Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[F:27][C:28]1[CH:33]=[C:32]([C:34]#[N:35])[CH:31]=[CH:30][C:29]=1[CH3:36]>C(Cl)(Cl)(Cl)Cl.CCOCC>[F:27][C:28]1[CH:33]=[C:32]([CH:31]=[CH:30][C:29]=1[CH2:36][Br:8])[C:34]#[N:35]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)cc1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)c(F)c1
Temperature: 80 °C
Yield: 31.1 %

Procedure:
NBS (Aldrich, 3.02 g, 17 mmol) and benzoylperoxide (Aldrich, 0.37 g, 1.5 mmol) was added to a solution of 2-fluoro-4-cyanotoluene (compound 5-2, 2.08 g, 15 mmol) in CCl4. The reaction mixture was heated at 80° C. for 14 hours. After cooling down to ambient temperature, the mixture was diluted with ether (100 ml) and washed with aqueous Na2S3O3, and dried (MgSO4). Removal of solvent under vacuum led to a yellow oil which was purified by flash chromatography. The title compound 5-3 (1.4 g, 42%) was obtained, together with a by-product, 3-fluoro-4-(bromomethyl)benzonitrile (5-4) (1.0 g, 30%). For the title compound (5-3): 1H NMR (CDCl3): δ 4.46 (s, 2H), 7.35 (d, 1H, J=8.0 Hz), 7.42 (d, 1H, J=8.0 Hz), 7.52 (t, 1H, J=8.0 Hz). For the by-product (5-4): 1H NMR (CDCl3): δ 6.90 (s, 1H), 7.35 (d, 1H, J=8.0 Hz), 7.55 (d, 1H, J=8.0 Hz), 7.96 (t, 1H, J=8.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:7]2[CH2:9][CH2:8]2)=[N:5][N:6]=1.[Cl:10][C:11]1[C:16]2[O:17][C:18]3[C:27]([CH3:28])=[CH:26][C:25]([C:29]([OH:31])=[O:30])=[CH:24][C:19]=3[S:20](=[O:23])(=[O:22])[CH2:21][C:15]=2[CH:14]=[C:13]([S:32](Cl)(=[O:34])=[O:33])[CH:12]=1.N1C=CC=CC=1>C(OCC)(=O)C>[Cl:10][C:11]1[C:16]2[O:17][C:18]3[C:27]([CH3:28])=[CH:26][C:25]([C:29]([OH:31])=[O:30])=[CH:24][C:19]=3[S:20](=[O:23])(=[O:22])[CH2:21][C:15]=2[CH:14]=[C:13]([S:32](=[O:33])(=[O:34])[NH:1][C:2]2[S:3][C:4]([CH:7]3[CH2:9][CH2:8]3)=[N:5][N:6]=2)[CH:12]=1
Reactant: Nc1nnc(C2CC2)s1
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(S(=O)(=O)Cl)cc1CS2(=O)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(S(=O)(=O)Nc3nnc(C4CC4)s3)cc1CS2(=O)=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2-Amino-5-cyclopropyl-1,3,4-thiadiazole (0.236 g, 0.126 mmol) was added to a mixture of Example 49j (0.3 g, 0.68 mmol) and pyridine (8 mL) in ethyl acetate (10 mL). The reaction mixture was stirred at room temperature for 15 h, concentrated, treated with water and extracted with n-butanol. The organic extract was washed with water, dried concentrated and purified using flash chromatography (silica gel, 4% methanol/chloroform) to obtain the title compound. Yield: 0.03 g, (8%); 1H NMR (DMSO-d6): δ 0.98 (m, 2H, CH2), 1.12 (d, 2H, CH2), 2.3 (m, 1H, CH), 2.7 (s, 3H, CH3), 5.46 (s, 2H, CH2), 7.95 (d, 1H, Ar,), 8.06 (s, 1H, Ar), 8.14 (s, 1H, Ar), 8.16 (s, 1H, Ar).
Reaction SMILES: CO[C:3]([CH2:5][CH2:6][C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[O:4].C(CC(=O)C)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH2:26]([NH2:28])[CH3:27]>CO>[NH2:11][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][CH2:5][C:3]([NH:28][CH2:26][CH3:27])=[O:4]
Reactant: CCN
Reactant: COC(=O)CC[C@H](N)C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)=O
Solvent: CO
Product: CCNC(=O)CC[C@H](N)C(=O)O
Temperature: 60 °C
Yield: 37 %

Procedure:
First, 5.0 g (31 mmol) of L-glutamic acid-γ-methyl ester was suspended in 15 mL of methanol. To this, 3.4 g (34 mmol) of acetylacetone and 5.0 g of anhydrous sodium sulfate were added. The mixture was heated at 60° C. for 6 hours. Subsequently, sodium sulfate was filtrated off. To the filtrate, 20 g (310 mmol) of 70% ethylamine was added and the same procedure as in Example 1 was performed to obtain 2.0 g of theanine (yield: 37.0%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][CH2:19][C:18]=4[CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:23].[CH3:24][O:25][C:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:30]5[CH:29]=[CH:28][N:27]=[C:26]([O:25][CH3:24])[CH:31]=5)[C:3]([CH3:23])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: COc1cc(B(O)O)ccn1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)CCO5)CC3)ccc2C)ccn1
Yield: 34.9 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide (95 mg, 0.3 mmol) in 1,2-dimethoxyethane (3 mL) was added 2-methoxypyridin-4-ylboronic acid (66 mg, 0.4 mmol), tetrakis(triphenylphosphine)palladium (0) (33 mg, 0.03 mmol), and 2 M sodium carbonate (0.45 mL, 0.9 mmol). The reaction mixture was irradiated in the microwave at 120° C. for twenty minutes. The reaction mixture was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The crude reaction mixture was purified by silica gel chromatography eluting with (0-50% ethyl acetate/hexanes) to yield the product (42 mg, 34%). ESI-MS m/z calc. 401.17. found 402.5 (M+1)+. Retention time 1.88 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2Cl)=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:4][CH:3]=1.[CH3:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)=[O:18].[OH-].[Na+]>CCO.Cl>[Cl:1][C:2]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH:25][C:22]2[CH:23]=[CH:24][C:19]([C:17](=[O:18])[CH3:16])=[CH:20][CH:21]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:4][CH:3]=1
Reactant: Clc1coc2nc3ccccc3c(Cl)c12
Reactant: CC(=O)c1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)c1ccc(Nc2c3ccccc3nc3occ(Cl)c23)cc1
Temperature: 0 °C
Yield: 76.2 %

Procedure:
To a solution of 3,4-dichlorofuro[2,3-b]quinoline (compound 12, 0.92 g, 3.86 mmol) and 4-aminoacetophenone (0.88 g, 6.52 mmol) in EtOH (40 mL), concentrated HCl was added until a pH of 6 was reached. The mixture was refluxed for 16 h and the solvent evaporated in vacuo to yield a residual solid, which was suspended in ice-water (80 mL) and neutralized with a 1N NaOH solution. The resultant precipitate was collected by filtration, washed with H2O, and then chromatographed on a column of silica gel using CH2Cl2—MeOH=10/1 to obtain the title compound 13 (0.99 g, 75% yield).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32]([OH:34])=O)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]1>>[C:45]([O:44][C:43](=[O:49])[NH:42][C@H:39]1[CH2:38][CH2:37][C@H:36]([NH:35][C:32]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:7]4[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:15]=3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[C:21]=2[CH3:31])=[O:34])[CH2:41][CH2:40]1)([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c6) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36](Br)[CH:35]=1)[C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[C:33]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:27]4[C:22]3=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1.C(=O)=O.C([Li])CCC.Cl[Si:50](Cl)([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CC(C)=O.C1COCC1>[CH:23]1[C:22]2[N:21]([C:17]3[CH:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([N:8]5[C:3]6[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=6[Si:50]([C:57]6[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=6)([C:51]6[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=6)[C:35]6[CH:36]=[CH:37][CH:38]=[CH:39][C:34]5=6)[CH:10]=4)[CH:20]=[CH:19][CH:18]=3)[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: Brc1cccc(N(c2cccc(-c3cccc(-n4c5ccccc5c5ccccc54)c3)c2)c2ccccc2Br)c1
Reactant: Cl[Si](Cl)(c1ccccc1)c1ccccc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: c1ccc([Si]2(c3ccccc3)c3ccccc3N(c3cccc(-c4cccc(-n5c6ccccc6c6ccccc65)c4)c3)c3ccccc32)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
N-(2-bromophenyl)-N-(3-bromophenyl)-3′-(9H-carbazol-9-yl)-[1,1′-biphenyl]-3-amine was added into a 250 mL round bottom flask, and solubilized in dry THF (155 ml). The solution was cooled down to −78° C. using dry ice and Acetone. Butyllithium (7.45 ml, 18.62 mmol) was added dropwise and the reaction mixture was stirred −78° C. for 2 hours. Dichlorodiphenylsilane (2.108 ml, 10.24 mmol) was then added dropwise. The reaction mixture was allowed to slowly warm to room temperature and was stirred overnight. The reaction was quenched with water, extracted three times with ether, washed with brine and water. The crude material was purified with column chromatography using hexane/DCM (75/25). The product was collected as a white powder with a purity of 99.3% by HPLC. The product was recrystallized twice from DCM and hexane. The target 5-(3′-(9H-carbazol-9-yl)-[1,1′-biphenyl]-3-yl)-10,10-diphenyl-5,10-dihydrodibenzo[b,e][1,4]azasiline (Compound 10) was afforded as a white powder (1.8 g, 29% yield). Compound 10 was then sublimed and 1.2 g was collected.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:9]([CH3:11])[CH3:10])=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].NC1C(Cl)=NC=NC=1Cl.CNC.[C:24](Cl)(=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>>[CH3:10][N:9]([CH3:11])[C:3]1[C:2]([NH:1][C:24](=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[C:7]([Cl:8])[N:6]=[CH:5][N:4]=1
Reactant: CN(C)c1ncnc(Cl)c1N
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Agent: CNC
Agent: Nc1c(Cl)ncnc1Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1c(Cl)ncnc1N(C)C

Procedure:
5-Amino-4-(dimethyl)amino-6-chloropyrimidine (prepared by reacting commercially available 5-amino-4,6-dichloropyrimidine with excess dimethylamine) was coupled with oleoyl chloride according to the procedure described in Example 4 to give the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[CH:19]=[C:20]([C:23]6[CH:28]=[CH:27][C:26]([C:29]7([C:32]([OH:34])=O)[CH2:31][CH2:30]7)=[CH:25][CH:24]=6)[CH:21]=[N:22][C:17]5=[N:16][CH:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:35]([NH2:37])[CH3:36].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:35]([NH:37][C:32]([C:29]1([C:26]2[CH:25]=[CH:24][C:23]([C:20]3[CH:21]=[N:22][C:17]4[N:18]([C:14]([C:11]5([C:7]6[CH:6]=[C:5]7[C:10](=[CH:9][CH:8]=6)[N:1]=[CH:2][CH:3]=[CH:4]7)[CH2:13][CH2:12]5)=[CH:15][N:16]=4)[CH:19]=3)=[CH:28][CH:27]=2)[CH2:31][CH2:30]1)=[O:34])[CH3:36]
Reactant: CCN
Reactant: O=C(O)C1(c2ccc(-c3cnc4ncc(C5(c6ccc7ncccc7c6)CC5)n4c3)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)C1(c2ccc(-c3cnc4ncc(C5(c6ccc7ncccc7c6)CC5)n4c3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-{4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}cyclopropanecarboxylic acid (20 mg, 0.045 mmol), ethylamine (2.4 mg, 0.054 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (24 mg, 0.054 mmol), and N,N-diisopropylethylamine (23 μL, 0.13 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at RT for 2 h. The reaction mixture was purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=474.1.
Reaction SMILES: N1CCCC1.[F:6][C:7]1[C:8]([OH:16])=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=1.[O:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.Cl>C1(C)C=CC=CC=1>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:8]=1[O:16][C:20]1([CH2:21][CH2:22][O:17][CH2:18][CH2:19]1)[CH2:14][C:13]2=[O:15]
Reactant: CC(=O)c1cccc(F)c1O
Reactant: O=C1CCOCC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: O=C1CC2(CCOCC2)Oc2c(F)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
Pyrrolidine (4.8 ml, 58 mmol) was added to a stirred solution of 1-(3-fluoro-2-hydroxyphenyl)ethanone (28) (5.9 g, 39 mmol) and tetrahydro-4h-pyran-4-one (4.6 ml, 50 mmol) in toluene (40 mL) at rt. After the exotherm subsided, the reaction mixture was stirred at rt for 1 h. then subjected to Dean-Stark reflux conditions for 6 h. The reaction mixture was cooled, poured into ice and 2 N HCl aqueous solution, and extracted with EtOAc (2×). The combined organics were washed with 2 N HCl aqueous solution (1×), 2 N NaOH aqueous solution (2×), brine (1×), and dried over Na2SO4. Concentration in vacuo gave 8-fluoro-2′,3′,5′,6′-tetrahydrospiro[chromene-2,4′-pyran]-4(3H)-one (29) (4.4 g, 48% yield) which was taken onto the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.51-7.60 (2H, m), 7.00-7.07 (1H, m), 3.60-3.73 (4H, m), 2.93 (2H, s), 1.71-1.92 (4H, m).
Reaction SMILES: [C:1]([CH2:4][C:5]([O:7][C@H:8]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[C:21]([O:29][CH2:30][CH:31]2[CH2:33][CH2:32]2)[CH:20]=1)[CH2:9][C:10]1[C:15]([Cl:16])=[CH:14][N+:13]([O-:17])=[CH:12][C:11]=1[Cl:18])=[O:6])([OH:3])=[O:2].[CH:34]1([CH2:37][O:38][C:39]2[CH:44]=[C:43]([CH2:45]O)[CH:42]=[CH:41][C:40]=2[N:47]([S:55]([CH3:58])(=[O:57])=[O:56])[C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:36][CH2:35]1>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:50]([O:49][C:48]([N:47]([C:40]1[CH:41]=[CH:42][C:43]([CH2:45][O:2][C:1](=[O:3])[CH2:4][C:5]([O:7][C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[C:21]([O:29][CH2:30][CH:31]3[CH2:32][CH2:33]3)[CH:20]=2)[CH2:9][C:10]2[C:15]([Cl:16])=[CH:14][N+:13]([O-:17])=[CH:12][C:11]=2[Cl:18])=[O:6])=[CH:44][C:39]=1[O:38][CH2:37][CH:34]1[CH2:35][CH2:36]1)[S:55]([CH3:58])(=[O:56])=[O:57])=[O:54])([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)N(c1ccc(CO)cc1OCC1CC1)S(C)(=O)=O
Reactant: O=C(O)CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(c1ccc(COC(=O)CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-4-(2-(2-carboxyacetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (50 mg, 0.099 mmol), tert-butyl 2-(cyclopropylmethoxy)-4-(hydroxymethyl)phenyl-(methylsulfonyl)-carbamate (73 mg, 0.2 mmol), DMAP (14.5 mg, 0.12 mmol), and ECD (57 mg, 0.3 mmol) in DMF (1.5 ml) was stirred at RT overnight. The reaction mixture was quenched with water, and the product was extracted with EtOAc. The organic phase was washed with HCl 1M, NaHCO3 sat. sol. and brine. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude (70 mg) was used for the next step without any further purification.
Reaction SMILES: Br.[CH3:2][O:3][C:4](=[O:39])[C@H:5]([CH2:20][C:21]1[CH:28]=[C:26]([I:27])[C:25]([O:29][C:30]2[CH:37]=[C:35]([I:36])[C:34]([OH:38])=[C:32]([I:33])[CH:31]=2)=[C:23]([I:24])[CH:22]=1)[NH:6][C:7](=[O:19])[CH2:8][O:9][CH2:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12].[C:40]1(=[O:46])[O:45][C:43](=[O:44])[CH2:42][CH2:41]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:2][O:3][C:4](=[O:39])[C@H:5]([CH2:20][C:21]1[CH:22]=[C:23]([I:24])[C:25]([O:29][C:30]2[CH:31]=[C:32]([I:33])[C:34]([OH:38])=[C:35]([I:36])[CH:37]=2)=[C:26]([I:27])[CH:28]=1)[NH:6][C:7](=[O:19])[CH2:8][O:9][CH2:10][C:11]([N:13]1[CH2:14][CH2:15][N:16]([C:40](=[O:46])[CH2:41][CH2:42][C:43]([OH:45])=[O:44])[CH2:17][CH2:18]1)=[O:12]
Reactant: COC(=O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)COCC(=O)N1CCNCC1
Reactant: O=C1CCC(=O)O1
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)COCC(=O)N1CCN(C(=O)CCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-(piperazinocarbonylmethoxyacetyl)thyroxine methyl ester Hydrobromide from step 5 (9.5 g, 0.01 mole) and succinic anhydride (2.0 g, 0.02 mole), in chloroform (400 mL) was added triethylamine (3.3 g, 0.033 mole). The slurry immediately begins to dissolve and the mixture was stirred overnight at room temperature. The next day the solid had all dissolved and the solution was washed with 5% HCl solution (3×100 mL), water (100 mL), saturated NaCl solution (100 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent removed on a rotary evaporator in vacuo. This material was further purified by chromatography using SiO2.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[I-:10].[Na+].CNCCNC.O>O1CCOCC1.[Cu]I>[F:8][C:7]1[C:2]([I:10])=[N:3][C:4]([CH3:9])=[CH:5][CH:6]=1
Reactant: [I-]
Reactant: Cc1ccc(F)c(Br)n1
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(F)c(I)n1
Temperature: 25 °C
Yield: 93.8 %

Procedure:
To a solution of 2-bromo-3-fluoro-6-methylpyridine (1000 mg, 5.26 mmol) in 1,4-dioxane (16 mL) were added sodium iodide (1580 mg, 10.52 mmol), copper (I) iodide (150 mg, 0.26 mmol), N,N′-dimethylethylenediamine (62 μL, 0.58 mmol) under argon atmosphere. The reaction solution was heated to reflux for 4 hours, cooled to room temperature, and then to the reaction solution was added water. The mixture was extracted with ethyl acetate twice. The organic layer was combined, washed with aqueous citric acid solution and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give 3-fluoro-2-iodo-6-methylpyridine (1169 mg, 94%) as a white powder.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]([Cl:8])=[CH2:7])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[C:20](Cl)=[O:21]>C1C=CC=CC=1>[Cl:8][C:6](=[CH2:7])[CH2:5][N:4]([CH2:1][CH:2]=[CH2:3])[C:20](=[O:21])[C:19]1[CH:18]=[C:17]([CH3:16])[CH:25]=[C:24]([CH3:26])[CH:23]=1
Reactant: C=CCNCC(=C)Cl
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CCN(CC(=C)Cl)C(=O)c1cc(C)cc(C)c1
Temperature: 10 °C

Procedure:
A solution was formed by dissolving N-allyl-2-chloroallylamine (0.032 moles) in 40 ml. of benzene. Then, triethylamine (0.032 moles) was added thereto. This solution was then cooled to 10° C. in an ice bath. Then, 3,5-dimethylbenzoylchloride was diluted with 40 ml. of benzene and added to the amine solution. The temperature rose to about 35° C. with triethylamine hydrogen chloride separation. The next day the reaction mixture was washed two times with diluted HCl and then two times with dilute (5% solution) sodium carbonate and dried. The solvent was removed to yield 7.0 grams of product ND30 1.5367.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])(=O)[CH3:2].Cl.[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][NH2:28])=[CH:23][CH:22]=1.CC([O-])=O.[Na+]>CCO>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([NH:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[C:4]([C:1](=[N:28][O:27][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)[CH3:2])[CH:9]=1
Reactant: CC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: NOc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=NOc1ccc(F)cc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Yield: 96.1 %

Procedure:
A solution of N-(2-acetyl-4-chlorophenyl)trifluoromethanesulfonamide 19 (350 mg, 1.16 mmol), O-(4-fluorophenyl)hydroxylamine hydrochloride (190 mg, 1.16 mmol) and anhydrous NaOAc (104 mg, 1.27 mmol) in EtOH (16 mL) was stirred for 15 h at RT. The reaction mixture was concentrated under vacuum, the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 3:2) and the solvent removed under reduced pressure. The residue was purified by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:4) to afford N-{4-chloro-2-[1-(4-fluorophenoxyimino)ethyl]phenyl}trifluoromethanesulfonamide 129 (458 mg, 96%), as a pale yellow solid. M.p. 71-73° C. 1H n.m.r. (200 MHz, CDCl3) δ 11.23, br s, 1H; 7.69, d, J=9.0 Hz, 1H; 7.59, d, J=2.4 Hz, 1H; 7.40, dd, J=2.4 and 9.0 Hz, 1H; 7.18-7.03, m, 4H; 2.55, s, 3H.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C([O:7][C:8](=O)[C:9]([C:11]1[CH:19]=[CH:18][C:14]2[O:15][CH2:16][O:17][C:13]=2[CH:12]=1)=[O:10])C>C(O)C>[O:15]1[C:14]2[CH:18]=[CH:19][C:11]([C:9](=[O:10])[C:8]([NH:4][CH2:3][CH2:1][OH:2])=[O:7])=[CH:12][C:13]=2[O:17][CH2:16]1
Reactant: CCOC(=O)C(=O)c1ccc2c(c1)OCO2
Reactant: NCCO
Solvent: CCO
Product: O=C(NCCO)C(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.5 %

Procedure:
Ethanolamine (3.5 g, 49 mmol) was added to a stirred solution of benzo[1,3]dioxol-5-yl-oxo-acetic acid ethyl ester (2.5 g, 11 mmol)) in ethanol (40 ml)) at room temperature. The resulting reaction mixture was heated to reflux for 2 hours. Then ethanol was distilled off and stirring was continued at 120° C. for 1 hour. The reaction mixture was cooled to room temperature and then 50 ml of THF and 100 ml of aqueous HCl solution were added and stirred for 30 minutes. The mixture was extracted twice with DCM (50 ml). The organic layer was washed twice with water (50 ml) and evaporated to provide a dark sticky product. The product was further crystallized in pentane/ethyl acetate. Red crystals of the title compound (0.9 g, 34.5% yield) were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:29])=[C:16]([OH:30])[CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[C:32]([O-])([O-])=O.[K+].[K+].CI>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].COCCOC>[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:23]([Cl:29])=[CH:24][CH:25]=[CH:26][C:27]=2[Cl:28])=[C:16]([O:30][CH3:32])[CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(OCc2c(Cl)cccc2Cl)c(O)c1)NC(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: CI
Solvent: COCCOC
Product: COC(=O)[C@H](Cc1ccc(OCc2c(Cl)cccc2Cl)c(OC)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a suspension of N-(tert-butoxycarbonyl)-4-(2,6-dichlorobenzyloxy)-3-hydroxy-L-phenylalanine methyl ester (0.45 g), K2CO3 (0.199 g), and n-Bu4NI (0.035 g) in DME (4.0 mL) was added CH3I (0.072 mL) and the mixture was stirred overnight at room temperature. DMF was removed and the residue was partitioned between water and EtOAc. The organic layer was separated and the aqueous solution was extracted with EtOAc. The combined extract was dried (MgSO4) and evaporated. The residue was purified by preparative TLC (silica gel; eluent: hexanes/CH2Cl2/EtOAc, 3:3:1) to yield 0.396 g of N-(tert-butoxycarbonyl)-4-(2,6-dichlorobenzyloxy)-3-methoxy-L-phenylalanine methyl ester. ESMS: m/z 484 (MH+).