Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[C:10]([O:15][CH2:16][C:17](C)=[CH:18][CH3:19])(=[O:14])[C:11]([CH3:13])=[CH2:12].O1CCOC[CH2:22]1>N(C(C)(C)C#N)=NC(C)(C)C#N.C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[C:10]([O:15][CH2:16][CH:17]=[C:18]([CH3:19])[CH3:22])(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: C1COCCO1
Reactant: C=C(C)C(=O)OCC(C)=CC
Agent: C=Cc1ccc(O)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1C
Product: C=C(C)C(=O)OCC=C(C)C
Temperature: 20 °C
Reaction time: 20 h

Procedure:
A 1-liter flask was charged with 72.1 g (0.60 mol) of 4-hydroxystyrene, 49.2 g (0.60 mol) of 2-methyl-2-butenyl methacrylate, 1.5 g (0.009 mol) of azobisisobutyronitrile and 300 ml of dioxane, and the mixture was stirred for 20 hours at 20° C. in a nitrogen gas stream. The resultant reaction mixture was poured into 5 liters of xylene, and precipitate formed was collected by filtration. The resultant solids were dissolved in 300 ml of acetone, and the solution was poured into 4 liters of n-hexane to collect precipitate formed by filtration (reprecipitation process). This reprecipitation process was repeated 3 times, and the resultant precipitate was then dried to obtain 103.5 g of a 4-hydroxystyrene/3-methyl-2-butenyl methacrylate copolymer. The GPC analysis of the copolymer thus obtained revealed that its Mw was 8,800. Besides, the 1H-NMR spectrum analysis of the polymer revealed that the copolymerization ratio of 4-hydroxystyrene to 3-methyl-2-butenyl methacrylate was 53/47.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([CH:25]3[CH2:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]3)=[O:24])=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:38][C:39]([NH2:41])=[O:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC1C=C(NC2C=CC(NC(C3CN(C(OC(C)(C)C)=O)C=CC=3)=O)=CC=2)N=CC=1CC(N)=O)C1C=CC=CC=1.[ClH:83].C(OCC)(=O)C>CO>[ClH:83].[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23]([CH:25]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]3)=[O:24])=[CH:20][CH:21]=2)[N:12]=[CH:11][C:10]=1[CH2:38][C:39]([NH2:41])=[O:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)Nc2ccc(Nc3cc(NCc4ccccc4)c(CC(N)=O)cn3)cc2)C1
Agent: CC(C)(C)OC(=O)N1C=CC=C(C(=O)Nc2ccc(Nc3cc(NCc4ccccc4)c(CC(N)=O)cn3)cc2)C1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: NC(=O)Cc1cnc(Nc2ccc(NC(=O)C3CCCNC3)cc2)cc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
25.9 mg of 4-(benzylamino)-6-[(4-{[1-(tert-butoxycarbonyl)piperidin-3-ylcarbonyl]amino}phenyl)amino]pyridine-3-carboxyamide (the compound of Example 308) was dissolved in 1 mL of methanol, to which 1 mL of 4 mol/L hydrochloric acid-ethyl acetate was added, and stirred at room temperature for 30 minutes. The solvent was evaporated, ether was added to the residue, the deposited crystals were filtered to obtain 20.7 mg (91%) of the title compound as a light brown crystalline powder.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.[CH2:31]([NH:34][C:35]([NH2:37])=[O:36])[C:32]#[CH:33].C(Cl)Cl>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.CCN(CC)CC.CCO>[NH2:37][C:35]([NH:34][CH2:31][C:32]1[N:12]2[C:13]3[C:18]([C:19](=[O:20])[C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:29]=[CH:30][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:9])=[CH:11]2)=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3[CH:33]=1)=[O:36]
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Reactant: C#CCNC(N)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)NCc1cc2cc(CN3CCOCC3)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn1c23
Temperature: 25 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (300 mg), PdCl2(PPh3)2 (19.7 mg), CuI (5.3 mg), Et3N (10.4 mL), and prop-2-ynylurea (60.3 mg) is stirred at room temperature overnight. Distilled CH2Cl2 (10.4 mL) and additional PdCl2(PPh3)2 (19.7 mg) and CuI (5.3 mg) are added. The reaction is stirred at room temperature overnight. The reaction mixture is condensed, adsorbed onto silica, and chromatographed eluting with 2% MeOH in CH2Cl2 to 6.5% MeOH in CH2Cl2. Product containing fractions are combined and condensed to afford a mixture of cyclized and uncyclized materials. To a scintillation vial is added the mixture, EtOH (4 mL), Et3N (0.1 mL), and CuI (˜1 mg). The suspension is heated at 70° C. overnight. The reaction mixture is condensed, adsorbed onto silica, and chromatographed eluting with 6% MeOH in CH2Cl2 then 7% MeOH in CH2Cl2. Product-containing fractions are combined and condensed to afford a solid. The solid is suspended in CH2CT2/hexanes and filtered to afford 19.7 mg (7%) of 2-{[(aminocarbonyl)amino]methyl}-N-(4-chlorobenzyl)-8-(4-morpholinylmethyl)-6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide as a white solid.
Reaction SMILES: CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.C([C:62]1[CH:63]=[C:64]([CH3:69])[C:65]([Cl:68])=[N:66][CH:67]=1)C=C.S([O-])([O-])=O.[Na+].[Na+].[C:76]([OH:80])(C)([CH3:78])[CH3:77]>O>[Cl:68][C:65]1[N:66]=[CH:67][C:62]([CH2:77][C@@H:76]([OH:80])[CH2:78][OH:22])=[CH:63][C:64]=1[CH3:69]
Reactant: C=CCc1cnc(Cl)c(C)c1
Reactant: CC(C)(C)O
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C[C@@H](O)CO)cnc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
AD-mix-beta (27.8 g) was added portion wise to a solution of 51 (2.7 g, 16.2 mmol) in t-butanol (83 mL) and H2O (83 mL) at 5° C. The mixture was stirred at room temperature for 16 hrs and then cooled to 5° C. and treated with excess sodium sulfite for 20 min. It was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, concentrated and chromatographed on silica gel eluted with 67% ethyl acetate in hexanes and ethyl acetate to afford 3.2 g (98%) of 52 as an oil which was confirmed by LC/MS and was used directly for the next step.
Reaction SMILES: [OH:1][CH:2]([CH3:15])[CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[C:23]([O:1][CH:2]([CH3:15])[CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:6])(=[O:25])[CH3:24]
Reactant: CC(O)CCC(=O)OCc1ccccc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC(C)CCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
63 g (302.5 mmol) of benzyl 4-hydroxypentanoate and 46.4 ml (332.8 mmol) of triethylamine are charged under nitrogen at room temperature to 300 ml of CH2Cl2. The mixture is cooled to 0° C. and 21.5 ml (302.5 mmol) of acetyl chloride are added dropwise at 0°-5° C. When the dropwise addition is complete, the ice bath is removed and stirring is continued overnight at room temperature. The reaction mixture is mixed with ice-water and the organic phase is separated and washed twice with water. The aqueous phases are extracted twice with CH2Cl2. The organic phases are combined, dried over MgSO4, filtered and concentrated by evaporation. Distillation of the residue gives benzyl 4-acetoxypentanoate as a colourless oil of b.p. 126°-127° C./2.10-2 torr.
Reaction SMILES: [Cl:1][C:2]1[C:9]([C:10]#[N:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1.O=[C:19]([CH2:26][CH2:27][CH3:28])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[Cl:1][C:2]1[C:9]([C:10]#[N:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([CH2:26][CH2:27][CH3:28])[NH:12][C:13]2=[N:14][NH:15][CH:16]=[C:17]12
Reactant: N#Cc1cccc(C=O)c1Cl
Reactant: Nc1cc[nH]n1
Reactant: CCCC(=O)CC(=O)OCC
Product: CCCC1=C(C(=O)OCC)C(c2cccc(C#N)c2Cl)c2c[nH]nc2N1

Procedure:
To a solution of 2-chloro-3-methylbenzaldehyde (19.4 g) in ethanol (45 ml) was added an aqueous hydroxylamine hydrochloride (9.7 g) solution (12 ml), and an aqueous sodium hydroxide (6.9 g) solution (10 ml) was added. The mixture was stirred at room temperature for 1.5 hours. Water (500 ml) was added and the precipitated crystals were collected by filtration. The obtained white crystals (16.1 g) were dissolved in acetic anhydride (50 ml) and the mixture was heated under reflux for 2.5 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (5:1)) to give 2-cyano-6-methylchlorobenzene (10.9 g) as a white solid. A suspension of 2-cyano-6-methylchlorobenzene (10.9 g), N-bromosuccinimide (12.8 g) and benzoyl peroxide (523 mg) in carbon tetrachloride (100 ml) was heated under reflux for 3.5 hours. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (20:1)) to give 2-chloro-3-cyanobenzaldehyde (12.8 g) as a colorless oil. Subsequently, the title compound was prepared from 2-chloro-3-cyanobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [O:1]1CCCC[CH:2]1[N:7]=C=O.[NH2:10][CH:11]([C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1)[CH2:12][N:13]1[CH2:20][CH:19]2[CH2:21][CH:15]([CH2:16][N:17]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH2:18]2)[CH2:14]1>C1C=CC=CC=1>[C:2]([NH:10][CH:11]([C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1)[CH2:12][N:13]1[CH2:14][CH:15]2[CH2:21][CH:19]([CH2:18][N:17]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH2:16]2)[CH2:20]1)(=[O:1])[NH2:7]
Reactant: O=C=NC1CCCCO1
Reactant: CC(C)OC(=O)N1CC2CC(CN(CC(N)c3ccc(C#N)cc3)C2)C1
Solvent: c1ccccc1
Product: CC(C)OC(=O)N1CC2CC(CN(CC(NC(N)=O)c3ccc(C#N)cc3)C2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
A solution of tetrahydro-2-pyranyl isocyanate (382 mg, 3.0 mmol) in benzene (10 mL) was added to a stirred solution of iso-propyl 7-[2-amino-2-(4-cyanophenyl)ethyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (see Example 9 above; 1.07 g; 3.0 mmol) in benzene (35 mL). The reaction mixture was stirred for 2 h at rt, after which the solvent was evaporated and the residue re-dissolved in a mixture of MeOH (27 mL) and dilute HCl (4.5 mL; 0.1 M). The resulting solution was refluxed for 3 h, before the acid was neutralized (NaHCO3) and the MeOH removed by evaporation to give a precipitate which was collected and recrystallized from IPA to give the title compound in 67% yield.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[C:24]([CH3:28])=[N:25][O:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:29].C1COCC1.[N:35]1([CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1>CCOC(C)=O.CCCCCC>[O:29]=[C:4]1[C:3](=[CH:2][NH:48][C:45]2[CH:46]=[CH:47][C:42]([CH2:41][CH2:40][N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:43][CH:44]=2)[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[C:24]([CH3:28])=[N:25][O:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5]1
Reactant: Nc1ccc(CCN2CCCC2)cc1
Reactant: Cc1nocc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1nocc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(CCN3CCCC3)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 41 %

Procedure:
A small screw cap test tube was charged with 3-Methyl-isoxazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 359, 100 mg, 0.257 mmol) and THF (2.5 mL). To the resulting solution was added 4-(2-Pyrrolidin-1-yl-ethyl)-phenylamine (48.9 mg, 0.257 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and diluted with EtOAc (˜5 mL) and Hexane (˜50 mL). The precipitate that formed was collected by filtration and washed with 0° C. iPrOH (˜5 mL) to afford the title compound in 41% yield (0.059 g, 0.105 mmol).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[NH:18][C:19]1[NH:20][CH2:21][CH2:22][N:23]=1>O1CCCC1.CS(C)=O>[CH3:1][C:2]1[S:3][C:4]([C:7]([N:23]2[CH2:22][CH2:21][N:20]=[C:19]2[NH:18][C:12]2[C:13]([Cl:17])=[CH:14][CH:15]=[CH:16][C:11]=2[Cl:10])=[O:9])=[CH:5][N:6]=1
Reactant: Cc1ncc(C(=O)O)s1
Reactant: Clc1cccc(Cl)c1NC1=NCCN1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1ncc(C(=O)N2CCN=C2Nc2c(Cl)cccc2Cl)s1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 72.6 %

Procedure:
3.15 g (22.0 millimoles) of 2-methyl-thiazole-5-carboxylic acid are dissolved in 500 ml of absolute tetrahydrofuran and 50 ml of absolute dimethylsulfoxide, 3.6 g (22.2 millimoles) of N,N'-carbonyldiimidazole are added and the mixture is stirred for 45 minutes at room temperature. A solution of 5.0 g (21.7 millimoles) of 2-(2',6'-dichlorophenylamino)-2-imidazoline in 100 ml of absolute tetrahydrofuran is then added dropwise and the mixture is stirred overnight at room temperature. The solvents are stripped off under reduced pressure on a rotary evaporator and the residue is stirred thoroughly with 100 ml of 0.5 percent strength sodium bicarbonate solution, whereupon crystallization occurs. The crystals are filtered off, washed with water and dried under reduced pressure, over a phosphorus pentoxide desiccant. 5.6 g of crude 1-(2-methylthiazol-5-oyl)-2-(2',6'-dichlorophenylamino)-2-imidazoline are obtained and are recrystallized from isopropanol, giving 2.7 g of pure product, of melting point 183°-185° C.
Reaction SMILES: [SH-:1].[C+4:2].[SH-:3].[SH-].[SH-].[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([N+:17]([O-:19])=[O:18])=[C:11]([CH:16]=1)[C:12]([NH:14][NH2:15])=O.[OH-].[K+]>CO>[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([N+:17]([O-:19])=[O:18])=[C:11]([C:12]2[S:1][C:2]([SH:3])=[N:15][N:14]=2)[CH:16]=1
Reactant: [SH-]
Reactant: [C+4]
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)NN)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc([N+](=O)[O-])c(-c2nnc(S)s2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 51 %

Procedure:
Carbon bisulfide (4 ml) was added to a solution of 1.95 g (10 mmol) of 5-methyl-2-nitrobenzohydrazide in methanol (8 ml). A solution of 616 mg (11 mmol) of potassium hydroxide in methanol (10 ml) was then added thereto, and the mixture was stirred at room temperature for 6 hr. The precipitated crystal was collected by filtration and was dried. The dried crystal was then added dropwise to concentrated sulfuric acid (5 ml), and the mixture was stirred at room temperature for 3 hr. The reaction solution was added dropwise to 100 ml of iced water. The resultant precipitate was collected by filtration and was dried to give 1.28 g (yield 51%) of the title compound.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:34])[CH2:18][N:19]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][C:12]=1[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(Cl)Cl>CO.O1CCCC1>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:34])[CH2:18][N:19]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][C:12]=1[NH:35][S:36]([CH3:39])(=[O:37])=[O:38])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)Nc1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)Nc1cc(C(O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Reaction time: 2 h

Procedure:
Sodium borohydride (0.37 g, 9.7 mmol) was added in portions to a stirred solution of N-[2-benzyloxy-5-(2-dibenzylamino-1-oxo-ethyl)-phenyl]-methanesulfonamide (1.0 g, 1.9 mmol) in 20 mL of methanol/tetrahydrofuran (5:2) at room temperature and the resulting solution was stirred for 2 hours. Methylene chloride was added and the resulting solution was washed with aqueous sodium bicarbonate, dried over MgSO4 and the solvent was removed. Recrystallization from methylene chloride/hexanes gave the title compound as a crystalline solid; 1H NMR (300 MHz, CDCl3) δ 2.58 (d, J=6.7 Hz, 2 H), 2.86 (s, 2 H), 2.92 (s, 2 H), 3.55 (d, J=13.5 Hz, 2 H), 3.70 (d, J=13.5 Hz, 2 H), 4.11 (s, 1 H), 4.64 (t, J=6.7 Hz, 1 H), 5.10 (s, 2 H), 6.92 (d, J=8.5 Hz, 1 H), 7.00 (dd, J=8.5, 2.0 Hz, 1 H), 7.20-7.50 (m, 16 H), 7.89 (brs, 1 H); MS (ES) m/z: 517.1 (M++H); HRMS Calcd. for C30H32N2O4S(M+): 516.2083. Found: 516.2074.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[CH:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CCOCC>[CH2:12]([O:8][CH2:7][CH:5]([CH2:4][O:3][C:2]([C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:1]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:6])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[CH2:2]([O:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6])[CH2:9][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: c1ccccc1
Reactant: CC1(C)OCC(CO)O1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCOCC(O)CO
Product: CCCCCCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
1-Hexadecyl-3-tritylglycerol was prepared as described in U.S. Pat. No. 6,838,452. In brief, D-acetone glycerol (4 grams), powdered potassium hydroxide (approximately 10 grams) and hexadecyl bromide (9.3 grams) in benzene (100 ml) were stirred and refluxed for 5 hours, while removing the water formed by azeotropic distillation (compare W. J. Baumann and H. K. Mangold, J. Org. Chem. 29: 3055, 1964 and F. Paltauf, Monatsh. 99:1277, 1968). The volume of the solvent was gradually reduced to about 20 ml, and the resulting mixture was cooled to room temperature and dissolved in ether (100 ml). The resulting solution was washed with water (2×50 ml), and the solvent was removed under reduced pressure. A 100 ml mixture of 90:10:5 methanol:water:concentrated hydrochloric acid was added to the residue and the mixture was refluxed for 10 minutes. The product was extracted with ether (200 ml) and was washed consecutively with water (50 ml), 10% sodium hydroxide (20 ml) and again with water (volumes of 20 ml) until neutral. The solvent was removed under reduced pressure and the product (8.8 grams) was crystallized from hexane to give 7.4 grams of pure 1-hexadecyl-glycerol.
Reaction SMILES: Br[C:2]1[C:3]([CH3:11])=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.[C:12]([O-])([O-])=O.[K+].[K+].[CH3:18][N:19]1[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22]C=N1>O1CCOCC1.O.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>[CH3:18][N:19]([CH3:12])[C:23]([C:2]1[C:3]([CH3:11])=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1)=[CH2:22]
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1scc(Br)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=C(c1csc(C(=O)OC)c1C)N(C)C
Temperature: 70 °C
Yield: 94.4 %

Procedure:
To a solution of methyl 4-bromo-3-methyl-2-thiophenecarboxylate (300 mg, 1.27 mmol) in dioxane/H2O (5 mL/1 mL) was added K2CO3 (525 mg, 3.80 mmol), tetrakistriphenylphosphine Pd(0) (15 mg, 0.01 mmol), and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (345 mg, 1.7 mmol). The reaction mixture was heated to 70° C. in a sealed tube for 2 h. The reaction solution was concentrated under vacuum and purified on silica gel (hexanes/EtOAc, 9:1 to 4:1) to give the title compound (270 mg, 90%): LC-MS (ES) m/z 237 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:4]=1[CH2:5][C:6]#N.[H-].[Na+].[CH3:15]I.O.C[N:19]([CH3:22])C=O>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:4]=1[C:5]([C:22]#[N:19])([CH3:15])[CH3:6]
Reactant: COc1ccc(Br)cc1CC#N
Reactant: CI
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(Br)cc1C(C)(C)C#N
Reaction time: 0.25 h

Procedure:
2-Methoxy-5-bromobenzyl cyanide (prepared by reaction of 2-methyl-4-bromoanisole, benzoyl peroxide and bromine, followed by reaction with sodium cyanide) (47 g, 0.208 mole) in dimethyl formamide (100 ml) was added cautiously to a cooled, stirred mixture of sodium hydride 10 g (0.416 mole) and dry dimethyl formamide (500 ml). After 15 minutes, methyl iodide (59 g, 0.416 mole) was added dropwise at 15°-20° C. (external cooling) and the mixture stirred at room temperature for 21/2 hours. Water was then added very cautiously until no further reaction occurred. Addition to a large excess of ice and filtration gave after drying 49 g (92%) buff solid which was shown to be the title product by NMR.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:36]CO.[CH2:39](OC(C1SC(C2C=CC(OC(F)(F)F)=CC=2)=NC=1C)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:39][CH2:19][C:20]3[S:24][C:23]([C:25]4[CH:26]=[CH:27][C:28]([O:31][C:32]([F:33])([F:34])[F:35])=[CH:29][CH:30]=4)=[N:22][C:21]=3[CH3:36])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1sc(-c2ccc(OC(F)(F)F)cc2)nc1C
Reactant: Cc1sc(-c2ccc(OC(F)(F)F)cc2)nc1CCO
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nc(-c2ccc(OC(F)(F)F)cc2)sc1CCOc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 6 b]) was reacted with 2-[5-methyl-2-(4-trifluoromethoxy-phenyl)-thiazol-4-yl]-ethanol {prepared from 4-methyl-2-(4-trifluoromethoxy-phenyl)-thiazole-5-carboxylic acid ethyl ester (PCT Int. Appl. (2001), WO 2001040207 A1) in analogy to the procedures described in examples 19 b] to 19 f]} in the presence of triphenylphosphine and di-tert-butyl azodicarboxylate to yield (6-{2-[4-methyl-2-(4-trifluoromethoxy-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester as yellow oil.