Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][CH2:9][C:10]([C@H:12]2[C@H:19]3[C@H:15]([O:16][C:17]([CH3:21])([CH3:20])[O:18]3)[C:14]([CH2:22][O:23][C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1.N1C=CC=CC=1.C(O)(C(F)(F)F)=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([C@H:12]3[C@H:19]4[C@H:15]([O:16][C:17]([CH3:20])([CH3:21])[O:18]4)[C:14]([CH2:22][O:23][C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:13]3)=[CH:9][N:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CC1(C)O[C@@H]2[C@H](O1)C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)=C[C@H]2C(=O)CNc1nccnc1Cl
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC1(C)O[C@@H]2[C@H](O1)C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)=C[C@H]2c1cnc2c(Cl)nccn12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-(3-chloropyrazin-2-ylamino)-1-((3aS,4R,6aR)-2,2-dimethyl-6-(trityloxymethyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethanone (1-7) (401 mg, 0.69 mmol, 1 equiv) was dissolved in toluene (5.1 mL) and cooled to 0° C. Pyridine (0.67 mL, 8.27 mmol, 12 equiv) was added followed by TFA (0.37 mL, 4.82 mmol, 7 equiv). After 30 minutes, TFAA (0.68 mL, 4.82 mmol, 7 equiv) was added. The resulting mixture was allowed to warm to 15° C. and stirred for 20 h. The reaction was diluted with toluene, washed with sodium bicarbonate, dried (MgSO4), and concentrated. The yellow residue was purified via flash chromatography on silica gel column (ethyl acetate/hexanes) to yield of 8-chloro-3-((3aS,4S,6aR)-2,2-dimethyl-6-(trityloxymethyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)imidazo[1,2-a]pyrazine (1-8) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 7.93 (d, 1H, J=3 Hz), 7.64 (d, 1H, J=3 Hz), 7.21-7.49 (m, 15H), 5.94 (br s, 2H), 5.06 (d, 1H, J=5.5 Hz), 4.98 (d, 1H, J=5.5 Hz), 4.45 (m, 2H), 3.89 (d, 1H, J=14.5 Hz), 3.76 (m, 1H), 3.71 (d, 1H, J=14.5 Hz), 1.36 (s, 3H), 1.33 (s, 3H). LRMS m/z (M+H) 563.9 found, 564.2 required.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([F:15])[C:11](F)=[N:12][CH:13]=2)=[N:6][CH:7]=1.[NH2:16][NH2:17]>CC(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([F:15])[C:11]([NH:16][NH2:17])=[N:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: Fc1cc(-c2ccc(Cl)cn2)cnc1F
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: NNc1ncc(-c2ccc(Cl)cn2)cc1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 5-(5-chloropyridin-2-yl)-2,3-difluoropyridine (2.4 g, 11 mmol) in IPA (35 mL, 0.3 M) at room temperature was added hydrazine (4 mL, 127 mmol). The reaction mixture was stirred at 60° C. for 2 h, at which point the reaction was cooled to room temperature and concentrated in vacuo. The concentrated material was suspended in saturated NaHCO3 and filtered to obtain product as a white, fluffy solid. The material was re-suspended in water (30 mL), and filtered to obtain 1-(5-(5-chloropyridin-2-yl)-3-fluoropyridin-2-yl)hydrazine (2.1 g, 83% yield). MS m/z=239.2 [M+1]+. Calc'd for C10H8ClFN4: 238.6.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C@@:9]1([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[O:14][C:13](=[O:15])[N:12]([C@H:16]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH3:17])[CH2:11][CH2:10]1)(=O)=O.[N-:31]=[N+:32]=[N-:33].[Na+]>CN(C=O)C>[N:31]([CH2:6][CH2:7][CH2:8][C@@:9]1([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[O:14][C:13](=[O:15])[N:12]([C@H:16]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH3:17])[CH2:11][CH2:10]1)=[N+:32]=[N-:33]
Reactant: C[C@@H](C1CCCCC1)N1CC[C@](CCCOS(C)(=O)=O)(c2ccc(F)cc2)OC1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](C1CCCCC1)N1CC[C@](CCCN=[N+]=[N-])(c2ccc(F)cc2)OC1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 85.8 %

Procedure:
To a solution of 3-((R)-3-((S)-1-cyclohexylethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propyl methanesulfonate (240 mg, 0.54 mmol) in DMF (10 mL) was added NaN3 (112 mg, 1.72 mmol). After stirring at 100° C. for 3 h, the reaction was quenched by H2O, and the mixture was extracted with EtOAc. The organic phase was washed with brine and concentrated to give (R)-6-(3-azidopropyl)-3-((S)-1-cyclohexylethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (180 mg, 88%). 1H NMR (CDCl3): δ=1.04 (m, 6H), 1.21 (m, 1H), 1.41 (m, 1H), 1.5 (m, 2H), 1.7 (m, 1H), 1.8 (m, 7H), 2.12 (m, 1H), 2.3 (m, 1H), 2.6 (m, 1H), 3.01 (m, 2H), 3.22 (m, 2H), 3.92 (m, 1H), 7.02 (m, 2H), 7.3 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[F:18][C:19]([F:32])([F:31])[O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][C:19]([F:18])([F:31])[F:32])=[CH:26][CH:25]=2)(=[O:29])=[O:28])=[C:3]([C:9]([C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:4]=1
Reactant: Cc1ncccc1C(=O)c1cc(Cl)ccc1N
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Product: Cc1ncccc1C(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(OC(F)(F)F)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2 amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and 4-trifluoromethoxy-benzenesulfonyl chloride and purified by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11](S(C1C=CC(C)=CC=1)(=O)=O)[C:10]1[C:9](=[O:26])[CH2:8][CH2:7][CH2:6][C:5]2=1.[OH-].[K+].[C:29]1([CH:35]=O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CO>[CH:35](=[C:8]1[CH2:7][CH2:6][C:5]2[C:4]3[C:12](=[CH:13][C:14]([Cl:15])=[C:2]([Cl:1])[CH:3]=3)[NH:11][C:10]=2[C:9]1=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4cc(Cl)c(Cl)cc42)CCCC3=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1C(=Cc2ccccc2)CCc2c1[nH]c1cc(Cl)c(Cl)cc21
Temperature: 75 °C
Yield: 69.4 %

Procedure:
To a solution of 6,7-dichloro-2,3,4,9-tetrahydro-1H-carbazol-1-one (intermediate 1c) (0.8 g, 3.16 mmol) in MeOH (15 mL), KOH (53 mg, 0.94 mmol) followed by PhCHO (2.6 g, 24.5 mmol) were added. The reaction mixture was heated to 70-80° C. for 12 h. The solids were filtered and dried in vacuo to afford the title compound as a light yellow solid (0.75 g, 70%). 1H NMR (500 MHz, DMSO-d6, δ in ppm) 12.07 (s, 1H), 8.05 (s, 1H), 7.64 (d, J=13.0 Hz, 2H), 7.54 (d, J=7.0 Hz, 2H), 7.49-7.46 (m, 2H), 7.41 (d, J=7.5 Hz, 1H), 3.21-3.18 (m, 2H), 3.05-3.02 (m, 2H).
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[N:13]([CH2:31][CH2:32][CH3:33])[C:14](=[O:30])[C:15]3[NH:16][C:17]([C:21]45[CH2:28][CH:27]6[CH2:29][CH:23]([CH2:24][CH:25]4[CH2:26]6)[CH2:22]5)=[N:18][C:19]=3[N:20]=2)[CH:6]=1)C.[OH-].[Na+]>C(O)C.C1COCC1>[CH2:24]1[CH:25]2[C:21]3([C:17]4[NH:16][C:15]5[C:14](=[O:30])[N:13]([CH2:31][CH2:32][CH3:33])[C:12]([O:11][C:7]6[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=6)[C:4]([OH:34])=[O:3])=[N:20][C:19]=5[N:18]=4)[CH2:28][CH:27]([CH2:29][CH:23]1[CH2:22]3)[CH2:26]2
Reactant: CCCn1c(Oc2cccc(C(=O)OCC)c2)nc2nc(C34CC5CC(CC3C5)C4)[nH]c2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCn1c(Oc2cccc(C(=O)O)c2)nc2nc(C34CC5CC(CC3C5)C4)[nH]c2c1=O
Temperature: 50 °C
Yield: 60.1 %

Procedure:
To a solution of 3-[8-(Hexahydro-2,5-methano-pentalen-3a-yl)-6-oxo-1-propyl-6,7-dihydro-1H-purin-2-yloxy]-benzoic acid ethyl ester (prepared by following similar, procedure as Example 1, 0.073 g, 0.157 mmol) in a mixture of ethanol (5 ml) water (5 ml) and THF (5 ml) was added sodium hydroxide (0.019 g, 0.473 mmol) and the reaction mixture was heated at 50° C. overnight. The reaction mixture after cooling to room temperature was concentrated under vacuum to remove THF. The aqueous layer was acidified with 1N HCl. The precipitate obtained was extracted with ethylacetate. The ethyl acetate layer was dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by column chromatography using 5% methanol in DCM as the eluant to give the product (0.041 g, 59%) as an off white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:20](=[O:28])[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH:7]=1)=[O:5])[CH3:2].[H][H]>C(O)(=O)C.O=[Pt]=O>[CH2:1]([O:3][C:4]([CH:6]1[C:12]2[NH:13][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:20](=[O:28])[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1ccccc21
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CCOC(=O)C1CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1c2CCCC1

Procedure:
A solution of 3-(4-fluoro-benzoyl)-1,2,3,6-tetrahydro-azepino[4,5-b]indole-5-carboxylic acid ethyl ester (Example 5, 1.3 g, 3.4 mmol) in 60 mL of glacial acetic acid containing 500 mg of Adams catalyst was subjected to hydrogenation for 14 hours at room temperature and under 45psi of hydrogen. (Boekelheide, V. and Liu, C-T, J. Am. Chem. Soc. 1952, 74, 4920-4922). The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The crude product was purified by preparative normal-phase HPLC eluting with 40% EtOAc-Hexane . 1H-NMR(CDCl3): δ 7.99 (1H, s), 7.40-7.37 (2H, m), 7.11-7.06 (2H, m), 4.22-4.15 (4H, m), 3.54 (1H, m), 2.75 (1H, m), 2.54-2.45 (2H, m), 2.31 (2H, m), 1.76 (4H, m), 1.61 (2H, m), 1.32 (3H, m); MS (ES): 385 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3](=[CH:9][CH:10]=[C:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]([O:6][CH2:7][CH3:8])=[S:5].F[B-](F)(F)F.CN(C)[C:31]([C:37](OCC)=O)=[CH:32][CH:33]=[N+](C)C.C([Li])CCC.C1(SCC(OC2CCCCC2)=O)C=CC=CC=1>CCCCCC.O1CCCC1>[CH3:23][N:2]([CH3:1])[C:3](=[CH:9][CH:10]=[C:11]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:12]([O:14][CH:15]1[CH2:33][CH2:32][CH2:31][CH2:37][CH2:16]1)=[O:13])[C:4]([O:6][CH2:7][CH3:8])=[S:5]
Reactant: CCOC(=O)C(=CC=C(C(=S)OCC)N(C)C)c1ccccc1
Reactant: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Agent: F[B-](F)(F)F
Agent: O=C(CSc1ccccc1)OC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=S)C(=CC=C(C(=O)OC1CCCCC1)c1ccccc1)N(C)C

Procedure:
The procedure is as in Example 2 for the preparation of diethyl 2-dimethylamino-5-phenylthio-2,4-hexadienedioate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (13.7 g), a 1.6M solution (33.1 cc) of n-butyllithium in hexane and cyclohexyl (phenylthio)acetate (12 g) in tetrahydrofuran (150 cc). After purification by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (80:20 by volume) as eluent, 1-ethyl 6-cyclohexyl 2-dimethylamino-5-phenylthio-2,4-hexadienedioate (9.7 g) is obtained, and is used in the crude state in the subsequent phases.
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:40])([F:39])[C:5]1[CH:6]=[C:7]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:8][N:9]1[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[C:12]([C:20](=[O:31])[CH2:21][C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])=[O:23])[N:11]=[N:10]1.O>C(Cl)Cl>[F:40][C:4]([F:3])([F:39])[C:5]1[CH:6]=[C:7]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:8][N:9]1[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[C:12]([C:20](=[O:31])[CH:21]([Br:1])[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])=[O:23])[N:11]=[N:10]1
Reactant: O=C(CC(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1)c1ccccc1Cl
Reactant: BrBr
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccccc1Cl)C(Br)C(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
Add bromine (28 μL, 0.54 mmol) to a mixture of 1-[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-3-(2-chloro-phenyl)-propane-1,3-dione (256 mg, 0.463 mmol) in 1:1 CH2Cl2:H2O (4 mL). Stir mixture at RT for 30 min, then dilute with additional CH2Cl2 (20 mL) and wash with NaHCO3 (20 mL). Dry, filter, and concentrate the organic layer to give the title compound (287 mg, 98%). MS (IS) 553.2 (M+1), MS (ES−) 551.2 (M−1). 1HNMR (400 MHz, CDCl3): δ 7.80 (m, 1H), 8.53 (m, 1H), 7.85 (m, 2H), 7.63 (m, 1H), 7.46 (m, 7H), 7.04 (s, 1H), 5.60 (m, 2H).
Reaction SMILES: [Na:1][Na].[NH2:3][C@H:4]([C:24]([OH:26])=[O:25])[CH2:5][C:6]1[CH:13]=[C:11]([I:12])[C:10]([O:14][C:15]2[CH:22]=[C:20]([I:21])[C:19]([OH:23])=[C:17]([I:18])[CH:16]=2)=[C:8]([I:9])[CH:7]=1.II.[OH-].[Na+]>>[Na+:1].[Na+:1].[NH2:3][C@H:4]([C:24]([O-:26])=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([I:9])[C:10]([O:14][C:15]2[CH:16]=[C:17]([I:18])[C:19]([OH:23])=[C:20]([I:21])[CH:22]=2)=[C:11]([I:12])[CH:13]=1.[NH2:3][C@H:4]([C:24]([O-:26])=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([I:9])[C:10]([O:14][C:15]2[CH:16]=[C:17]([I:18])[C:19]([OH:23])=[C:20]([I:21])[CH:22]=2)=[C:11]([I:12])[CH:13]=1.[NH2:3][C@H:4]([C:24]([OH:26])=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([I:9])[C:10]([O:14][C:15]2[CH:16]=[C:17]([I:18])[C:19]([OH:23])=[C:20]([I:21])[CH:22]=2)=[C:11]([I:12])[CH:13]=1
Reactant: [Na][Na]
Agent: II
Agent: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Agent: [Na+]
Product: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)[O-]

Procedure:
FIG. 2: Preparation of the disodium salt of L-thyroxine (compound of Formula II) i.e. according to IT1302201 by iodination of compound of Formula I with KI/I2 in the presence of a suitable amine. The mono and di-potassium salts mixture is subjected to a subsequent separation and purification steps, including:(a) the addition of an organic acid; (b) the separation of the thus obtained “free form” (as a precipitate); and (c) the addition of an excess of sodium hydroxide to obtain the L-thyroxine di-sodium salt of Formula II.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([N+:11]([O-])=O)=[CH:5][C:4]=1[OH:14].Cl>CO.[Pd]>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([NH2:11])=[CH:5][C:4]=1[OH:14]
Reactant: COc1cc([N+](=O)[O-])cc(O)c1OC
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1cc(N)cc(O)c1OC
Yield: 107 %

Procedure:
A solution of 1.1 g of 2,3-dimethoxy-5-nitrophenol in 45 mL dry methanol with 200 mg of 10% Pd/C (Degussa) was hydrogenated under a hydrogen balloon overnight. The reaction was filtered through a bed of celite and evaporated and the residue was chromatographed over silica gel (ethyl acetate/hexanes 3:2 gradient to 100% ethyl acetate). The appropriate fractions were evaporated to dryness to yield an oil that was taken up in methanol to which methanolic HCl solution was added and the solvent evaporated to yield 1.0 g of the desired product 4,5-dimethoxy-3-hydroxyaniline hydrochloride. MS (m/e): 170 (MH+).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]([CH3:13])=[CH:11][C:6]2[C:7]([CH3:10])=[CH:8][O:9][C:5]=2[CH:4]=1.CO[CH:16]1[CH2:20][CH2:19][CH:18](OC)O1>O1CCOCC1>[CH3:10][C:7]1[C:6]2[CH:11]=[C:12]([CH3:13])[C:3]([N:2]3[CH:16]=[CH:20][CH:19]=[CH:18]3)=[CH:4][C:5]=2[O:9][CH:8]=1
Reactant: Cc1cc2c(C)coc2cc1N
Reactant: COC1CCC(OC)O1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc2c(C)coc2cc1-n1cccc1

Procedure:
5 ml of 6N hydrochloric acid are added to a mixture of 7.5 g (46.5 mmole) of 6-amino-3,5-dimethylbenzofuran, 7.5 ml (58 mmole) of 2,5-dimethoxytetrahyrofuran and 150 ml of dioxane and the whole is boiled under reflux for 40 minutes. The whole is concentrated by evaporation in vacuo and the residue is taken up in methylene chloride and washed three times with water. The crude product obtained after drying and concentration by evaporation of the organic phase is chromatographed over silica gel with petroleum ether/ether. Subsequent distillation of the pure fractions in a bulb tube (120°/4.10-2 torr) yields 3,5-dimethyl-6-(pyrrol-1-yl)-benzofuran having a melting point of 43°-45°.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:32](O)=[O:33])=[C:21]([CH3:31])[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]=23)[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>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:32]([NH:35][C@@H:36]4[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH2:38][CH2:37]4)=[O:33])=[C:21]([CH3:31])[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]=23)[CH2:2][CH2:3]1
Reactant: COc1ccc(-c2ccnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Product: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c4) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[C:12]([NH2:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:14])[CH3:13].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8]([NH:21][C:12]([CH3:14])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])=[O:9]
Reactant: CC(C)(N)c1ccccc1
Reactant: O=C(Cl)c1cc(Cl)cnc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)c1cc(Cl)cnc1Cl)c1ccccc1
Yield: 93.9 %

Procedure:
In a similar manner to Step 1 of Example 16, 2,5-dichloropyridine-3-carbonylchloride (669 mg, 3.19 mmol) was dissolved in dichloromethane (13 mL), and the solution was treated with cumylamine (0.505 mL, 3.51 mmol), triethylamine (0.667 mL, 4.79 mmol) and DMAP (39.0 mg, 0.319 mmol), followed by purification by slurry using diisopropylether/hexane to obtain 2,5-dichloro-N-(1-methyl-1-phenylethyl)nicotinamide (926 mg, yield 94%).
Reaction SMILES: BrC1C=CC(OC)=C([N+]([O-])=O)C=1.C[Sn](C)(C)[C:15]1[CH:19]=[CH:18][S:17][CH:16]=1.[CH3:22][O:23][C:24]1[C:29]2[N:30]=[C:31]([NH:33][C:34]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[O:35])[S:32][C:28]=2[C:27](C2C=CC=CC=2)=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[C:29]2[N:30]=[C:31]([NH:33][C:34]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[O:35])[S:32][C:28]=2[C:27]([C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)=[CH:26][CH:25]=1
Reactant: COc1ccc(-c2ccccc2)c2sc(NC(=O)N3CCOCC3)nc12
Reactant: C[Sn](C)(C)c1ccsc1
Agent: COc1ccc(Br)cc1[N+](=O)[O-]
Product: COc1ccc(-c2ccsc2)c2sc(NC(=O)N3CCOCC3)nc12

Procedure:
The title compound was prepared strarting from 4-bromo-1-methoxy-2-nitro-benzene and trimethyl-thiophen-3-yl-stannane as described for morpholine-4-carboxylic acid (4-methoxy-7-phenyl-benzothiazol-2-yl)-amide (Example 157) and obtained as a light yellow solid in about 10% overall yield, MS: m/e=376 (M+H+).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH:6]([CH:9]1[CH:13]([C:14]([F:17])([F:16])[F:15])[O:12][C:11](=[O:18])[NH:10]1)([CH3:8])[CH3:7]>CCCCCC.C1COCC1>[CH:6]([C@H:9]1[C@H:13]([C:14]([F:15])([F:17])[F:16])[O:12][C:11](=[O:18])[N:10]1[C:11]([O:18][C@H:1]1[C@H:9]([CH:6]([CH3:8])[CH3:7])[CH2:13][CH2:14][C@@H:3]([CH3:4])[CH2:2]1)=[O:12])([CH3:8])[CH3:7]
Reactant: [Li]CCCC
Reactant: CC(C)C1NC(=O)OC1C(F)(F)F
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)N1C(=O)O[C@@H](C(F)(F)F)[C@@H]1C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (20 ml of a 10M solution in hexane) was added to a solution of (4RS),5SR)-4-isopropyl-5-trifluoromethyl-oxazolidin-2-one (35.8 g) in THF (600 ml) at -78° C., followed by stirring for 0.5 hours. (-)-Menthyl chloroformate (41 ml, freshly distilled) was added followed by continuation of stirring at -78° C. for 0.5 hours. The solution was warmed to 25° C. and the reaction quenched by addition of saturated aqueous sodium bicarbonate solution. The product was extracted into ether and washed with water and brine. The solution was dried (MgSO4) and the solvent removed under vacuum. The resulting oil crystallized upon standing to give a solid which was collected by filtration. The solid was washed with ether:hexane (1:1) and dried to give (4S,5R)-4-isopropyl-3-[(1R,3R,4S)-3-p-menthyloxycarbonyl]-5-trifluoromethyloxazolidin-2-one (23.15 g); m.p. 138-140° C.; 1H NMR (300 MHz, DMSO):5.51 (dd, 1H), 4.68 (m, 1H), 4.26 (m, 1H), 2.27 (m, 1H), 1.94 (d, 1H), 1.78 (m, 1H), 1.62 (d, 2H), 1.42 (m, 2H), 1.01 (dd, 2H), 0.95-0.84 (m, 24H), 0.71 (d, 3H); 19FNMR (376.5 MHz,DMSO): -76.9910; 99% d.e. (A further crop of 4.3 g (99% d.e.) was obtained from the mother liquor). [Note: the (4R,5S) isomer has m.p. 80-82° C. and 19FNMR (376.5 MHz, DMSO): -77.0019.
Reaction SMILES: CCOCC.Cl[C:7]1[N:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]([Cl:17])[N:8]=1.[NH2:18][C:19]1[CH:33]=[CH:32][C:22]([CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[CH:21][C:20]=1[Br:34].C(N(C(C)C)CC)(C)C>ClC(Cl)C.C(O)(C)(C)C.[Cl-].[Zn+2].[Cl-]>[Br:34][C:20]1[CH:21]=[C:22]([CH:32]=[CH:33][C:19]=1[NH:18][C:7]1[N:8]=[C:9]([Cl:17])[C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][N:12]=1)[CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27]
Reactant: CCOP(=O)(Cc1ccc(N)c(Br)c1)OCC
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(Br)c1)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
A 1M solution of zinc chloride in ether (18.7 mL, 18.7 mmol) was added to a solution of 2,6-dichloro-5-trifluoromethylpyrimidine (4 g, 18.72 mmol) in 20 mL of dichloroethane and t-butanol (1:1) under nitrogen atmosphere. The reaction mixture was stirred at rt for 30 min, cooled to 0° C. and then treated slowly over 10 min with a solution of diethyl (4-amino-3-bromobenzyl)phosphonate (Compound 32D, 3.35 gm, 10.4 mmol) in dichloroethane and t-butanol (10 mL, 1:1) through an addition funnel and stirred for 1 hr. Diisopropylethylamine (3.2 mL, 10.4 mmol) was added and the mixture was allowed to stir at rt for 3 days. The solvents were evaporated and the residue was purified using flash column chromatography (0-30% EtOAc/DCM) to afford 1.2 g of the title compound (23%). 1H NMR (400 MHz, CDCl3): δ 1.23-1.25 (m, 6H), 3.10 (d, J=22.0 Hz, 2H), 3.99-4.06 (m, 4H), 7.28 (d, J=8.4 Hz, 1H), 7.52 (s, 1H), 7.8 (s, 1H), 8.26 (d, J=8.4 Hz, 1H), 8.57 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: CC(C)(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COC(=O)C(C)(C)C)CC1
Temperature: 60 °C

Procedure:
To 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butylester (480 mg, 2.1 mmol) dissolved in dry DMF (10 ml) was added NaH (120 mg, 3.0 mmol, 55-65% in mineral oil) and the mixture was warmed to 60° C. for 2 h. The mixture was allowed to cool to rt and then pivaloyl chloride (0.1.6 ml, 1.3 mmol) was added. The reaction was allowed to stir over night and then poured into water and the mixture was extracted with ether. The combined organic phases were washed with brine, dried (Na2SO4), filtered, concentrated under reduced pressure and the oily residue was purified by Flash column chromatography (SiO2; heptane/EtOAc 70:30) to yield 4-(2,2-dimethylpropionyloxymethyl)piperidine-1-carboxylic acid t-butyl ester as an oil. Deprotection of 4-(2,2-dimethylpropionyloxymethyl)piperidine-1-carboxylic acid t-butyl ester was conducted using the method (CH2Cl2:TFA; 1:1) to yield the title compound as an oil (85 mg, 0.43 mmol, 33 %). This crude was used without further purification.