Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([O:14][CH2:15][C@H:16]2[CH2:18][O:17]2)[C@H:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]=[CH2:28])=[CH:21][CH:20]=2)[C@@H:10]([O:29][CH2:30][C:31]2[CH:40]=[C:39]([O:41][CH3:42])[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:43][O-:44].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@H:10]([O:29][CH2:30][C:31]2[CH:40]=[C:39]([O:41][CH3:42])[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=2)[C@@H:11]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH:27]=[CH2:28])=[CH:23][CH:24]=2)[C@H:12]([O:14][CH2:15][C@H:16]([OH:17])[CH2:18][O:44][CH3:43])[CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C=CCOc1ccc([C@@H]2[C@@H](OCc3cc(OC)c4ccccc4c3)CN(C(=O)OC(C)(C)C)C[C@H]2OC[C@H]2CO2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc([C@@H]2[C@@H](OCc3cc(OC)c4ccccc4c3)CN(C(=O)OC(C)(C)C)C[C@H]2OC[C@H](O)COC)cc1

Procedure:
In analogy to the procedure described in example 1 (k) the (3R,4R,5S)-4-(4-allyloxy-phenyl)-3-(4-methoxy-naphthalen-2-ylmethoxy)-5-[(2R)-oxiranylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester was treated with sodium methylate in N,N-dimethylformamide to yield the (3S,4R,5R)-4-(4-allyloxy-phenyl)-3-[(2R)-2-hydroxy-3-methoxy-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as colorless oil; MS: 608 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[N:23][N:22]([CH:25]([CH3:29])[C:26](=O)[CH3:27])[C:21]4=[O:30])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:31][C@@H:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH2:33].S1C=CC=C1>C1COCC1.[Pd]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH:24]=[N:23][N:22]([CH:25]([CH3:29])[CH:26]([NH:33][CH:32]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH3:31])[CH3:27])[C:21]4=[O:30])=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CC(=O)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: c1ccsc1
Product: CC(NC(C)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O)c1ccccc1
Reaction time: 48 h

Procedure:
A mixture of (±)-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-(1-methyl-2-oxopropyl)-3H-1,2,4-triazol-3-one (0.05 mol) and (−)-(S)-α-methyl-benzenemethanamine (0.1 mol) in THF (500 ml) was hydrogenated at 50° C. for 48 hours with Pd/C 10% (3 g) as a catalyst in the presence of titanium(VI) n-butoxide (28.4 g) and thiophene solution (3 ml). The catalyst was filtered off. Pd/C 10% (10 g) and thiophene solution (10 ml) were added again. Hydrogenation was continued at 50° C. for 48 hours. After uptake of H2, the catalyst was filtered off and the filtrate was evaporated. The residue was stirred in CH2Cl2, CH3OH and H2O. The mixture was alkalized with NaOH and filtered over dicalite. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was triturated in DIPE, filtered off and dried, yielding 19 g (74%) of [(R*,R*)(S)+(R*,S*)(S)]-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-[2-[(1-phenylethyl)amino)-1-methylpropyl]-3H-1,2,4-triazol-3-one (interm. 2).
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH2:14][S:15][C:16]1[O:17][CH:18]=[CH:19][N:20]=1.[Br:22]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:22][C:18]1[O:17][C:16]([S:15][CH2:14][C:5]2[C:6]([C:10]([F:12])([F:13])[F:11])=[N:7][N:8]([CH3:9])[C:4]=2[O:3][CH:2]([F:1])[F:21])=[N:20][CH:19]=1
Reactant: Cn1nc(C(F)(F)F)c(CSc2ncco2)c1OC(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(C(F)(F)F)c(CSc2ncc(Br)o2)c1OC(F)F

Procedure:
2-({[5-(Difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}sulfanyl)-1,3-oxazole (1.24 g, 4 mmol) is initially charged in 20 ml of dimethylformamide. N-Bromosuccinimide (0.892 g, 5 mmol) is then added a little at a time with stirring. The mixture is stirred at 40° C. for a further 6 hours. For work-up, the reaction mixture is added to water and extracted twice with dichloromethane, and the extracts are then washed with water and finally with saturated NaCl solution. The combined organic phases are dried over magnesium sulfate, filtered off and concentrated. The crude product is purified chromatographically (heptane:ethyl acetate, gradient 10:0 to 7:3). This gives 0.70 g of product (43.2% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].P(Cl)(Cl)([Cl:18])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=c1[nH]cnc2cc(Cl)c([N+](=O)[O-])cc12
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1Cl

Procedure:
7-Chloro-6-nitro-quinazolin-4-one (1.002 g, 4.44mmol), phosphorous oxychloride (11.5 g, 7.51 mmol) and phosphorous pentachloride (1.62 g, 7.74 mmol) were refluxed for 2 hours and the reaction mixture was concentrated in vacuo to a residue which was triturated with toluene and then again with chloroform and dried in vacuo to afford crude 4,7-dichloro-6-nitro-quinazoline. This was dissolved in 35 mL of isopropyl alcohol and 3-ethynylaniline (639 mg, 5.45 mmol) and refluxed for 3 hours. The cooled reaction mixture was filtered to afford the title product as a solid which was washed with 10 mL of isopropyl alcohol and dried in vacuo at 70° C., 1.055 g (66%); mp 230.8°-232.6° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH2:8][CH2:9][N:10]([CH3:15])[CH2:11][C:12]=3[C:13]=2[CH:14]=1.Br[CH:17]=[C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C.O>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]([CH3:19])=[CH:17][N:6]2[C:5]3[N:4]=[CH:3][C:2]([CH3:1])=[CH:14][C:13]=3[C:12]3[CH2:11][N:10]([CH3:15])[CH2:9][CH2:8][C:7]2=3)=[CH:21][CH:22]=1
Reactant: CC(=CBr)c1ccc(F)cc1
Reactant: Cc1cnc2[nH]c3c(c2c1)CN(C)CC3
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=Cn1c2c(c3cc(C)cnc31)CN(C)CC2)c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a degassed solution of 3,6-dimethyl-6,7,8,9-tetrahydro-5H-1,6,9-triaza-fluorene (201 mg, 1.0 mmol), 1-(2-bromo-1-methyl-vinyl)-4-fluoro-benzene (279 mg, 1.3 mmol), potassium phosphate (530 mg, 2.5 mmol) in DMF (4 mL), L-proline (28 mg, 0.25 mmol) and cuprous iodide (47 mg, 0.25 mmol) were added. The reaction mixture was stirred at 120° C. for 8 h. The reaction mixture was cooled to RT, diluted with water (20 mL) and extracted with EtOAc (4×20 mL). The organic layer was washed with water (5×20 mL), dried over anhydrous sodium sulfate and evaporated to afford crude material, which was purified by silica gel flash chromatography to yield 9-[2-(4-fluoro-phenyl)-propenyl]-3,6-dimethyl-6,7,8,9-tetrahydro-5H-1,6,9-triaza-fluorene. 1H NMR (CDCl3, freebase) δ (ppm): 8.1 (s, 1H), 7.57 (m, 3H), 7.07 (t, 2H), 6.92 (s, 1H), 3.62 (s, 2H), 2.8 (s, 4H), 2.6 (s, 3H), 2.4 (s, 3H), 2.0 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:8][CH:7]=1)=O.NC1C=CC=C2C=1N=CC=C2C1C=CC=CC=1.[As](=O)(O)(O)O.[N+:41]([C:44]1[CH:45]=[CH:46][CH:47]=[C:48]2[C:53]=1[N:52]=[CH:51][CH:50]=[C:49]2[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([O-])=O>P(=O)(O)(O)O>[C:54]1([C:49]2[C:48]3[C:53]([N:52]=[CH:51][CH:50]=2)=[C:44]2[C:45]([C:4]([C:6]4[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:8][CH:7]=4)=[CH:3][CH:2]=[N:41]2)=[CH:46][CH:47]=3)[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: O=C(CCCl)c1ccc(CCCCCCO)cc1
Reactant: O=[N+]([O-])c1cccc2c(-c3ccccc3)ccnc12
Agent: Nc1cccc2c(-c3ccccc3)ccnc12
Agent: O=P(O)(O)O
Agent: O=[As](O)(O)O
Product: OCCCCCCc1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1

Procedure:
The procedure followed was similar to that of Case and Strohm (Case, F. H.; Strohm, P. F. J. Org. Chem, 1962, 27, 1641-1643). 3-Chloro-1-[4-(6-hydroxyhexyl)phenyl]propan-1-one (0.73 g), 8-amino-4-phenylquinoline (0.27 g), arsenic acid (0.99 g) and 85% phosphoric acid (10 mL) were reacted as described in the procedure for the synthesis of 8-nitro-4-phenylquinoline. However during precipitation of the crude product, a pH of 6-8 was maintained in order to ensure that the alcohol functionality remained protonated. The crude product was re-crystallized with a 50:50 mixture of petroleum ether and chloroform. Further purification of the desired product was achieved using preparatory TLC with 2% methanol and 98% chloroform.
Reaction SMILES: [Mg].[CH2:2](Br)[C:3]#[CH:4].[CH3:6][C:7](=[O:12])[C:8]#[C:9][CH2:10][CH3:11].S(=O)(=O)(O)O>C1C=CC=CC=1.CCOCC>[CH3:6][C:7]([OH:12])([C:8]#[C:9][CH2:10][CH3:11])[CH2:4][C:3]#[CH:2]
Reactant: CCC#CC(C)=O
Reactant: C#CCBr
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CCOCC
Product: C#CCC(C)(O)C#CCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution consisting of 6.06 parts of magnesium, 15 parts by volume of ether and 0.06 part of mercuric chloride, stirred at room temperature in an atmosphere of nitrogen, was added 0.5 part by volume of a solution consisting of 29.74 parts of propargyl bromide and 70 parts by volume of ether. The resulting mixture was then cooled to -10° to -15° and the remaining propargyl bromide solution was slowly added over a period of 45 minutes. At the end of the addition period, stirring was continued at -10° for about 15 minutes longer. To that mixture was then added, with stirring, over a period of 45 minutes at -3° to -5°, a mixture consisting of 22 parts of 3-hexyn-2-one and 60 parts by volume of benzene. At the end of the addition period, stirring was continued for about 20 minutes at -3°, and the reaction mixture was then poured carefully into cold dilute sulfuric acid. The aqueous phase was separated, extracted with ether and the combined ether extracts were washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. Vacuum distillation of the residue afforded 4-methyl-1,5-octadiyn-4(RS)-ol, characterized by infrared absorption maxima of about 3620, 3330, 2250, 1385, 1355, 1085, 940, and 770 cm.-1.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([N:5]=[C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:9]=[C:8]([CH3:21])[S:7]1)=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:33]2)=CC=1>C1COCC1>[F:1][C:2]([F:23])([F:22])[C:3]([N:5]=[C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:9]=[C:8]([CH3:21])[S:7]1)=[S:33]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=O)C(F)(F)F)s1
Solvent: C1CCOC1
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=S)C(F)(F)F)s1
Yield: 47.8 %

Procedure:
A solution of 2-(trifluoroacetyl)imino-3-[3-(trifluoromethyl)phenyl]-5-methylthiazoline (1 g) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (2 g) in THF (10 ml) was refluxed for 2 days. After cooling and removal of the solvent under reduced pressure, the concentrated residue was added pottasium hydrogencarbonate, The obtained crystallines were recrystallized to give 0.5 g of 2-[trifluoromethyl(thiocarbonyl)imino]-3-[3-(trifluoromethyl)phenyl]-5-methylthiazoline (Compound No. 2)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:23])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1)[CH2:7][CH2:6][CH2:5]2.[NH2:24][C:25]1[C:30]([Cl:31])=[CH:29][C:28]([S:32](Cl)(=[O:34])=[O:33])=[CH:27][C:26]=1[Cl:36]>N1C=CC=CC=1>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][C:12]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([NH:1][S:32]([C:28]4[CH:29]=[C:30]([Cl:31])[C:25]([NH2:24])=[C:26]([Cl:36])[CH:27]=4)(=[O:34])=[O:33])=[CH:11][CH:10]=3)[CH2:5][CH2:6][CH2:7]2)=[O:23])=[CH:20][CH:19]=1)#[N:22]
Reactant: N#Cc1ccc(CCC(=O)N2CCCc3cc(N)ccc32)cc1
Reactant: Nc1c(Cl)cc(S(=O)(=O)Cl)cc1Cl
Solvent: c1ccncc1
Product: N#Cc1ccc(CCC(=O)N2CCCc3cc(NS(=O)(=O)c4cc(Cl)c(N)c(Cl)c4)ccc32)cc1

Procedure:
1.0 g 6-amino-1-[3-(4-cyano-phenyl)propionyl]-1,2,3,4-tetrahydro-quinoline (see Example, 5) are dissolved in 8 ml of pyridine, combined with 1 g of 4-amino-3,5-dichloro-phenylsulphonic acid chloride in batches and then heated for 40 minutes to 100° C. Then the solvent is eliminated, the residue is triturated with 1N hydrochloric acid and extracted with methylene chloride. The organic phase is dried over sodium sulphate and concentrated by evaporation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@:20]([CH3:27])([C:24]([OH:26])=O)[CH2:19]4)[C:14]([F:28])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.F[P-](F)(F)(F)(F)F.[N:36]1([O+]=C(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.N>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@:20]([CH3:27])([C:24]([NH2:36])=[O:26])[CH2:19]4)[C:14]([F:28])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C[C@@]1(C(=O)O)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: CN(C)C(=[O+]n1nnc2ccccc21)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@@]1(C(N)=O)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-1-methyl-cyclohexanecarboxylic acid, 826, (0.050 g, 0.108 mmol), benzotriazol-1-yl-[bis(dimethylamino)methylene]oxonium hexafluorophosphate (0.081 g, 0.216 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.075 mL, 0.432 mmol) were combined in 5 mL of THF. To the reaction was then added ammonia hydrochloride (0.002 g, 0.032 mmol) and the reaction was allowed to stir overnight at room temperature. After concentration under reduced pressure, the mixture was purified by reverse phase HPLC chromatography, yielding 3.3 mg of desired product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCOC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCOC(=O)N1CCNCC1
Reaction time: 12 h

Procedure:
To a solution of 18.0 g piperazine-1,4-dicarboxylic acid butyl ester tert-butyl ester in 70 ml dichloromethane were added 23 ml TFA. After stirring for 12 h the solution was concentrated and the residue codistilled with toluene twice. Yield: 18.5 g.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH:7]=[CH:6][CH2:5][N:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]1=[O:17].[Cl:18][C:19]1[CH:35]=[CH:34][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH2:10]([O:9][N:4]1[CH2:5][CH:6]=[CH:7][CH2:8][C@@H:2]([NH:1][S:30]([C:27]2[CH:28]=[CH:29][C:24]([O:23][C:22]3[CH:34]=[CH:35][C:19]([Cl:18])=[CH:20][CH:21]=3)=[CH:25][CH:26]=2)(=[O:31])=[O:32])[C:3]1=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: N[C@@H]1CC=CCN(OCc2ccccc2)C1=O
Solvent: c1ccncc1
Product: O=C1[C@H](NS(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CC=CCN1OCc1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 57.9 %

Procedure:
To a solution of 3.69 g of 3-(R)-amino-1-benzyloxy-1,3,4,7-tetrahydro-azepin-2-one from Step D in 30 mL of pyridine was added 6.28 g of 4-(4-chloro-phenoxy)-benzene sulfonyl chloride. The reaction was stirred at room temperature for 5 days. The reaction was extracted with ethyl acetate, and washed with 5% HCl (aq.) twice, NaHCO3 (aq.) twice, and NaCl (aq.) once. The aqueous layers were re-extracted with ethyl acetate, and the organic layers combined and dried over Na2SO4(s). The reaction mixture was filtered and the solvent removed. The mixture was dissolved in dichloromethane, and filtered over silica gel. The dichloromethane layer was discarded. The silica gel was eluted with ethyl acetate, and the solvent removed under vacuum. Next, ethyl ether was added, and the solids collected under vacuum. The solids were washed with ethyl ether, and dried. Obtained 4.59 g of a white solid. MS: 521 (M+Na), 499 (M+H).
Reaction SMILES: O.[NH2:2][NH2:3].[NH2:4][C:5]1[N:6]=[CH:7][C:8]([C:20]#[N:21])=[N:9][C:10]=1[C:11]1[O:12][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[N:14][N:15]=1>CC(O)C>[NH2:4][C:5]1[N:6]=[CH:7][C:8](/[C:20](=[N:2]/[NH2:3])/[NH2:21])=[N:9][C:10]=1[C:11]1[O:12][C:13]([C:16]([CH3:18])([CH3:17])[CH3:19])=[N:14][N:15]=1
Reactant: NN
Reactant: CC(C)(C)c1nnc(-c2nc(C#N)cnc2N)o1
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)c1nnc(-c2nc(/C(N)=N/N)cnc2N)o1
Temperature: 50 °C
Yield: 79.1 %

Procedure:
Hydrazine hydrate (82 mL, 1.69 mol) was added to 5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazine-2-carbonitrile (55 g, 225.18 mmol) in IPA (200 mL) and the mixture was heated at 50° C. under nitrogen for 16 hours. The mixture was cooled in an ice bath. The resulting precipitate was collected by filtration, washed with IPA and diethyl ether and dried to a constant weight to afford (Z)-5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazine-2-carbohydrazonamide (49.2 g, 79%) as a yellow solid: 1H NMR Spectrum: (DMSO-d6) 1.45 (9H, s), 5.26 (2H, s), 5.58 (2H, s), 7.56 (2H, s), 8.75 (1H, s); Mass Spectrum [M+H]+=277.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[C:19]([CH:20]([NH:32][C:33]([N:35]3[CH2:40][CH2:39][CH:38]([N:41]4[CH2:50][C:49]5[C:44](=[C:45]([F:51])[CH:46]=[CH:47][CH:48]=5)[NH:43][C:42]4=[O:52])[CH2:37][CH2:36]3)=[O:34])[CH2:21][C:22]3[CH:23]=[C:24]4[C:28](=[C:29]([CH3:31])[CH:30]=3)[NH:27][N:26]=[CH:25]4)=[N:18][N:17]=[N:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[F:51][C:45]1[CH:46]=[CH:47][CH:48]=[C:49]2[C:44]=1[NH:43][C:42](=[O:52])[N:41]([CH:38]1[CH2:37][CH2:36][N:35]([C:33]([NH:32][CH:20]([C:19]3[N:15]([CH2:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[N:16]=[N:17][N:18]=3)[CH2:21][C:22]3[CH:23]=[C:24]4[C:28](=[C:29]([CH3:31])[CH:30]=3)[NH:27][N:26]=[CH:25]4)=[O:34])[CH2:40][CH2:39]1)[CH2:50]2
Reactant: Cc1cc(CC(NC(=O)N2CCC(N3Cc4cccc(F)c4NC3=O)CC2)c2nnnn2CC2CCN(C(=O)OC(C)(C)C)CC2)cc2cn[nH]c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4cccc(F)c4NC3=O)CC2)c2nnnn2CC2CCNCC2)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl-4-({5-(1-[4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3[4H]-yl)piperidine-1-carboxamido]-2-(7-methyl-1H-indazol-5-yl)ethyl)-1H-tetrazol-1-yl}methyl)piperidine-1-carboxylate (10 mg, 0.014 mmol) was dissolved in a 1:1 mixture of trifluoroacetic acid and methylene chloride (1.0 mL) and stirred at room temperature for 30 min. The solvent was removed under reduced pressure and the compound dried in vacuo for 2 h to afford 5.9 mg (68%). 1H-NMR (CD3OD, 500 MHz) δ 1.20-1.48 (m, 4H), 1.50-1.79 (m, 5H) 2.24 (dd, J=12.5, 8.6, 1H), 2.50 (s, 3H), 2.57 (dd, J=11.6, 11.3, 1H), 3.18 (bs, 2H), 3.47 (s, 1H), 4.01-4.40 (m, 7H), 5.29 (dd, J=8.2, 7.9, 1H), 6.90-7.15 (m, 4H), 7.37 (s, 1H), 7.98 (s, 1H), 8.00 (s, 1H). Mass spec.: 616.20 (MH)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)#[N:22]>>[CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:21]#[N:22])[CH:9]=2)[C:4](=[O:19])[CH2:3]1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: N#Cc1ccccc1B(O)O
Product: CC1(C)CC(=O)c2ccc(-c3ccccc3C#N)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 2-cyanophenyl boronic acid according to the procedure described in example 21. MS (ESI) m/z 262; HRMS: calcd for C18H15NO+H+, 262.12264; found (ESI, [M+H]+), 262.1234.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[O:8]1[CH2:12]CC[CH2:9]1.CC(C)([O-])C.[K+].COCCl>CN(C)C=O>[CH3:9][O:8][CH2:12][O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccnc1
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: COCCl
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOc1cccnc1
Reaction time: 0.42 h
Yield: 75 %

Procedure:
To a mixture of 3-hydroxypyridine (50.0 g, 0.525 mol), tetrahydrofuran (107 mL) and N,N-dimethylformamide (285 mL), potassium t-butoxide (65 g, 0.579 mol) was added at −15° C. After 25 minutes, chloromethyl methyl ether (44.4 g, 0.552 mol) was slowly added at −15° C. The reaction temperature was elevated over 2 hours and the reaction mixture was concentrated. The resulting oil was poured into saturated aqueous sodium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50) to give 3-(methoxymethoxy)pyridine (54.7 g, 75%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:22]5[CH2:26][CH2:25][CH2:24][CH2:23]5)[CH:16]=4)[C:4]=2[C:3]=1[CH3:27])[CH:12]=[CH:11][CH:10]=[CH:9]3.Cl[S:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[C:34]([OH:41])[CH:33]=1)(=[O:31])=[O:30]>>[CH:22]1([C:17]2[CH:16]=[C:15]([C:14]3[C:4]4[C:3]([CH3:27])=[C:2]([CH3:1])[S:6][C:5]=4[CH:7]=[C:8]4[C:13]=3[CH:12]=[CH:11][CH:10]=[CH:9]4)[CH:20]=[CH:19][C:18]=2[O:21][S:29]([C:32]2[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[C:34]([OH:41])[CH:33]=2)(=[O:31])=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: Cc1sc2cc3ccccc3c(-c3ccc(O)c(C4CCCC4)c3)c2c1C
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: Cc1sc2cc3ccccc3c(-c3ccc(OS(=O)(=O)c4ccc(C(=O)O)c(O)c4)c(C4CCCC4)c3)c2c1C

Procedure:
Using 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenol and 4-chlorosulphonyl-2-hydroxybenzoic acid the title compound was prepared according to the procedure in Example 1, step 9. Purification on 2% H3PO4 /MeOH treated silica gel eluting with a 0 & 10% EtOAc/hexane step gradient gave 0.66 g of the title compound as a pale yellow solid, mp 230-237° C.; 1H NMR (DMSO-d6) δ 1.30-1.35 (m, 2 H), 1.45-1.52 (m, 5 H), 1.58-1.63 (m, 3 H), 2.40 (s, 2 H), 3.05 (q, 1 H), 7.21-7.29 (m, 4 H), 7.35-7.47 (m, 4 H), 7.97 (d, 1 H), 8.03 (d, 1 H), 8.49 (s, 1 H). IR (KBr) 2950, 1675, 1390, 1190 and 850 cm-1. mass spectrum (-ESI), m/z 571 (M-H). Anal. Calcd. for C32H28O6S2.0.2H2O: C, 66.69; H, 4.97 N, 0.00. Found: C, 66.69; H, 5.01 N, 0.03.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([CH3:15])=[C:10]([C:16]3[C:17](=[O:29])[NH:18][C:19]4([CH2:26][CH2:25][N:24]([O:27][CH3:28])[CH2:23][CH2:22]4)[C:20]=3[OH:21])[CH:9]=2)=[CH:4][CH:3]=1.[C:30](Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].N1C=CC=CC=1.Cl>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([CH3:15])=[C:10]([C:16]3[C:17](=[O:29])[NH:18][C:19]4([CH2:22][CH2:23][N:24]([O:27][CH3:28])[CH2:25][CH2:26]4)[C:20]=3[O:21][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CON1CCC2(CC1)NC(=O)C(c1cc(-c3ccc(Cl)cc3)c(F)cc1C)=C2O
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CON1CCC2(CC1)NC(=O)C(c1cc(-c3ccc(Cl)cc3)c(F)cc1C)=C2OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(4′-chloro-6-fluoro-4-methyl-biphenyl-3-yl)-4-hydroxy-8-methoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one (170 mg) and pivaloyl chloride (98 mg) in acetonitrile (5 ml) was added pyridine (64 mg) and the reaction mixture stirred at room temperature for 8 hours. The mixture was poured on diluted HCl and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with heptane, filtered and dried. Yield: 100 mg of 2,2-dimethyl-propionic acid 3-(4′-chloro-6-fluoro-4-methyl-biphenyl-3-yl)-8-methoxy-2-oxo-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester (title compound A82) as a solid, mp: 150-151° C.