Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[OH:8][CH2:9][C:10]1([N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1.F[B-](F)(F)F.[H+].O>C(Cl)Cl>[CH3:1][O:8][CH2:9][C:10]1([N:19]2[C:20](=[O:29])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]2=[O:28])[CH2:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:18]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C1c2ccccc2C(=O)N1C1(CO)Cc2ccccc2C1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCl
Solvent: O
Product: COCC1(N2C(=O)c3ccccc3C2=O)Cc2ccccc2C1
Reaction time: 0.33 h

Procedure:
(Trimethylsilyl)diazomethane (2 M hexanes, 0.51 ml, 1.03 mmol) is added dropwise to a cooled (0° C.) solution of 2-(2-hydroxymethylindan-2-yl)-isoindole-1,3-dione (0.150 g, 0.511 mmol) and fluoroboric acid (48% aqueous, 93.5 μl, 0.511 mmol) in CH2Cl2 (4 ml). The reaction is stirred for 20 minutes, then three further portions of (trimethylsilyl)diazomethane (2 M hexanes, 0.128 ml, 0.25 mmol; 64 μl, 0.12 mol; 64 μl, 0.12 mmol)) are made at 20 minute intervals. The reaction is stirred for a further 40 minutes after the final addition, poured into water and extracted with dichloromethane. The organic phase is washed with brine, dried (MgSO4) and evaporated. The crude product is purified by flash chromatography (CH2Cl2 elution) to afford 2-(2-methoxymethylindan-2-yl)-isoindole-1,3-dione, MH+308.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(C)cc(C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(C)cc(CBr)c1

Procedure:
A solution of 3,5-dimethylanisole (1.11 g, 8.15 mmol), N-bromosuccinimide (1.52 g, 8.55 mmol), and 2,2′-bisisobutyronitrile (27 mg, 0.16 mmol) in carbontetrachloride (10 mL) was refluxed for 2 hrs. The reaction mixture was cooled, filtered and concentrated in vacuo to afford 1-bromomethyl-3-methoxy-5-methyl-benzene as a slightly yellow oil (1.66 g). This material was used without further purification: 1H NMR (300 MHz) compatible.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]([CH3:17])=[O:16])[CH:11]=[CH:10][C:9]=1Br.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CO.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>[CH3:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]([CH3:17])=[O:16])[CH:11]=[CH:10][C:9]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(=O)Nc1ccc(Br)c(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)Nc1ccc(-c2ccccc2)c(C)c1

Procedure:
225 g of sodium carbonate and 0.15 g of PdCl2(PPh3)2 in 450 ml of methanol are heated to reflux temperature. A solution of 342 g of 4-bromo-3-methylacetanilide and 270 g of the ethylene glycol ester of phenylboronic acid in 225 ml of methanol, which has been heated to 50° C., is added dropwise over a period of 60 minutes. During the addition, methanol is distilled off in such an amount that the internal temperature can be kept at at least 85° C. After addition is complete, a further 0.1 g of the Pd catalyst is added and the reaction mixture is refluxed for another 6 hours. After this time, the monitoring of the reaction by HPLC indicates a conversion of 99.9%. The remaining methanol is distilled off as completely as possible (620 ml), with the reaction mixture having to remain stirrable. 1250 ml of chlorobenzene are subsequently added. Hydrolysis is carried out by addition of 85 ml of water. At 70-80° C., the phases are separated and the aqueous phase is discarded. The organic phase is washed once with 50 ml of water and is subsequently filtered through a 0.5 cm thick layer of aluminum oxide. The chlorobenzene is distilled off at 300-500 mbar. The residue of crude 2-methyl-4-acetaminobiphenyl which remains is used further without further purification. The yield is quantitative.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>>[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: O=Cc1ccc(O)cc1
Product: N#Cc1ccc(NCc2ccc(O)cc2)cc1
Yield: 49.6 %

Procedure:
The procedure of Example 40 was repeated, except that 3.58 g of 4-aminobenzonitrile was used in place of aniline, and 4.62 g of 4-hydroxybenzaldehyde was used in place of 4-formylphenyl sulfamate. The resulting crude product was purified by silica gel column chromatography (using a 39:1 mixture of chloroform and acetone as the eluent) to obtain 3.37 g of 4-[N-(4-hydroxybenzyl)amino]-benzonitrile.
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:4]([C:5]([O:7]C)=[O:6])[C:3]=1[C:13]([O:15]C)=[O:14].[OH-].[Na+]>C(O)C.O>[NH2:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1ccc(O)c(N)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1c(O)ccc(C(=O)O)c1C(=O)O

Procedure:
A solution of dimethyl 3-amino-4-hydroxyphthalate C1-4 (11.25 g, 50 mmol) and NaOH (14.0 g, 350 mmol) in ethanol (140 mL) and H2O (50 mL) was stirred at 70° C. overnight. LCMS indicated that the reaction was complete. The reaction mixture was concentrated in vacuo, neutralized to pH<3, and filtered to yield 3-amino-4-hydroxyphthalic acid C1-5 as a white solid (9.6 g, yield: 97%), which was used directly in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH:18]1([CH2:17][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:24]3[S:23][CH:27]=[CH:26][CH:25]=3)=[CH:3][CH:4]=2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(Br)cc1
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(-c2cccs2)cc1
Temperature: 25 °C
Yield: 4.4 %

Procedure:
A mixture of 2-(4-bromo-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (102.5 mg, 0.27 mmol), tetrakis(triphenylphosphine)palladium(0) (15.6 mg, 0.014 mmol), 2-thiopheneboronic acid (69.2 mg, 0.54 mmol), and a 2M aqueous sodium carbonate solution (405 μL, 0.81 mmol) in 1,2-dimethoxyethane (9 mL) was heated under reflux for 24 h. The reaction mixture was allowed to cool to 25° C. and then filtered to remove the catalyst. The filtrate was concentrated in, vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-N-thiazol-2-yl-2-(4-thiophen-2-yl-phenyl)-propionamide (4.5 mg, 4%) as a yellow solid: mp 194° C. (dec); EI-HRMS m/e calcd for C21H22N2OS2 (M+) 382.1174, found 382.1175.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][C:3]=1[CH2:4][N:5]1[C@@H:9]([CH3:10])[C@@H:8]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=2)[O:7][C:6]1=[O:25].[CH:35](=O)[CH3:36].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[F:24][C:21]([F:22])([F:23])[C:13]1[CH:12]=[C:11]([C@H:8]2[O:7][C:6](=[O:25])[N:5]([CH2:4][C:3]3[CH:26]=[C:27]([O:30][C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:29][C:2]=3[NH:1][CH2:35][CH3:36])[C@H:9]2[CH3:10])[CH:16]=[C:15]([C:17]([F:19])([F:20])[F:18])[CH:14]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(OC(F)(F)F)ccc1N
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CCNc1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C

Procedure:
To a solution of (4S,5R)-3-[2-amino-5-(trifluoromethoxy)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (80 mg, 0.159 mmol) in dichloroethane (1.6 mL) was added acetaldehyde (9 μL, 0.159 mmol) and NaBH(OAc)3 (67 mg, 0.318 mmol). The reaction was stirred at room temperature, and after 30 minutes acetaldehyde (4.5 μL, 0.80 mmol) was added. After an hour, additional acetaldehyde (4.5 μL, 0.80 mmol) was added. After an additional hour, the reaction was diluted with EtOAc (20 ml) and washed with saturated NH4Cl solution and brine (10 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (10 to 20% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(ethylamino)-5-(trifluoromethoxy)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.66 (25% EtOAc/hexanes). LCMS=531.2 (M+1)+. 1H NMR (CDCl3, 500 MHz), 7.88 (s, 1H), 7.73 (s, 2H), 7.10 (dd, J=2.1, 8.8 Hz, 1H), 6.90 (d, J=2.4 Hz, 1H), 6.59 (d, J=8.9 Hz, 1H), 5.66 (d, J=8.4 Hz, 1H), 4.81 (s, 1H), 4.70 (d, J=15.4 Hz, 1H), 4.08 (d, J=15.4 Hz, 1H), 4.06-4.00 (m, 1H), 3.20-3.13 (m, 2H), 1.32 (t, J=7.1 Hz, 3H), 0.78 (d, J=6.6 Hz, 3H).
Reaction SMILES: [N:1]([C:4]1[C:8]([CH3:9])=[CH:7][S:6][C:5]=1[C:10]([O:12]C)=O)=[C:2]=[S:3].[N:14]1([CH2:19][CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][N:16]=[CH:15]1>>[CH3:9][C:8]1[C:4]2[NH:1][C:2](=[S:3])[N:22]([CH2:21][CH2:20][CH2:19][N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)[C:10](=[O:12])[C:5]=2[S:6][CH:7]=1
Reactant: COC(=O)c1scc(C)c1N=C=S
Reactant: NCCCn1ccnc1
Product: Cc1csc2c(=O)n(CCCn3ccnc3)c(=S)[nH]c12

Procedure:
The compound was synthesized starting from methyl 3-isothiocyanato4-methylthiophene-2-carboxylate (0.853 g, 4.0 mmol) and 3-(1H-imidazol-1-yl)propan-1-amine (0.5 g, 4.0 mmol) as described above.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:12])[C:6]([C:9]([OH:11])=[O:10])=[N:7][CH:8]=1)#[N:2].S(Cl)(Cl)=O.[C:17]1(C)C=CC=CC=1>CO>[CH3:17][O:10][C:9]([C:6]1[C:5]([CH3:12])=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=1)=[O:11]
Reactant: Cc1ccccc1
Reactant: Cc1cc(C#N)cnc1C(=O)O
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ncc(C#N)cc1C
Reaction time: 1 h

Procedure:
To a solution of 5-cyano-3-methylpyridine-2-carboxylic acid (2 g, 12.4 mmol) in methanol (20 mL) was added thionyl chloride dropwise under reflux. The mixture was then heated at reflux with stirring. After 60 min, HPLC analysis revealed completion of reaction. To the reaction mixture was added toluene and the mixture was concentrated in vacuo to give the title compound as a pale yellow solid: ESIMS: 177; [(M+H)+]; 1H NMR (400 MHz, DMSO-d6): δ 8.92 (s, 1H), 8.39 (s, 1H), 3.90 (s, 3H), 2.46 (s, 3H).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.C(N(CC)CC)C.Cl.Cl.[CH:46]1([N:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)[CH2:48][CH2:47]1>ClCCl>[CH:46]1([N:49]2[CH2:54][CH2:53][N:52]([CH2:6][C:7]3[N:12]=[CH:11][C:10]4[N:13]=[CH:14][N:15]([C:16]5[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]6[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=6[C:30]([F:33])([F:31])[F:32])[CH3:23])[CH:20]=5)[C:9]=4[CH:8]=3)[CH2:51][CH2:50]2)[CH2:48][CH2:47]1
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Reactant: C1CN(C2CC2)CCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CN4CCN(C5CC5)CC4)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Temperature: 40 °C
Reaction time: 1 h

Procedure:
100 mg of [1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate and 205 mg triethylamine are dissolved in 2.5 ml dichloromethane. Under N2 atmosphere 1-cyclopropylpiperazine dihydrochloride (184 mg) is added. The reaction mixture is stirred at 40° C. for 1 hour and then concentrated to dryness under vacuum. The residue is purified by preparative HPLC (ammonium formate buffer/acetonitrile, elution gradient 97/3 to 0/100 (v/v)) to obtain the title product.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:13])=O.CN(C)C=O>ClCCl>[S:1]1[CH2:6][CH2:5][CH:4]([C:7]([Cl:13])=[O:9])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CCSCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1CCSCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To an ice cold solution of 1.36 g (9.32 mmol) tetrahydro-thiopyran-4-carboxylic acid in 25 mL of dichloromethane (DCM) was added dropwise 1.1 mL (12.6 mmol) of oxalyl chloride, and the resulting mixture was stirred at 0° C. for 2 h. Then 2 μL of dimethylformamide (DMF cat) was added, and the reaction mixture was stirred at rt for 2 h, and concentrated to give 1.43 g (93%) of desired tetrahydro-thiopyran-4-carbonyl chloride as a brown oil as indicated by 1H NMR. The product was used without any further purification in the next step toward the preparation of 6-(4-Benzyloxy-phenyl)-7-(tetrahydro-thiopyran-4-yl)-3-(1H-tetrazol-5-yl)-pyrazolo[1,5-a]pyrimidine (below, entry 375).
Reaction SMILES: C(Cl)Cl.[CH3:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].N([C@@:13]1(O)[C@@H:19](O)[C@H:18](O)[C@@H:17]([CH2:22]O)O[CH:14]1O)=[N+]=[N-]>C(Cl)(Cl)(Cl)Cl>[C:6]1([CH:13]2[CH2:19][CH2:18][CH2:17][CH:22]=[CH:14]2)[CH:5]=[CH:4][CH:9]=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=N[C@]1(O)C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CCCCCC
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: C1=CC(c2ccccc2)CCC1

Procedure:
TLC Rf=0.67 (10% CH2Cl2/hexane); IR (CCl4) 3088 (m),3063 (m),3025 (s), 2938 (s), 2863 (s), 2838 (s), 1656 (w), 1606 (m), 1543 (m); 1H NMR (CDCl3) δ0.85-2.09 (m, 6H), 3.38 (bs, 1H), 5.70 (dd, J=10.0, 2.1, 1H), 5.86-5.88 (m, 1H), 7.16-7.30 (m, 5H); 13C NMR (CDCl3) δ21.2, 22.7, 32.6, 41.8, 125.9, 127.7, 128.2, 128.3, 130.2, 146.6; LRMS (EI) 159 ((M+1), 15), 158 ((M+), 100), 143 (43), 129 (79); HRMS (EI) calculated for C12H14 158.1096 (M+), found 158.1098. The IR, 1H NMR and 13C NMR, and MS matched spectral data reported by Arnold, D. R. and Mines, S. A., Can. J. Chem. 67:689-698 (1989).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10]1>>[C:18]([O:17][C:16](=[O:22])[NH:15][CH:11]1[CH2:12][CH2:13][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:10]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Product: CC(C)(C)OC(=O)NC1CCCN(c2ccnc(Cl)n2)C1

Procedure:
tert-butyl(1-(2-chloropyrimidin-4-yl)piperidin-3-yl)carbamate was prepared using the procedure similar to COMPOUND 54 using 2,4-dichloropyrimidine and tert-butyl piperidin-3-ylcarbamate. MS (ES+) C14H21ClN4O2 requires: 312. Found: 313 [M+H]+
Reaction SMILES: [CH:1]([O:4][C:5]1[N:6]=[CH:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C@@H:17]4[O:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]4)[CH:15]=3)[NH:10][C:9]=2[N:30]=1)([CH3:3])[CH3:2].[ClH:31].CCOCC>O1CCOCC1>[ClH:31].[CH:1]([O:4][C:5]1[N:6]=[CH:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C@@H:17]4[O:22][CH2:21][CH2:20][NH:19][CH2:18]4)[CH:15]=3)[NH:10][C:9]=2[N:30]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ncc2c(n1)[nH]c1ccc([C@H]3CN(C(=O)OC(C)(C)C)CCO3)cc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)Oc1ncc2c(n1)[nH]c1ccc([C@H]3CNCCO3)cc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
(S)-tert-Butyl 2-(2-isopropoxy-9H-pyrimido[4,5-b]indol-6-yl)morpholine-4-carboxylate (11 mg, 0.027 mmol) was dissolved in dioxane (0.5 ml) and a solution of HCl in dioxane (4M, 0.08 ml, 0.32 mmol) was added. The reaction mixture was stirred for 1 h at 60° C. After cooling ether (1 ml) was added and the solid was filtered off. It was washed with ether and dried in vacuo to afford (S)-2-(2-isopropoxy-9H-pyrimido[4,5-b]indol-6-yl)morpholine hydrochloride (6 mg, 64%) as an off-white solid. MS (ISP): 313.3 ([M+H]+).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:5]=1[CH2:6][C:7]1[O:11][N:10]=[C:9]([C:12]([O:14]CC)=[O:13])[CH:8]=1>C(O)C>[F:3][C:4]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:5]=1[CH2:6][C:7]1[O:11][N:10]=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=1
Reactant: CCOC(=O)c1cc(Cc2cc(F)ccc2F)on1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
A solution of sodium hydroxide 1M (28 mL; 28 mmol) was added to a solution of ethyl 5-(2,5-difluorobenzyl)isoxazole-3-carboxylate (2.50 g; 9.36 mmol) in ethanol (3 mL). The mixture was stirred at room temperature. After 1 hour, a precipitation occurred and the reaction mixture was allowed to stir for 30 minutes. The solution was acidified to pH 1 by addition of a solution of hydrochloric acid 6N. The precipitate was collected by filtration and dried under reduced pressure to give 1.90 g (84%) of 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][NH2:27])=[CH:22][CH:21]=1)([O-:19])=[O:18]>C(O)(=O)C>[N+:17]([C:20]1[CH:21]=[CH:22][C:23]([O:26][N:27]=[C:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[O:16])=[CH:24][CH:25]=1)([O-:19])=[O:18]
Reactant: NOc1ccc([N+](=O)[O-])cc1
Reactant: CCCCC(=O)CC(=O)c1ccc(O)cc1
Solvent: CC(=O)O
Product: CCCCC(CC(=O)c1ccc(O)cc1)=NOc1ccc([N+](=O)[O-])cc1
Temperature: 15 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
1-(4-Hydroxyphenyl)-1,3-heptandione, 1121 g, is dissolved in 4070 g acetic acid. O-(4-Nitrophenyl)hydroxylamine, 784 g, is added in portions keeping the temperature at ca 20° C. The formed slurry is stirred for 3 h, cooled to 15° C., filtered and washed with 1590 g acetic acid. 1944 g wet cake corresponding to 1596 g dry 1-(4-hydroxyphenyl)heptane-1,3-dione-3-[O-(4-nitrophenyl)oxime] is obtained. Yield 88%.
Reaction SMILES: C([O:8][C@:9]([CH3:17])([CH2:15][OH:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:8][C@:9]([CH3:17])([CH2:15][OH:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)[C@@](C)(CO)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@](C)(O)CO
Yield: 92.8 %

Procedure:
22 g of ethyl (R)-2-benzyloxy-3-hydroxy-2-methyl-propionate (manufactured in accordance with Example 1) in 150 ml of ethyl acetate were hydrogenated with hydrogen gas in the presence of 11 g of 5% by weight palladium/carbon catalyst up to the cessation of the hydrogen uptake. The catalyst was filtered off, washed with ethyl acetate (2×50 ml), the filtrate was concentrated in the vacuum and the residual oil was distilled at 56-57°/0.1 mmHg. There were obtained 12.7 g of ethyl (R)-2,3-dihydroxy-2-methyl-propionate in the form of a colorless viscous liquid. [α]D =+0.339° (undiluted);=+11.6° (c=2.12 in chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][C:11]#[N:12].Br[CH2:14][CH2:15]Br.[OH-].[Na+].[Br-]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1([C:11]#[N:12])[CH2:15][CH2:14]1
Reactant: BrCCBr
Reactant: N#CCc1cc(F)c(Cl)cc1Cl
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC1(c2cc(F)c(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(2,4-dichloro-5-fluorophenyl)acetonitrile (1 g, 4.9 mmol, Eq: 1.00) was dissolved in toluene (4 mL). 1,2-Dibromoethane (1.38 g, 634 μL, 7.35 mmol, Eq: 1.50), aqueous NaOH-solution (4.31 mL, 12.5 M; 53.9 mmol, Eq: 11.0) and tertrabutylammonium bromide (348 mg, 1.08 mmol, Eq: 0.22) were added to the above suspension and vigorously stirred at RT for 4 h. The reaction mixture was diluted with water and extracted with AcOEt. The organic solution was washed with 1 N aqueous HCl, then with brine, dried over Na2SO4, filtered and evaporated to dryness. The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 50% EtOAc in heptane) to yield example 461a) (1.13 g; 100%) as an off-white solid. 1H-NMR (CDCl3, 250 MHz) δ [ppm]: 7.51 (1 proton, d, 6.7 Hz); 7.16 (1, proton, d; 8.9 Hz); 1.76-1.80 (2 protons, m); 1.31-1.36 (2 protons, m)
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:58])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:54]([CH3:57])[CH2:55][CH3:56])[C@H:24]([O:52][CH3:53])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:50][CH3:51])[C@@H:34]([CH3:49])[C:35]([NH:37][CH2:38][CH2:39][C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[NH:42][CH:41]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[O:92]=[C:93]1[CH:97]=[CH:96][C:95](=[O:98])[N:94]1[CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][C:104]([NH:106][NH2:107])=[O:105]>CN(C=O)C>[O:98]=[C:95]1[CH:96]=[CH:97][C:93](=[O:92])[N:94]1[CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][C:104]([NH:106][NH:107][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:58])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:54]([CH3:57])[CH2:55][CH3:56])[C@H:24]([O:52][CH3:53])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:50][CH3:51])[C@@H:34]([CH3:49])[C:35]([NH:37][CH2:38][CH2:39][C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[NH:42][CH:41]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:105]
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCc1c[nH]c2ccccc12)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCc1c[nH]c2ccccc12)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
38 mg (47 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[2-(1H-indol-3-yl)ethyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide were dissolved in 37 ml of DMF and then admixed with 71 mg (187 μmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 33 μl of N,N-diisopropylethylamine and with 37 mg (140 μmol) of commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide. The mixture was stirred at RT for 1 h. This was followed by concentration under high vacuum and purification of the remaining residue by means of preparative HPLC. Thus, 12.2 mg (26% of theory) of the title compound were obtained as a colourless foam.