Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH:5]=1)([O-:3])=[O:2].CN(C1C=CC=CN=1)C.[CH2:29]([N:36]1[CH2:41][CH2:40][CH:39](O)[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH:39]2[CH2:38][CH2:37][N:36]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:41][CH2:40]2)=[O:9])=[C:6]([NH:13][C:14](=[O:19])[C:15]([F:16])([F:17])[F:18])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1NC(=O)C(F)(F)F
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccc([N+](=O)[O-])cc1NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.3 %

Procedure:
0.39 g (0.0014 mol) of 4-nitro-2-trifluoroacetamido-benzoic acid was dissolved in 7 ml of dimethylformamide, treated with 0.0855 g (0.0007 mol) of dimethylaminopyridine and cooled to 0°. 0.268 g (0.0014 mol) of 1-benzyl-4-hydroxy-piperidine and 0.295 g (0.00154 mol) of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride were added and the mixture was stirred at 0° for 2 hrs. Thereafter, the mixture was warmed to room temperature. The mixture was stirred at room temperature for 48 hrs., the solvent was distilled off and the residue was taken up in ethyl acetate and washed with semi-saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate and concentrated and the residue was chromatographed on silica gel with ethyl acetate/hexane (1:2) as the eluent. 0.28 g (44%) of 1-benzyl-piperidin-4-yl 4-nitro-2-trifluoroacetamido-benzoate was obtained as a yellow oil. MS: me/e=452 (C21H21F3N3O5 +).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:23][C:24]1[C:25]([O:30]C)=[N:26][CH:27]=[CH:28][CH:29]=1.C(O)C.Cl.C(=O)([O-])O.[Na+]>O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:20])([CH3:21])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:23][C:24]1[C:25]([OH:30])=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ncccc1Cn1c2c(c(=O)n1-c1ccc(F)cc1F)[C@@H]1CC[C@@]2(C)C1(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1Cc1cccnc1O
Temperature: 75 °C
Reaction time: 0.67 h
Yield: 75 %

Procedure:
A mixture of (4R,7S)-2-(2,4-difluoro-phenyl)-1-(2-methoxy-pyridin-3-ylmethyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Example 113; 149 mg, 0.35 mmol), ethanol (440 μL) and concentrated aqueous hydrochloric acid (440 μL) was heated at 75° C. overnight, and then at ˜100° C. for 40 min. Water (10 mL) was added and the mixture was neutralized to pH 7-8 by the dropwise addition of saturated aqueous sodium hydrogen carbonate solution. The resulting mixture was extracted with dichloromethane (2×25 mL). The combined organic layers were washed with brine (10 mL), dried (magnesium sulfate), filtered, evaporated, purified using a Biotage 40S system, eluting with 3-4% methanol/dichcloromethane, and then dried in a vacuum overn for 3 days to give (4R,7S)-2-(2,4-difluoro-phenyl)-1-(2-hydroxy-pyridin-3-ylmethyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (108 mg, 75%) as an off-white solid. APCI(+)-MS (M+H) 412.
Reaction SMILES: [CH2:1]([CH:3]([CH2:17][CH3:18])[C@@H:4]([C:14]([NH2:16])=[O:15])[NH:5][C@H](C1C=CC=CC=1)C)[CH3:2]>[Pd]>[CH2:1]([CH:3]([CH2:17][CH3:18])[C@@H:4]([C:14]([NH2:16])=[O:15])[NH2:5])[CH3:2]
Reactant: CCC(CC)[C@H](N[C@@H](C)c1ccccc1)C(N)=O
Agent: [Pd]
Product: CCC(CC)[C@H](N)C(N)=O
Reaction time: 24 h
Yield: 92.5 %

Procedure:
A mixture of 3-ethyl-N2-[(S)-1-phenylethyl]-L-norvalinamide (2.6 g, 10.5 mmol) and 5% Pd/C (800 mg) was shaken for 24 h in a Parr apparatus under 3 atm of H2. The mixture was filtered through a plug of Celite and the solvent was removed in vacuo to give 3-ethyl-L-norvalinamide as a white solid (1.4 g, 93%), which was used in the next reaction without further purification. Mass Spectrum (+ESI): 145 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38](=O)[CH:39]([CH3:41])[CH3:40])=[CH:34][CH:33]=3)[CH2:27][CH2:26]2)[C:10]([CH:12]2[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([CH2:38][CH:39]([CH3:41])[CH3:40])=[CH:34][CH:33]=3)[CH2:27][CH2:26]2)[C:10]([CH:12]2[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)C(=O)c1ccc(CC2CCN(CCCN(C(=O)C3CCN(S(C)(=O)=O)CC3)c3ccc(Cl)c(Cl)c3)CC2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1ccc(CC2CCN(CCCN(C(=O)C3CCN(S(C)(=O)=O)CC3)c3ccc(Cl)c(Cl)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76 %

Procedure:
To a stirred solution of the title compound of example 335 (318 mg, 0.50 mmol) in trifluoroacetic acid (5 mL) was added triethylsilane (0.399 mL, 2.50 mmol), and the mixture was stirred at room temperature for 2 days. The reaction mixture was evaporated under reduced pressure, 1N aqueous sodium hydroxide (15 mL) was added and the aqueous layer was extracted with ethyl acetate (15 mL, 2×10 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was subjected to column chromatography (silica gel 10 g, ethyl acetate/methanol=1/0 to 9/1). The fractions containing the product were collected and evaporated under reduced pressure. Diisopropyl ether was added to the residue, the resulting precipitate was collected by filtration, washed with diisopropyl ether and dried under reduced pressure to afford the title compound (236 mg, 0.38 mmol, yield 76%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]([C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH3:2].[C:26]1([NH:32][NH2:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O)(=O)C>C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[N:33][N:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)CC(C(=O)c1ccc(Cl)cc1)C(=O)c1ccc(Cl)cc1
Reactant: NNc1ccccc1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1-c1ccc(Cl)cc1
Yield: 91 %

Procedure:
12.0 grams 3,3-bis-(p-chlorobenzoyl)-propionic acid ethyl ester, 3.9 grams phenylhydrazine and 2.7 grams glacial acetic acid were mixed and the mixture was heated in a nitrogen atmosphere to the boiling temperature under reflux for 6 hours. To the reaction mixture were then added benzene, and the pH was adjusted to 2-3, followed by extraction with water. The benzene was evaporated from the benzene phase and the dry, crystalline residue was recrystallized from a mixture of cyclohexane and petroleum ether boiling in a range from 50°-70° C. 13.0 grams 1-phenyl-3,5-bis-(p-chlorophenyl)-pyrazol-4-acetic acid ethyl ester, melting at 120°-122° C., were obtained, representing a yield of 91%.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:7][C:6]2[CH:8]=[C:9]3[C:14](=[CH:15][C:5]=2[N:4]=1)[CH:13]=[CH:12][CH:11]=[CH:10]3.SC[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.O>C(O)C>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:1][S:2][C:3]1[NH:4][C:5]2[CH:15]=[C:14]3[C:9](=[CH:8][C:6]=2[N:7]=1)[CH:10]=[CH:11][CH:12]=[CH:13]3
Reactant: CSc1nc2cc3ccccc3cc2[nH]1
Reactant: SCc1ccccn1
Solvent: CCO
Solvent: O
Product: c1ccc(CSc2nc3cc4ccccc4cc3[nH]2)nc1
Yield: 81.7 %

Procedure:
0.45 g of 2-methylthio-1H-naphth[2,3-d]imidazole and 0.64 g of 2-mercaptomethylpyridine were heated for 40 hours under reflux in 10 ml of ethanol. 10 ml of water were added to the homogeneous solution and the precipitate formed was filtered off. 0.50 g of 2-[(2-pyridylmethyl)thio]-1H-naphth[2,3-d]imidazole having a m.p. of 170° was obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:8][C:9]=1[CH2:10][N:11]1[C:15]2=[N:16][CH:17]=[C:18]([OH:20])[CH:19]=[C:14]2[CH:13]=[CH:12]1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:37](Br)[CH:38]=[CH2:39].C(OCC)(=O)C>CN(C)C=O>[CH2:39]([O:20][C:18]1[CH:19]=[C:14]2[CH:13]=[CH:12][N:11]([CH2:10][C:9]3[S:8][C:7]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][CH:22]=4)=[N:6][C:5]=3[CH2:1][CH2:2][CH2:3][CH3:4])[C:15]2=[N:16][CH:17]=1)[CH:38]=[CH2:37]
Reactant: C=CCBr
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1Cn1ccc2cc(O)cnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOc1cnc2c(ccn2Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
730 mg 1-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-1H-pyrrolo[2,3-b]pyridin-5-ol were dissolved in 20 ml dimethylformamide and 1.1 mg cesium carbonate and 410 mg allylbromide were added. The reaction mixture was stirred at room temperature for one hour then 100 ml ethyl acetate were added and the mixture was washed five times with portions of 20 ml of water The organic layer was dried over MgSO4 and the solvent removed under reduced pressure. This gives 800 mg 5-Allyloxy-1-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-1H-pyrrolo[2,3-b]pyridine as yellow oil.
Reaction SMILES: OO.[OH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][S:9][CH2:8][C:7]1=[O:12].C(OC(=O)C)(=[O:15])C.C(OC(C)C)(C)C.C(O)(C)C>>[OH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][S:9](=[O:15])[CH2:8][C:7]1=[O:12]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CSCCN1CCO
Agent: OO
Solvent: CC(C)O
Solvent: CC(C)OC(C)C
Product: O=C1CS(=O)CCN1CCO

Procedure:
This sulfoxide is prepared by reacting, for a week, one equivalent of H2O2 with 4-(2-hydroxyethyl) 3-thiamorpholinone (obtained in Example 9) solubilized at 0° C. in an acetic acid-acetic anhydride mixture. After concentration of the mixture the resulting liquid is solubilized in a minimum of an isopropyl ether-isopropyl alcohol mixture. Starting with this solution, placed at -25° C., white crystals whose melting point is 45° C. are isolated.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[O:6][CH:7]=1.[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14].C(OCC)(=O)C>C(OCC)(=O)C.C(O)C>[CH:8]([C:5]1[O:6][CH:7]=[C:3]([CH2:2][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[N:4]=1)([CH3:10])[CH3:9]
Reactant: CCOP(OCC)OCC
Reactant: CC(C)c1nc(CCl)co1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1coc(C(C)C)n1)OCC
Temperature: 160 °C
Reaction time: 16 h
Yield: 91.1 %

Procedure:
A mixture of 4-chloromethyl-2-isopropyl-1,3-oxazole (1.12 g) and triethyl phosphite (2.57 g) was stirred at 160° C. for 16 hrs. Excess triethyl phosphite was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v), ethyl acetate, then ethyl acetate-ethanol (10:1, v/v) to give diethyl [(2-isopropyl-1,3-oxazol-4-yl)methyl]phosphonate as a colorless oil (1.67 g, yield 91%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[O:5][CH:6]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[Cl:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:3]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[O:5][CH:6]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1cc(Br)co1
Reactant: OB(O)c1cccc(Cl)c1
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
Product: CCOC(=O)c1cc(-c2cccc(Cl)c2)co1
Temperature: 80 °C

Procedure:
Under argon, 100 mg (0.46 mmol) of the compound from Example 3A are provided in 3 ml of 1,2-dimethoxyethane, and 107 mg (0.69 mmol) of 3-chlorophenylboronic acid, 2.4 ml (2.28 mmol) of an aqueous sodium carbonate solution (10%) and 32 mg (0.03 mmol) of tetrakis(triphenylphosphine)palladium(0) are added. Under microwave irradiation, the mixture is heated in a closed vessel at 80° C. for 15 min. The crude product is purified by preparative HPLC (RP18 column; eluent: acetonitrile/water gradient). 81.0 mg (71% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:28]([CH:29]4[CH2:31][CH2:30]4)=[CH:27][C:16]([C:17]([NH:19][S:20]([CH2:23][CH2:24][O:25]C)(=[O:22])=[O:21])=[O:18])=[CH:15][N:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.B(Br)(Br)Br>ClCCl.C(OCC)(=O)C>[C:1]12([CH2:11][O:12][C:13]3[C:28]([CH:29]4[CH2:31][CH2:30]4)=[CH:27][C:16]([C:17]([NH:19][S:20]([CH2:23][CH2:24][OH:25])(=[O:22])=[O:21])=[O:18])=[CH:15][N:14]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: COCCS(=O)(=O)NC(=O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NS(=O)(=O)CCO)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Reaction time: 0.42 h
Yield: 98.6 %

Procedure:
A solution of 6-(adamantan-1-ylmethoxy)-5-cyclopropyl-N-((2-methoxyethyl)-sulfonyl)nicotinamide (0.19 g, 0.42 mmol) in anhydrous dichloromethane (10 mL) at 0° C. was treated with boron tribromide (0.079 mL, 0.84 mmol) under nitrogen. The reaction mixture was stirred for 25 minutes and then diluted with ethyl acetate (50 mL). The mixture was washed with 1 M aqueous hydrochloric acid solution (2×30 mL), brine (30 mL); dried over anhydrous sodium sulfate; filtered and concentrated in vacuo to provide the title compound (0.18 g, quant.): 1H NMR (300 MHz, DMSO-d6) δ 11.91 (br s, 1H), 8.45 (d, J=2.3 Hz, 1H), 7.70 (d, J=2.3 Hz, 1H), 4.95 (br s, 1H), 3.93 (s, 2H), 3.80-3.73 (m, 2H), 3.65-3.58 (m, 2H), 2.07-1.98 (m, 1H), 1.98-1.90 (m, 3H), 1.73-1.57 (m, 12H), 0.98-0.90 (m, 2H), 0.76-0.70 (m, 2H); MS (ES+) m/z 435.2 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:16][NH:17][NH2:18]>CO>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:17]([CH3:16])[NH2:18])[CH:7]=1
Reactant: CNN
Reactant: Clc1cc(Cl)ncn1
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(N)c1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2g of 4,6-dichloropyrimidine were dissolved in 30 ml of methanol, mixed with 1.37 g of triethylamine and 0.63 g of methyl hydrazine and stirred for 2 days at room temperature. 0.1 ml of methyl hydrazine and 0.2 ml of triethylamine were then added and stirred for 4 days at room temperature. After rotating out the solvent, a residue of 2.4 g of crude 6-chloro-4-(1-methyl-hydrazino)-pyrimidine were obtained, which was immediately processed further.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([O:11]C)=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)[CH:6]=[N:5]1.Br.O>C(O)(=O)C>[F:22][C:2]([F:1])([F:21])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([OH:11])=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)[CH:6]=[N:5]1
Reactant: COc1c(-c2ccc(SC)cc2)cnn(CC(F)(F)F)c1=O
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CSc1ccc(-c2cnn(CC(F)(F)F)c(=O)c2O)cc1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
A solution of 2-(2,2,2-Trifluoroethyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (2 g, 6.1 mmol) and hydrobromic acid (40% in water, 20 mL) in acetic acid (40 mL) was heated at reflux for 3 hours. The reaction mixture was cooled to room temperature and water (50 mL) was added. The crystals formed were filtered, washed with water and 5% ethyl acetate in hexanes, and dried to constant weight. The product was obtained as a white solid (yield: 1.75 g, 91%). 1H NMR (300 MHz, CDCl3) δ 2.54 (s, 3H), 4.82 (q, J=9 Hz, 2H), 7.47 (d, J=9 Hz, 2H), 7.65 (d, J=9 Hz, 2H), 7.73 (br s, 1H), 8.00 (s, 1H). MS (DCI) m/z 317 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:11])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:17][O:16][C:12](=[O:15])/[CH:13]=[CH:14]/[C:2]1[CH:3]=[C:4]([F:11])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: C=CC(=O)OC
Reactant: Fc1cc(Br)c2[nH]ccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)/C=C/c1cc(F)cc2cc[nH]c12
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a mixture of 7-Bromo-5-fluoro-1H-indole [which was prepared according to the known method (Dobbs, A., J. Org. Chem., 66, 638-641 (2001)], (400 mg, 1.87 mmol) and methyl acrylate (241 mg, 2.8 mmol) in triethylamine (1.5 ml), palladium(II) acetate (43 mg, 0.19 mmol) and tri-o-tolylphosphine (170 mg, 0.56 mmol) was added under argon at rt The reaction mixture was stirred at 100° C. for 4 hrs in a sealed pressure tube and then cooled to rt The reaction mixture was diluted with CH2Cl2 (50 ml), washed with water (3×30 ml), brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by column chromatography on silica gel with EtOAc/hexane as an eluent to give 300 mg of compound I-30 as a yellow solid. 1H-NMR (500 MHz, CDCl3).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][CH2:23][N:24]([CH2:32][C@@H:33]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=3)[O:34][Si](C(C)(C)C)(C)C)C(OC(C)(C)C)=O)[CH:16]=2)=[CH:7][CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)=[O:4]>Cl.O1CCOCC1>[ClH:48].[ClH:48].[CH3:1][O:2][C:3]([C:5]1[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][CH2:23][NH:24][CH2:32][C@@H:33]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=3)[OH:34])[CH:16]=2)=[CH:7][CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(-c2cccc(NCCN(C[C@H](O[Si](C)(C)C(C)(C)C)c3cccc(Cl)c3)C(=O)OC(C)(C)C)c2)c(C(=O)OC)c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2cccc(NCCNC[C@H](O)c3cccc(Cl)c3)c2)c(C(=O)OC)c1

Procedure:
Assay Found: C 55.95; H 5.26; N 4.98%; C26H27Cl1N2O5.2HCl requires C 56.18; H 5.26; N 5.04%; from (R)-3′-[[2-[[2-(3-chlorophenyl)-2-[[(tert-butyl)dimethylsilyl]oxy]ethyl][(tert-butoxy)carbonyl]amino]ethyl]amino]-[1,1′-biphenyl]-2,4-dicarboxylic acid dimethyl ester (508 mg) in 4 N hydrochloric acid in dioxane (10 mL).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:5]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Zn]>[C:14]1([S:11]([CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[NH2:1])(=[O:12])=[O:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1cccc(CS(=O)(=O)c2ccccc2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: Nc1cccc(CS(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
A solution of 1-nitro-3-[(phenylsulfonyl)methyl]benzene (5.15 g) in ethanol (55 mL) and water (11.4 mL) was treated with ammonium chlorid (4.99 g) at 0° C. Then zinc powder (6.10 g) was cautiously added in portions and stirred for 3 hours at RT. Then the mixture was filtered over Cellite, washed with ethanol, condensed to dryness, treated with ethyl acetate, washed with brine, dried with sodium sulfate and condensed to dryness. Crystallization of the crude product (5.20 g) from diethyl ether furnished the pure title compound (3.80 g).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][S:24][CH2:25][C@H:26]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20]([OH:22])=O)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][P:66](=[O:73])([O:70][CH2:71][CH3:72])[O:67][CH2:68][CH3:69].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][S:24][CH2:25][C@H:26]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20](=[O:22])[NH:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][P:66](=[O:73])([O:67][CH2:68][CH3:69])[O:70][CH2:71][CH3:72])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CCOP(=O)(CCOCCOCCOCCN)OCC
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OCCCCCCCCCCCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)OCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(((R)-2,3-bis(dodecyloxy)propyl)thio)propanoic acid (1 eq) in DCM (0.1 M) was added diethyl 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethylphosphonate (1.3 eq, from example 18, step 4), DIEA (2.5 eq) and HBTU (1.2 eq). The reaction mixture was then stirred at room temperature for 2 hours. The mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% MeOH/DCM to give the product.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([CH2:34][OH:35])[CH:28]=1)[CH2:10][NH:11][C@H:12]([CH3:26])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[CH3:65][O:66][C:67]1[CH:74]=[CH:73][CH:72]=[CH:71][C:68]=1[CH2:69][NH2:70]>CN(C)C=O>[Si:1]([O:8][C@H:9]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([CH2:34][OH:35])[CH:28]=1)[CH2:10][NH:11][C@H:12]([CH3:26])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([NH:70][CH2:69][C:68]1[CH:71]=[CH:72][CH:73]=[CH:74][C:67]=1[O:66][CH3:65])=[O:25])=[CH:17]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C[C@H](Cc1ccc2[nH]c(C(=O)O)cc2c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Reactant: COc1ccccc1CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccccc1CNC(=O)c1cc2cc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(CO)c3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.6 %

Procedure:
A solution of 5-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-1H-indole-2-carboxylic acid (Preparation 5, 0.25 g, 0.50 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (106 mg, 0.55 mmol), hydroxybenzotriazole (75 mg, 0.55 mmol) in N,N-dimethylformamide (5 ml) was treated with triethylamine (0.15 ml, 0.55 mmol) and 2-methoxybenzylamine (0.07 ml, 0.55 mmol) and the resulting suspension left to stir at room temperature under a nitrogen atmosphere for 18 hours. The solvent was removed in vacuo and the residue partitioned between dichloromethane (50 ml) and saturated aqueous sodium bicarbonate (20 ml). The organic phase was separated, dried (sodium sulphate) and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol (95:5 changing to 90:10, by volume) to give the title compound as a colourless foam (76 mg).