Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41](C)[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[CH2:8][N:7]([CH3:48])[C@H:6]([CH3:49])[C@@H:5]([OH:50])[C@@:4]1([OH:52])[CH3:51].C([O-])(=O)C.[Na+].II.[OH-].[Na+].[NH4+].[OH-]>CO.O>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([NH:41][CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[CH2:8][N:7]([CH3:48])[C@H:6]([CH3:49])[C@@H:5]([OH:50])[C@@:4]1([OH:52])[CH3:51]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)CN(C)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: CC(=O)[O-]
Agent: II
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](NC)[C@H]2O)[C@](C)(O)C[C@@H](C)CN(C)[C@H](C)[C@@H](O)[C@]1(C)O
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 54.7 %

Procedure:
Azithromycin 1 (0.80 grams (g), 1.02 millimoles (mmol)) and sodium acetate (NaOAc) (0.712 g, 8.06 mmol) were dissolved in 80% aqueous methanol (MeOH) (25 mL). The solution was heated to 50° C. followed by addition of iodine (I2) (0.272 g, 1.07 mmol) in three batches within 3 minutes. The reaction was maintained at a pH between 8-9 by adding 1N sodium hydroxide (NaOH) (1 mL) at 10 min and 45 minute intervals. The solution turned colorless within 45 minutes (min), however, stirring was continued for 2 hours (hr). TLC methylene chloride(CH2Cl2)/MeOH/ammonium chloride (NH4OH) 10:1:0.05) after 2 hours showed a single major product (Rf=0.66). The reaction was cooled to room temperature (rt), poured into H2O (75 mL) containing NH4OH (1.5 mL) and extracted with chloroform (CHCl3) (3×30 mL). The combined organic layers were washed with H2O (30 mL) containing NH4OH (1.5 mL), dried over Na2SO4 and the solvent evaporated to give a white residue. The crude was purified on a silica gel column eluting with CH2Cl2/MeOH/NH4OH 18:1:0.05 to 10:1:0.05 to provide amine 2 (0.41 g, 55%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[C:10]([C:18](=[O:22])[C:19]([OH:21])=[O:20])=[C:9]1[CH2:23]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].[C:26]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:38]3[CH:39]=[CH:40][C:35]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:36][CH:37]=3)=[CH:14][CH:15]=2)[C:10]2[C:18](=[O:22])[C:19](=[O:21])[O:20][CH2:23][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)C(=O)c1c(CO)n(Cc2ccccc2)c2ccc(Br)cc12
Agent: [K]
Product: O=C1OCc2c(c3cc(-c4ccc(-c5ccccc5)cc4)ccc3n2Cc2ccccc2)C1=O

Procedure:
The title compound was prepared from [1-benzyl-5-bromo-2-(hydroxymethyl)-1H-indol-3-yl](oxo)acetic acid, potassium salt and 4-biphenylboronic acid in substantially the same manner, as described in step 4 of Example 9. The product was obtained as a white solid, mp: 254–255° C.; Mass spectrum (ESI, [M+H]+) m/z 444. 1H NMR (400 MHz, DMSO-d6) δ 8.26(s, 1H), 7.75–7.68 (m, 8H), 7.45–7.43 (m, 2H), 7.36–7.23 (m, 6H), 5.89 (s, 2H), 5.53 ppm (s, 2H).
Reaction SMILES: [CH2:1]([C@@H:8](/[CH:25]=[CH:26]/[C@H:27]([CH2:44][C:45]([CH3:47])=[CH2:46])[C:28]([N:30]1[C@H:34]2[CH2:35][CH:36]3[C:39]([CH3:41])([CH3:40])[C:33]2([CH2:38][CH2:37]3)[CH2:32][S:31]1(=[O:43])=[O:42])=[O:29])[C:9]([N:11]1[C@H:15]2[CH2:16][CH:17]3[C:20]([CH3:22])([CH3:21])[C:14]2([CH2:19][CH2:18]3)[CH2:13][S:12]1(=[O:24])=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(O)=O.CCOC(C)=O.[Pd]>[CH2:1]([C@@H:8](/[CH:25]=[CH:26]/[C@H:27]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:28]([N:30]1[C@H:34]2[CH2:35][CH:36]3[C:39]([CH3:40])([CH3:41])[C:33]2([CH2:38][CH2:37]3)[CH2:32][S:31]1(=[O:42])=[O:43])=[O:29])[C:9]([N:11]1[C@H:15]2[CH2:16][CH:17]3[C:20]([CH3:22])([CH3:21])[C:14]2([CH2:19][CH2:18]3)[CH2:13][S:12]1(=[O:24])=[O:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)C[C@@H](/C=C/[C@H](Cc1ccccc1)C(=O)N1[C@H]2CC3CCC2(CS1(=O)=O)C3(C)C)C(=O)N1[C@H]2CC3CCC2(CS1(=O)=O)C3(C)C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](/C=C/[C@H](Cc1ccccc1)C(=O)N1[C@H]2CC3CCC2(CS1(=O)=O)C3(C)C)C(=O)N1[C@H]2CC3CCC2(CS1(=O)=O)C3(C)C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a round bottom flask was added a solution of (2S,3E,5S)-2-benzyl-1,6-bis((7aS)-8,8-dimethyl-2,2-dioxidotetrahydro-3a,6-methano-2,1-benzothiazol-1(3H,4H)-yl)-5-(2-methylprop-2-en-1-yl)hex-3-ene-1,6-dione (67 mg, 0.098 mmol) in AcOH (10.5 mL) and 10% Pd/C (12 mg, 0.011 mmol). The reaction was stirred under an atmosphere of hydrogen (balloon) for 2 hr. The reaction mixture was diluted with EtOAc and filtered. The catalyst was rinsed with EtOAc and the filtrate was concentrated to give (2S,3E,5S)-2-benzyl-1,6-bis((7aS)-8,8-dimethyl-2,2-dioxidotetrahydro-3a,6-methano-2,1-benzothiazol-1(3H,4H)-yl)-5-(2-methylpropyl)hex-3-ene-1,6-dione (54 mg, 0.079 mmol, 80% yield) as a syrup. Anal. Calcd. for C32H52N2O6S2 m/z 684.2. found: 685.2 (M+H)+.
Reaction SMILES: [O:1]([CH:19]([CH3:24])[CH2:20][CH2:21][CH2:22][OH:23])[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.[S:31](Cl)([C:34]1[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=1)(=[O:33])=[O:32]>C(Cl)Cl>[O:1]([CH:19]([CH3:24])[CH2:20][CH2:21][CH2:22][O:23][S:31]([C:34]1[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=1)(=[O:33])=[O:32])[Si:2]([C:15]([CH3:16])([CH3:17])[CH3:18])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(CCCO)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCC(C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Reaction time: 8 h
Yield: 85 %

Procedure:
4-(t-Butyldiphenylsiloxy)-pentanol (15 g, 0.04 mol) was dissolved in methylene chloride (100 mL) containing pyridine (7 g). Tosyl chloride (15.3 g, 0.08 mol) was added slowly and the mixture stirred overnight. The mixture was washed with saturated NaHCO3 (2×100 mL) and the aqueous then backwashed with methylene chloride (100 mL). The organic phases were combined and washed with 2M HCl (100 mL) and water. The solution was dried over Na2SO4, evaporated and purified by column chromatography (light petroleum:ethyl acetate, 3:1) to give the title compound as a thick oil (yield 85%). δC (CDCl3, 62.9 MHz): 19.2, 21.7, 21.8, 26.9, 28.6, 31.8, 63.5, 70.6, 127.7, 127.9, 129.6, 129.9, 133.2, 133.9, 135.6 and 144.7
Reaction SMILES: [CH3:1][N:2](C(OC(C)(C)C)=O)[CH:3]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([NH2:15])[CH:9]=1)[CH3:4].Br>>[CH3:1][NH:2][CH:3]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([NH2:15])[CH:9]=1)[CH3:4]
Reactant: Cc1ccc(/C=C/CC(C)N(C)C(=O)OC(C)(C)C)cc1N
Agent: Br
Product: CNC(C)C/C=C/c1ccc(C)c(N)c1
Temperature: 0 °C
Yield: 93.1 %

Procedure:
A solution of (4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(3-amino-4-methylphenyl)-4-penten-2-amine (1.50 g, 4.93 mmol) and aqueous hydrobromic acid (50%, 25 mL) was stirred at 0° C. to ambient temperature for ˜16 h. The reaction mixture was extracted with chloroform (40 mL). The aqueous layer was cooled to 0° C. and basified with aqueous sodium hydroxide solution to pH 8-9 and extracted with chloroform (3×50 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated on a rotary evaporator to yield 0.938 g (93.3%) of a brown oil.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C1COCC1>[F:1][C:2]1[C:3]([NH:17][S:29]([CH3:28])(=[O:31])=[O:30])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(COc2ncc(F)c(N)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(COc2ncc(F)c(NS(C)(=O)=O)n2)cc1
Reaction time: 0.33 h
Yield: 25.4 %

Procedure:
To a solution of 5-fluoro-2-(4-methylbenzyloxy)pyrimidin-4-ylamine (0.100 g, 0.43 mmol) in anhydrous THF (4 mL) was added LiHMDS (1.07 mL of 1.0M, 1.07 mmol) dropwise at room temperature, and the resulting orange solution was stirred for 20 min. Methanesulfonyl chloride (0.108 g, 0.94 mmol) was added in one portion and the turbid, light orange solution was stirred for 60 min. The reaction was quenched with brine (5 mL) and the THF phase was separated. The aq. phase was extracted w/ EtOAc (5 mL), and the organics were combined, dried over Na2SO4, filtered, and concentrated to an orange gummy residue. The residue was purified by flash chromatography (SiO2, 0→100% EtOac/hexanes) to give 0.034 g (26%) of the title compound as a white solid: mp 145-148° C.; 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.33 (d, J=7.9 Hz, 2H), 7.17 (d, J=7.9 Hz, 2H), 5.35 (s, 2H), 3.37 (s, 3H), 2.35 (s, 3H); HPLC-MS (ESI) m/z 312 (M+H)+, 310 (M−H)−.
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[F:15][C:16]1[CH:17]=[C:18]([N:28]2[CH2:32][CH:31]([CH2:33][NH2:34])[O:30][C:29]2=[O:35])[CH:19]=[CH:20][C:21]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(N(CC)CC)C.[C:43](OC(=O)C)(=[O:45])[CH3:44]>ClCCl>[F:15][C:16]1[CH:17]=[C:18]([N:28]2[CH2:32][CH:31]([CH2:33][NH:34][C:43](=[O:45])[CH3:44])[O:30][C:29]2=[O:35])[CH:19]=[CH:20][C:21]=1[N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: NCC1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCC1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Yield: 85 %

Procedure:
To a reaction flask were added 6.53 mmol of dihydrochloride of 3-(3-fluoro-4-morpholinylphenyl-5-aminomethyl-1,3-oxazolidin-2-one (5a), 100 ml of dichloromethane and 2.95 ml (21.2 mmol) of triethylamine. Then 0.8 ml (8.45 mmol) of acetic anhydride was added while being stirred in an ice-bath. The mixture was then allowed to react at room temperature for 2 hours before being washed successively with 5% aqueous NaOH solution and saturated aqueous NaCl solution. The organic layer was then dried by anhydrous sodium sulfate and filtered, and subsequently put under reduced pressure for solvent removal. The residue was then subjected to recrystallization using ethyl acetate to give white needle crystals at a yield of 85%, HR-TOF-MS (+Q) m/z: 338.1520 (Calculated [C16H20FN3O4+H]+: 338.1516).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[C:5]([NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])=[N:6][CH:7]=1.O.O.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C.C(OCC)(=O)C>[NH2:13][C:4]1[C:5]([NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: C[C@@H](CO)Nc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[C@@H](CO)Nc1ncc(Br)cc1N
Temperature: 75 °C
Reaction time: 3 h
Yield: 98.2 %

Procedure:
A 500-mL round bottomed flask equipped with a magnetic stir bar was charged with a solution of (S)-2-(5-bromo-3-nitropyridin-2-ylamino)propane-1-ol (6.8 g, 24.63 mmol) in ethanol (55 mL). Tin(II) chloride dihydrate (22.23 g, 99 mmol) was added, and the mixture was heated to 75° C. The dark orange color faded to a pale orange color over time. After 3 h, heating was discontinued. After the reaction mixture had cooled to ambient temperature, it was slowly diluted with 2 M sodium hydroxide solution (100 mL, 200 mmol). The thick slurry was further diluted with ethyl acetate. The biphasic mixture was rapidly stirred for 10-15 min, and then the organic layer was decanted into a separatory funnel. The small aqueous layer that carried with the ethyl acetate was drained, and the ethyl acetate extract was washed with 5% aqueous sodium chloride solution (2×100 mL). The original aqueous slurry was extracted with ethyl acetate, and the extract subsequently washed with the 5% aqueous sodium chloride solution. The combined ethyl acetate extracts were concentrated under reduced pressure. The biphasic residue was dissolved in acetonitrile (ca. 100 mL), which was then removed under reduced pressure. The process was repeated to yield crude (S)-2-(3-amino-5-bromopyridin-2-ylamino)propane-1-ol (5.95 g, 24.18 mmol, 98%) as a dark purple-green syrup, which eventually solidified upon standing. MS (ESI, pos. ion) m/z 246, 248 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[C:11]([Cl:19])[CH:10]=2)=[N:6][CH:7]=1.[CH3:20][Si:21]([CH3:40])([CH3:39])[CH2:22][CH2:23][O:24][CH2:25][N:26]1[C:35]2[C:30](=[CH:31][C:32]([CH:36]=[CH2:37])=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]1=[O:38]>CN(C=O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:19][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:4]=[CH:3][C:2](/[CH:37]=[CH:36]/[C:32]3[CH:31]=[C:30]4[C:35](=[CH:34][CH:33]=3)[N:26]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:20])([CH3:40])[CH3:39])[C:27](=[O:38])[CH:28]=[CH:29]4)=[CH:7][N:6]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH:16]([F:18])[F:17]
Reactant: C=Cc1ccc2c(ccc(=O)n2COCC[Si](C)(C)C)c1
Reactant: FC(F)Oc1ccc(Nc2ncc(Br)cn2)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(=O)ccc2cc(/C=C/c3cnc(Nc4ccc(OC(F)F)c(Cl)c4)nc3)ccc21
Temperature: 120 °C
Yield: 49.1 %

Procedure:
To a solution of 5-bromo-N-(3-chloro-4-(difluoromethoxy)phenyl)pyrimidin-2-amine (0.3 g, 0.856 mmol) in DMF (5 mL), were added 1-((2-(trimethylsilyl)ethoxy)methyl)-6-vinylquinolin-2(1H)-one (0.258 g, 0.856 mmol) triethylamine (0.358 mL, 2.57 mmol), tetrabutylammonium chloride, hydrate (0.380 g, 1.284 mmol) and PdOAc2 (0.019 g, 0.086 mmol). The reaction mixture was heated at 120° C. for 12 h. The reaction mixture was concentrated, dissolved in ethyl acetate, filtered through celite, and washed with water. The organic layer was dried over anhydrous sodium sulfate, concentrated and purified by flash chromatography on silica gel using 15% ethyl acetate in petroleum ether to give (E)-6-(2-(2-(3-chloro-4-(difluoromethoxy)phenylamino)pyrimidin-5-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)quinolin-2(1H)-one (0.24 g, 49%). LCMS (ES-API), RT: 2.56 m/z 571.2 (M+H).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])(C)(C)C.[C:20]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](C)=[CH:32][O:33][CH2:34][CH3:35])=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21].C(C1C=CC(CC(C)C=O)=CC=1)(C)(C)C>C1(C)C=CC=CC=1.C1COCC1.CC1C=CC(S(O)(=O)=O)=CC=1>[C:20]([C:24]1[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][CH:32]([O:17][C:15](=[O:16])/[CH:14]=[CH:13]/[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[OH:6])[O:33][CH2:34][CH3:35])=[CH:28][CH:29]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC=C(C)Cc1ccc(C(C)(C)C)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1/C=C/C(=O)O
Agent: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(CCc1ccc(C(C)(C)C)cc1)OC(=O)/C=C/c1ccccc1O
Reaction time: 0.5 h
Yield: 28.2 %

Procedure:
A solution of 3.1 g of (E)-3-[2-(tert-Butyl-dimethyl-silanoxy)-phenyl]-acrylic acid, 3.0 g of 1-tert-butyl-4-(3-ethoxy-2-methyl-allyl)-benzene, accessible from 3-(4-tert-butyl-phenyl)-2-methyl-propionaldehyde via a two step procedure according to P. D. Bartlett and A A. Frimer, Heterocycles 11, 419-435, (1978), and 20 mg of p-TSA in 25 ml of toluene was stirred at 0° C. for 4 h and at room temperature for 14 h. The reaction mixture was partitioned between saturated sodium carbonate and hexane and the organic layer was washed with brine, dried over (Na2SO4) and evaporated to dryness to yield 5.3 g of the crude intermediate (E)-3-[2-(tert-Butyl-dimethyl-silanoxy)-phenyl]-acrylic acid 3-(4-tert-butyl-phenyl)-1-ethoxy-propyl ester as a pale yellow oil. This was dissolved in 20 ml of THF and treated at 0° C. with 3.2 g of solid TBAF-3H2O. After 30 min., the mixture was concentrated and purification by repeated flash chromatography yielded 1.2 g of the title ester (a mixture of diastereoisomers) as a pale yellow oil.
Reaction SMILES: [Li]CCCC.[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1.[Si:14]([O:21][CH:22]([CH2:28][CH2:29][CH2:30][CH3:31])[C:23](OCC)=[O:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>C1COCC1.CCOC(C)=O>[Si:14]([O:21][CH:22]([CH2:28][CH2:29][CH2:30][CH3:31])[C:23]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1)=[O:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16]
Reactant: CCCCC(O[Si](C)(C)C(C)(C)C)C(=O)OCC
Reactant: Cc1ccc(N)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCC(O[Si](C)(C)C(C)(C)C)C(=O)Nc1ccc(C)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.1 %

Procedure:
n-BuLi (2.25 mL, 1.6 M in hexanes, 3.60 mmol) was added slowly to a stirred solution of 2-amino-5-picoline (390 mg, 3.60 mmol) in anhydrous THF (6 mL). The reaction mixture was kept at ambient temperature for 10 minutes before it was added to a solution of ethyl 2-{[tert-butyl(dimethyl)silyl]oxy}hexanoate (Step 1) (820 mg, 3.00 mmol) in anhydrous THF (4 mL). The reaction mixture was stirred at ambient temperature for 1 h. Water and EtOAc were added and the two phases were separated. The organic phase was washed with water, dried over MgSO4 and concentrated in vacuo. The residue was purified with column chromatography (silica gel, eluting with a gradient consisting of 0-100% EtOAc in heptane) to give the title compound as a colourless oil (223 mg), 1H NMR (300 MHz, CDCl3) δ 8.87 (br s, 1H), 8.13 (m, 2H), 7.51 (dd, 1H), 4.25 (t, 1H), 2.29 (s, 3H), 1.79 (m, 2H), 1.35 (m, 4H), 0.98 (s, 8H), 0.89 (t, 3H), 0.14 (d, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:15]([OH:19])[CH2:16][C:17]#[CH:18].C(NC(C)C)(C)C.Cl>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O.CCOCC>[OH:19][CH2:15][CH2:16][C:17]#[C:18][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: C#CCCO
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: OCCC#Cc1ccc(-c2ccc(O)cc2)cc1

Procedure:
17.2 g (69.0 mmol) of 4-bromo-4′-hydroxybiphenyl, 10.0 g (143 mmol) of but-3-yn-1-ol, 2.00 g (2.85 mmol) of bis(triphenylphosphine)palladium(II) chloride, 0.7 g of copper(I) iodide and 25 ml (178 mmol) of diisopropylamine are heated under reflux overnight in 150 ml of THF. The batch is subsequently added to 200 ml of MTB ether, 400 ml of water are added, and the mixture is acidified using hydrochloric acid. The aqueous phase is separated off and extracted three times with ethyl acetate. The combined org. phases are evaporated in vacuo, and the residue is filtered through silica gel with dichloromethane/ethyl acetate (3:1). Crystallisation of the crude product from toluene gives 4′-(4-hydroxybut-1-ynyl)biphenyl-4-ol as a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.N1CCCC1.[CH2:14]([OH:17])[C:15]#[CH:16]>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:16]#[C:15][CH2:14][OH:17])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: C#CCO
Solvent: C1CCNC1
Product: Nc1ccc(C#CCO)cn1
Temperature: 80 °C

Procedure:
2-Amino5-bromopyridine (7-1), 10.0 g (57.8 mmol) was stirred in pyrrolidine (96.5 mL, 1.16 mol, 20 equiv) in a flame dried round bottom flask under argon. Propargyl alcohol (10.1 mL, 173 mmol) and tetrakis triphenylphosphine palladium(0) (1.34 g, 1.16 mmol) were added and the solution was degassed 3× by alternating vacuum/Ar. Heat to 80° C. After 18 h the bulk of the pyrrolidine was removed in vacuo and the residue was diluted with water. Extract with CH2Cl2 three times, and the extracts were dried over Na2SO4, filtered and concentrated to provide impure product. The aqueous layer was further extracted ten times with CH2Cl2/nBuOH (95:5). The extracts were dried over Na2SO4, filtered and concentrated. The two samples were combined and were purified in two batches by flash column chromatography (gradient: CH2Cl2 to CH2Cl2/MeOH, 90:10). The product was triurated with ice cold CH2Cl2, filtered, and washed with ice cold CH2Cl2. Afforded the titled compound as a pale yellow solid. 1H NMR (CD3OD) δ 7.96 (d, 1H, J=2.2 Hz), 7.45 (dd, 1H, J=2.4, 8.8 Hz), 6.51 (d, 1H, J=8.8 Hz), 4.36 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([S:11](=[O:18])(=[O:17])[NH:12][C:13]([F:16])([F:15])[F:14])=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[OH:19][CH:20]([CH:23]1[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24]1)[CH2:21][NH2:22]>>[OH:19][CH:20]([CH:23]1[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24]1)[CH2:21][NH:22][C:5](=[O:7])[C:4]1[C:8]([S:11](=[O:18])(=[O:17])[NH:12][C:13]([F:16])([F:15])[F:14])=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=1
Reactant: O=C(O)c1cc(F)ccc1S(=O)(=O)NC(F)(F)F
Reactant: CC1(C)OCC(C(O)CN)O1
Product: CC1(C)OCC(C(O)CNC(=O)c2cc(F)ccc2S(=O)(=O)NC(F)(F)F)O1

Procedure:
Analogously to Example 22(a), 4.31 g (15 mmol) of 3-fluoro-6-(trifluoromethylsulfamoyl)-benzoic acid is reacted with 3.22 g (20 mmol) of 2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamine and the crude product is purified by chromatography on silica gel with ethyl acetate/hexane. 4.93 g=76.3% of the theoretical yield is obtained as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]1[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:5]2=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:22])[C:6]1[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:5]2=1
Reactant: O=c1[nH]c2ccc(Cl)cc2c2c1[nH]c1ccccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc2nc(Cl)c3[nH]c4ccccc4c3c2c1

Procedure:
A suspension of 60 g. of 2-chloro-7H-indolo[2,3-c]quinolin-6(5H)-one in 950 ml. of phosphorous oxychloride was heated under nitrogen on a steam bath for 2 hours. The deep yellow granular complex that formed was collected and washed thoroughly with anhydrous ether (85.5 g.). After drying, this complex was suspended in 500 ml. of water to which 300 ml. of concentrated aqueous ammonium hydroxide solution was added, in portions, with stirring. The resulting pale yellow solid was collected and washed with water. After recrystallization from 2 l. of acetonitrile, 37.5 g. (68 percent) of colorless needles of 2,6-dichloro-7H-indolo[2,3-c]quinoline was obtained, which had a melting point of 262°-264°. sample, melting point 265°-266°.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:13])=[C:7]([Cl:22])[CH:6]=[CH:5][C:4]=2[N:3]=1.[NH:23]1[CH2:34][CH2:33][CH2:32][C@H:24]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>>[CH3:31][C:28]([O:27][C:25](=[O:26])[C@@H:24]1[CH2:32][CH2:33][CH2:34][N:23]1[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[C:12]([NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:13])[N:3]=1)([CH3:29])[CH3:30]
Reactant: O=C(NCC1CCCCC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1c1ccc2c(C(=O)NCC3CCCCC3)c(Cl)ccc2n1

Procedure:
Prepared according to the method of example 30, using 2,6-dichloro-N-(cyclohexylmethyl)-5-quinolinecarboxamide Example 43(a)) (200 mg) and L-proline, 1,1-dimethylethyl ester (305 mg). Purification (SiO2, ethyl acetate:isohexane 20:80 as eluant) gave the sub-title compound as an oil (200 mg).