][CH:20]([CH3:22])[CH3:21])=[O:29])[C:26](=[O:27])[CH3:28]
Reactant: COC(=O)C(=Cc1cccc2nonc12)[N+](=O)[O-]
Reactant: CC(=O)CC(=O)OC(C)C
Agent: Cl
Agent: [Na]
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)C(C(c1cccc2nonc12)C(C(C)=O)C(=O)OC(C)C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5.7 g of 3-(2,1,3-benzoxadiazol-4-yl)-2-nitro-propenoic acid methylester (IV,R1 =CH3) in 120 ml of dioxane is added to 4.2 g of the dry sodium salt of acetoacetic acid isopropylester. The suspension is stirred for 3 hours at room temperature. The mixture is poured into 120 ml of ice water and shaken with ether. The aqueous phase is acidified with hydrochloric acid whilst cooling, and extracted with methylene chloride. The methylene chloride solution is dried over magnesium sulphate and the solvent is evaporated under vacuum, after which the substance is obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]([O:15]C(C)(C)C)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][CH2:31]C(O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>FC(F)(F)C(O)=O.ClCCl.CN(C=O)C>[CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13](=[O:15])[CH2:31][CH2:30][C:24]2[C:23]3[C:27](=[CH:28][CH:29]=[C:21]([Cl:20])[CH:22]=3)[NH:26][CH:25]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C1
Reactant: O=C(O)CCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCc1c[nH]c2ccc(Cl)cc12)N1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.4 %

Procedure:
The tert-butyl 3-benzylimidazolidine-1-carboxylate (0.122 g; 0.465 mmol) was dissolved in a mixture of trifluoroacetic acid (4 mL) and dichloromethane (6 mL), stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was dissolved in dichloromethane and added to a mixture of 3-(5-chloro-1H-indol-3-yl)propanoic acid (0.080 g; 0.358 mmol), HATU (0.150 g; 0.393 mmol), N,N diisopropylethylamine (0.152 mL; 0.894 mmol) in dichloromethane (5 mL) and DMF (1 mL) and stirred at room temperature overnight. The reaction mixture was concentrated underreduced pressure and dissolved in ethyl acetate, washed with sodium hydrogen sulphate, sodium carbonate, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (0 to 10% MeOH in dichloromethane) and by preparative HPLC method 4 to yield 0.0097 g (7%) of 1-(3-benzylimidazolidin-1-yl)-3-(5-chloro-1H-indol-3-yl)propan-1-one as a solid.
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[F:29][C:30]1[CH:31]=[C:32]([S:37](Cl)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[CH3:36]>N.CO>[F:29][C:30]1[CH:31]=[C:32]([S:37]([N:11]2[C:12]3[C:8](=[C:7]4[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]4=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1F
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c4c(ccc32)OCCNC4)cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 7.8 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 3-Fluoro-4-methylbenzenesulfonyl chloride (21 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (1.4 mg). MS m/z 361 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30][NH2:31])=[CH:29][C:24]=2[N:23]=[CH:22]1.C(N(CC)C(C)C)(C)C>C(#N)C>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30][NH:31][C:2]3[C:3]4[CH2:11][N:10]([C:12]5[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=5[C:14]#[N:15])[CH2:9][CH2:8][C:4]=4[N:5]=[CH:6][N:7]=3)=[CH:29][C:24]=2[N:23]=[CH:22]1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Reactant: NCc1ccc2ocnc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(NCc4ccc5ocnc5c4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (100 mg, 0.35 mmol) and benzo[d]oxazol-5-ylmethanamine (150 mg, 0.41 mmol) in acetonitrile (3 mL) and N,N-diisopropylethylamine (0.37 mL, 2.1 mmol) was subjected to microwave irradiation at 185° C. for 2.5 h. The reaction mixture was concentrated and purified by preparative HPLC (100×20.2 mm, C18 column; 30-60% CH3CN-water [10 mM Et2NH]) to yield a light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH2:11][C:12]([CH3:21])([CH3:20])[S:13](=[O:19])(=[O:18])[C:14]([CH3:17])([CH3:16])[CH:15]=2)=[N:8][CH:9]=1)([O-])=O>CO.[Pd]>[CH3:20][C:12]1([CH3:21])[CH2:11][CH:10]([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:15][C:14]([CH3:16])([CH3:17])[S:13]1(=[O:19])=[O:18]
Reactant: CC1(C)C=C(c2ccc([N+](=O)[O-])cn2)CC(C)(C)S1(=O)=O
Agent: [Pd]
Solvent: CO
Product: CC1(C)CC(c2ccc(N)cn2)CC(C)(C)S1(=O)=O
Reaction time: 0.03 h
Yield: 64 %

Procedure:
A solution of 5-nitro-2-(2,2,6,6-tetramethyl-1,1-dioxo-1,2,3,6-tetrahydro-1λ6-thiopyran-4-yl)-pyridine (322 mg, 1.04 mmol, as prepared in the previous step) in MeOH (10 mL) was hydrogenated with 5% Pd/C and 1 atm H2 at RT for 17 h. The mixture was filtered through Celite, and the filter cake was washed with MeOH. The solvents were evaporated in vacuo. The residue was purified on a 25-g Sepra Si 50 SPE column (Isco system: Flow rate=20 mL/min; Eluent=10% EtOAc-hexane for 0-3 min, then 10-50% EtOAc-hexane for 5-30 min, then 50-65% EtOAc-hexane over 40 min, then 65-100% EtOAc-hexane over 40 min) to afford the title compound (187 mg, 64%) as an off-white solid. Mass spectrum (ESI, m/z): Calcd. for C14H22N2O2S, 283.1 (M+H), found 283.1.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]1[CH2:25][O:26][CH3:27])=[O:10]>Cl.O1CCOCC1.CO>[ClH:1].[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]1[CH2:25][O:26][CH3:27])=[O:10]
Reactant: COC[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC[C@@H]1CNCC[C@@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Cis(±)tert-butyl 4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(methoxymethyl)piperidine-1-carboxylate (Intermediate 73; 192 mg, 0.45 mmol) was dissolved in 4N HCl in dioxane (10 ml) and 10 ml of MeOH. The mixture was stirred at room temperature for 3 h, concentrated to dryness and azeotroped with MeOH to remove excess HCl (5×20 ml) to yield the title compound which was used without purification. (crude mixture 195 mg). MS (ES)(MH+): 320 for C13H19Cl2N3O2.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[OH:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13].Br[CH2:24][CH2:25][CH2:26][N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37]>O>[O:37]=[C:28]1[C:29]2[C:30](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](=[O:32])[N:27]1[CH2:26][CH2:25][CH2:24][O:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13]
Reactant: O=C(c1cccc(O)c1)N1CCCCC1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cccc(OCCCN2C(=O)c3ccccc3C2=O)c1)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 0.09 g. (0.0024 mole) of 60% sodium hydride in 10 ml. of dry N,N-dimethylformamide is added dropwise over 5 minutes a solution of 0.5 g. (0.0024 mole) of 1-(3-hydroxybenzoyl)piperidine, prepared according to the method of G. Tilly, Chem. Ther. 2 (1), 57-65 (1967); C. A. 67 32432S, in 10 ml. of dry N,N-dimethylformamide. The mixture is stirred at room temperature for 5 minutes and then 0.64 g. (0.0024 mole) of N-(3-bromopropyl)phthalimide is added. The mixture is stirred at room temperature for 1 hour and is diluted with water to the cloudy point. The precipitate which forms is collected and is air dried to give 0.5 g. of product. A small amount is recrystallized from ethanol to give the analytical sample, m.p. 120°-122° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][C:27]([NH:32]C(=O)C)([CH2:30][OH:31])[CH2:28][OH:29])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2>Cl>[NH2:32][C:27]([CH2:26][C:4]1[CH:5]=[CH:6][C:7]([C:8]2[S:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:19][CH2:18]2)[N:11]=3)=[C:2]([F:1])[CH:3]=1)([CH2:30][OH:31])[CH2:28][OH:29]
Reactant: CC(=O)NC(CO)(CO)Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: Cl
Product: NC(CO)(CO)Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reaction time: 2 h

Procedure:
In a sealable tube a slurry of N-(3-(3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridin-2-yl)phenyl)-1-hydroxy-2-(hydroxymethyl)propan-2-yl)acetamide (0.14 g, 0.28 mmol) in hydrochloric acid, 5 N (5.00 mL, 165 mmol) was heated to 120° C. The heterogeneous reaction mixture turned light green after 2 h of heating. The reaction mixture was cooled, filtered through a glass frit, and the solid was rinsed with water, EtOH, and CHCl3. The EtOH and CHCl3 filtrate was combined and concentrated, and this was combined with the isolated solid, and the material was purified by SFC (Sepapak 2 (250×21 mm, 5 micron) column using 50% methanol with 0.2% DEA as additive in supercritical CO2 with a flow rate of 60 mL/min) to give 2-amino-2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)propane-1,3-diol. MS (ESI) m/z: calculated: 449.2; Observed: 450.0 (M++1).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:31])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[N:9]=3)[CH2:2]1.[O:32]1[CH2:36][CH2:35][C:34](=O)[CH2:33]1>>[CH3:31][N:7]1[C:6]([CH2:5][CH:3]2[CH2:2][N:1]([C@@H:34]3[CH2:35][CH2:36][O:32][CH2:33]3)[CH2:4]2)=[N:14][C:13]2[C:8]1=[N:9][C:10]([N:21]1[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N:23]=[C:22]1[CH3:30])=[N:11][C:12]=2[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Reactant: O=C1CCOC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN([C@@H]4CCOC4)C3)n(C)c2n1

Procedure:
Following General Procedure L, 4-(8-(azetidin-3-ylmethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and dihydrofuran-3(2H)-one were reacted to give the racemic mixture. The enantiomers were separated by SFC to give 573. LCMS m/z: 245.2 (2M+H+)
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@H:7]1[CH2:10][C@@H:9]([NH2:11])[CH2:8]1)=[O:6])[CH3:3].C(N(CC)CC)C.[CH2:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:33][N:32]=[C:31]([C:34]3[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=3)[CH:37]=O)[N:30]=2)=[CH:25][CH:24]=1)[CH:20]([CH3:22])[CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OCC)(=O)C.C(O)(=O)C.C1COCC1>[CH2:2]([O:4][C:5]([C@H:7]1[CH2:10][C@@H:9]([NH:11][CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[C:34]([C:31]3[N:30]=[C:29]([C:26]4[CH:27]=[CH:28][C:23]([CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:24][CH:25]=4)[O:33][N:32]=3)[CH:35]=2)[CH2:8]1)=[O:6])[CH3:3]
Reactant: CC(C)Cc1ccc(-c2nc(-c3cccc(C=O)c3)no2)cc1
Reactant: CCOC(=O)[C@H]1C[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H]1C[C@@H](NCc2cccc(-c3noc(-c4ccc(CC(C)C)cc4)n3)c2)C1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A solution of cis-3-amino-cyclobutanecarboxylic acid ethyl ester hydrochloride (34 mg, 0.189 mmol), triethyl amine (39.5 uL, 0.284 mmol) and THF (1.7 mL) was stirred at ambient temperature for 30 minutes. Acetic acid (300 uL) and 3-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]benzaldehyde (58 mg, 0.189 mmol) were added to the reaction mixture and stirred for 30 minutes. Sodium triacetoxy borohydride (80 mg, 0.379 mmol) was added to the mixture and stirred for 18 hours. The reaction was diluted with ethyl acetate, washed with saturated sodium bicarbonate and the organic layer was separated and concentrated in vacuo. Purification by flash chromatography (silica, 1:99 to 1:9 MeOH:chloroform) provided the title compound (68 mg, 83% yield) as a solid.