Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+].[NH2:2][C@H:3]([C:23]([O-:25])=[O:24])[CH2:4][C:5]1[CH:12]=[C:10]([I:11])[C:9]([O:13][C:14]2[CH:21]=[C:19]([I:20])[C:18]([OH:22])=[C:16]([I:17])[CH:15]=2)=[C:7]([I:8])[CH:6]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].Cl>CCO.CN(C=O)C.O.[OH-].[Na+]>[C:26]([NH:2][C@H:3]([C:23]([OH:25])=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([I:8])[C:9]([O:13][C:14]2[CH:15]=[C:16]([I:17])[C:18]([OH:22])=[C:19]([I:20])[CH:21]=2)=[C:10]([I:11])[CH:12]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: CC(=O)N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Reaction time: 1.5 h
Yield: 90 %

Procedure:
L-Thyroxine sodium salt, pentahydrate (1) (10 g, 11 mmol) was nearly completely dissolved in 400 mL of EtOH/2N NH4OH (1/1, v/v), filtered, and filtrate poured into 425 mL of 5% HCl. The resulting precipitate was isolated by vacuum filtration and dried under high vacuum to afford a white solid. This material was dissolved in 160 mL DMF, 100 mL (1.06 mol) of acetic anhydride added, and reaction stirred for 1.5 hours, then diluted with 850 mL H2O and allowed to stand at 4° C. for 16 hours. The resulting precipitate was isolated by filtration, then dissolved in 350 mL EtOH and 41 mL of 1N NaOH, stirred for 2.5 hours, 680 mL of 5% HCl added, and mixture allowed to stand at 4° C. for 16 hours. The resulting precipitate was isolated by vacuum filtration and dried under high vacuum to yield 8.1 g (90%) of the desired N-acetyl L-thyroxine (5) as a white solid; 1H NMR (200 MHz, CD3OD) d 7.8 (s, 2H), 7.1 (s, 2H), 4.6-4.7 (m, 1H), 2.8-3.0 (m, 2H), 2.0 (s, 3H); mass spec (FAB) (M+H)+ 820.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:36][CH2:37][CH3:38])=[C:16]([CH:22]4[CH2:25][N:24](C(OCC5C=CC=CC=5)=O)[CH2:23]4)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12>[Pd]>[NH:24]1[CH2:23][CH:22]([C:16]2[C:15]([O:36][CH2:37][CH3:38])=[C:14]([CH:12]([N:8]3[C:4]4=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]4[C:10]([CH3:11])=[N:9]3)[CH3:13])[CH:19]=[C:18]([Cl:20])[C:17]=2[CH3:21])[CH2:25]1
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1

Procedure:
Benzyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidine-1-carboxylate (chiral intermediate from first peak of previous step) was hydrogenated in the presence of 5% palladium as described in Example 94, Step 2 to give the desired chiral product. LCMS calculated for C20H26ClN6O (M+H)+: m/z=401.2; Found: 401.1.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[N:18]=[C:17]([NH2:19])[CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.C(N(CC)CC)C>C1COCC1>[CH3:5][N:6]1[CH2:7][CH2:8][CH:9]([O:12][C:13]2[N:18]=[C:17]([NH:19][C:1](=[O:3])[CH3:2])[CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:11]1
Reactant: CC(=O)Cl
Reactant: CN1CCC(Oc2cccc(N)n2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(OC2CCN(C)CC2)n1
Temperature: 40 °C
Yield: 76.4 %

Procedure:
Add acetyl chloride (118 mg, 0.11 mL, 1.50 mmol) slowly to a solution of 6-(1-methyl-piperidin-4-yloxy)-pyridin-2-ylamine (preparation 72, 260 mg, 1.25 mmol) in triethylamine (190 mg, 0.26 mL, 1.88 mmol) and THF (10 mL), heat at 40° C. overnight. Quench the reaction with 0.1N NaOH, extract with methylene dichloride three times. Combine the organic layers, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel) eluting with 4.5% 2M NH3-methanol in methylene dichloride provides 238 mg (76%) of the title compound as an oil: mass spectrum (ion spray): m/z=250.0 (M+1); 1H NMR (CDCl3, ppm): 7.70 (m, 2H), 7.56 (t, 1H), 6.44 (d, 1H), 4.91 (m, 1H), 2.68 (m, 2H), 2.34 (m, 5H), 2.20 (s, 3H), 2.00 (m, 2H), 1.81 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH2:9][CH2:8]3.[N:18]#[C:19]Br>O1CCCC1>[C:19]([NH:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH2:9][CH2:8]3)#[N:18]
Reactant: N#CBr
Reactant: Cc1cc2c(c3c1NC(=O)CC3)OC(CN)C2
Solvent: C1CCOC1
Product: Cc1cc2c(c3c1NC(=O)CC3)OC(CNC#N)C2
Yield: 43.8 %

Procedure:
Using 2-aminomethyl-5-methyl-2,3,6,7,8,9-hexahydrofuro[2,3-f]quinoline-7-one (1.30 g, 5.6 mmol), cyanogen bromide (3.56 g, 33.6 mmol), and tetrahydrofuran (150 ml), the procedure of Example 342 was followed. 0.631 g of the title compound was obtained as yellow crystals (43.8%). Recrystallization from chloroform-methanol yielded the title compound as colorless needles (mp.: 209°-210° C.).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([F:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:13]1[N:14]=[CH:15][N:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=12.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:13]1[N:14]=[C:15]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([F:12])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)[N:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=12
Reactant: Fc1cccc2ccc(Cl)nc12
Reactant: c1ccn2cnnc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Fc1cccc2ccc(-c3nnc4ccccn34)nc12

Procedure:
2-Chloro-8-fluoroquinoline (0.75 g, 4.13 mmol) was combined with [1,2,4]triazolo[4,3-a]pyridine (0.541 g, 4.54 mmol), micronized Cs2CO3 (2.69 g, 8.26 mmol), and PdCl2(PPh3)2 (0.290 g, 0.413 mmol) then the mixture was slurried in dioxane (20 mL). The reaction was deoxygenated with argon and heated to reflux for 20 hours, then cooled, diluted with CHCl3 and filtered through a pad of Celite®. The filtrate was concentrated onto Na2SO4 powder (15 g) and the mixture was chromatographed on SiO2 eluting with a stepped gradient of 0-2% MeOH/ethyl acetate. The desired product was isolated as a cream-colored solid (1.12 g). MS APCI (+) m/z 265.3 (M+1) detected.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:26])[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:11]=2)[NH:6][CH:5]=1.[CH3:27][NH:28][CH3:29]>>[CH3:27][N:28]([CH3:29])[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:26])[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:11]=2)[NH:6][CH:5]=1
Reactant: CNC
Reactant: COc1ccc(CC(=O)NCCc2ccc3[nH]cc(CCBr)c3c2)cc1
Product: COc1ccc(CC(=O)NCCc2ccc3[nH]cc(CCN(C)C)c3c2)cc1

Procedure:
A solution of the product of Section (b) (117 mg) in ethanolic dimethylamine (33% w/w; 10 ml) was stirred at room temperature for 19 h. The solvent was removed in vacuo and the residue purified by `flash` chromatography (C) to give the title compound of the invention as a colourless oil (96 mg). T.l.c. (C), Rf 0.27.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].[Cl:21][C:22]1[CH:35]=[CH:34][C:25]([CH2:26][N:27]([CH2:31][CH2:32]Cl)[CH2:28][CH2:29]Cl)=[CH:24][CH:23]=1>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:29][CH2:28][N:27]([CH2:26][C:25]2[CH:34]=[CH:35][C:22]([Cl:21])=[CH:23][CH:24]=2)[CH2:31][CH2:32]1)=[O:20])[CH3:2]
Reactant: CC#CCOc1ccc(S(=O)(=O)CC(=O)OCC)cc1
Reactant: ClCCN(CCCl)Cc1ccc(Cl)cc1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(Cl)cc3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-chloro-benzyl)-piperdine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in Example 1 (Step 6). Starting from (4-but-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (4 g, 13.5 mmol) and (4-chloro-benzyl)-bis-(2-chloro-ethyl)-amine (4.9 g, 16.2 mmol). Yield 3.5 g (53%); white crystals; MP 91.8° C.; MS: 490 (M+H)+
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:12][C:13]([C:15]1[S:16][CH:17]=[CH:18][C:19]=1[NH:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]2[NH:27][CH:28]=[CH:29][C:22]=12)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][C@@H:5]([NH:12][C:13]([C:15]1[S:16][CH:17]=[CH:18][C:19]=1[NH:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]2[NH:27][CH:28]=[CH:29][C:22]=12)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=NC[C@@H](NC(=O)c1sccc1Nc1ccnc2[nH]ccc12)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC[C@@H](NC(=O)c1sccc1Nc1ccnc2[nH]ccc12)c1ccccc1
Yield: 66 %

Procedure:
A solution of 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid ((S)-2-azido-1-phenyl-ethyl)-amide (130.00 mg; 0.32 mmol; 1.00 eq.) in methanol (50.00 ml) was subjected to hydrogenation with 10% palladium on carbon via H-Cube at 1 mL/min. After completion the solution was concentrated in vacuo. The crude was purified by Yamazen (basic condition, 0.1% NH4OH in Water/ACN) to afford the title compound as white solid in 66% yield. LCMS: m/e 378 (M+H). 1H NMR (DMSO-d6): ppm 11.53 (1H, br. s.), 8.00 (1H, d, J=5.48 Hz), 7.82 (1H, d, J=5.12 Hz), 7.45 (1H, d, J=5.48 Hz), 7.26-7.33 (5H, m), 7.18-7.22 (1H, m), 6.75 (1H, d, J=5.52 Hz), 6.39 (1H, d, J=3.28 Hz), 4.96 (1H, dd, J=8.08, 5.52 Hz), 2.78-2.88 (2H, m).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]([OH:9])[CH3:8])[CH:2]=1.[CH2:10]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]([O:9][C:31]([C:28]2[CH:27]=[CH:26][C:25]([C:22]3[CH:23]=[CH:24][C:19]([O:18][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:20][CH:21]=3)=[CH:30][CH:29]=2)=[O:32])[CH3:8])[CH:2]=1
Reactant: C[C@H](O)c1cccnc1
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)O[C@@H](C)c3cccnc3)cc2)cc1
Reaction time: 15 h
Yield: 7.1 %

Procedure:
(S)-1-(3-pyridyl)ethanol (2.0 g) prepared in the above item (ii), 4-octyloxybiphenyl-4'-carboxylic acid (5.3 g), dicyclohexylcarbodiimide (5.7 g) and dimethylaminopyridine (0.2 g) were dissolved in methylene chloride (100 ml), followed by agitating the solution for 15 hours, thereafter filtering off insolubles, washing the filtrate with water, concentrating it and recrystallizing from a mixed solvent of heptane-toluene to obtain (S)-4-octyloxybiphenyl-4'-carboxylic acid-1-(3-pyridyl)ethyl ester (0.5 g). M.P.: 77.5-78.5° C. Specific angle of rotation [a]D25 =+95° (c=1.0, CHCl3). Further, the structure of this product was confirmed according to NMR spectra and the product accorded with the captioned compound.
Reaction SMILES: I.[C:2]([NH:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[N:14]=[C:15]([NH:18][C:19](=[NH:22])SC)[S:16][CH:17]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:4])[CH3:3].[CH3:23][O:24][CH2:25][CH2:26][NH2:27]>C(O)C>[C:2]([NH:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[N:14]=[C:15]([N:18]=[C:19]([NH2:22])[NH:27][CH2:26][CH2:25][O:24][CH3:23])[S:16][CH:17]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:4])[CH3:3]
Reactant: COCCN
Reactant: CSC(=N)Nc1nc(-c2cccc(CNC(C)=O)c2)cs1
Agent: I
Solvent: CCO
Product: COCCNC(N)=Nc1nc(-c2cccc(CNC(C)=O)c2)cs1

Procedure:
A solution of 4-(3-acetylaminomethylphenyl)-2-(2-methyl-1-isothioureido)thiazole hydriodide (2.0 g) and 2-methoxyethylamine (5 ml) in ethanol (50 ml) was refluxed for 25 hours. The solvent was removed under reduced pressure and the residue was suspended in water (100 ml). The mixture was alkalized with 30% aqueous potassium carbonate solution and then extracted with a mixture of ethyl acetate (200 ml) and tetrahydrofuran (50 ml). The extract was dried with magnesium sulfate. The solvent was removed under reduced pressure and the residue was crystallized from ethyl acetate. Recrystallization from ethyl acetate afforded 4-(3-acetylaminomethylphenyl)-2-[[(amino)(2-methoxyethylamino)methylene]amino]thiazole (0.65 g).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH3:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[CH2:19][N:20]1[C:26](=[O:27])[C@@H:25]([NH:28]C(=O)OC(C)(C)C)[CH2:24][O:23][C:22]2[C:36]([C:40]([F:43])([F:42])[F:41])=[CH:37][CH:38]=[CH:39][C:21]1=2>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[NH2:28][C@H:25]1[CH2:24][O:23][C:22]2[C:36]([C:40]([F:42])([F:41])[F:43])=[CH:37][CH:38]=[CH:39][C:21]=2[N:20]([CH2:19][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:17]=[CH:18][C:9]=2[CH3:8])[C:26]1=[O:27]
Reactant: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)COc2c1cccc2C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](N)COc2c1cccc2C(F)(F)F
Yield: 100 %

Procedure:
TFA (533 μl) was added to a solution of (S)-tert-butyl 5-((2-methylnaphthalen-1-yl)methyl)-4-oxo-9-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (71 mg, 142 μmol) in DCM (2 mL) at 0° C. After 2.5 h the mixture was concentrated and the residue azeotroped with MeCN to afford (S)-3-amino-5-((2-methylnaphthalen-1-yl)methyl)-9-(trifluoromethyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one trifluoroacetate (73 mg, 100%) which was used without purification.
Reaction SMILES: C(OC([N:8]([C:32]1[CH:33]=[CH:34][C:35]([C:38]([O:40][CH3:41])=[O:39])=[N:36][CH:37]=1)[CH:9]1[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=2[CH2:11][CH2:10]1)[N:19]=[C:18]([CH3:22])[N:17]([CH2:23][O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[O:31])=O)(C)(C)C>FC(F)(F)C(O)=O>[CH3:22][C:18]1[N:17]([CH2:23][O:24][C:25](=[O:30])[C:26]([CH3:27])([CH3:28])[CH3:29])[C:16](=[O:31])[C:15]2[C:20](=[CH:21][C:12]3[CH2:11][CH2:10][CH:9]([NH:8][C:32]4[CH:33]=[CH:34][C:35]([C:38]([O:40][CH3:41])=[O:39])=[N:36][CH:37]=4)[C:13]=3[CH:14]=2)[N:19]=1
Reactant: COC(=O)c1ccc(N(C(=O)OC(C)(C)C)C2CCc3cc4nc(C)n(COC(=O)C(C)(C)C)c(=O)c4cc32)cn1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(NC2CCc3cc4nc(C)n(COC(=O)C(C)(C)C)c(=O)c4cc32)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 5-[N-(tert-butoxycarbonyl)-N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]pyridine-2-carboxylate (0.3 g) and trifluoroacetic acid (10 ml) was stirred at ambient temperature for 1 hour. The mixture was evaporated and the residue was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluant. There was thus obtained methyl 5-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]pyridine-2-carboxylate (0.24 g);
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O.ClCCl>[N:8]1([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12][O:11][CH:10]([C:14]([O:16][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOC(C(=O)OCc2ccccc2)C1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 85.7 %

Procedure:
4-{[(1,1-Dimethylethyl)oxy]carbonyl}-2-morpholinecarboxylic acid [Supplied by NeoMPS] (1 g, 4.32 mmol) was dissolved in N,N-dimethylformamide (20 ml) and potassium carbonate (0.598 g, 4.32 mmol) added. The mixture was stirred under nitrogen for 15 minutes at 20° C. Bromomethylbenzene (0.514 ml, 4.32 mmol) was added and the mixture stirred under nitrogen at room temperature for 18 hr. Water (25 ml) and dichloromethane (20 ml) were added and separated by hydrophobic fit. The aqueous phase was extracted with dichloromethane (2×20 ml). The organic phases were combined and the solvent was removed in vacuo. To the residue 1% lithium chloride solution (20 ml) and diethyl ether (20 ml) were added. The phases were separated and the aqueous phase was extracted with diethyl ether (2×15 ml). The combined organic phases were dried over magnesium sulphate and the solvent was removed in vacuo to give the title compound (1.19 g) as a colourless oil.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]([C:13]1([CH3:30])[C:17](=[O:18])[NH:16][C:15]([C:19]2[N:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:20]=2[C:21]([O:23][CH3:24])=[O:22])=[N:14]1)([CH3:12])[CH3:11].C(Cl)Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([N:16]1[C:17](=[O:18])[C:13]([CH:10]([CH3:12])[CH3:11])([CH3:30])[N:14]=[C:15]1[C:19]1[N:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1cc(C)cnc1C1=NC(C)(C(C)C)C(=O)N1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(C)cnc1C1=NC(C)(C(C)C)C(=O)N1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 67.9 %

Procedure:
Benzoyl chloride (42.1 mL, 0.363 mol) is added dropwise to a 0° C. solution of 2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-5-methylnicotinic acid, methyl ester (50 g, 0.173 mol) and 4-dimethylaminopyridine (4.2 g, 0.0344 mol) in pyridine. The reaction mixture is stirred for 1 hour at 0° C. and 4 hours at room temperature. Concentration in vacuo gives a liquid that is dissolved into methylene chloride and washed sequentially with 2 normal hydrochloric acid and saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield a solid that upon trituration with ether gives the title compound as a white solid (46.2 g, 68%), mp 104°-106° C., identified by IR and NMR spectral analyses.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[CH2:6]([O:8][C:9]([C:11]1[C:12]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:13]([CH2:32][CH2:33][CH2:34][OH:35])[N:14]2[C:19]=1[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[N:15]2)=[O:10])[CH3:7]>C(N(C(C)C)CC)(C)C.CC#N>[CH2:6]([O:8][C:9]([C:11]1[C:12]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:13]([CH2:32][CH2:33][CH2:34][O:35][C:4](=[O:5])[NH:3][CH2:1][CH3:2])[N:14]2[C:19]=1[C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:17][C:16]([N:26]1[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1)=[N:15]2)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn2c1CCCO
Reactant: CCN=C=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)OCCCc1c(C(=O)OCC)c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn12
Temperature: 50 °C

Procedure:
Ethyl isocyanate (50 μL, 0.063 mmol) and diisopropylethyl amine (1 drop) were added to a solution of 41 (30 mg, 0.062 mmol) in CH3CN (10 mL). The reaction mixture was heated at 50° C. for 18 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, 35% EtOAc/hexane) to provide the title compound as a white solid. 1H NMR (DMSO-d6) δ 0.89 (t, J=7.1 Hz, 3H), 0.99 (t, J=7.2 Hz, 3H), 1.20 (t, J=7.1 Hz, 3H), 1.91 (m, 2H), 2.96 (m, 2H), 3.22 (m, 2H), 3.53 (m, 6H), 3.71 (m, 4H), 3.96 (m, 2H), 4.19 (q, J=7.1 Hz, 2H), 6.78 (s, 1H), 7.00 (m, 1H), 7.41 (m, 2H), 7.46 (m, 3H). Mass Spectrum (ESI+) m/e=553.2 (M+H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:34])=[N:13][C:14]2[N:15]([N:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=3)[CH:26]=2)[C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:34])=[N:13][C:14]2[N:15]([N:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=3)[CH:26]=2)[C:16]=1[C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2cc(-c3cccc(Cl)c3)nn2c(-c2ccc(F)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Yield: 86.9 %

Procedure:
A solution of (S)-methyl 2-(tert-butoxy)-2-(2-(3-chlorophenyl)-7-(4-fluorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (0.0475 g, 0.099 mmol) and 1M NaOH (0.986 ml, 0.986 mmol) in MeOH was heated at reflux for 3 h. Then, cooled, neutralized with 1M HCl (1 mL), concentrated and the residue was taken up in Et2O (25 mL), washed with water (5 mL), brine (5 mL), dried (MgSO4), filtered and concentrated to give (S)-2-(tert-butoxy)-2-(2-(3-chlorophenyl)-7-(4-fluorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetic acid (0.0407 g, 0.086 mmol, 87% yield) as while solid. 1H NMR (500 MHz, 13) δ: 7.87-7.83 (m, 2H), 7.82-7.78 (m, 1H), 7.75-7.71 (m, 1H), 7.36-7.28 (m, 4H), 6.90 (s, 1H), 5.19 (s, 1H), 2.67 (s, 3H), 1.02 (s, 9H). LCMS (M+H) calcd for C25H24ClFN3O3: 468.15. found: 468.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@@H:4]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:5][C:6]1[CH:25]=[CH:24][C:9]2[O:10][CH:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.Cl.[CH3:36]OC(=O)[C@@H](N)CC1C=CC2OC(C3C=CC(OC(=O)C)=CC=3)COC=2C=1.C=O.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.CCN(C(C)C)C(C)C>O1CCOCC1.C(O)(C(F)(F)F)=O.C(Cl)Cl.O>[CH3:1][O:2][C:3]([C@@H:4]1[CH2:5][C:6]2[CH:7]=[C:8]3[O:13][CH2:12][C@H:11]([C:14]4[CH:15]=[CH:16][C:17]([O:20][C:21](=[O:23])[CH3:22])=[CH:18][CH:19]=4)[O:10][C:9]3=[CH:24][C:25]=2[CH2:36][N:26]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:34]
Reactant: COC(=O)[C@@H](N)Cc1ccc2c(c1)OCC(c1ccc(OC(C)=O)cc1)O2
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OCC(c1ccc(OC(C)=O)cc1)O2)NC(=O)OC(C)(C)C
Agent: C=O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OC(C)=O)cc1)CO3
Reaction time: 6 h

Procedure:
(S)-3-[2-(4-Acetoxy-phenyl)-2,3-dihydro-benzo[1,4]dioxin-6-yl]-2-tert-butoxycarbonylamino-propionic acid methyl ester was converted to the HCl salt of (S)-3-[2-(4-acetoxy-phenyl)-2,3-dihydro-benzo[1,4]dioxin-6-yl]-2-amino-propionic acid methyl ester according to General Procedure C. This intermediate (450 mg) was dissolved in dioxane (32 mL) and TFA (8 mL). To this solution was added paraformaldehyde (60 mg) and stirred at rom temperature for 6 hours. After completion of the reaction, the mixture was poured into water (100 mL) and extracted with EtOAc. The organic layer was neutralized to a pH of 7 using NaHCO3 and washed with water and brine, and dried to get an oil. The oil was taken in fresh DCM (200 mL) and Boc anhydride and DIEA (3 mL) were added. The mixture was stirred for 2-3 h and the organic layer was separated, washed dried and concentrated and purified (silica; hexanes/EtOAc, 8:2 to 7:3) to get (3S,8S)-3-(4-acetoxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester 8-methyl ester. This Boc ester (485 mg) was dissolved in methanol (20 mL). To this solution was added NaHCO3 (2.0 g). The mixture was stirred at room temperature for 3 h. After completion of the reaction, the mixture was poured into water (200 mL) and was extracted with EtOAc (300 mL). The organic layer was washed with water, brine, dried and concentrated to get the desired product as a white solid (380 mg). This intermediate was coupled with cyclohexane methanol according to General Procedure K furnished (3S,8S)-3-(4-cyclohexylmethoxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester 8-methyl ester. This ester upon hydrolysis according to General Procedure B furnished (3S,8S)-3-(4-cyclohexylmethoxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (C). LCMS (m/z): 525.