Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2].ClC(Cl)(Cl)C(=N)O[C:60]([CH2:62][CH3:63])=[CH2:61].FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][C:60]([CH2:62][CH3:63])=[CH2:61])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: C=C(CC)OC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: C=C(CC)OC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1O
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (150 mg in 3 ml 33% methylene chloride in cyclohexane), sec-butenyl trichloroacetimidate (62 μl neat) was added and the reagents allows to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 15 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×8 ml). The combined organic were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate:hexane (1:1)+1% methanol) gave the title compounds (11 mg 4"-ether; 3"-ether).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>>[C:11]([O:10][C:8]([N:15]1[CH2:20][CH2:19][CH:18]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:17][CH2:16]1)=[O:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1cccnc1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccnc2)CC1
Yield: 1135.7 %

Procedure:
Using general procedure A, 3-aminopyridine (1.43 g, 1.01 mmol) and 1-Boc-4-piperidone (3.0 g, 1.0 mmol) afforded 4-(pyridin-3-ylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (3.15 g, 92%).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:15]([F:17])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[C:24]=1[C:25](O)=[O:26])(=[O:3])[NH2:2].O1CC(N)C1>>[F:17][C:15]1[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:21])[CH3:22])=[CH:13][C:12]2[C:6]3[N:7]([C:24]([CH2:25][OH:26])=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=3)[CH2:8][CH2:9][O:10][C:11]=2[CH:16]=1
Reactant: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)O
Agent: NC1COC1
Product: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1CO
Yield: 20.7 %

Procedure:
2-Carbamoyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (0.09 g) was reacted with 3-oxetanamine, 3-methyl similar to as described in Example 2 to afford 17.9 mg of 9-fluoro-3-(hydroxymethyl)-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide following reverse phase hplc purification. MS (Q1) 443 (M)+. 1H NMR (400 MHz, DMSO) δ 11.84 (s, 1H), 8.62 (d, J=8.4 Hz, 1H), 8.44 (s, 1H), 7.93 (s, 1H), 7.02 (d, J=10.5 Hz, 1H), 5.49 (s, 1H), 5.07-4.92 (m, 2H), 4.69 (d, J=6.1 Hz, 2H), 4.66-4.49 (m, 2H), 4.42 (d, J=6.1 Hz, 2H), 1.63 (s, 3H), 1.49 (s, 6H).
Reaction SMILES: CC([O-])=O.[K+].CC1(C)C(C)(C)OB([C:14]2[CH:15]=[N:16][N:17]3[CH:22]=[CH:21][CH:20]=[N:19][C:18]=23)O1.Cl[C:25]1[CH:30]=[C:29]([NH2:31])[CH:28]=[CH:27][N:26]=1>O1CCOCC1>[N:16]1[N:17]2[CH:22]=[CH:21][CH:20]=[N:19][C:18]2=[C:14]([C:25]2[CH:30]=[C:29]([NH2:31])[CH:28]=[CH:27][N:26]=2)[CH:15]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: CC1(C)OB(c2cnn3cccnc23)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Nc1ccnc(-c2cnn3cccnc23)c1
Temperature: 120 °C
Yield: 31 %

Procedure:
A suspension of 10 ml 1,4-dioxane and 8 ml 4N KOAc (5.9 g) with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidine (13 g, 3.68 g) and 2-chloro-4-aminopyridine (3.68 g) was purged with nitrogen for 30 min. Then, to the suspension was added Pd(PPh3)4 (867 mg) and the reaction mixture was heated at 120° C. in microwave for 20 min. Upon cooling, the precipitated solid was filtered and used without further purification (1.0 g, 31% yield).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[C:27]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](S(C)(=O)=O)[N:29]=3)=[C:26]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[C:25](=[O:45])[N:24]2[CH3:46])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[C:27]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([O:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:29]=3)=[C:26]([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)[C:25](=[O:45])[N:24]2[CH3:46])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: Oc1ccccc1
Reactant: Cn1c(=O)c(-c2ccc(F)cc2)c(-c2ccnc(S(C)(=O)=O)n2)n1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(=O)c(-c2ccc(F)cc2)c(-c2ccnc(Oc3ccccc3)n2)n1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of phenol (0.11 g, 1.16 mmol) in THF (5 mL) is added NaH (0.024 g of a 60% dispersion in mineral oil, 0.58 mmol). After stirring for 5 min at room temp, a solution of 4-[4-(4-fluorophenyl)-2-methyl-5-(2-methanesulfonyl-pyrimidin-4-yl)-3-oxo-2,3-dihydro-pyrazol-1-yl]-piperidine-1 carboxylic acid tert-butyl ester, 12, (0.154 g, 0.29 mmol) in THF (3 mL) is added all at once. The reaction mixture is stirred at room temp for 14 hours and then quenched by pouring into aqueous saturated NaHCO3 solution. The aqueous phase is extracted three times with CH2Cl2, the combined organic phases washed with saturated sodium bicarbonate, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was used without further purification in the next step.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:24])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:23])[CH:17]([CH:19]([CH2:21][CH3:22])[CH3:20])[NH2:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[CH2:2]([O:9][C:10](=[O:24])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:23])[CH:17]([CH:19]([CH2:21][CH3:22])[CH3:20])[NH:18][C:34](=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCC(C)C(N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(C)C(NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 77 %

Procedure:
D,L-isoleucyl-L-proline benzyl ester hydrochloride (1.2 g) was dissolved in dichloromethane (10 ml), cooled down to 0° C., and DIEA (860 mg) and benzoyl chloride (477 mg) were added dropwisely. The resulting mixture was allowed to warm up naturally to room temperature to react for 2 h, concentrated under reduced pressure to remove the solvent, and purified on a column to give a pale yellow oil (1.1 g, 79%).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.C(OC(OCC)OCC)C.[Cl-].[NH4+]>C(O)C>[CH3:14][CH2:13][O:12][C:5]([C:6]([CH2:1][C:2]([CH3:4])=[O:3])=[O:8])=[O:11]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(OCC)OCC
Solvent: CCO
Product: CCOC(=O)C(=O)CC(C)=O

Procedure:
Ethyl acetopyruvate was prepared from acetone and diethyl oxalate as described in Org. Synthesis, Coll. Vol. 1, 238 (1958). Further reaction with triethylorthoformate and ammonium chloride in ethanol afforded the known enol ether 1. See L. Claisen, Chem. Ber., 40, 3903 (1907).
Reaction SMILES: CN(C)C=O.[C:6]1([SH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[H-].[Na+].Br[C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][N:17]=1>O>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([S:12][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[N:17][CH:18]=1
Reactant: Sc1ccccc1
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(Sc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
To an N,N-dimethylformamide (20 mL) solution of thiophenol (1.02 g, 9.28 mmol) was added sodium hydride (446 mg, 9.28 mmol, 50% in oil), which was stirred for 15 minutes at room temperature. 2,5-Dibromopyridine (2.00 g, 8.44 mmol) was then added to this reaction mixture and stirred for 35 minutes at room temperature, and then for a further 45 minutes at 55° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate:=4:1) to obtain the title compound (2.24 g, quant.).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[CH:3]([C:30]1[CH:35]=[CH:34][N+:33]([O-])=[CH:32][CH:31]=1)[O:4][C:5]1[C:14]([N:15]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[S:16]([CH2:19][CH2:20][CH3:21])(=[O:18])=[O:17])=[N:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.C[Si]([C:43]#[N:44])(C)C.CN(C)C(Cl)=O.C(=O)(O)[O-].[Na+]>ClCCl.O>[C:43]([C:34]1[CH:35]=[C:30]([CH:3]([O:4][C:5]2[C:14]([N:15]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[S:16]([CH2:19][CH2:20][CH3:21])(=[O:18])=[O:17])=[N:13][C:12]3[C:7]([N:6]=2)=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:2]([F:38])([F:37])[F:1])[CH:31]=[CH:32][N:33]=1)#[N:44]
Reactant: C[Si](C)(C)C#N
Reactant: CCCS(=O)(=O)N(COCC[Si](C)(C)C)c1nc2ccccc2nc1OC(c1cc[n+]([O-])cc1)C(F)(F)F
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCS(=O)(=O)N(COCC[Si](C)(C)C)c1nc2ccccc2nc1OC(c1ccnc(C#N)c1)C(F)(F)F
Yield: 102.1 %

Procedure:
Compound B4 (210 mg, 0.367 mmol) obtained in Step 1 was dissolved in dichloromethane (4 mL). To the solution were added trimethylsilyl cyanide (0.25 mL, 1.8 mmol) and dimethylcarbamoyl chloride (0.17 mL, 1.8 mmol), and the mixture was refluxed for 24 hours. A saturated aqueous sodium bicarbonate solution and water were added to the reaction mixture. Extraction with ethyl acetate and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give Compound B5 (218 mg, 100% yield).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([OH:15])(=O)/[CH:6]=[CH:7]/[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[ClH:16]>>[C:5]([Cl:16])(=[O:15])/[CH:6]=[CH:7]/[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: Cl
Reactant: CCCCCC/C=C/C(=O)O
Solvent: O=S(Cl)Cl
Product: CCCCCC/C=C/C(=O)Cl
Temperature: 130 °C
Yield: 91 %

Procedure:
Thionyl chloride (131 g, 1.1 mole) is added to trans-2-nonenoic acid (156 g, 1.0 mole). Reaction occurs immediately with the evolution of HCl and SO2. After the initial reaction subsides, the mixture is heated slowly to 130°C. The dark mixture is vacuum distilled to yield trans-2-nonenoyl chloride, b.p. 90°C/2 mm, 155 g, 91% yield.
Reaction SMILES: C(OC(N1CCN(C2N=CC(C3C=CC(F)=CC=3)=CN=2)CC1)=O)(C)(C)C.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=[CH:44][C:43](Br)=[CH:42][N:41]=2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].[Cl:47][C:48]1[CH:53]=[CH:52][C:51](B(O)O)=[CH:50][CH:49]=1>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=[CH:44][C:43]([C:51]3[CH:52]=[CH:53][C:48]([Cl:47])=[CH:49][CH:50]=3)=[CH:42][N:41]=2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cn2)CC1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ccc(Cl)cc3)cn2)CC1
Yield: 99.1 %

Procedure:
Prepared according to the method for the preparation of 4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-carboxylic acid tert-butyl ester, from 4-(5-bromo-pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (0.536 g) and 4-chlorophenylboronic acid (0.269 g), to yield the title compound as a beige solid (0.580 g, 99%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH3:24])[N:18]=1)[CH:11]=[C:10]2[NH:25][CH:26]1[CH2:31][CH2:30]N[CH2:28][CH2:27]1>>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14]([CH:13]=[C:12]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH3:24])[N:18]=3)[CH:11]=[C:10]2[NH:25][CH:26]2[CH2:27][CH2:28][N:3]([C:2](=[NH:4])[NH2:1])[CH2:30][CH2:31]2)=[CH:15][CH:16]=1
Reactant: CNc1nccc(-c2cc(NC3CCNCC3)c3cc(OC)ccc3c2)n1
Reactant: N=C(N)N
Product: CNc1nccc(-c2cc(NC3CCN(C(=N)N)CC3)c3cc(OC)ccc3c2)n1

Procedure:
4-({7-methoxy-3-[2-(methylamino)pyrimidin-4-yl]-1-naphthyl}amino)piperidine-1-carboximidamide was synthesized according to General Procedure A: guanidine formation except 4-(6-methoxy-4-(piperidin-4-ylamino)naphthalen-2-yl)-N-methylpyrimidin-2-amine 150 (0.018 g, 0.050 mmol) was used. The reaction mixture was triturated with ether (10 mL) to obtain 4-({7-methoxy-3-[2-(methylamino)pyrimidin-4-yl]-1-naphthyl}amino)piperidine-1-carboximidamide 204 as a solid (0.007 g). LC/MS (m/z): 406 [M+H].
Reaction SMILES: [ClH:1].CS(SCCN)=[C:4]([OH:6])[OH:5].C(N[C@@:15]1(O)[C@@H:21]([O:22]C(=O)C)[C@H:20](OC(=O)C)[C@@H:19]([CH2:30]OC(=O)C)[O:18][C@H]1S)(=O)C>CO>[ClH:1].[CH3:30][C:19]([CH2:20][C:21]([CH2:15][C:4]([OH:5])=[O:6])=[O:22])=[O:18]
Reactant: CS(SCCN)=C(O)O
Reactant: CC(=O)N[C@]1(O)[C@H](S)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: CO
Product: CC(=O)CC(=O)CC(=O)O
Temperature: 25 °C

Procedure:
HCl was prepared as follows. To a stirred solution of methyl-2-aminoethylsulfenylthiocarbonate HCl (447 mg, 2.196 mmol) in methanol (5 ml) was added 2-acetamido-3,4,6-tri-O-acetyl-1-thio-β-D-glucose (798 mg, 2.196 mmol) in methanol (10 ml). After stirring at room temperature over night, the mixture was evaporated to dryness yielding the triacetate as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]([CH2:12]O)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].C1(P([N:29]=[N+:30]=[N-:31])(C2C=CC=CC=2)=O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>O1CCCC1>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]([CH2:12][N:29]=[N+:30]=[N-:31])[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Yield: 96.5 %

Procedure:
To a solution of ((1S)-1-hydroxymethyl-2-methylpropyl)carbamic acid t-butyl ester (3.00 g, 14.8 mmol) (obtained as described in Reference Example 61(1)) in tetrahydrofuran (150 ml) were added diphenylphosphoryl azide (4.78 ml, 22.2 mmol), triphenylphosphine (5.82 g, 22.2 mmol) and a 40% solution of diethylazodicarboxylate in toluene (9.67 g, 22.2 mmol) in an ice bath under an atmosphere of nitrogen, and the mixture was stirred for 2 hours under the same conditions. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (9:1) as the eluant to afford ((1S)-1-azidomethyl-2-methylpropyl)carbamic acid t-butyl ester (3.26 g, yield 90%) as a colorless oil.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:11])[NH:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:12][C:13]1[C:14]([CH:19]=O)=[N:15][CH:16]=[CH:17][CH:18]=1>O.C(O)C>[OH:12][C:13]1[C:14]([CH:19]=[N:10][NH:9][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: NNC(=O)Nc1ccccc1
Reactant: O=Cc1ncccc1O
Solvent: O
Solvent: CCO
Product: O=C(NN=Cc1ncccc1O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
4-Phenyl semicarbazide (4.91 g, 33 mmol) was added to a suspension of 3-hydroxy-2-pyridine carbaldehyde (4.0 g, 33 mmol) in a mixture of ethanol water (30 mL:40 mL). The reaction mixture was stirred at room temperature for 3 h and the yellow product was collected by filtration. The yellow precipitate was washed with EtOH/H2O 1:1 and dried under P2 O5 to yield 8.22 g (99%) of product. It can be recrystallized from EtOH/H2O; m.p. 201°-2° C. (dec.). 1H NMR (d6 -DMSO) d: 10.85 (br.s., 1H); 10.6 (br.s., 1H); 9.14 (s, 1H); 8.27 (s, 1H); 8.15 (d of d, 1H); 7.55 (d, 2H); 7.26-7.36 (m, 4H); 7.01 (t, 1H).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].CC(C)([O-])C.[K+].F[C:13]1[C:18]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1>O1CCCC1>[CH2:32]([O:31][CH:27]([O:28][CH2:29][CH3:30])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:19]([C:18]1[C:13]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:20])[CH3:33]
Reactant: CCOC(OCC)c1ccccc1C(=O)c1cccnc1F
Reactant: CC(C)=NO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(OCC)c1ccccc1C(=O)c1cccnc1ON=C(C)C
Reaction time: 0.25 h

Procedure:
To a solution of 0.49 g of acetone oxime in 8 ml of dry tetrahydrofuran was added 0.75 g of potassium tert-butoxide. The solution was stirred for 15 min. then a solution of 1.86 g of (2-fluoropyridin-3-yl)-2-(diethoxymethyl)-phenylmethanone in 8 ml of tetrahydrofuran was added. The solution was stirred at room temperature for 30 min. then quenched by the addition of 25 ml of a 1:1 water-saturated ammonium chloride solution. The solution was extracted with two 50 ml portions of ether and the combined ether extracts were washed with brine and dried over sodium sulfate. Evaporation afforded the intermediate 3-[2-(diethyloxymethyl)-benzoyl]-2-[((isopropylidene)amino]oxy]-pyridine which was not characterised but dissolved in 30 ml of ethanol and 20 ml of 2 M hydrochloric acid added and the solution refluxed for 15 min. The solution was cooled to room temperature and the crystals of 2-(isoxazolo[5,4-b]pyridin-3-yl)-benzaldehyde were collected by filtration and dried in vacuo, 1H-NMR (200 MHz, CDCl3) d 10.26 (CHO).
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[CH:5][C:4]([CH3:8])=[N:3]1.Cl[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[N:11]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[CH3:1][N:2]1[C:6]([O:7][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[N:11]=2)=[CH:5][C:4]([CH3:8])=[N:3]1
Reactant: N#Cc1cccc(Cl)n1
Reactant: Cc1cc(O)n(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Oc2cccc(C#N)n2)n(C)n1
Reaction time: 5 h

Procedure:
5.6 g of 1,3-dimethyl-5-hydroxypyrazole (50 mmol) was added to a suspension of 7.7 g 2-chloro-6-cyanopyridine (55 mmol) and 7.6 g K2CO3 (55 mmol) in 50 ml N,N-dimethylformamide and heated to reflux with vigorous stirring for 5 hours. After cooling, the mixture was poured into water (100 ml) and the aqueous layer extracted 3 times with each 100 ml ethyl acetate. The combined extracts were dried with anhydrous magnesium sulphate and the solvent was removed in vacuo. The residue was purified by flash silica gel column chromatography using hexane/ethyl acetate 7/3. The title compound was obtained after recrystallisation from isopropanol as 5.9 g (55%) of white crystals of m.p. 95° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]2[CH2:10][CH2:9]2)[O:6][CH:7]=1.[K].[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.O>CN(C=O)C>[CH:8]1([C:5]2[O:6][CH:7]=[C:3]([CH2:2][N:16]3[C:12](=[O:22])[C:13]4[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:15]3=[O:17])[N:4]=2)[CH2:10][CH2:9]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCc1coc(C2CC2)n1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1coc(C2CC2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.4 %

Procedure:
To the stirred solution of 4-chloromethyl-2-cyclopropyl-oxazole (4.0 g, 25.38 mmol) in dry DMF (30 mL), was added potassium salt of phthalimide (4.7 g, 25.38 mmol) at rt. The resulting mixture was stirred for 24 h at rt and monitored through TLC. After completion of the reaction, water (200 mL) was added and the crude was extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtained crude residue which was purified via column chromatography (100-200 silica gel, elution with 20% EtOAc in hexane). 3.5 g of 2-(2-cyclopropyl-oxazol-4-ylmethyl)-isoindole-1,3-dione was obtained as a white solid, 269.2 (M+H)+, which contained phthalimide. This compound was used for the next step as such.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:15]2[C:16]3[C:23]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:10][C@H:9]1[CH2:38][CH2:39][C:40]([OH:42])=[O:41])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([C:23]2[C:16]3[C:15]([O:14][C@@H:11]4[CH2:12][CH2:13][NH:8][C@H:9]([CH2:38][CH2:39][C:40]([OH:42])=[O:41])[CH2:10]4)=[N:20][CH:19]=[N:18][C:17]=3[O:21][C:22]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:29][CH:28]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(O[C@@H]4CCN(C(=O)OC(C)(C)C)[C@H](CCC(=O)O)C4)c23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(O[C@@H]4CCN[C@H](CCC(=O)O)C4)c23)cc1

Procedure:
Stir 34 mg of 3-[(2R,4R)-1-(tert-butoxycarbonyl)-4-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}piperidin-2-yl]propanoic acid in approx. 0.1 ml of a 3:2 mixture of trifluoroacetic acid and dichloromethane at RT for 30 min. Then remove the volatile components under reduced pressure and dry the residue under high vacuum. Take up the residue in acetonitrile/water and neutralize with 1N sodium hydroxide solution (pH approx. 7). Filter off the precipitated colourless solid with suction, wash twice with water and twice with acetonitrile and dry under high vacuum. 20 mg (71.3% of theory) of the target compound are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].[N:24]1([C:29]2[CH:30]=[C:31]([C:35]3[O:40]C(C)(C)[O:38][C:37](=O)[CH:36]=3)[CH:32]=[CH:33][CH:34]=2)[CH:28]=[CH:27][N:26]=[CH:25]1>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:22][C:37](=[O:38])[CH2:36][C:35]([C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)[CH:30]=1)=[O:40])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnc3)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C#N)cc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C#N)cc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1

Procedure:
Prepared from (3-amino-4′-cyano-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G40) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10) according to the general procedure K. Obtained as a yellow solid (228 mg).