Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH:18][CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[NH4+:35].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)Cl.O.CO.C(Cl)(Cl)Cl>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH:18][CH:19]([CH2:20][CH3:21])[CH2:22][CH3:23])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:35])[C:8]=2[N:17]=1)[CH3:2]
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3ccccc3c2n1NC(CC)CC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1NC(CC)CC
Reaction time: 0.5 h

Procedure:
A solution of N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)(1-ethylpropyl)amine (1.01 g, 3.23 mmol) in 30 mL of CH2Cl2 was treated with MCPBA (1.04 g, 4.20 mmol, 77% max). After 1.5 h the reaction mixture was treated with 15 mL of concentrated NH4OH solution and p-toluenesulfonyl chloride (0.65 g, 3.39 mmol). After 30 min, the reaction mixture was diluted with CH2Cl2 and water and the phases were separated. The organic portion was washed with 2% Na2CO3 solution and water. The combined aqueous washes were back extracted with CHCl3 (2×). The combined organic portions were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield a light yellow foam. Chromatography (SiO2, 97:3 CHCl3:MeOH) gave a white foam. The foam was triturated with CH2Cl2/hexanes and filtered to give 2-ethoxymethyl-N1-(1-ethylpropyl)-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.652 g) as a white solid. mp 125–128° C.; 1H NMR (300 MHz, CDCl3) δ 8.66 (dd, J=8.3, 1.1 Hz, 1H), 7.77 (dd, J=7.6, 0.8 Hz, 1H), 7.55–7.48 (m, 1H), 7.33–7.26 (m, 1H), 5.66, (d, J=3.0 Hz, 1H), 5.41 (s, 2H), 4.87 (s, 2H), 3.64 (q, J=7.0 Hz, 2H), 3.32–3.23 (m, 1H), 1.70–1.56 (m, 2H), 1.55–1.41 (m, 2H), 1.27 (t, J=7.1 Hz, 3H), 0.94 (t, J=7.5 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 151.5, 149.1, 145.4, 135.0, 132.4, 128.1, 126.9, 124.1, 122.2, 122.0, 115.9, 67.2, 66.2, 64.0, 24.5, 15.5, 10.2; MS (APCI) m/z 328 (M+H)+; Anal. Calcd for C18H25N5O: C, 66.03; H, 7.70; N, 21.39; Found: C, 65.64; H, 7.89; N, 21.02.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:16](=[O:34])[C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:33])[C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)=[CH:19][CH:18]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>O.C(O)C>[C:4]([CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:16](=[O:34])[C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:33])[C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)=[CH:21][CH:22]=2)[CH2:7]1)([OH:5])=[O:3]
Reactant: CCOC(=O)C1Cc2ccccc2N(C(=O)c2ccc(NC(=O)c3cc(Cl)cc(Cl)c3)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccc(C(=O)N2CC(C(=O)O)Cc3ccccc32)cc1)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.7 %

Procedure:
To 3-ethoxycarbonyl-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.6 g) are added an aqueous solution of sodium hydroxide (0.1 g) in water (1 ml) and ethanol (5 ml). The mixture is stirred at room temperature for 15 minutes, and acidified with diluted hydrochloric acid, extracted with dichloromethane. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane→dichloromethane:methanol=50:1), and recrystallized from ethanol to give 3-carboxy-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.4 g) as white powder, m.p. 221-223° C.
Reaction SMILES: [N:1]1([CH:7](O)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.OO>C1COCC1.C(OCC)C>[N:1]1([CH2:7][CH2:8][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(O)N1CCCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: OO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1ccc(OCCN2CCCCC2)cc1
Reaction time: 0.83 h
Yield: 34.3 %

Procedure:
A 1 L 3-neck round bottom flask was charged with anhydrous THF (200 mL), 1-piperidinylethanol (14.9 g, 15.27 mL, 0.115 mol), 4-hydroxybenzaldehyde (14.16 g, 0.116 mol), and triphenylphosphine (31,21 g, 0.119 mol) under a nitrogen atmosphere. The above mixture was stirred and diethylazodicarboxylate (DEAD; 22.6 g, 20.4 mL, 0.130 mol) in anhydrous THF (25 mL) was added dropwise over 15 min during which time the temperature was carefully monitored and not allowed to exceed 60° C. The reaction was stirred overnight at ambient temperature and then worked up by the addition of 10 mL 30% hydrogen peroxide and extraction of by ethyl ether. The organic layer was washed eight times with water, dried over anhydrous sodium sulfate, and concentrated to an oil. The oil was purified by chromatography over silica gel using a Waters LC2000 instrument. The elution solvent employed a gradient system beginning with 100% methylene chloride and ramping to 9:1 methylene chloride:methanol over 50 min at a flow rate of 150 mL/min. Concentration of appropriate fractions provided 9.2 g (35%) of the desired product as a pale brown oil.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][CH:4]=1.BrCC1CCCCO1.[F:20][C:21]([F:44])([F:43])[C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:30]=1[NH:29][C:28](=[O:31])[C:27]12[C:35]2=[CH:36][C:37]3[O:41][CH2:40][O:39][C:38]=3[CH:42]=[C:34]2[O:33][CH2:32]1>>[F:44][C:21]([F:20])([F:43])[C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:30]=1[N:29]([CH2:2][C:3]1[O:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][CH:4]=1)[C:28](=[O:31])[C:27]12[C:35]2=[CH:36][C:37]3[O:41][CH2:40][O:39][C:38]=3[CH:42]=[C:34]2[O:33][CH2:32]1
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: O=C1Nc2c(C(F)(F)F)cccc2C12COc1cc3c(cc12)OCO3
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2c(C(F)(F)F)cccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 5-bromomethyl-2-(trifluoromethyl)furan to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 7′-(trifluoromethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 7′-(trifluoromethyl)-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (43%) as a colorless solid: mp 95-98° C.; 1H NMR (300 MHz, CDCl3) δ7.59 (d, J=8.1 Hz, 1H), 7.36 (d, J=7.3 Hz, 1H), 7.15 (dd, J=7.8, 7.8 Hz, 1H), 6.69 (d, J=3.2 Hz, 1H), 6.50 (s, 1H), 6.23 (d, J=3.0 Hz, 1H), 6.10 (s, 1H), 5.86 (d, J=3.0 Hz, 2H), 5.23 (ABq, 2H), 4.78 (ABq, 2H); 13C NMR (75 MHz, CDCl3) δ178.6, 156.0, 152.2, 149.3, 142.7, 141.4 (q), 139.1, 135.1, 127.9, 127.0 (m), 122.9 (d), 121.1 (d), 119.3 (d), 118.7, 113.4 (q), 112.5, 108.2, 102.8, 101.7, 93.7, 80.8, 56.9, 39.4; MS (ES+) m/z 498.4 (M+1).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:16]([O:19][CH2:20][CH3:21])(=[O:18])[CH3:17]>>[CH2:20]([O:19][C:16](=[O:18])/[CH:17]=[CH:14]/[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH3:21]
Reactant: CCOC(C)=O
Reactant: CCCCCCCCCCCCCC=O
Product: CCCCCCCCCCCCC/C=C/C(=O)OCC

Procedure:
IR (thin film) 2920, 2850, 1725, 1465, 1265, 1175, 1045 cm-1 ;1H NMR (CDCl3, 300 MHz) δ 7.00 (dt, 1, J=15.5, 6.8 Hz, CH2CH=), 5.84 (dt, 1 J=15.5, 1.2 Hz, COCH=), 4.21 (dd, 2, J=14.2, 7.2 Hz, CH2O), 2.23 (qd, 2, J=6.9, 1.2 Hz, CH2CH=), 1.49 (t, 2, J=7 Hz, CH2CH2CH3), 1.3 (m, 20, CH2CH2CH2), 0.92 (t, 3, J=7 Hz, CH2CH2CH3). Rf (5% ethyl acetate:hexanes): tetradecanal, 0.29; ester product, 0 31. MS (FD): m/e 282 (M+).
Reaction SMILES: [N:1]([C@H:4]1[C@H:11]([C:12]([O:14][CH3:15])=[O:13])[C@@H:10]([CH3:16])[O:9][C@H:6]([O:7][CH3:8])[CH2:5]1)=[N+]=[N-].C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>CO.[Pd]>[NH2:1][C@H:4]1[C@H:11]([C:12]([O:14][CH3:15])=[O:13])[C@@H:10]([CH3:16])[O:9][C@H:6]([O:7][CH3:8])[CH2:5]1
Reactant: COC(=O)[C@H]1[C@H](N=[N+]=[N-])C[C@@H](OC)O[C@@H]1C
Agent: [Pd]
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: CO
Product: COC(=O)[C@H]1[C@H](N)C[C@@H](OC)O[C@@H]1C
Reaction time: 5 h

Procedure:
A mixture of methyl 3-azido-4-C-carbomethoxy-2,3,4,6-tetradeoxy-α-D-arabino-hexopyranoside (1.19 g, 5.19 mmol) and 5% palladium-on-charcoal (500 mg) in methanol (35 ml) is hydrogenated at a pressure of 1 atmosphere for 5 hours at room temperature. The catalyst is then removed by filtration through Celite and the filtrate evaporated and dried in vacuo to give TLC-chromatographically-homogeneous, ninhydrin positive amino ester; yield 1.01 g (96%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([N:11]1[CH2:16][C@H:15]2[CH2:17][C@@H:12]1[CH2:13][N:14]2[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[S:27][C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[N:30]=2)=[CH:21][CH:20]=1)=[O:10])(C)(C)C.Cl>C(Cl)Cl>[NH2:7][CH2:8][C:9]([N:11]1[CH2:16][C@H:15]2[CH2:17][C@@H:12]1[CH2:13][N:14]2[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[S:27][C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[N:30]=2)=[CH:21][CH:20]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1C[C@H]2C[C@@H]1CN2Cc1ccc(Oc2nc3ccccc3s2)cc1
Agent: Cl
Solvent: ClCCl
Product: NCC(=O)N1C[C@H]2C[C@@H]1CN2Cc1ccc(Oc2nc3ccccc3s2)cc1
Reaction time: 2 h
Yield: 34.2 %

Procedure:
To a mixture of (R,R)-(2-{5-[4-(benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-2-oxo-ethyl)-carbamic acid tert-butyl ester (8.2 mg, 0.02 mmol) in CH2Cl2 (0.3 mL) was added HCl (4.0 N in 1,4-dioxane, 0.3 mL). The solution was stirred for 2 h and concentrated under a stream of dry nitrogen. Purification via preparative reverse phase HPLC afforded the title compound (2.7 mg, 38%). MS (ESI): mass calcd. for C21H22N4O2S, 394.15; m/z found, 395.1 [M+H]+. 1H NMR (400 MHz, CDCl3, mixture of rotamers): 7.74 (d, J=8.1 Hz, 1H), 7.67 (d, J=7.9 Hz, 1H), 7.44-7.36 (m, 3H), 7.34-7.28 (m, 2H), 7.28-7.23 (m, 1H), 4.81 (s, 0.5H), 4.21 (s, 0.5H), 3.81-3.72 (m, 2.5H), 3.58 (s, 1H), 3.54-3.46 (m, 1H), 3.39-3.24 (m, 2.5H), 3.00 (dd, J=9.6, 2.0 Hz, 0.5H), 2.86 (dd, J=9.7, 2.1 Hz, 0.5H), 2.76 (d, J=9.8 Hz, 0.5H), 2.67-2.58 (m, 0.25H), 2.54 (d, J=9.6 Hz, 0.5H), 2.00 (d, J=9.6 Hz, 0.5H), 1.93 (d, J=9.9 Hz, 0.5H), 1.86-1.30 (m, 2.75H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)=[O:14])=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Oc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1

Procedure:
Phenol is reacted with p-chlorobenzoyl chloride in a Friedel-Crafts reaction in the presence of aluminium chloride to give 4-chloro-4'-hydroxybenzophenone, 179°-181° C. (A). To a solution of this (5 g.) in pyridine (6 ml.) was added methanesulphonyl chloride (2.5 g.), at room temperature. The reactants were heated on a steam bath for 11/2 hours and the liquid reaction product poured into dilute hydrochloric acid to give a solid which was filtered and air-dried. This solid was recrystallised from industrial methylated spirits to give 4-chloro-4'-methylsulphonyl-oxybenzophenone, m.p. 120°-121° C. (B). A solution of 9.4 g of this product and ethyl carbazate (7.8 g.) in glacial acetic acid (8 ml.) and ethanol (200 ml.) was heated under reflux for 48 hours and then evaporated to dryness in vacuo. The residue was extracted with methylene chloride (250 ml.) and the extract washed with water, aqueous sodium hydroxide (2.5 N) and water and then dried and evaporated to dryness to give 4-chloro-4'-methylsulphonyloxybenzophenone ethoxycarbonylhydrazone, m.p. 132.5°-140° C. (C).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[NH2:16][CH:17]([CH2:21][CH3:22])[C:18](O)=[O:19].[CH2:23]([NH:30][CH2:31][C:32](OCC)=[O:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:21]([C@@H:17]1[NH:16][C:32](=[O:33])[CH2:31][N:30]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]1=[O:19])[CH3:22]
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: CCC(N)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H]1NC(=O)CN(Cc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of DCC (5.07 g) in DCM (140 mL) at 0° C. was added N—BOC-L-□-aminobutyric acid (5 g) followed by ethyl JV-benzylglycinate (4.6 mL) dropwise. The resulting solution was stirred at 0° C. for 2 h and RT 1 h, filtered and the concentrated to give an oil. This was dissolved in DCM (100 mL) and TFA (100 ml) and stirred for 1 h. The solution was concentrated under reduced pressure. The residue was stirred in saturated aq NaHCO3 (125 ml) and EtOAc (125 ml) for 6 h. The organics were separated, dried (Na2SO4), and concentrated to give the sub title compound as a white solid. (5.68 g).
Reaction SMILES: [Cl:1][C:2]1[C:27]([O:28]C)=[CH:26][C:5]2[C:6]([C:9]3[C:10]([CH2:23][CH2:24][CH3:25])=[N:11][CH:12]=[CH:13][C:14]=3[O:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:7][O:8][C:4]=2[CH:3]=1>ClC(Cl)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:27]([OH:28])=[CH:26][C:5]2[C:6]([C:9]3[C:10]([CH2:23][CH2:24][CH3:25])=[N:11][CH:12]=[CH:13][C:14]=3[O:15][C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CCCc1nccc(Oc2ccc(Cl)cc2)c1-c1noc2cc(Cl)c(OC)cc12
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CCCc1nccc(Oc2ccc(Cl)cc2)c1-c1noc2cc(Cl)c(O)cc12
Temperature: 85 °C

Procedure:
The product from Step 9 (4.3 g, 10 mmol) and boron tribromide dimethyl sulfide complex (12.4 g, 40 mmol) were mixed in dichloroethane (100 mL). The resulting solution was heated at 85° C. for 18 h. The mixture was diluted with ethyl acetate (200 mL), washed with a saturated solution of sodium bicarbonate, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel to give the title product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.Br[CH2:17][CH2:18][CH2:19][C:20]#[N:21]>>[Cl:1][C:2]1[C:3]([CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:11][CH:12]=[CH:13][C:14]=1[O:15][CH2:17][CH2:18][CH2:19][C:20]#[N:21]
Reactant: N#CCCCBr
Reactant: Oc1cccc(CN2CCCCC2)c1Cl
Product: N#CCCCOc1cccc(CN2CCCCC2)c1Cl

Procedure:
In a similar manner to that described in Example 17 2-chloro-3-hydroxybenzaldehyde (9 g) in absolute ethanol (60 ml) was treated with piperidine (11.7 ml) and sodium borohydride (2.2 g) to yield N-(2-chloro-3-hydroxybenzyl)piperidine. The piperidine thus prepared was reacted with 4-bromobutyronitrile to give 4-(2-chloro-3-piperidinomethylphenoxy)butyronitrile.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([N+:15]([O-])=O)=[CH:7][CH:6]=1)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH2:15])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c2ccccc12
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(N)c2ccccc12
Yield: 99.9 %

Procedure:
Compound 13B (92 mg, 0.398 mmol) and 10% Pd/C (10 mg) in MeOH (5 mL) was hydrogenated under a hydrogen balloon for 30 minutes. The mixture was filtered and the filtrate concentrated under reduced pressure to give the title compound (80 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:18]=[CH:17][S:16][C:4]=2[N:5]([CH:13]([CH3:15])[CH3:14])[C:6](=[O:12])[C:7]=1[C:8]([O:10]C)=O.[CH2:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)[CH3:20].C(N(C(C)C)CC)(C)C>C1(C)C(C)=CC=CC=1>[CH2:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:8]([C:7]2[C:6](=[O:12])[N:5]([CH:13]([CH3:15])[CH3:14])[C:4]3[S:16][CH:17]=[CH:18][C:3]=3[C:2]=2[OH:1])=[O:10])[CH2:23][CH2:22]1)[CH3:20]
Reactant: CCN1CCC(N)CC1
Reactant: COC(=O)c1c(O)c2ccsc2n(C(C)C)c1=O
Solvent: Cc1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCC(NC(=O)c2c(O)c3ccsc3n(C(C)C)c2=O)CC1
Temperature: 25 °C
Yield: 67.1 %

Procedure:
A solution of methyl 6,7-dihydro-4-hydroxy-7-isopropyl-6-oxothieno-[2,3-b]pyridine-5-carboxylate (0.22 g, 0.82 mmol), 1-ethylpiperidin-4-amine (0.44 g, 1.24 mmol) and diisopropylethylamine (0.35 mL, 2.48 mmol) in xylene (3 mL) was heated at 120° C. for 2 h. The reaction mixture was cooled to room temperature, washed with water and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography eluted with 3% methanol-dichloromethane to give the title compound (0.20 g, 67% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 10.34 (br s, 1 H, 7.37 (d, 1 H, 6.95 (d, 1 H, 4.01 (m, 2 H, 3.03 (m, 2 H, 2.63 (d, 2 H, 2.41 (m, 2 H, 2.12 (d, 2 H, 1.81 (q, 2 H, 1.62 (d, 6 H, 1.18 (t, 3 H; MS: m/e 364 (M+H+).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[C:14]([C:16](O)=[O:17])[N:15]=2)[C:8]([CH3:26])=[CH:7][N:6]=1)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH3:33][O:34][CH:35]([O:38][CH3:39])[CH2:36][NH2:37]>C(Cl)Cl.CN(C=O)C>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[C:14]([C:16]([NH:37][CH2:36][CH:35]([O:38][CH3:39])[O:34][CH3:33])=[O:17])[N:15]=2)[C:8]([CH3:26])=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: COC(CN)OC
Reactant: CC(=O)Nc1cc(-c2nc(C(=O)O)c(-c3ccccc3Cl)o2)c(C)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(CNC(=O)c1nc(-c2cc(NC(C)=O)ncc2C)oc1-c1ccccc1Cl)OC
Temperature: 0 °C
Yield: 36.8 %

Procedure:
A solution of 2-(2-acetamido-5-methylpyridin-4-yl)-5-(2-chlorophenyl)-1,3-oxazole-4-carboxylic acid (0.50 g, 1.34 mmol) in DCM (15 mL) and DMF (0.05 mL) was allowed to stir at 0° C. To this solution was added oxalyl chloride (0.23 mL, 2.69 mmol) dropwise. The reaction mixture was allowed to stir at 0° C. for 15 minutes and then allowed to warm to rt and stir for 2 hr. The reaction mixture was concentrated, and then DCM (15 mL) and TEA (0.38 mL, 2.69 mmol) were added. The reaction mixture was allowed to stir at 0° C. and a solution of 2,2-dimethoxyethanamine (0.29 mL, 2.69 mmol) in DCM (5 mL) was added dropwise. The reaction mixture was allowed to warm to rt and to stir overnight and then concentrated. The residue was redissolved in water and EtOAc. The organic solution was separated and the aqueous solution was further extracted with EtOAc. The organic solutions were combined, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give 2-(2-acetamido-5-methylpyridin-4-yl)-5-(2-chlorophenyl)-N-(2,2-dimethoxyethyl)-1,3-oxazole-4-carboxamide (0.226 g, 37%). LCMS (FA): m/z=459 (M+H).
Reaction SMILES: I[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[CH:25][N:26]3[C:35]=2[CH:34]=[C:33]2[C@@:28]([CH3:38])([C@@H:29]([CH:36]=[O:37])[CH2:30][CH2:31][CH2:32]2)[CH2:27]3)=[CH:19][CH:18]=1.[Cl-].[NH4+]>C1COCC1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[CH:25][N:26]3[C:35]=2[CH:34]=[C:33]2[C@@:28]([CH3:38])([C@@H:29]([CH:36]([OH:37])[C:2]4[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=4)[CH2:30][CH2:31][CH2:32]2)[CH2:27]3)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(I)s1
Reactant: C[C@]12Cn3cnc(-c4ccc(F)cc4)c3C=C1CCC[C@@H]2C=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)[C@H]2CCCC3=Cc4c(-c5ccc(F)cc5)ncn4C[C@@]32C)s1
Reaction time: 1 h

Procedure:
To a stirred solution of the above methyl 5-iodothiophene-2-carboxylate (175 mg, 0.65 mmol) in anhydrous THF (2 mL) cooled in an acetonitrile-dry ice bath was added isopropylmagnesium chloride solution (2 M in THF, 0.32 mL, 0.64 mmol) dropwise under nitrogen. The reaction mixture was stirred at the same temperature for 40 min before (5aR,6S)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinoline-6-carbaldehyde (Example 1g, 100 mg, 0.32 mmol) was added. After the reaction mixture was stirred at the same temperature for 1 hr, saturated aqueous ammonium chloride solution (3 mL) was added. The mixture was extracted with ethyl acetate (3×2 mL). The combined organic solutions were dried (Na2SO4) and concentrated. Silica gel flash chromatography (50-100% ethyl acetate in heptanes then 0-20% methanol in ethyl acetate) gave methyl 5-(((5aR,6S)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinolin-6-yl)(hydroxy)methyl)thiophene-2-carboxylate as a solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]([N:16]1[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18][CH:17]1C(O)=O)=O.[C:26]([O:34][CH3:35])(=[O:33])[C:27]#[C:28][C:29]([O:31][CH3:32])=[O:30]>CC(OC(C)=O)=O>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][C:14]1[N:16]2[C:17](=[C:27]([C:26]([O:34][CH3:35])=[O:33])[C:28]=1[C:29]([O:31][CH3:32])=[O:30])[CH2:18][C:19]([CH3:22])([CH3:21])[CH2:20]2
Reactant: COC(=O)C#CC(=O)OC
Reactant: CC1(C)CC(C(=O)O)N(C(=O)CCN2C(=O)c3ccccc3C2=O)C1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1c(C(=O)OC)c2n(c1CCN1C(=O)c3ccccc3C1=O)CC(C)(C)C2
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
A mixture of 137i (crude, 72.5 mmol) and Ac2O (100 mL) was stirred at 90° C. for 0.5 h. Then dimethyl but-2-ynedioate 137j (20.6 g, 145 mmol) was added. See FIG. 2. The mixture was stirred at 110° C. for 2 h. Upon reaction completion, the mixture was concentrated under reduced pressure. The crude was purified by silica gel chromatography (PE/EA=50/1 to 1/1) to give dimethyl 5-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-2,2-dimethyl-2,3-dihydro-1H-pyrrolizine-6,7-dicarboxylate 137k (15 g, 48%).
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:6](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:5][N:4]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:3]1.[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C=O)C>[N:28]([C@H:6]1[C@@H:2]([CH3:1])[CH2:3][N:4]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:5]1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2C)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N=[N+]=[N-]
Temperature: 85 °C
Yield: 97.2 %

Procedure:
(3S,4R)-Benzyl 3-methyl-4-(tosyloxy)pyrrolidine-1-carboxylate (20 g, 51.4 mmol) was dissolved in DMF (42.8 ml). Sodium azide (5.68 g, 87 mmol) was added at rt and heated up to 85° C. overnight. LCMS shows a complete conversion. The reaction mixture was cooled to rt, quenched with ice water, extracted with ethyl acetate. Organic phases were combined, washed with water, brine, then dried with Na2SO4. After concentration, (3S,4S)-benzyl 3-azido-4-methylpyrrolidine-1-carboxylate (13 g, 97% yield) was obtained as a yellowish oil and used directly for the next reduction. 1H NMR (400 MHz, chloroform-d) δ ppm 7.29-7.44 (5H, m), 5.08-5.22 (2H, m), 3.94-4.04 (1H, m), 3.52-3.76 (3H, m), 3.00-3.15 (1H, m), 2.29-2.48 (1H, m), 1.13 (3H, t, J=7.04 Hz); LCMS (CHROMOLITH® RP-18e 2.0×50 mm, 0.8 mL/min, Solvent A: 10% MeOH/water with 0.1% TFA, Solvent B: 90% MeOH/water with 0.1% TFA, gradient with 0-100% B over 4 minutes) retention time: 3.41 min; MS(ES+) m/z: 261.0 (M+H+).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@@H:2]([C:10]([N:12]1[CH2:23][CH2:22][CH2:21][C@H:13]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C.[Pd]>[NH2:1][C@@H:2]([C:10]([N:12]1[CH2:23][CH2:22][CH2:21][C@H:13]1[C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)[C@H](N)Cc1ccccc1
Reaction time: 16 h
Yield: 85.9 %

Procedure:
To a solution of Cbz-D-Phe-Pro-O-t-Bu (29 g, 64 mmol) in ethanol (500 mL) was added 5% Pd/C (14.5 g). The mixture was shaken on a hydrogenation apparatus for 16 h under 60 psi H2. The solution was then filtered through a pad of Celite® and concentrated in vacuo to give 17.5 g (86%) of thick oil.