Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][C:28]1([CH2:44][O:45][Si](C(C)(C)C)(C)C)[O:33][C:32]2[CH:34]=[CH:35][C:36]([N+:38]([O-:40])=[O:39])=[CH:37][C:31]=2[N:30]2[N:41]=[N:42][N:43]=[C:29]12)(C(C)(C)C)(C)C.CC(O)=O>C1COCC1>[N+:38]([C:36]1[CH:35]=[CH:34][C:32]2[O:33][C:28]([CH2:27][OH:26])([CH2:44][OH:45])[C:29]3[N:30]([N:41]=[N:42][N:43]=3)[C:31]=2[CH:37]=1)([O-:40])=[O:39]
Reactant: CC(C)(C)[Si](C)(C)OCC1(CO[Si](C)(C)C(C)(C)C)Oc2ccc([N+](=O)[O-])cc2-n2nnnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)-n1nnnc1C(CO)(CO)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
Tetra-butylammonium fluoride (1M solution in THF; 37.2 mL, 37.2 mmol) was added to a stirred solution of 4,4-bis(((tert-butyldimethylsilyl)oxy)methyl)-8-nitro-4H-benzo[b]tetrazolo[1,5-d][1,4]oxazine (6.3 g, 12.4 mmol) and AcOH (2.1 mL, 37.2 mmol) in THF (200 mL). The mixture was stirred at room temperature for 2 hr then concentrated under vacuum. The residue was partitioned between EtOAc (200 mL) and H2O (150 mL) and the organic layer was washed with brine (1×100 mL), dried (Na2SO4), filtered and the solvent removed under vacuum to leave a crude residue. The residue was dry-loaded on to silica gel then purified by column chromatography on silica gel using DCM/MeOH (1:0 to 92:8) as eluent to provide the desired compound (1.6 g). The desired compound was dissolved in EtOAc (150 mL) and washed with H2O (12×100 mL). The organic layer was dried (Na2SO4), filtered and the solvent removed under vacuum to leave the product (0.9 g) as a solid.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[N:9]=[C:8]([NH2:10])[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1>FC(F)(F)C(O)=O>[Br:1][C:5]1[CH:6]=[C:7]([C:11]([F:14])([F:12])[F:13])[C:8]([NH2:10])=[N:9][C:4]=1[CH3:3]
Reactant: Cc1ccc(C(F)(F)F)c(N)n1
Reactant: BrBr
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)c(C(F)(F)F)cc1Br
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
Bromine (1.7 g, 548 μl, 10.6 mmol, Eq: 5) was added to 6-methyl-3-(trifluoromethyl)pyridin-2-amine (375 mg, 2.13 mmol, Eq: 1) in trifluoroacetic acid (7 ml). The mixture was stirred for 30 min and then concentrated to an oil. Water (30 ml) and dichloromethane (10 ml) were added. The mixture was alkalized by addition of sodium bicarbonate and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to an oil. The crude product was purified by chromatography (SiO2, ethyl acetate/n-heptane) to give the desired product (450 mg, 82.9%) as a yellow solid. MS: m/z=255.1 (M+H+)
Reaction SMILES: [CH2:1]([O:19][CH:20]1[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23][CH:22]([CH2:64][OH:65])[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O[C:67]1[CH:74]=[CH:73][C:70]([CH:71]=[O:72])=[C:69]([O:75][CH3:76])[CH:68]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[CH3:76][O:75][C:69]1[CH:68]=[C:67]([O:65][CH2:64][CH:22]2[CH2:21][CH:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23]2)[CH:74]=[CH:73][C:70]=1[CH:71]=[O:72]
Reactant: COc1cc(O)ccc1C=O
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(CO)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc(C=O)c(OC)c2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Reaction time: 5.5 h
Yield: 100 %

Procedure:
3,4,5-Tris(octadecyloxy)cyclohexylmethyl alcohol (238 mg, 0.26 mmol), 4-hydroxy-2-methoxybenzaldehyde (79 mg, 0.52 mmol) and triphenylphosphine (149 mg, 0.57 mmol) were dissolved in THF (6 ml), diisopropyl azodicarboxylate (115 mg, 0.57 mmol) was added, and the mixture was stirred for 5.5 hr. Water (1 ml) was added to the reaction mixture and the mixture was concentrated. The residue was precipitated with acetonitrile (2.5 ml) to give 2-methoxy-4-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzaldehyde (272 mg, 0.26 mmol, 100%).
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][OH:8])[CH2:5][OH:6])[CH2:2][CH3:3].[CH2:9]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:24][C:23]([CH:25]=O)=[CH:22][CH:21]=2)=[CH:16][N:15]=1)[CH2:10][CH2:11][CH2:12][CH3:13].C(C1C=CC(C2SC=CC=2)=CN=1)CCCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1(C)C=CC=CC=1>[CH2:9]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:24][C:23]([C@H:25]3[O:8][CH2:7][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][O:6]3)=[CH:22][CH:21]=2)=[CH:16][N:15]=1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCC(CO)CO
Reactant: CCCCCc1ccc(-c2ccc(C=O)s2)cn1
Agent: CCCCCc1ccc(-c2cccs2)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCc1ccc(-c2ccc([C@H]3OC[C@H](CCC)CO3)s2)cn1
Reaction time: 3 h

Procedure:
A mixture of 1.2 g of 2-propylpropane-1,3-diol, 2.59 g of 5-(2-pentyl-5-pyridyl)-2-formyl-thiophene (obtainable by formylation of 5-(2-pentyl-5-pyridyl)-thiophene via a Vilsmeier reaction), 0.01 g of p-toluenesulfonic acid and 15 ml of toluene is boiled for 3 hours, using a water separator, cooled, washed with water and evaporated. 5-(2-Pentyl-5-pyridyl)-2-(trans-5-propyl-1,3-dioxan-2-yl)-thiophene is obtained.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].C1(C)C=CC=CC=1.[Cl:13][C:14]1[CH:34]=[CH:33][C:17]([CH2:18][N:19]([N:28]2[CH:32]=[N:31][N:30]=[CH:29]2)[C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)=[CH:16][C:15]=1[OH:35]>O.C(OCC)(=O)C.CN(C)C(=O)C>[Cl:13][C:14]1[CH:34]=[CH:33][C:17]([CH2:18][N:19]([C:20]2[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=2)[N:28]2[CH:29]=[N:30][N:31]=[CH:32]2)=[CH:16][C:15]=1[O:35][S:1](=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)Cl
Reactant: N#Cc1ccc(N(Cc2ccc(Cl)c(O)c2)n2cnnc2)cc1
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(Cc2ccc(Cl)c(OS(N)(=O)=O)c2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sulphamoyl chloride solution in toluene (3 mL, 0.7 M, 2.1 mmol) was concentrated under reduced pressure (30° C. water bath temperature) to ca. 0.5 mL volume. The residue was cooled to 0° C. (ice bath) and N,N-dimethylacetamide (5 mL) was added. 4-[(4-Chloro-3-hydroxy-benzyl)-[1,2,4]triazol-4-yl-amino]-benzonitrile (CAB02141, 200 mg, 0.614 mmol) was added to the colourless solution and the mixture was stirred for 18 hours at room temperature. Ethyl acetate (50 mL) and water (30 mL) were added to the solution, the organic layer was separated, washed with water (2×30 mL) and brine (20 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in a small amount of acetone and precipitated by addition of diethyl ether and hexane. The precipitate was filtered off and dried under high vacuum. Yield: 136 mg (55%) white powder. 1H-NMR (400 MHz, d6-DMSO) δ=5.11 (s, 2H), 6.75 (d, J=9.0 Hz, 2H), 7.25 (dd, J=8.2, 2.0 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.54 (d, J=8.2 Hz, 1H), 7.77 (d, J=9.0 Hz, 2H), 8.32 (s, 2H, —NH2), 8.82 (s, 2H). LRMS (FAB+): 87.0 (100), 404.9 (40, [M+H]+). HRMS (FAB+): 405.05338 C16H14N6O3SCl requires 405.053663.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=1)=O.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:1][C:3]2[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=2)[CH2:15][CH2:14]1
Reactant: O=Cc1cccc(C(=O)O)n1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2cccc(C(=O)O)n2)CC1
Reaction time: 8 h

Procedure:
To a solution of 6-formyl-2-pyridinecarboxylic acid [Chemstep Product List] (0.25 g) in dichloromethane (6.8 ml) was added 1-methylpiperazine (0.481 ml) and acetic acid (0.083 ml). The mixture was stirred at room temperature for 15 min when sodium triacetoxyborohydride (0.459 g) was added and the mixture stirred overnight. The crude reaction mixture was diluted with dichloromethane (60 ml) and methanol was added until a clear solution was observed. The mixture was loaded onto an aminopropyl-SPE cartridge (5 g) pre-eluted with dichloromethane. The cartridge was eluted with dichloromethane and methanol and fractions containing product were combined and blown to dryness under a stream of nitrogen. The crude product was taken up in dichloromethane (2×25 ml) and washed with 2M sodium hydroxide solution (25 ml). The aqueous layer was acidified to pH7 using 5N hydrochloric acid and concentrated under vacuum to approximately 25 ml. The solution was loaded onto an Oasis cartridge (6 g) and eluted with water (one volume) and methanol. Fractions containing product were combined and dried to give the title compound (0.171 g).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:7][CH2:8][CH2:9][CH3:10])(=[O:6])O)[CH3:2].[C:11](#[N:14])[CH:12]=[CH2:13].[Na].C(O)(=O)C>C(O)C>[CH2:1]([O:3][P:4]([CH2:13][CH2:12][C:11]#[N:14])([CH2:7][CH2:8][CH2:9][CH3:10])=[O:6])[CH3:2]
Reactant: CCCCP(=O)(O)OCC
Reactant: C=CC#N
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCP(=O)(CCC#N)OCC
Temperature: 25 °C

Procedure:
15.0 g of n-butylphosphonic acid ethyl ester and 5.3 g of acrylonitrile are dissolved under argon in 25 ml of ethanol. The solution is cooled to 10°, and a solution of 1.15 g of sodium in 50 ml of ethanol is added dropwise, whereupon an exothermic reaction takes place. The mixture is then heated under reflux for one hour and cooled to room temperature, and 3.3 g of glacial acetic acid are added. The solvent is removed and the residue is taken up in dichloromethane. The resulting solution is washed with water, dried over sodium sulfate and concentrated by evaporation. The oil that remains is distilled, yielding 2-cyanoethyl(n-butyl)phosphinic acid ethyl ester having a boiling point of 120° (10-1 bar).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH:18]([N-]C(C)C)(C)[CH3:19].[Li+].C(Br)C.[Cl-].[NH4+]>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[C:1]([O:5][C:6](=[O:17])[CH:7]([CH2:18][CH3:19])[CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)OC(=O)CCNC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCBr
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCC(CNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 38.9 %

Procedure:
t-Butyloxycarbonyl-β-alanine t-butyl ester (2.26 g) was added dropwise to a solution of lithium diisopropylamide (LDA) (6.9 ml, 13.8 mmol) in tetrahydrofuran (10 ml) at -78° C. and hexamethylphosphoroamide (HMPA) (2 ml) was added thereto. The temperature of the reaction solution was elevated gradually to -20° C. over 1 hour and lowered again to -78° C. To the reaction solution, ethyl bromide (0.76 ml) was added dropwise. The temperature of the solution was elevated to 0° C. over 2 hours and the reaction was stopped by adding a saturated aqueous solution of ammonium chloride. After the solvent was distilled off, the residue was dissolved in ethyl acetate and washed sequentially with a 5% aqueous solution of sodium hydrogencarbonate, a 5% aqueous solution of citric acid and a saturated aqueous solution of NaCl 3 times each. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was then distilled off to yield an oil. The obtained oil was applied to a silica gel column (2.5×40 cm) and eluted with a mixed solution (hexane:ethyl acetate=40:1). The desired fractions were collected and the solvents were distilled off to yield an oil of N-t-butyloxycarbonyl-α-ethyl-β-alanine-t-butyl ester (0.98 g, 38.9%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:15].OS(O)(=O)=O.O=[Cr](=O)=O.C(OCC)(=O)C>CC(C)=O>[CH2:1]([O:8][CH2:9][CH2:10][C:11]([OH:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCOCc1ccccc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: O=C(O)CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 3-benzyloxy-1-propanol (1.66 g) dissolved in acetone (10 ml) was added 2N Jones reagent (10 ml) while cooling on ice, and the mixture was stirred for 4 hours at room temperature. Ethyl acetate was added, and the resultant mixture was washed with water. The organic layer was extracted with a sat. aq. K2CO3, and the aqueous layer was washed with ethyl acetate. The washed material was acidified with dilute HCl, again extracted with ethyl acetate, then washed with saturated brine. Drying over anhydrous magnesium sulfate and concentrating under reduced pressure yielded 1.27 g of 3-benzyloxypropionic acid as a colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=1)=O.[CH:18]1([C:24](=O)[CH2:25][C:26]#[N:27])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:24]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:25]([C:26]#[N:27])=[C:9]2[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)ccc2N)ccn1
Reactant: N#CCC(=O)C1CCCCC1
Product: Cc1cc(-c2c(C#N)c(C3CCCCC3)nc3ccc(Cl)cc23)ccn1

Procedure:
The title compound was prepared in analogy to example 101 step B from (2-amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and 3-cyclohexyl-3-oxo-propionitrile (prepared as described in example 110 step A). White solid. MS (ESI): 362.5 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[F:28])[C:10]2[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH2:18])=[O:17])=[N:14][CH:15]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:37])C=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:9]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[F:28])[C:10]2[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH2:18])=[O:17])=[N:14][CH:15]=2)=[O:37])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C(N)=O)ncc1C(Sc1ccc(F)cc1)c1c(F)ccc(F)c1F
Solvent: ClCCl
Product: Cc1cc(C(N)=O)ncc1C(c1c(F)ccc(F)c1F)S(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 312 h
Yield: 18.8 %

Procedure:
To a solution of 5-[[(4-fluorophenyl)thio](2,3,6-trifluorophenyl)methyl]-4-m ethylpyridine-2-carboxamide (389 mg, 0.96 mmol) in methylene chloride (10 ml), 3-chloroperbenzoic acid (254 mg, 0.96 mmol) was added at 0° C. After stirring for 13 days at room temperature, the reaction mixture was washed with 1 N aqueous sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to preparative thin-layer chromatography (developed with hexane:ethyl acetate=1:2, eluted with methylene chloride:methanol=4:1). The obtained fraction was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol and diethyl ether, and was collected by filtration, to obtain the title compound (78 mg, 0.18 mmol, 19%) as a white solid.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])[CH:10]=2)=[O:5])C.[NH2:27][CH2:28][C@@H:29]([C:31]([OH:33])=[O:32])[OH:30]>>[OH:30][C@@H:29]([CH2:28][NH:27][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])[CH:10]=2)=[O:5])[C:31]([OH:33])=[O:32]
Reactant: CCOC(=O)c1ncc2cc(NC(=O)Nc3ccccc3)ccc2c1O
Reactant: NC[C@H](O)C(=O)O
Product: O=C(Nc1ccccc1)Nc1ccc2c(O)c(C(=O)NC[C@H](O)C(=O)O)ncc2c1

Procedure:
(S)-2-Hydroxy-3-{[4-hydroxy-7-(3-phenyl-ureido)-isoquinoline-3-carbonyl]-amino}-propionic acid was prepared from 4-Hydroxy-7-(3-phenyl-ureido)-isoquinoline-3-carboxylic acid ethyl ester from under conditions analogous to Example 116(b) using (S)-isoserine. MS ESI(+) m/e: 411.0449 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]([I:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(O)(=[O:15])C>O>[I:12][C:11]1[C:2](=[O:15])[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Clc1nc2ccccc2cc1I
Reactant: CC(=O)O
Solvent: O
Product: O=c1[nH]c2ccccc2cc1I
Temperature: 100 °C

Procedure:
The 2-chloro-3-iodoquinoline (1-2, 30.0 g) was weighed into a 250 mL flask and suspended in of 50% aqueous acetic acid (125 mL). The mixture was heated to 100° C. and allowed to reflux for 16 hours to completion by TLC analysis of the crude reaction mixture. The mixture was allowed to cool to ambient temperature followed by dilution with 200 mL of water. A suspension of the desired product was isolated by vacuum filtration followed by washing with water (50 mL). The water and traces of acetic acid were removed under vacuum for 5 hours to afford 3-iodo-1H-quinolin-2-one (1-3) as a tan powder. 1H NMR (500 MHz, CDCl3) δ 12.13 (br s, 1H), 8.71 (s, 1H), 7.65 (d, 1H, J=7.5 Hz), 7.54 (m, 1H), 7.31 (d, 1H, J=8.0 Hz), 7.20 (m, 1H).
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1>>[CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[S:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(S)cc1
Reactant: CC(C)c1c[nH]c2ccccc12
Product: COc1ccc(Sc2[nH]c3ccccc3c2C(C)C)cc1
Yield: 72 %

Procedure:
coupling 3-isopropylindole with 4-methoxybenzenethiol to give 3-isopropyl-2-(4-methoxyphenylthio)indole (yield: 72% of pure product);
Reaction SMILES: [O:1]([CH2:9][CH2:10][C:11]#[CH:12])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].C([Li])CCC.[CH3:18][Si:19](Cl)([CH3:21])[CH3:20]>C1COCC1.CCCCCC>[CH3:18][Si:19]([CH3:21])([CH3:20])[C:12]#[C:11][CH2:10][CH2:9][O:1][Si:2]([C:5]([CH3:6])([CH3:7])[CH3:8])([CH3:3])[CH3:4]
Reactant: C#CCCO[Si](C)(C)C(C)(C)C
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCC#C[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
To a solution of 1-(t-butyldimethylsiloxy)-3-butyne (49.0 g, 0.27 mol) in 250 mL of THF, at -78° C. under Ar, was added a solution of n-butyllithium (1.6 M in hexane, 170 mL, 0.27 mol) over ca. 45 min. The mixture was stirred at -78° C. for 30 min and then at 0° C. for 1.5 h. The resulting solution was recooled at -78° C. and then trimethylsilyl chloride (34.0 mL, 0.27 mol) was added dropwise. After the addition the mixture was allowed to warm to room temperature over 18 h and then it was diluted with hexane, washed (H2O, sat. aq. NaHCO3, brine), dried (Na2SO4) and evaporated to give an oil. Distillation at reduced pressure afforded the title compound (60.0 g, 88%) as a colourless oil, bp 70°-75° C./0.1 mm: IR (neat) 2180, 1253, 1112, 841 cm-1 ; 1H NMR (CDCl3, 200 MHz) δ3.72 (t, J=7.0 Hz, 2H), 2.43 (t, J=7.0 Hz, 2H), 0.90 (s, 9H), 0.14 (s, 9H), 0.07 (s, 6H).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.C[O:14][B:15](OC)[O:16]C.O>CCOCC>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([B:15]([OH:16])[OH:14])[CH:8]=1
Reactant: Brc1cccnc1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: OB(O)c1cccnc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To -78° C. cooled n-BuLi (61 ml; 2.5 M hexane solution) was added 3-bromopyridine (20.0 g), dissolved in Et2O (-78° C.) (100 ml) by cannula during 5 minutes. After 10 minutes, a precooled (-78° C.) solution of trimethyl-borate (17.1 g) in Et2O (80 ml) was added. The reaction mixture was stirred at -78° C. for 1 hour, warmed to room temperature during 1 hour, and stirred at room temperature for 1/2 hour. To the reaction mixture was added 20 ml water and stirring continued. The resulting solid percipitate was collected and the supernatent concentrated to a residue. To the residue was added ethyl alcohol (100 ml) and acetic acid (8 ml) followed by heating at reflux for 35 minutes, cooling to room temperature and concentrating to dryness to give a pale yellow foamy material. The crude product was used directly in the next step.
Reaction SMILES: Cl.Cl.[C:3]1([CH:9]2[C:14]3[N:15]=[C:16]([NH:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[S:17][C:13]=3[CH2:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.Cl[C:35]1[CH:40]=[CH:39][N:38]=[C:37]([CH3:41])[N:36]=1.O>CN1CCCC1=O>[CH3:41][C:37]1[N:38]=[C:39]([N:22]2[CH2:21][CH2:20][CH:19]([NH:18][C:16]3[S:17][C:13]4[CH2:12][CH2:11][CH2:10][CH:9]([C:3]5[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=5)[C:14]=4[N:15]=3)[CH2:24][CH2:23]2)[CH:40]=[CH:35][N:36]=1
Reactant: c1ccc(C2CCCc3sc(NC4CCNCC4)nc32)cc1
Reactant: Cc1nccc(Cl)n1
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nccc(N2CCC(Nc3nc4c(s3)CCCC4c3ccccc3)CC2)n1
Temperature: 200 °C

Procedure:
(4-Phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-piperidin-4-yl-amine dihydrochloride (115.9 mg, 0.3 mmol) was dissolved in N-methylpyrrolidone (3 mL). N,N-diisopropylethylamine (165 1, 0.96 mmol) and 4-chloro-2-methylpyrimidine (44.7 mg, 0.33 mmol) were added at room temperature under nitrogen and stirring. The reaction was heated in a microwave oven to 200° C. for 30 minutes. Water was added and the reaction was extracted twice with diethyl ether. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient from EtOAc to EtOAc/EtOH 9:1 (v/v) as eluent. The title compound was obtained as a light yellow viscous oil (34 mg, 28%).
Reaction SMILES: [Br:1][CH:2]=CC=C(C)CC(OC)OC.[CH2:13]([O:15][CH:16]([O:23][CH2:24][CH3:25])[CH2:17][C:18]([CH3:22])=[CH:19][CH:20]=O)[CH3:14]>>[Br:1][CH:2]=[CH:20][CH:19]=[C:18]([CH3:22])[CH2:17][CH:16]([O:23][CH2:24][CH3:25])[O:15][CH2:13][CH3:14]
Reactant: CCOC(CC(C)=CC=O)OCC
Reactant: COC(CC(C)=CC=CBr)OC
Product: CCOC(CC(C)=CC=CBr)OCC

Procedure:
6-Bromo-3-methyl-1,1-diethoxy-3,5-hexadiene is prepared under the conditions described earlier for the preparation of 6-bromo-3-methyl-1,1-dimethoxy-3,5-hexadiene. Starting with 5,5-diethoxy-3-methyl-2-pentenal (4.67 g; 25.1 mmol), 6-bromo-3-methyl-1,1-diethoxy-3,5-hexadiene (5.1 g) is obtained in 77.5% yield. The structure of the product obtained is confirmed by the infrared spectrum and the proton nuclear magnetic resonance spectrum.
Reaction SMILES: C(O[C@H]1C2C(=CC(OCCC)=CC=2)[C@@H](N)C1)C=C.[CH2:19]([O:22][C@H:23]1[C:31]2[C:26](=[CH:27][C:28]([CH3:33])=[CH:29][C:30]=2[CH3:32])[C@@H:25]([NH:34]C(=O)C(F)(F)F)[CH2:24]1)[CH:20]=[CH2:21].FC(F)(F)C(N[C@H]1C2C(=CC=C(C)C=2)[C@@H](O)C1)=O>>[CH2:19]([O:22][C@H:23]1[C:31]2[C:26](=[CH:27][C:28]([CH3:33])=[CH:29][C:30]=2[CH3:32])[C@@H:25]([NH2:34])[CH2:24]1)[CH:20]=[CH2:21]
Reactant: C=CCO[C@@H]1C[C@H](NC(=O)C(F)(F)F)c2cc(C)cc(C)c21
Agent: C=CCO[C@@H]1C[C@H](N)c2cc(OCCC)ccc21
Agent: Cc1ccc2c(c1)[C@H](NC(=O)C(F)(F)F)C[C@@H]2O
Product: C=CCO[C@@H]1C[C@H](N)c2cc(C)cc(C)c21
Yield: 94 %

Procedure:
Step BN (1): N-((1S,3R)-3-(allyloxy)-4,6-Dimethyl-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoroacetamide from Preparation BM was N-deprotected by a procedure analogous to Step U (2) to afford 900 mg (94% yield) of (1S,3R)-3-(allyloxy)-4,6-dimethyl-2,3-dihydro-1H-inden-1-amine as a white solid. LC-MS (M+H)+=218.15; 1H NMR (500 MHz, CDCl3) δ ppm 7.00 (s, 1H) 6.90 (s, 1H) 5.91-6.04 (m, 1H) 5.26-5.34 (m, 1H) 5.13-5.20 (m, J=10.38, 1.53 Hz, 1H) 4.18-4.05 (m, 2H) 4.05-4.00 (m, 1H) 2.57-2.67 (m, 1H) 2.34 (s, 3H) 2.32 (s, 3H) 1.80-1.92 (m, 4H).