Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(O[C:5](=[NH:16])[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8])C.[OH-].[Na+].C(=O)(O)[O-].[Na+].[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29]([NH:31][NH2:32])=[O:30]>C(Cl)(Cl)Cl>[NH2:16][C:5](=[N:32][NH:31][C:29]([C:25]1[O:24][CH:28]=[CH:27][CH:26]=1)=[O:30])[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: NNC(=O)c1ccco1
Reactant: CCOC(=N)CS(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: NC(CS(=O)(=O)c1ccccc1)=NNC(=O)c1ccco1

Procedure:
A suspension of 85.0 g (0.32 mol) 2-(phenylsulfonyl)-ethanimidic acid ethyl ester hydrochloride in 700 ml chloroform was treated with 320 ml 1N aqueous sodium hydoxide. 100 ml of a saturated aqueous sodiumbicarbonate solution was added and the mixture was extracted with chloroform. The extracts were combined and dried with sodium sulfate and the solvents were distilled off under reduced pressure. The resulting colorless oil was stirred together with 42.6 g (0.34 mol) 2-furancarboxylic acid hydrazide in 600 ml chloroform for 24 hours at 50° C. The resulting precipitate was filtered off and dried. A quantitative yield of furan-2-carboxylic acid (1-amino-2-benzenesulfonyl-ethylidene)-hydrazide was obtained as pale crystals, mp. 195° C. (decomposition), MS m/e (%): 308 (M+H+, 100).
Reaction SMILES: [OH:1][CH:2]([N:15]1[C@H:18]([SH:19])[C@H:17]([NH:20][C:21](=[O:29])[CH2:22]C2C=CC=CC=2)[C:16]1=[O:30])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4].Br[CH2:32][C:33]([CH:35]1[CH2:39][CH2:38][CH2:37][O:36]1)=[O:34].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[OH:1][CH:2]([N:15]1[C@H:18]([S:19][CH2:32][C:33]([CH:35]2[CH2:39][CH2:38][CH2:37][O:36]2)=[O:34])[C@@:17]([NH:20][C:21](=[O:29])[CH3:22])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:16]1=[O:30])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4]
Reactant: O=C(CBr)C1CCCO1
Reactant: COc1ccc(COC(=O)C(O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)C(O)N2C(=O)[C@](NC(C)=O)(c3ccccc3)[C@H]2SCC(=O)C2CCCO2)cc1
Reaction time: 0.17 h

Procedure:
The crude thiol was dissolved in acetone (35 ml) and treated with a solution of (RS)-2-bromoacetyltetrahydrofuran (3.48 g, 18.0 mmol) in acetone (5 ml). After 10 min, potassium carbonate (1.24 g, 8.9 mmol) was added, and the mixture stirred for a further 30min. The reaction mixture was diluted with ethyl acetate, washed successively with water (x2) and brine, dried and concentrated. The residue was flash chromatographed on silica gel eluting with 50, 70 and 80% ethyl acetate in hexane yielding the title compound as a colourless foam (5.40 g, 55%); νmax (CH2Cl2) 3409, 1781, 1745, 1684, 1613, 1516 cm-1. [Mass spectrum +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (565)].
Reaction SMILES: [F:1][C:2]1[CH:46]=[CH:45][C:5]([O:6][C@@H:7]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][N:28]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=4)=[CH:33][CH:32]=3)[CH3:30])=[CH:20][CH:19]=2)[C:8]([O:10]CC[Si](C)(C)C)=[O:9])=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C@@H:7]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][O:27][N:28]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)[CH3:30])=[CH:22][CH:23]=2)[C:8]([OH:10])=[O:9])=[CH:45][CH:46]=1
Reactant: COc1ccc(-c2ccc(C(C)=NOCCOc3ccc(C[C@H](Oc4ccc(F)cc4)C(=O)OCC[Si](C)(C)C)cc3)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C(C)=NOCCOc3ccc(C[C@H](Oc4ccc(F)cc4)C(=O)O)cc3)cc2)cc1

Procedure:
The target compound (243 mg) was obtained as colorless crystals by carrying out the reaction and the post-treatment according to Reference example 7 using 2-trimethylsilylethyl (S)-2-(4-fluorophenoxy)-3-[4-[2-[[1-(4′-methoxy-4-biphenylyl)ethylidene]aminoxy]ethoxy]phenyl]propionate (438 mg) obtained from Reference example 16 and a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (1.7 ml).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([Mg]Cl)(C)C.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27]([CH:33]=[O:34])([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27]([CH:33]([OH:34])[C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:25]1)=[O:23])([CH3:19])([CH3:20])[CH3:18]
Reactant: Ic1ccc2ccccc2n1
Reactant: CCCC1(C=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC1(C(O)c2ccc3ccccc3n2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 19 %

Procedure:
To a solution of 2-iodoquinoline (670 mg, 2.6 mmol) in THF (10 mL) at 0° C. was slowly added isopropyl magnesium chloride (2.0 M in THF, 1.6 mL, 3.2 mmol). The reaction mixture was stirred at 0° C. for 30 minutes, then a solution of 4-formyl-4-propyl-piperidine-1-carboxylic acid tert-butyl ester (670 mg, 2.6 mmol) in THF (3 mL) was slowly added. The reaction mixture was stirred at 0° C. for 30 minutes, then warmed to room temperature, quenched with saturated aqueous NH4Cl solution, and extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (0% to 20% EtOAc in hexanes) to afford 190 mg (19%) of 4-(hydroxy-quinolin-2-yl-methyl)-4-propyl-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]1[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=1[C:17]([F:20])([F:19])[F:18].[CH3:21][NH:22][C:23]([CH3:26])([CH3:25])[CH3:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:23]([N:22]([CH3:21])[C:14]([C:12]1[CH:11]=[CH:10][C:9]([C:17]([F:20])([F:19])[F:18])=[C:8]([O:7][CH2:6][CH:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[N:13]=1)=[O:16])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCC2CCCO2)n1
Reactant: CNC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ccc(C(F)(F)F)c(OCC2CCCO2)n1)C(C)(C)C

Procedure:
In analogy to the procedure described in Example 47 b), 6-((tetrahydrofuran-2-yl)methoxy)-5-(trifluoromethyl)picolinic acid was reacted with N,2-dimethylpropan-2-amine (CAN 94896-77-2) in the presence of TBTU and DIEA to give the title compound as colorless oil; MS (EI): m/e=361.5 [MH+].
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=[N:3]1.[H-].[Na+].[CH:15](OCC)=[O:16]>C(O)C.O1CCCC1>[OH:16][CH:15]=[C:10]1[C:11](=[O:12])[C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[CH2:7][CH2:8][CH2:9]1
Reactant: CCOC=O
Reactant: Cn1ncc2c1CCCCC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1ncc2c1CCCC(=CO)C2=O

Procedure:
A mixture of 7 grams of 5,6,7,8-tetrahydro-1-methyl4(1H)-cycloheptapyrazolone, 2.3 grams of sodium hydride (97%), 12 ml of ethyl formate, 2 drops of ethanol and 100 ml of tetrahydrofuran was heated at reflux for 3 hours. The mixture was then cooled and partitioned between water and ether. The aqueous layer was washed once with ether and acidified to a pH of 5 with 1 N hydrochloric acid. The white precipitate which formed was separated by filtration and dried to give 5,6,7,8-tetrahydro-5-hydroxymethylene-1-methyl-4(1H)-cycloheptapyrazolone as a cream colored powder melting at about 133°-135° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([O:42][C:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50]O)=[CH:45][CH:44]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH-].[Na+]>C1COCC1.CO>[CH2:35]([O:42][C:43]1[CH:44]=[CH:45][C:46]([CH2:49][CH2:50][O:32][C:29]2[CH:28]=[CH:27][C:26]([C:16]3[C:17]([N:18]4[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23]4)=[C:12]([C@H:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:7]([OH:9])=[O:8])[C:13]([CH3:34])=[N:14][C:15]=3[CH3:33])=[CH:31][CH:30]=2)=[CH:47][CH:48]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: OCCc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(OCCc2ccc(OCc3ccccc3)cc2)cc1
Reaction time: 18 h
Yield: 13.9 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (20 mg, 0.043 mmol), 2-(4-(benzyloxy)phenyl)ethanol (48.7 mg, 0.213 mmol) and Ph3P-resin (55.8 mg, 0.213 mmol) in THF (2 mL) was added DEAD (0.014 mL, 0.085 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with 1N NaOH (0.854 mL, 0.854 mmol) in MeOH (1 mL) at 75° C. for 16 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(5-(4-(4-(benzyloxy)phenethoxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetic acid (3.9 mg, 5.99 μmol, 14.04% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.50-7.29 (m, 6H), 7.28-7.12 (m, 3H), 7.07-6.89 (m, 4H), 5.85 (br. s., 1H), 5.09 (br. s., 2H), 4.20 (d, J=11.0 Hz, 2H), 3.34 (br. s., 1H), 3.25 (br. s., 2H), 2.99 (br. s., 1H), 2.80 (br. s., 1H), 2.43 (br. s., 3H), 2.17 (br. s., 1H), 2.06 (br. s., 3H), 1.92 (br. s., 1H), 1.48 (br. s., 1H), 1.28 (br. s., 1H), 1.13 (br. s., 9H), 1.04 (br. s., 1H), 0.85 (br. s., 3H), 0.60 (br. s., 3H). LCMS (M+H)=651.6.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([NH:8]C(=O)OC(C)(C)C)=[N:5][CH:4]=1)#[CH:2].[CH:16]1([C:19]2[CH:20]=[C:21]([NH:33][C:34](=[O:43])[C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[C:37](I)[CH:36]=3)[CH:22]=[CH:23][C:24]=2[CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)[CH2:18][CH2:17]1>>[NH2:8][C:6]1[S:7][C:3]([C:1]#[C:2][C:41]2[C:36]([CH3:37])=[C:35]([CH:40]=[CH:39][CH:38]=2)[C:34]([NH:33][C:21]2[CH:22]=[CH:23][C:24]([CH2:25][N:26]3[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]3)=[C:19]([CH:16]3[CH2:18][CH2:17]3)[CH:20]=2)=[O:43])=[CH:4][N:5]=1
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C3CC3)c2)cc1I
Reactant: C#Cc1cnc(NC(=O)OC(C)(C)C)s1
Product: Cc1c(C#Cc2cnc(N)s2)cccc1C(=O)Nc1ccc(CN2CCN(C)CC2)c(C2CC2)c1

Procedure:
The title compound can be synthesized from tert-butyl (5-ethynyl-1,3-thiazol-2-yl)carbamate and N-(3-cyclopropyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-iodo-4-methylbenzamide in a manner similar to that described for Example 2 (nitro reduction performed in a manner similar to that described for Example 8; 0.25M in MeOH/10% AcOH). T-BOC deprotection can be performed after coupling as described in Example 5.
Reaction SMILES: [C:1]([N:3]=[C:4](OCC)[CH3:5])#[N:2].Cl.[NH2:10][CH2:11][CH2:12][C:13]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:17]([C:18](=[O:23])[C@@H:19]([O:21][CH3:22])[CH3:20])[N:16]=[C:15]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[S:14]1.C(N(C(C)C)CC)(C)C>CCO.C([O-])([O-])=O.[Na+].[Na+]>[C:1]([N:3]=[C:4]([NH:10][CH2:11][CH2:12][C:13]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:17]([C:18](=[O:23])[C@@H:19]([O:21][CH3:22])[CH3:20])[N:16]=[C:15]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[S:14]1)[CH3:5])#[N:2]
Reactant: CCOC(C)=NC#N
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCN)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCNC(C)=NC#N)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 73 %

Procedure:
Preparation of N′-cyano-N-(2-(5-(2,5-difluorophenyl)-3-((S-2-methoxypropanoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethyl)acetamidine: To a solution of ethyl N-cyanoacetimidate (0.025 g, 0.22 mmol) and (2S)—(2-(2-aminoethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one hydrochloride (0.018 g, 0.038 mmol) in EtOH (0.3 mL) was added diisopropylethylamine (0.033 mL, 0.19 mmol). After stirring at room temperature for 14 hours, the mixture was diluted with 10% Na2CO3 (30 mL) and extracted with dichloromethane. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed (3% MeOH in dichloromethane) to provide the product as a mixture of diastereomers (13.0 mg, 73% yield). MS ESI (+) m/z 472 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.51 (m, 2H), 7.37 (m, 6H), 7.33 (m, 4H), 7.16 (m, 4H), 6.93 (br. t, 1H, J=4.7 Hz), 6.73 (br. t, 1H, J=4.7 Hz), 4.73 (m, 2H), 4.00 (m, 2H), 3.45-3.29 (m, 9H), 3.21 (m, 1H), 2.82 (m, 1H), 2.75 (m, 1H), 2.16 (s, 3H), 2.15 (s, 3H), 1.46 (d, 3H, J=6.3 Hz), 1.43 (d, 3H, J=7.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:16][O:15][C@H:14]([CH3:17])[C@H:13]1[C:12](=[O:18])[N:11]([CH3:19])[C:10]([NH:20]C(=O)OC(C)(C)C)=[N:9]2.[OH-].[Na+].[NH4+].[Cl-].[N+:32]([O-])([OH:34])=[O:33]>>[NH2:20][C:10]1[N:11]([CH3:19])[C:12](=[O:18])[C@@H:13]2[C@@H:14]([CH3:17])[O:15][CH2:16][C@:8]2([C:3]2[CH:4]=[C:5]([N+:32]([O-:34])=[O:33])[CH:6]=[CH:7][C:2]=2[F:1])[N:9]=1
Reactant: O=[N+]([O-])O
Reactant: C[C@H]1OC[C@]2(c3ccccc3F)N=C(NC(=O)OC(C)(C)C)N(C)C(=O)[C@H]12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: C[C@H]1OC[C@]2(c3cc([N+](=O)[O-])ccc3F)N=C(N)N(C)C(=O)[C@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl ((4aS,5R,7aS)-7a-(2-fluorophenyl)-3,5-dimethyl-4-oxo-3,4,4a,5,7,7a-hexahydrofuro[3,4-d]pyrimidin-2-yl)carbamate (2.15 g, 5.7 mmol) was taken up in fuming nitric acid (5 ml) at RT—note exotherm. The dark brown solution was stirred at RT overnight and then at 50° C. for 24 h. The reaction was allowed to cool to RT. Ice (˜25 g) was added and then the mixture was basified with 50% aqueous NaOH with ice bath cooling. The pH was readjusted with saturated aqueous NH4Cl and then the mixture was extracted with DCM (×4). The combined extracts were dried (Na2SO4), filtered and evaporated to give the title compound (1.8 g, yellow foam). LCMS (Method A) Rt 3.00 min; ESI-MS: m/z 323 [M+H]+. This material was used without further manipulation.
Reaction SMILES: [C:1]1([S:7]([CH2:9][C:10]2[C:15]([C:16]([O:18][CH2:19]C)=[O:17])=[C:14]([O:21][CH3:22])[C:13]([CH2:23][CH3:24])=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:25]1[CH:29]=CC(C2C(OC)=C(C(C3C=CC=CC=3)=CC=2)C(OC)=S)=[CH:26]1>>[C:1]1([S:7]([CH2:9][C:10]2[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([O:21][CH3:22])[C:13]([C:23]3[CH:24]=[CH:29][O:25][CH:26]=3)=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c(CS(=O)c2ccccc2)ccc(CC)c1OC
Reactant: COC(=S)c1c(-c2ccccc2)ccc(-c2ccoc2)c1OC
Product: COC(=O)c1c(CS(=O)c2ccccc2)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 2, starting from methyl 3-(furan-3-yl)-2-methoxy-6-phenylthiobenzoate (Intermediate 217).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH:22]=1)[C:19]([OH:21])=O.[C:23]1([C:29]2[CH2:33][CH2:32][NH:31][N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH:22]=1)[C:19]([N:31]1[CH2:32][CH2:33][C:29]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:30]1)=[O:21]
Reactant: c1ccc(C2=NNCC2)cc1
Reactant: O=C(O)c1cncc(Br)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(c1cncc(Br)c1)N1CCC(c2ccccc2)=N1
Reaction time: 1 h
Yield: 42.8 %

Procedure:
1,1′-Carbonyldiimidazole (1.7 g) was added to a solution of 5-bromonicotinic acid (2 g) dissolved in DMF (20 ml), at room temperature. The mixture was stirred for 1 hour in a nitrogen atmosphere. To the reaction mixture was dropwise added a solution of 3-phenyl-2-pyrazoline (5.7 g) dissolved in DMF (15 ml), with ice-cooling. The mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated. The residue was dissolved in chloroform. The solution was washed with ice water, dried over anhydrous sodium sulfate, and concentrated. The organic layer was purified by silica gel column chromatography (methanol chloroform=1/100) to obtain 1.4 g of a title compound (yield: 41%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([I:23])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([I:22])[CH:16]=1)[CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7].[Br:24][CH2:25][C:26](Br)=[O:27]>C(OCC)(=O)C>[Br:24][CH2:25][C:26]([NH:7][C@H:6]([C:8]([OH:10])=[O:9])[CH2:5][C:4]1[CH:3]=[C:2]([I:1])[C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([I:22])[CH:16]=2)=[C:12]([I:23])[CH:11]=1)=[O:27]
Reactant: O=C(Br)CBr
Reactant: N[C@@H](Cc1cc(I)c(Oc2ccc(O)c(I)c2)c(I)c1)C(=O)O
Solvent: CCOC(C)=O
Product: O=C(CBr)N[C@@H](Cc1cc(I)c(Oc2ccc(O)c(I)c2)c(I)c1)C(=O)O

Procedure:
According to the present invention a solution of 3,3',5-triiodo-L-thyronine and bromoacetyl bromide in ethyl acetate is refluxed for a period of time to produce the bromoacetylated hormone which is then fractionated by high speed countercurrent chromatography to yield highly pure N-bromoacetyl-3,3',5-triiodo-L-thyronine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH:18]2[CH2:21][N:20]([CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19]2)=[O:17])=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>O1CCCC1.CO>[C:23]1([CH:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:20]2[CH2:21][CH:18]([CH:16]([OH:17])[C:13]3[CH:14]=[CH:15][C:10]([C@@H:8]([NH:7][C:6](=[O:35])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH3:9])=[CH:11][CH:12]=3)[CH2:19]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(=O)C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(O)C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 6.3 %

Procedure:
9.94 g of the compound [88-1] was dissolved in 100 mL of tetrahydrofuran and 20 mL of methanol, 799 mg of sodium borohydride was added thereto at room temperature, and the mixture was stirred at the same temperature for 2.5 hours. To the reaction mixture, water was added, and the mixture was extracted with chloroform. The obtained organic layer was dried over anhydrous magnesium sulfate. Then, the insolubles were filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0 to 30/70) to obtain 632 mg of tert-butyl ((1S)-1-{4-[[1-(diphenyl methyl)azetidin-3-yl](hydroxy)methyl]phenyl}ethyl)carbamate [88-2] (hereinafter, referred to as the compound [88-2]).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]2[O:14][CH2:15][C:16]([O:19][CH3:20])([O:17][CH3:18])[C@@H:9]12)=[O:7])([CH3:4])(C)C.Cl.N1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(Cl)(OCC1C=CC=CC=1)=O>C(Cl)Cl.CO>[CH2:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]2[O:14][CH2:15][C:16]([O:17][CH3:18])([O:19][CH3:20])[C@@H:9]12)=[O:7])[C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC1(OC)CO[C@@H]2[C@H](O)CN(C(=O)OC(C)(C)C)[C@@H]21
Reactant: c1ccncc1
Agent: Cl
Agent: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: COC1(OC)CO[C@@H]2[C@H](O)CN(C(=O)OCc3ccccc3)[C@@H]21
Temperature: 0 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
To a stirred solution of compound 12c (3.8 g, 13.13 mmol) in CH2Cl2 (100 mL) was added 2M HCl in MeOH (50 mL). The resulting solution was stirred overnight and then concentrated in vacuo and azeotroped with toluene (3×100 mL). The crude residue was dissolved in CH2Cl2 (100 mL) cooled to 0° C. and pyridine (1071 μL, 13.13 mmol) added followed by dropwise addition of CbzCl (1875 μL, 13.13 mmol). The reaction was stirred at room temperature for 2 hours then washed with 2 M HCl (2×50 mL), saturated NaHCO3 (2×50 mL), dried (MgSO4) and concentrated. The residue was purified by flash column chromatography (5-100% isohexane:EtOAc) to obtain the title compound as a clear oil (2510 mg, 59%). MS M+H 324.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][NH2:10])[CH:4]=1.[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[S:21](Cl)(=[O:23])=[O:22]>O1CCOCC1>[NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[CH2:9][NH:10][S:21]([C:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=1)(=[O:23])=[O:22]
Reactant: NCc1cccc(CN)c1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: C1COCCO1
Product: NCc1cccc(CNS(=O)(=O)c2ccc3ccccc3c2)c1
Reaction time: 8 h
Yield: 55.7 %

Procedure:
α,α′-Diamino-m-xylene (24 g, 176 mmol) was dissolved in 50 ml 1,4-dioxane, and at 15-20° C. naphthalene-2-sulfonyl chloride (4 g, 17.6 mmol) dissolved in 50 ml of 1,4-dioxane was slowly added over 3 hours under stirring. Stirring was continued at RT. After standing overnight the formed precipitate was filtered off and the filtrate concentrated in vacuo. The residue was distributed between DCM and water. The organic layer was separated and washed with water and 1 N HCl. The oily layer formed between the organic and aqueous layer was separated. It solidified on standing. This solid material was treated with ethyl acetate, sucked off, and washed with ethyl acetate. The residue was dissolved in water and treated with potassium carbonate solution. The aqueous solution was extracted three times with ethyl acetate, and the combined organic phases were dried over magnesium sulfate, filtered, and concentrated to yield 3.2 g of the title compound. MS=327.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:14]([CH2:16][NH:17][C:18](=[O:47])[C@@H:19]([O:24][CH:25]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])#[N:15].[N].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:14]([CH2:16][NH:17][C:18](=[O:47])[C@@H:19]([O:24][C@@H:25]([C:41]1[CH:42]=[CH:43][C:44]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=2)=[CH:45][CH:46]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])#[N:15]
Reactant: Brc1ccc(N2CCOCC2)cc1
Reactant: CC(C)C[C@H](OC(c1ccccc1)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)NCC#N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)C[C@H](O[C@H](c1ccccc1)c1ccc(-c2ccc(N3CCOCC3)cc2)cc1)C(=O)NCC#N
Temperature: 85 °C

Procedure:
To a solution of N-(4-bromophenyl)morpholine (0.66 mmol, 159 mg) in DMF (7 mL) was added under a stream of nitrogen (2S)-N-(cyanomethyl)-4-methyl-2-{phenyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}pentanamide from Example 16 (0.66 mmol, 250 mg). PdCl2(dppf) (0.033 mmol, 24 mg) and 2N Na2CO3 (2.63 mmol) was added. The mixture was degassed with a rapid stream of nitrogen bubbling through the mixture and the mixture was heated to 85° C. for 18 h. EtOAc was added, the mixture was washed with water and brine. The organic extract was dried and chromatographed (20-40% EtOAc/hexane) to give the title compound.