Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:23])[S:4]([C:7]1[CH:22]=[CH:21][C:10]2[S:11][C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[CH:14](O)[CH2:15][C:9]=2[CH:8]=1)(=[O:6])=[O:5].[Cl-].[Ca+2].[Cl-]>C1C=CC=CC=1>[Cl:1][CH:14]1[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[S:11][C:10]2[CH:21]=[CH:22][C:7]([S:4](=[O:6])(=[O:5])[N:3]([CH3:23])[CH3:2])=[CH:8][C:9]=2[CH2:15]1
Reactant: Cl
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(O)c1ccccc1S2
Agent: [Ca+2]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CN(C)S(=O)(=O)c1ccc2c(c1)CC(Cl)c1ccccc1S2
Reaction time: 20 h

Procedure:
Hydrochloric acid gas is introduced at 10° C for 2 hours into a mixture of 12 g of 10,11-dihydro-2-dimethylsulphamoyl-dibenzo[b,f]thiepin-10-ol, 250 ml of benzene and 20 g of calcium chloride. The mixture is then left to stand at room temperature for 20 hours. The excess hydrochloric acid is driven off by the introduction of nitrogen. The mixture is filtered and evaporated under reduced pressure. 10-chloro-10,11-dihydro-2-dimethylsulphamoyl-dibenzo[b,f]thiepin is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:14][C:13]([C:15](OCC)=[O:16])=[CH:12][C:11](=[O:20])[CH:10]=2)=[CH:5][CH:4]=1.[NH3:21]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:14][C:13]([C:15]([NH2:21])=[O:16])=[CH:12][C:11](=[O:20])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: N
Reactant: CCOC(=O)c1cc(=O)cc(-c2ccc(OC)cc2)o1
Solvent: CCO
Product: COc1ccc(-c2cc(=O)cc(C(N)=O)o2)cc1

Procedure:
A mixture of ethyl 6-(4-methoxyphenyl)-4-oxo-4H-pyran-2-carboxylate (27.4 g), ammonia solution (30%, 50 ml) and ethanol (300 ml) was heated under reflux for an hour. The yellow solid which precipitated on cooling was filtered off and recrystallised from acetic acid-ethanol to yield the title product (mp 303°-308° C. with decomposition).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([CH2:13][C:14](Cl)=[N:15][OH:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.O1CCCC1.[C:25]([C:27]1[C:28]([NH2:34])=[N:29][C:30]([NH2:33])=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([CH2:13][C:14]3[CH:26]=[C:25]([C:27]4[C:28]([NH2:34])=[N:29][C:30]([NH2:33])=[CH:31][CH:32]=4)[O:16][N:15]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(Oc2ccc(F)cc2)nc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ccc(-c2cc(Cc3ccc(Oc4ccc(F)cc4)nc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 38.4 %

Procedure:
To a mixture of (6-(4-fluoro-phenoxy)-pyridin-3-yl)-acetohydroximoyl chloride (25 mg) described in Manufacturing Example 75-1-4 and tetrahydrofuran (1 mL) were added 3-ethynyl-pyridin-2,6-diamine (8 mg, 0.060 mmol) described in Manufacturing Example 13-1-3 and triethylamine (17 μL, 0.12 mmol), which was stirred for 5 hours at room temperature. Water was added to the reaction mixture at the same temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (8.7 mg, 38%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].CC1C=CC(S([O:24][CH2:25][C@@H:26]2O[CH2:27]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOCC>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[O:12][CH2:27][CH:26]([CH2:25][OH:24])[O:1][C:2]=2[C:3]=1[CH3:13])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: COC(=O)c1ccc(O)c(O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1C)OC(CO)CO2
Temperature: 60 °C
Yield: 78 %

Procedure:
To a round bottom flask equipped with magnetic stirring and a nitrogen inlet was added methyl 3,4-dihydroxy-2-methylbenzoate (24.0 g, 132 mmol), (2R)-(−)-glycidyl tosylate (30.1 g, 132 mmol), potassium carbonate (21.8 g, 158 mmol), and DMF (264 mL). This mixture was heated to 60° C. for 5 hours. The mixture was cooled to room temperature, diluted with ether, and washed once with water. The aqueous wash was back extracted once with ether and the ethereal solutions combined. These organic solutions were then washed 3 times with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to give a brown oil. This oil was chromatographed on silica gel eluting with 25% ether in hexanes to give a yellow oil, 3-hydroxymethyl-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid methyl ester, (24.6 g, 103 mmol) in 78% yield. 1H-NMR (300 MHz, CD3COCD3) δ (ppm): 2.42 (s, 2H), 3.80 (s, 3H), 3.83 (m, 1H), 4.12 (dd, 1H), 4.23 (m, 2H), 4.42 (dd, 1H), 6.75 (d, 1H), 7.42 (d, 1H); TLC Rf=0.40 (1:1 ethyl acetate/hexane).
Reaction SMILES: O[C:2]1[C:3]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[N:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:20][C:21]1[CH:30]=[CH:29]C2C(=CC=CC=2)N=1>>[N:4]1[C:5]2[C:6](=[CH:20][CH:21]=[CH:30][CH:29]=2)[CH:7]=[CH:2][C:3]=1[CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[N:10]1
Reactant: CC(=O)Nc1ccn(Cc2ncccc2O)n1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Product: CC(=O)Nc1ccn(Cc2ccc3ccccc3n2)n1

Procedure:
Title compound was prepared by a method analogous to that described for Intermediate 41 using Intermediate 1 (150 mg, 1.199 mmol), replacing 2-(Bromomethyl)-3-pyridinol hydrobromide with 2-(chloromethyl)quinoline hydrochloride (ALDRICH). Title compound was obtained (90 mg, 0.338 mmol, 28.2% yield). 1H NMR (300 MHz, CDCl3) δ ppm: 8.10 (d, 1H), 8.07 (d, 1H), 7.79 (d, 1H), 7.74 (m, 1H), 7.55 (m, 1H), 7.46 (d, 1H), 7.07 (d, 1H), 6.76 (d, 1H), 5.49 (s, 2H), br s 2.14 (s, 3H). [ES+MS] m/z 267 (MH+).
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].C(N(C(C)C)C(C)C)C.[C:19]([O:23][C:24](=[O:39])[NH:25][C@@H:26]1[C:32](=[O:33])[N:31]([CH3:34])[C:30]2[CH:35]=[CH:36][CH:37]=[CH:38][C:29]=2[NH:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[C:19]([O:23][C:24](=[O:39])[NH:25][C@@H:26]1[C:32](=[O:33])[N:31]([CH3:34])[C:30]2[CH:35]=[CH:36][CH:37]=[CH:38][C:29]=2[N:28]([S:2]([CH3:1])(=[O:5])=[O:3])[CH2:27]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CN(S(C)(=O)=O)c2ccccc21
Temperature: 0 °C
Reaction time: 18 h
Yield: 38.7 %

Procedure:
A mixture of 623 mg (3.4 mmol) of methanesulfonic acid anhydride and 0.12 ml (0.7 mmol) of N-ethyl-diisopropylamine was cooled to 0° C. and treated with a solution of 200 mg (0.7 mmol) of (S)-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester in 2 ml of dichloromethane. The reaction mixture was left to warm to room temperature and stirred during 18 h. For the working-up, the reaction mixture was cooled to 0° C. and treated with a saturated solution of sodium carbonate. The organic layer was separated, washed with a saturated solution of ammonium hydrochloride and water, finally dried over sodium sulphate and evaporated. For purification, the crude material was chromatographed on silical gel using a 96:4-mixture of dichloromethane and ethyl acetate as the eluent. There were obtained 100 mg (40% of theory) of the ((S)-5-methanesulfonyl-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester as a white foam;
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH3:13])=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:22]=[O:23])C>C1COCC1>[CH3:13][N:9]1[CH2:10][CH2:11][CH2:12][CH:8]1[C:5]1[CH:6]=[CH:7][C:2]([CH:22]=[O:23])=[CH:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: CN1CCCC1c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCCC1c1ccc(C=O)cc1
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 2-(4-bromophenyl)-1-methylpyrrolidine (0.45 g, 2 mmol) in dry THF (10 mL) was added dropwise n-BuLi (0.88 mL, 2.2 mmol, 2.5 mol/L in hexane) at −78° C., after the addition was completed the mixture was stirred for 1 h, then dry DMF (0.18 mL, 2.4 mmol) was added to the reaction system and stirring was continued for another 1 hr. Then the reaction mixture was partitioned between EtOAc and 1 N HCl, the aqueous solution was extracted with EtOAc (3×15 mL). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo to give crude product (0.28 g, yield 74%) as a yellow oil. The product was used directly in the next step without further purification. LC-MS (ESI) m/z: 189 (M+1)+.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][S:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1>>[Br:28][C:25]1[CH:26]=[CH:27][C:22]([S:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:38][CH2:37][C:36]4[CH:39]=[CH:40][C:33]([CH3:32])=[CH:34][CH:35]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:29])=[CH:23][CH:24]=1
Reactant: O=C(CSc1ccc(Br)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Reactant: Cc1ccc(CN)cc1
Product: Cc1ccc(CNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)CSc2ccc(Br)cc2)C3)cc1

Procedure:
The title compound was synthesized in the manner of Example 81 from 2,2,2-trichloro-1-[10-{[(4-bromophenyl)thio]acetyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl]-ethanone of Example 80 and 4-methylbenzylamine, m.p. 131-132° C. MS [(+)ESI, m/z]: 560 [M+H]+ Anal. Calcd for C29H26BrN3O2S: C, 62.14; H, 4.68; N, 7.50. Found: C, 62.23; H, 4.59; N, 7.37.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:64]=[CH:63][C:53]2[NH:54][C:55]([CH:57]([NH2:62])[CH2:58][CH:59]([CH3:61])[CH3:60])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.C(Cl)Cl.C(O)C>[Cl:49][C:50]1[CH:64]=[CH:63][C:53]2[NH:54][C:55]([CH:57]([NH:62][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:58][CH:59]([CH3:60])[CH3:61])=[N:56][C:52]=2[CH:51]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: CC(C)CC(N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NC(CC(C)C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 82 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and 1-(5-chloro-1H-benzimidazol-2-yl)-3-methylbutylamine in tetrahydrofuran. Yield: 82%; Rf value: 0.54 (silica gel; methylene chloride/ethanol=9:1); C25H29ClN4O2 (452.98); mass spectrum: (M+H)+=453/455 (chlorine isotope) and (M−H)-=451/453 (chlorine isotope).
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(O)C>[CH2:13]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCC(C(=O)OCC)C(=O)OCC
Reaction time: 0.17 h
Yield: 79 %

Procedure:
In a 10 liter-reaction vessel, 143 g (6.2 mol(M)) of metal sodium which had been cut small was added to 3.1 liters of anhydrous ethanol and dissolved therein. To the solution, 1025 g (6.4M) of diethyl malonate was added dropwise in 30 minutes at 40°-50° C. and 1200 g (6.2M) of n-octylbromide was further added thereto in 10 minutes at 40°-50° C., followed by heat-refluxing for 3 hours. After the reaction, about 2.5 liters of ethanol was distilled off from the reaction mixture. 2.5 liters of water was added to the residue and 2 liters of benzene was further added thereto to effect extraction. After the benzene layer was washed with saturated aqueous solution of common salt until the benzene layer showed neutrality, the resultant mixture was dried with anhydrous sodium sulfate, followed by distilling-off of benzene to obtain 1333 g of a crude product of diethyl 2-octylmalonate (Yield: 79%).
Reaction SMILES: [Br:1]CC(C1C=C2C(=CC=1)C(=O)OCC2)=O.C(N1CCN[C@H](CO)C1)(OC(C)(C)C)=O.[CH:31]([N:34]([CH:37]([CH3:39])[CH3:38])[CH2:35][CH3:36])([CH3:33])[CH3:32]>C1COCC1>[BrH:1].[CH3:36][CH2:35][N:34]([CH:37]([CH3:39])[CH3:38])[CH:31]([CH3:33])[CH3:32]
Reactant: O=C(CBr)c1ccc2c(c1)CCOC2=O
Agent: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Br
Temperature: 25 °C
Reaction time: 14 h

Procedure:
6-(Bromoacetyl)-3,4-dihydro-1H-isochromen-1-one (˜1.54 g, ˜5.72 mmol, presence of α-chloroketone was noted, ˜10%) and commercially available (S)-4-N-BOC-2-hydroxymethylpiperazine (1.24 g, 5.72 mmol) were added to a round bottom flask and diluted with THF (50 mL). Diisopropylethylamine (1.30 mL, 7.44 mmol) was then introduced and the mixture left stirring for 14 h at RT during which time a considerable amount of solid had formed (presumably HBr salt of DIPEA). The reaction mixture was diluted with EtOAc, then washed with saturated NH4Claq followed by H2O. Both aqueous layers were sequentially back extracted once with another portion of EtOAc, the organics were then combined, dried with MgSO4, filtered, and concentrated in vacuo. The recovered crude product was subjected to purification by flash chromatography (Biotage, 50% EtOAc/Hex) to afford the title compound.
Reaction SMILES: [K].[CH3:2][O:3][C:4]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:5]=1[CH:6]([C:19]1[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[CH:24][C:20]=1[C:21]([OH:23])=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:15])[CH3:14])=[CH:9][C:8]=1[N:16]([CH3:18])[CH3:17]>>[CH3:2][O:3][C:4]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:5]=1[C:6]1([C:7]2[CH:12]=[CH:11][C:10]([N:13]([CH3:15])[CH3:14])=[CH:9][C:8]=2[N:16]([CH3:17])[CH3:18])[C:19]2[C:20](=[CH:24][C:25]([N:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=2)[C:21](=[O:23])[O:22]1
Reactant: COc1ccc(C(c2ccc(N(C)C)cc2C(=O)O)c2ccc(N(C)C)cc2N(C)C)c(OC)c1
Agent: [K]
Product: COc1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3cc(N(C)C)ccc32)c(OC)c1

Procedure:
Following the procedure described in Example 1, part C above, for oxidizing the potassium salt of 2-[2,4-dimethoxy-2',4'-bis(dimethylamino)benzhydryl]-5-dimethylaminobenzoic acid, there was obtained 9.0 g of 3-(2,4-dimethoxyphenyl)-3-[2,4-bis(dimethylamino)phenyl]-6-dimethylaminophthalide (Formula I: R=CH3 ; X=H; Y=2,4-(CH3O)2C6H3 ; Z=2,4-[(CH3)2N]2C6H3) a reddish-brown-colored solid which melted over the range 153°-160° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][CH2:13][N:14]=[N+]=[N-])[C:5]=2[O:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][CH2:13][NH2:14])[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: [N-]=[N+]=NCCOc1cccc2c1OCCO2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCCOc1cccc2c1OCCO2
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.8 %

Procedure:
A solution of 2-(2,3-dihydrobenzo[1,4]dioxin-5-yloxy)ethylazide (3.43 g, 0.016 mol) and triphenylphosphine (6.3 g, 0.023 mol) in tetrahydrofuran (50 ml) and water (2 ml) was allowed to stir for 18 hours at room temperature. The solvent was removed under vacuum. Chromatography (30% methanol-methylene chloride plus ammonium hydroxide) afford 1.93 g (62%) of product as a yellow oil: MS FAB m/e 196 (M+H)+
Reaction SMILES: [OH:1][C:2]1[C:3]([C:10]([NH:12][C@H:13]2[CH2:21][CH2:20][CH2:19][C@H:18]([O:22][CH2:23][CH2:24][CH3:25])[C@@H:17]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C@H:16]([CH3:31])[O:15][C:14]2=[O:32])=[O:11])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:33](Cl)(=[O:35])[CH3:34]>C(Cl)Cl>[C:33]([O:1][C:2]1[C:3]([C:10](=[O:11])[NH:12][C@H:13]2[CH2:21][CH2:20][CH2:19][C@H:18]([O:22][CH2:23][CH2:24][CH3:25])[C@@H:17]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C@H:16]([CH3:31])[O:15][C:14]2=[O:32])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9])(=[O:35])[CH3:34]
Reactant: CCCO[C@H]1CCC[C@H](NC(=O)c2nccc(OC)c2O)C(=O)O[C@@H](C)[C@@H]1CCC(C)C
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CCCO[C@H]1CCC[C@H](NC(=O)c2nccc(OC)c2OC(C)=O)C(=O)O[C@@H](C)[C@@H]1CCC(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.4 %

Procedure:
To a solution of 3-hydroxy-N-((3S,7S,8S,9S)-8-isopentyl-9-methyl-2-oxo-7-propoxyoxonan-3-yl)-4-methoxypicolinamide (75 mg, 0.166 mmol) were added TEA (34.8 μL, 0.250 mmol) and acetyl chloride (17.8 μL, 0.250 mmol) in DCM (0.832 mL). The reaction was stirred at room temperature for 4 h and then treated with Celite® (3 scoopula tip-fulls). The solvent was removed under reduced pressure and the resulting adsorbed material was directly loaded onto a column and purified using flash column chromatography (24 g SiO2, 0→100% EtOAc/hexanes) to afford the title compound (74 mg, 0.150 mmol, 90%) as a white powder (hygroscopic): IR (thin film): 3383, 2953, 2871, 1772, 1737, 1678, 1506, 1197, 1173 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J=8.2 Hz, 1H), 8.33 (d, J=5.4 Hz, 1H), 7.00 (d, J=5.4 Hz, 1H), 4.74 (dq, J=9.9, 6.3 Hz, 1H), 4.65-4.53 (m, 1H), 3.90 (s, 3H), 3.52 (app dt, J=8.9, 6.4 Hz, 1H), 3.31-3.22 (m, 1H), 3.15 (app dt, J=8.9, 6.6 Hz, 1H), 2.43-2.30 (m, 4H), 2.22-2.07 (m, 1H), 1.96-1.84 (m, 1H), 1.83-1.69 (m, 1H), 1.68-0.98 (m, 12H), 0.96-0.84 (m, 10H); HRMS-ESI m/z [M+H]+ calcd for: C26H41N2O7, 493.2908; found 493.2936.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9](I)=[CH:10][C:3]=12.CC1(C)C(C)(C)OB([C:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH:31]=2)O1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9]([C:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH:31]=3)=[CH:10][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(Cl)ccnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc3c(Cl)ccnc32)cc1
Temperature: 85 °C

Procedure:
A mixture of 4-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (7.50 g, 17.33 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (6.43 g, 20.80 mmol), tetrakis(triphenylphospine)palladium (0.801 g, 0.693 mmol) and aqueous sodium bicarbonate (40 mL) in N,N-dimethylformamide (160 mL) was flushed with nitrogen and heated at 85° C. for 24 hours. The mixture was diluted with water and brine and extracted with ethyl acetate. The organic extracts were washed with water, dried over magnesium sulfate, filtered, concentrated, and purified by flash chromatography on silica (ISCO Companion), eluting with a gradient of 8:2 to 7:3 heptanes/ethyl acetate to give the title compound. MS (ESI+) m/z 488.0 (M+H)+.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[OH:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1.[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:26]Br>CCCCC>[F:22][C:23]1[CH:24]=[C:25]([CH2:26][O:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: Fc1ccc(CBr)cc1F
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(OCc2ccc(F)c(F)c2)C1
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To sodium hydride (60% w/w dispersion in oil, 0.62 g, 16.4 mmol) washed in pentane was added N,N-dimethylformamide (20 ml) and then 1,1-dimethylethyl 3-hydroxypiperidine-1-carboxylate (Preparation 117, 3.0 g, 14.9 mmol). The reaction mixture was stirred for 1 h, before adding 3,4-difluorobenzyl bromide (2.0 ml, 16.4 mmol) and stirring the reaction mixture for 18 h. The reaction mixture was concentrated in vacuo and the crude residue was dissolved in dichloromethane and washed with brine and dried (MgSO4) before concentrating in vacuo. The crude residue was purified by flash chromatography to give the title compound (4.58 g, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[CH3:11][C:12]1[N:13]=[CH:14][S:15][C:16]=1[CH2:17][CH2:18]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][CH2:17][C:16]2[S:15][CH:14]=[N:13][C:12]=2[CH3:11])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(Br)ccc1O
Reactant: Cc1ncsc1CCO
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(Br)ccc1OCCc1scnc1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 4-bromo-2-methoxy-phenol (50.8 mg, 0.25 mmol), 2-(4-methyl-thiazol-5-yl)-ethanol (49.5 mg, 0.25 mmol) and polymer-supported triphenyl phosphine (250 mg, 0.75 mmol) in THF (2.5 mL) was stirred at room temperature for 20 minutes. DBAD (86.3 mg, 0.375 mmol) was added and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through Celite®, rinsing with THF and methanol. The filtrate was concentrated, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered and concentrated. The concentrate was purified by column chromatography on silica gel (10 to 20% ethyl acetate in hexane) to give the title compound. MS (ESI) m/e 329 (M+H)+; 1H NMR (300 MHz, DMSO-d6) □ 8.82 (s, 1H), 7.12 (d, J=2.4 Hz, 1H), 7.03 (dd, J=8.5, 2.4 Hz, 1H), 6.91 (d, J=8.5 Hz, 1H), 4.10 (t, J=6.4 Hz, 2H), 3.77 (s, 3H), 3.20 (t, J=6.4 Hz, 2H), 2.35 (s, 3H).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[F:10][C:11]1[C:16]([F:17])=[C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:14]=[CH:13][C:12]=1[C:27]1[N:32]=[CH:31][C:30](Br)=[CH:29][N:28]=1>C(NC(C)C)(C)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.[Cu]I>[F:10][C:11]1[C:16]([F:17])=[C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:14]=[CH:13][C:12]=1[C:27]1[N:32]=[CH:31][C:30]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:29][N:28]=1
Reactant: CCCCCCCCOc1ccc(-c2ncc(Br)cn2)c(F)c1F
Reactant: C#CCCCCCCC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Product: CCCCCCCC#Cc1cnc(-c2ccc(OCCCCCCCC)c(F)c2F)nc1
Yield: 91.7 %

Procedure:
--Non-1-yne (1.0 ml, 6.4 mmol) was added via syringe to degassed mixture of 2-(2',3'-difluoro-4'-octyloxyphenyl)-5-bromopyrimidine 4 (1.27 g, 3.18 mmol), tetrakis(triphenylphosphine)palladium (173 mg, 0.15 mmol) and copper(I) iodide (29 mg, 0.15 mmol) in diisopropylamine (60 ml) under nitrogen. The mixture was heated under gentle reflux for 4 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (5% ethyl acetate-light petroleum, the sample was preloaded onto silica in dichoromethane) to give the nonynylpyrimidine 38 (1.29 g, 92%) (from MeOH), transitions/° C. K 64.4 (N 63.3) I; νmax /cm-1 (KBr) 2920, 2850, 2220, 1615, 1520, 1470, 1430s, 1295, 1205 and 1090s, δ 0.90 (6H, m), 1.20-1.55 (18H, m), 1.64 (2H, quint, J7, CH2CH2C≡C), 1.85 (2H, quint, J7, OCH2CH2), 2.46 (2H, t, J7, CH2C≡C), 4.10(2H, t, J7, OCH2), 6.83 (1H, ddd, J8, 7 and 2, 5'-H), 7.85 (1H, ddd, J8, 7 and 2, 6'-H) and 8.79 (2H, s, 4-and 6-H); m/z 442 (M+), 330, 288, 287, 274, 273, 247 and 220.