Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[Si](OCC)(OCC)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([Si](OCC)(OCC)OCC)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)C.Cl>C(O)C>[C:8]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1
Reactant: CCO[Si](OCC)(OCC)c1ccc(-c2ccc([Si](OCC)(OCC)OCC)cc2)cc1
Agent: Cl
Solvent: CCO
Product: c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
First, trimethyloctadecylammonium chloride (surfactant: 1.83 g, 5.26 mol) was dissolved in a mixed liquid of water (100 ml) and a 6 M aqueous solution of sodium hydroxide (10 g) to obtain a mixed solution. Then, 4,4′-bis(triethoxysilyl)biphenyl (2.00 g, 4.18 mol) was added dropwise into the obtained mixed solution while stirring at room temperature. Thereafter, the irradiation with ultrasonic waves for 20 minutes and the stirring were repeated to the mixed solution. Subsequently, the solution was stirred for 24 hours at room temperature to obtain a reaction solution. After that, the reaction solution was left at rest at a temperature condition of 98° C. for 48 hours. Then, the reaction solution was heated to obtain a silica porous material modified by a biphenyl group (BiPh-HMM) containing the surfactant. Subsequently, BiPh-HMM containing the surfactant was suspended in a mixed liquid containing ethanol (260 ml) and concentrated hydrochloric acid (11.7 g). Thereafter, the suspended liquid was stirred while heating at a temperature condition of 70° C. for 7 hours to extract the surfactant from the BiPh-HMM. After that, the suspended liquid was filtered. Then, the obtained white powders were washed with ethanol and dried in vacuum to obtain BiPh-HMM crystalline powders.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([C@H:28]4[CH2:32][O:31]C5(CCCCC5)[O:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[C:4]([CH3:38])[N:3]=1.[ClH:39]>C(O)C>[ClH:39].[CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([C@H:28]([OH:29])[CH2:32][OH:31])[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[C:4]([CH3:38])[N:3]=1
Reactant: Cc1ccc(Oc2cc(Sc3ccccn3)cnc2Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(C)n1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(Oc2cc(Sc3ccccn3)cnc2Nc2nc([C@H](O)CO)ns2)c(C)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 12 %

Procedure:
To a solution of (S)-N-(3-(2,6-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (0.70 g, 1.3 mmol) in ethanol (20 mL) was added concentrated HCl (2.4 ml) and the reaction was heated to 80° C. for 2 hours. The reaction was concentrated and the material triturated with EtOH. The solid was further purified by reverse phase HPLC to yield pure product. The product was taken up in ethanol and HCl (2M in ether) was added. The mixture was stirred for 2 hours and concentrated in vacuo and dried in vacuo to yield the product as the HCl salt (73.2 mg, 12%). Mass Spectrum (apci) m/z=469.2 (M+H—HCl).
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][C:5]1[CH:18]=[C:8]2[N:9]=[CH:10][C:11]([C:13]([O:15]CC)=[O:14])=[CH:12][N:7]2[N:6]=1.O>O1CCCC1>[OH:3][CH2:4][C:5]1[CH:18]=[C:8]2[N:9]=[CH:10][C:11]([C:13]([OH:15])=[O:14])=[CH:12][N:7]2[N:6]=1
Reactant: CCOC(=O)c1cnc2cc(CO)nn2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc2cc(CO)nn2c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 66.3 %

Procedure:
5 N Sodium hydroxide solution (0.1 ml) was added to a solution of the thus obtained ethyl 2-hydroxymethylpyrazolo[1,5-a]pyrimidine-6-carboxylate (19 mg) in tetrahydrofuran (1 ml), and stirred for 17 hours at room temperature. After water was added, the reaction mixture was washed with ethyl acetate. The aqueous phase was acidified by 2 N hydrochloric acid, extracted with ethyl acetate and dried over sodium sulfate anhydrous. The resulting product was concentrated under reduced pressure, and the residue was dissolved in hot ethyl acetate and then filtered. The filtrate was concentrated under reduced pressure to give the title compound (11 mg, Y.:65%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([NH:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[C:6]=2[N:7]=1.[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[N:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>>[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[N:35]=[CH:34][C:33]([NH:36][C:2]3[N:3]=[CH:4][C:5]4[S:10][CH:9]=[C:8]([NH:11][C:12]5[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=5)[C:6]=4[N:7]=3)=[CH:32][CH:31]=2)[CH2:26][CH2:25]1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: COc1cc(Nc2csc3cnc(Cl)nc23)cc(OC)c1OC
Product: COc1cc(Nc2csc3cnc(Nc4ccc(N5CCOCC5)nc4)nc23)cc(OC)c1OC
Yield: 74.5 %

Procedure:
N2-(6-Morpholinopyridin-3-yl)-N7-(3,4,5-trimethoxyphenyl)thieno[3,2-d]pyrimidin-2,7-diamine (21 mg, 74% yield) was prepared in the same manner as Step 10 of Example 1 using 2-chloro-N-(3,4,5-trimethoxyphenyl)thieno[3,2-d]pyrimidin-7-amine (20 mg, 0.057 mmol) and 6-morpholinopyridin-3-amine (12 mg, 0.068 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:19][CH2:18][CH2:17][C@H:13]2[C:14]([OH:16])=O)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O:22][C:23](=[O:33])[C@H:24]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH2:25])C>>[Cl:8][C:6]1[CH:5]=[C:4]([S:9]([N:12]2[CH2:19][CH2:18][CH2:17][C@H:13]2[C:14]([NH:25][C@H:24]([C:23]([OH:33])=[O:22])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:16])(=[O:10])=[O:11])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Product: O=C(O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Yield: 45 %

Procedure:
3,5-Dichlorophenyl-sulfonyl-L-proline was coupled to L-phenylalanine ethyl ester using the procedure described in Method 3 to give the ethyl ester of the title compound (348 mg, 45%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[CH:11][C:10]2[CH:9]=[N:8][CH:7]=[CH:6][C:5]=2[C:4]=1[NH2:13].[F:16][C:17]([F:29])([F:28])[C:18]1[CH:27]=[CH:26][C:21]([CH2:22][N:23]=[C:24]=[O:25])=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[F:15][C:2]([F:1])([F:14])[C:3]1[C:4]([NH:13][C:24]([NH:23][CH2:22][C:21]2[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:29])[F:28])=[CH:27][CH:26]=2)=[O:25])=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[CH:6]2
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Reactant: Nc1c(C(F)(F)F)ccc2cnccc12
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1c(C(F)(F)F)ccc2cnccc12
Reaction time: 96 h
Yield: 4 %

Procedure:
To a solution of 6-(trifluoromethyl)isoquinolin-5-amine (Description 98; 100 mg, 0.47 mmol) in anhydrous toluene (5 ml) was added [4-(trifluoromethyl)benzyl]isocyanate (Description 58) [0.506M soln in DCM] (1.88 ml; 0.94 mmol) and the mixture heated at reflux overnight. Further [4-(trifluoromethyl)benzyl]isocyanate [0.506M soln in DCM] (1.88 ml; 0.94 mmol) was added and heating continued for 4 days. The toluene was removed, the residue dissolved in methanol (10 ml) and a spatula end of potassium carbonate added. The mixture was then heated at reflux for 15 mins. The mixture was cooled and filtered and the filtrate evaporated. The residue was purified by mass directed HPLC to give the title compound (8 mg, 4%) as a white solid. m/z (ES+) 414 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:6](=[N:12]O)[CH2:5]2.C1(C)C=CC(S(Cl)(=O)=[O:21])=CC=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:7]([OH:11])=[O:21])=[C:4]([CH2:5][C:6]#[N:12])[CH:3]=1
Reactant: O=C1C(=NO)Cc2cc(Br)ccc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: N#CCc1cc(Br)ccc1C(=O)O

Procedure:
Similar procedure as described in example 9B was used, starting from 5-Bromo-indan-1,2-dione 2-oxime and p-Toluenesulfonyl chloride to give 4-Bromo-2-cyanomethyl-benzoic acid. LC-MS: m/e 238 (M−1).
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[N:19]=1>N1C=CC=CC=1>[NH2:17][C:18]1[N:19]=[C:20]([N:24]=[C:4]2[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:7]3[CH2:6][S:5]2)[CH:21]=[CH:22][CH:23]=1
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Reactant: Nc1cccc(N)n1
Agent: [I-]
Solvent: c1ccncc1
Product: Nc1cccc(N=C2SC[C@@H]3Cc4ccccc4CN23)n1
Temperature: 5 °C
Yield: 67.4 %

Procedure:
(S)-3-Methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (20 g) is added in small portions to a solution of 2,6-diaminopyridine (60 g) in pyridine (400 cc). The suspension passes rapidly into solution. After 15 hours at a temperature of about 20° C the solution is concentrated to dryness under reduced pressure (25 mm Hg). The residue is taken up in methylene chloride (500 cc); the insoluble material (47 g) consists of 2,6-diaminopyridine. The methylene chloride solution is washed with water (3 × 100 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (20 mm Hg). After addition to the residue obtained of a mixture (250 cc) of water and ethanol (4:1 by volume) the mixture is heated to the boiling point. After cooling to 5° C the resulting crystals are filtered off and washed with ethanol (50 cc) to give (S)-3-[(6-aminopyrid-2-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (11 g) in the form of white crystals melting at 128° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=3[O:22][CH3:23])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH2:33]([SH:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:33]([S:40][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=3[O:22][CH3:23])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COc1cc(C(F)(F)F)ccc1-c1ncnc2cc(Br)ccc12
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1cc(C(F)(F)F)ccc1-c1ncnc2cc(SCc3ccccc3)ccc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
Crude 7-bromo-4-(2-methoxy-4-(trifluoromethyl)phenyl)quinazoline was dissolved in 33 mL of dioxane, was treated with Pd2(dba)3 (0.376 g, 0.411 mmol), Xantphos (0.475 g, 0.821 mmol), and n,n-diisopropylethylamine (8.61 ml, 49.3 mmol), and was heated to 60° C. Benzyl mercaptan (1.943 ml, 16.43 mmol) was added, and the reaction mixture was allowed to stir for one hour at 60° C. The reaction mixture was concentrated and was purified by silica gel column chromatography (0 to 75% EtOAc/heptane) to yield 7-(benzylthio)-4-(2-methoxy-4-(trifluoromethyl)phenyl)quinazoline (4.616 g, 10.82 mmol, 65.9% yield) with minor impurities. m/z (ESI) 427.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)[CH:7]=[C:6]2[CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C[O:26][C:27](=[O:38])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[CH2:36]Br>>[CH3:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([C:27]([OH:38])=[O:26])=[C:29]([CH2:36][N:22]2[CH2:23][CH2:24][CH:19]([C:6]3[C:5]4[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=4)[N:8]([CH2:12][CH2:13][C:14]4[CH:18]=[CH:17][S:16][CH:15]=4)[CH:7]=3)[CH2:20][CH2:21]2)[CH:30]=1
Reactant: COC(=O)c1ccc(OC)cc1CBr
Reactant: COc1ccc2c(c1)c(C1CCNCC1)cn2CCc1ccsc1
Product: COc1ccc(C(=O)O)c(CN2CCC(c3cn(CCc4ccsc4)c4ccc(OC)cc34)CC2)c1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 0.05 g (0.16 mmol) of 5-methoxy-3-piperidin-4-yl-1-(2-thiophen-3-yl-ethyl)-1H-indole (example 87, part D) and 0.054 g (0.21 mmol) of 2-bromomethyl-4-methoxy-benzoic acid methyl ester. After standard work-up and purification by chromatography using a C18 column, 0.019 g (24% of yield) of the expected acid were obtained.
Reaction SMILES: [CH2:1]([N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[CH:6]1)[CH:2]([CH3:4])[CH3:3].[Br:19]Br>C(O)(=O)C>[Br:19][C:14]1[CH:13]=[CH:12][C:11]2[N:10]=[C:9]([NH2:18])[C:8]3[N:7]=[CH:6][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:17]=3[C:16]=2[CH:15]=1
Reactant: CC(C)Cn1cnc2c(N)nc3ccccc3c21
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(C)Cn1cnc2c(N)nc3ccc(Br)cc3c21
Reaction time: 24 h
Yield: 25.6 %

Procedure:
To a solution of 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine (10.0 g, 41.6 mmol) in acetic acid (150 mL) was added Br2 (10.0 g, 62.6 mmol), and after 24 h, the resulting solid was collected by filtration and washed with H2O. The orange solid was suspended in a saturated aqueous solution of NaHSO3, after which it was again collected and stirred with a 2 M solution of Na2CO3 for 18 h. The solid was collected by filtration, washed with H2O, and azeotropically dried with toluene on a rotary evaporator. Purification on silica gel (7%-10% methanol in CH2Cl2 gradient) afforded 3.4 g of 8-bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([CH:12]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH2:13][CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[NH:9][C:6]2=[N:7][CH:8]=1.[C-:29]#[N:30].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH:14]1([CH2:13][CH:12]([C:10]2[NH:9][C:6]3=[N:7][CH:8]=[C:3]([CH2:2][C:29]#[N:30])[CH:4]=[C:5]3[CH:11]=2)[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(CCl)cnc3[nH]2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(CC#N)cnc3[nH]2)cc1
Yield: 17.9 %

Procedure:
A mixture of 5-chloromethyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (798 mg, 1.92 mmol) and sodium cyanide (500 mg, 10.87 mmol) in N,N-dimethylformamide (3 mL) was subjected to microwave irradiation for 0.5 h at 100° C. The mixture was diluted with ethyl acetate (250 mL), washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 5% methanol/dichloromethane) afforded {2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-acetonitrile (140 mg, 18%) as a light yellow solid: LC/MS m/e calcd for C23H25N3O2S [M+H]+ 408.54, observed 408.0; 1H NMR (400 MHz, CDCl3) δ ppm 1.21 (m, 2H), 1.48 (m, 2H), 1.57-1.90 (m, 5H, H), 2.18 (m, 1H), 2.26 (m, 1H), 3.06 (s, 3H), 3.99 (s, 2H), 4.43 (m, 1H), 6.59 (s, 1H), 7.56 (d, J=8.2 Hz, 2H), 7.90 (d, J=8.2 Hz, 2H), 8.24 (s, 1H), 8.32 (s, 1H), 12.48 (br, 1H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[Si](C)(C)[CH2:13][C:14]([O:16][CH3:17])=[O:15].[CH2:20]([O:27][C:28]1[CH:36]=[C:35]2[C:31]([CH2:32][C:33]([CH3:39])([CH3:38])[C:34]2=O)=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.CCOC(C)=O>[CH2:20]([O:27][C:28]1[CH:36]=[C:35]2[C:31]([CH2:32][C:33]([CH3:39])([CH3:38])/[C:34]/2=[CH:13]\[C:14]([O:16][CH3:17])=[O:15])=[CH:30][CH:29]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)C[Si](C)(C)C
Reactant: CC1(C)Cc2ccc(OCc3ccccc3)cc2C1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)/C=C1/c2cc(OCc3ccccc3)ccc2CC1(C)C
Temperature: -78 °C
Yield: 45 %

Procedure:
At −78° C., lithium bis(trimethylsilyl)amide (1.0 M in THF) (3.6 mL, 3.6 mmol) was added slowly to a solution of methyl 2-(trimethylsilyl)acetate (0.59 mL, 3.6 mmol) in THF (20 mL). The mixture was maintained at −78° C. for 7 minutes and then 6-(benzyloxy)-2,2-dimethyl-2,3-dihydroinden-1-one (8.3) (0.535 g, 2.0 mmol) was added in one portion. The resulting mixture was stirred at −78° C. and allowed to warm to room temperature overnight. The reaction mixture was then diluted with EtOAc (200 mL), washed with water and brine, and dried over anhydrous sodium sulfate. After removing solvent, the residue was purified by chromatography (silica gel, 1:5 EtOAc/hexane) to give product 8.4 in 45% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[O:11][C:10]2=[O:20])[CH:5]=[CH:4][N:3]=1.[C:21]([O:26][CH2:27][CH2:28][N:29]=[C:30]=[O:31])(=[O:25])[C:22]([CH3:24])=[CH2:23]>N1C=CC=CC=1>[O:20]=[C:10]1[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:30](=[O:31])[NH:29][CH2:28][CH2:27][O:26][C:21](=[O:25])[C:22]([CH3:24])=[CH2:23])[CH:7]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[O:11]1
Reactant: C=C(C)C(=O)OCCN=C=O
Reactant: Nc1cc(Cn2c(=O)oc(=O)c3ccccc32)ccn1
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCCNC(=O)Nc1cc(Cn2c(=O)oc(=O)c3ccccc32)ccn1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-(2-amino-pyridin-4-ylmethyl)-1H-benzo[d][1,3]oxazine-2,4-dione (1.2 g, see preparation 7b) in pyridine was added isocyanatoethyl methacrylate (0.76 ml). The reaction mixture was heated to 40° C. and stirred for 2 hours. More isocyanatoethyl methacrylate (0.1 ml) was added and stirring was continued for 2 hours. The solvent was evaporated under reduced pressure and EtOAc (10 ml) was added to the residue. On scraping a solid material formed, that was isolated by filtration and dried in vacuo, affording 2-methyl-acrylic acid 2-{3-[4-(2,4-dioxo-4H-benzo[d][1,3]oxazin-1-ylmethyl)-pyridin-2-yl]-ureido}-ethyl ester (1.78 g). Step 2: This anhydride intermediate was converted into the title compound by reaction with O-(4-cyanobenzyl)hydroxylamine hydrochloride (see preparation 10), using general procedure 1A. 13C-NMR (DMSO-d6) δ 167.5, 166.5, 154.8, 153.7, 151.4, 148.6, 146.6, 141.9, 135.8, 132.8, 132.3, 129.2, 128.1, 125.9, 118.8, 115.4, 114.9, 113.0, 111.6, 110.9, 109.4, 76.1, 63.7, 45.4, 38.0, 18.0.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:27])=[N:12][CH:13]=[C:14]([C:16]2[CH:17]=[N:18][N:19]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:20]=2)[CH:15]=1.[C:28](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:27])=[N:12][CH:13]=[C:14]([C:16]2[CH:17]=[N:18][N:19]([CH:21]3[CH2:22][CH2:23][N:24]([CH3:28])[CH2:25][CH2:26]3)[CH:20]=2)[CH:15]=1
Reactant: CC(=O)O
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccccc2o1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)CC1
Reaction time: 0.25 h

Procedure:
3-(1,3-Benzoxazol-2-yl)-5-[1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (1.8 g) was added to a mixture of acetic acid (2.86 μL) and 37% aqueous formaldehyde (0.583 ml) dissolved in methanol (40 ml) and the resulting solution was stirred for 15 minutes. Sodium cyanoborohydride (0.377 g) was then added and the mixture was stirred for a further 3 hours. The reaction mixture was concentrated to dryness and diluted with DCM and purified by flash chromatography on silica gel (eluting with a gradient of 5 to 10% 7N methanolic ammonia in dichloromethane). The solvent was evaporated to dryness and there was thus obtained 3-(1,3-benzoxazol-2-yl)-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridin-2-amine (1.180 g); Mass Spectrum: M+H+ 375.1; RT 1.73 min; NMR Spectrum: (DMSOd6) 8.53 (d, 1H), 8.44 (d, 1H), 8.32 (d, 1H), 7.92 (d, 1H), 7.85 (m, 1H), 7.80 (m, 1H), 7.64 (br s, 2H), 7.46 (m, 2H), 4.13 (m, 1H), 2.88 (br m, 2H), 2.23 (s, 3H), 2.04 (m, 6H).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[CH:7]=[CH:8][CH:9]=1)=[O:3].[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:16]1[C:17]2[C:12](=[CH:11][C:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:2]([NH2:1])=[O:3])=[CH:19][CH:18]=2)[CH2:13][CH2:14][NH:15]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(-c3cccc(C(N)=O)c3)ccc2C1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cccc(-c2ccc3c(c2)CCNC3)c1
Reaction time: 3 h

Procedure:
To a solution of 1,1-dimethylethyl 6-[3-(aminocarbonyl)phenyl]-3,4-dihydro-2(1H)-isoquinolinecarboxylate (0.725 g; 2.20 mmol; I-VII-9) and Et3SiH (0.88 mL; 5.5 mmol) in CH2Cl2 (25 mL) at room temperature was added TFA (10 mL) in one portion. The mixture was aged 3 h and concentrated in vacuo (2×PhMe chase). The residue was partitioned between satd Na2CO3/CHCl3 (Note 1), layers were separated and the aqueous layer was extracted with CHCl3 (×4). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo, affording the title compound as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.76 (t, J=5.7 Hz, 2H), 2.96 (t, J=5.8 Hz, 2H), 3.87 (s, 2H), 7.11 (d, J=7.9 Hz, 1H), 7.40-7.48 (m, 3H), 7.51 (t, J=7.8 Hz, 1H), 7.78 (ddd, J=7.7, 1.8, 1.1 Hz, 1H), 7.82 (ddd, J=7.8, 1.4, 1.3 Hz, 1H), 8.10 (s, 1H), 8.12 (t, J=1.6 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]#[N:27])=[C:24]([C:28](=[O:31])[CH2:29][CH3:30])[N:23]=[C:22]2[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]#[N:27])=[C:24]([CH:28]([OH:31])[CH2:29][CH3:30])[N:23]=[C:22]2[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nc(C(=O)CC)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc(C(O)CC)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 81.5 %

Procedure:
Following a procedure similar to that described in Example 45(b), but using 451 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-propionylimidazole-5-carbonitrile [prepared as described in step (a) above] and 36 mg of sodium borohydride in 10 ml of ethanol, 369 mg of the title compound were obtained as a viscous oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].[OH-].[K+].S(O[CH:21]([CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:22])(C1C=CC(C)=CC=1)(=O)=O.O>O1CCOCC1>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH:21]([CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:22]
Reactant: OCCOCCO
Reactant: Cc1ccc(S(=O)(=O)OC(C)COCc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(COCc1ccccc1)OCCOCCO
Temperature: 63 °C
Reaction time: 13.5 h
Yield: 36.7 %

Procedure:
HO(CH2)2O(CH2)2OH (21.2 g), potassium hydroxide (11.2 g) and dioxane (100 ml) were charged into a four necked flask and heated to an internal temperature of 63° C. to dissolve potassium hydroxide. A solution obtained by dissolving 32.0 g of TsOCH(CH3)CH2OCH2Ph obtained in Example 2-1 in dioxane (50 ml), was dropwise added over a period of 30 minutes, and while maintaining the internal temperature within a range of from 60 to 100° C., stirring was continued for 13.5 hours. The mixture was left to cool, then added to water (200 ml) and extracted three times with dichloromethane (50 ml). The organic layer was washed with water (20 ml). It was dried over magnesium sulfate, filtered and then concentrated by an evaporator to obtain a crude product (52 g). it was purified by silica gel chromatography to obtain 9.32 g of the above-identified compound.