Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C(O)=C(OC)C(OC(F)F)=CC=1.C(=O)([O-])[O-].[K+].[K+].C(Br)C.Br[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]([F:34])[F:33])=[C:27]([O:35][CH3:36])[C:26]=1[O:37][CH2:38][CH3:39].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:54]2[CH:55]=[C:56]3[C:60](=[CH:61][CH:62]=2)[C:59](=[O:63])[NH:58][CH2:57]3)O1>C(#N)C.CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:33][CH:32]([F:34])[O:31][C:28]1[CH:29]=[CH:30][C:25]([C:54]2[CH:55]=[C:56]3[C:60](=[CH:61][CH:62]=2)[C:59](=[O:63])[NH:58][CH2:57]3)=[C:26]([O:37][CH2:38][CH3:39])[C:27]=1[O:35][CH3:36]
Reactant: CCOc1c(Br)ccc(OC(F)F)c1OC
Reactant: CC1(C)OB(c2ccc3c(c2)CNC3=O)OC1(C)C
Agent: [Pd]
Agent: COc1c(OC(F)F)ccc(Br)c1O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCBr
Solvent: CC#N
Product: CCOc1c(-c2ccc3c(c2)CNC3=O)ccc(OC(F)F)c1OC
Temperature: 80 °C
Yield: 12.8 %

Procedure:
To a stirring solution of 6-bromo-3-(difluoromethoxy)-2-methoxyphenol (200 mg, 0.74 mmol) in acetonitrile (10 mL) was added potassium carbonate (307 mg, 2.23 mmol) and ethyl bromide (0.6 mL, 2.23 mmol) and the resultant reaction mixture was heated to 80° C. for 2 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure to afford 200 mg of crude product, 1-Bromo-4-difluoromethoxy-2-ethoxy-3-methoxy-benzene, as a solid. A stirring solution of 1-bromo-4-(difluoromethoxy)-2-ethoxy-3-methoxybenzene (200 mg, 0.673 mmol) in N,N-dimethylformamide (5 mL) was purged with argon for 1 h, to this cesium carbonate (656 mg, 2.019 mmol), tetrakis(triphenylphosphine) palladium(0) (38 mg, 0.033 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (209 mg, 0.807 mmol) were added and the resultant reaction mixture was heated to 80-90° C. for 3 h. The reaction mixture was cooled to RT, filtered and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded the title compound as a solid (30 mg, 13%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:20][CH2:21][CH2:22][O:23][C:24](Cl)=[O:25].O>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:24](=[O:25])[O:23][CH2:22][CH2:21][Cl:20])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)OCCCl
Reactant: NCCCN1CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCCN1CCN(Cc2ccccc2)CC1)OCCCl
Reaction time: 24 h

Procedure:
To a stirred solution of 3-(4-benzyl-1-piperazinyl)propylamine (2.01 g/8.61 mmol) in tetrahydrofuran (15 ml) were added 2 N NaOH (6.5 ml/13.0 mmol) and 2-chloroethylchloroformate (1.38 ml/12.9 mmol), and the mixture was stirred for 1 d. Water (50 ml) was added to the mixture and the whole was extracted with ethyl acetate (50 ml). The extract was washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (NH2 gel/dichloromethane) to give a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=O)=[CH:4][N:3]=1.[NH:16]1[CH2:19][CH2:18][CH2:17]1>>[N:16]1([C:13]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][C:7]=3[CH3:12])[C:2]([Cl:1])=[N:3][CH:4]=2)=[O:15])[CH2:19][CH2:18][CH2:17]1
Reactant: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Reactant: C1CNC1
Product: Cc1cccc2c(Cl)ncc(C(=O)N3CCC3)c12

Procedure:
The title compound was prepared by using 1-chloro-5-methylisoquinolin-4-carboxylic acid (Intermediate-10) and azetidine by following the similar procedure as described for intermediate-11a.
Reaction SMILES: [C:1]([NH:4][C:5](=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:12]=1[O:19][CH2:20][C@H:21]([NH:34]C(OC(C)(C)C)=O)[CH2:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].[ClH:42]>O1CCOCC1>[ClH:42].[C:1]([NH:4][C:5](=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:12]=1[O:19][CH2:20][C@H:21]([NH2:34])[CH2:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)C(=Cc1ccc(C#N)cc1OC[C@@H](CCC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)NC(C)=O
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C(=Cc1ccc(C#N)cc1OC[C@H](N)CCC(=O)OCc1ccccc1)NC(C)=O

Procedure:
5 g of methyl 2-acetamido-3-[2-[(2R)-4-benzyloxycarbonyl-2-(t-butoxycarbonylamino)butoxy]-4-cyanophenyl]acrylate was stirred in 50 ml of dioxane containing 4 M of hydrogen chloride for 2 hours. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][OH:14])=[CH:4][CH:3]=1.[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][O:14][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][O:15]2)=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: OCCc1ccc(Br)c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Brc1ccc(CCOC2CCCCO2)c2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.1 %

Procedure:
To a solution of 1-bromo-4-(2-hydroxyethyl)naphthalene (1.71 g, 6.8 mmol) in dichloromethane (20 mL) was added 3,4-dihydro-2H-pyrane (1 mL, 0.92 g, 11.0 mmol) and p-toluene sulfonic acid (80 mg). The mixture was stirred at room temperature for 90 min, diluted with dichloromethane (20 mL), washed with satd. NaHCO3 sol. (20 mL), dried (MgSO4), and concentrated. Flash chromatography using hexane/ethyl acetate 9:1 as eluent provided 1.69 g (75%) of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:18]([CH3:19])=[N:17][N:16]([CH3:20])[C:10]=2[N:11]=[C:12](S)[CH2:13][N:14]=1.O1CCCC1.[CH2:26]([NH2:29])[C:27]#[CH:28]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:18]([CH3:19])=[N:17][N:16]([CH3:20])[C:10]=2[N:11]=[C:12]([NH:29][CH2:26][C:27]#[CH:28])[CH2:13][N:14]=1
Reactant: C#CCN
Reactant: Cc1nn(C)c2c1C(c1ccccc1Cl)=NCC(S)=N2
Solvent: C1CCOC1
Solvent: CO
Product: C#CCNC1=Nc2c(c(C)nn2C)C(c2ccccc2Cl)=NC1

Procedure:
A mixture of 4.65 g. of 4-(2-chlorophenyl)-1,6-dihydro-1,3-dimethylpyrazolo[3,4-e][1,4]diazepine-7-thiol (prepared as disclosed in U.S. Pat. No. 3,770,762), 250 ml. of tetrahydrofuran, 3.0 g. of 2-propynylamine and 20 ml. of methanol is allowed to stand at room temperature (20°-30° C.) for 3 days, then evaporated at reduced pressure to give a residue of 4-(2-chlorophenyl-1,6-dihydro-1,3-dimethyl-7-(2-propynylamino)pyrazolo[3,4-e][1,4]diazepine; m.p. 165°-167° C. after crystallization from acetonitrile. For further purification, the product is dissolved in 9:1 tolueneacetonitrile and chromatographed on a column of neutral alumina. The column is eluted with 9:1 methanol-acetonitrile and the eluate is evaporated at reduced pressure to give a residue of m.p. 176°-178° C. (dec.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[C:15]([NH:18][CH2:19][CH2:20][NH2:21])(=[O:17])[CH3:16].C(N(CC)C(C)C)(C)C>C(O)CC>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=[C:2]([NH:21][CH2:20][CH2:19][NH:18][C:15](=[O:17])[CH3:16])[CH:7]=1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Reactant: CC(=O)NCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCO
Product: CC(=O)NCCNc1cc(Cl)nc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 94 %

Procedure:
4,6-Dichloro-2-phenylpyrimidine (3) (5.59 g), N-acetylethylenediamine (2.79 g) and N,N-diisopropylethylamine (3.53 g) were added to propan-1-ol (50 ml). A calcium drying tube was fitted and the resulting suspension heated to reflux for 34 hrs, then left to cool to ambient temperature. The resulting solution was evaporated in vacuo onto silica gel (40 g) and purified by flash chromatography eluting with ethyl acetate then a mixture of ethyl acetate and methanol (10:1 v/v) to furnish the title compound (6.79 g).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[NH:15]([C:22]1[CH:30]=[C:29]([C:31](O)=[O:32])[C:28]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:27][C:23]=1[C:24](O)=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C)C=CC(NC2C=C(C(O)=O)C(NC3C=CC(C)=CC=3)=CC=2C(O)=O)=CC=1>>[CH:38]1[CH:39]=[C:40]2[C:31]([C:29]3[C:28]([NH:34][C:35]2=[CH:36][CH:37]=1)=[CH:27][C:23]1[C:24]([C:21]2[C:16]([NH:15][C:22]=1[CH:30]=3)=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:25])=[O:32]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)cc3)cc2C(=O)O)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 85 °C

Procedure:
382 parts of polyphosphoric acid, containing 85.0% P2O5, are introduced into a pressure vessel. Then 68.8 parts of 2,5-dianilinoterephthalic acid and 7.6 parts of 2,5-di(4-toluidino)terephthalic acid are introduced with stirring at from 80 to 90° C. and the mixture is heated at 125° C. for 1 hour during which ring closure takes place to form the quinacridone. The reaction mixture is then introduced into a second pressure vessel where it is hydrolyzed under pressure and with stirring with a mixture of 1719 parts of 30% phosphoric acid at 140° C. During this hydrolysis the temperature rises to 155° C. The mixture is stirred at 155° C. for 0.5 hour. Then it is cooled to 60° C. and the mixed crystal prepigment is filtered off with suction and washed to neutrality with water.
Reaction SMILES: C(C1C=CC=CC=1C([NH:8][CH:9]1[C:40](=[O:41])[N:11]2[C:12]([C:24]([O:26][CH:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[C:13]([CH2:16][S:17][C:18]3[S:19][C:20]([CH3:23])=[N:21][N:22]=3)[CH2:14][S:15][C@H:10]12)=O)(O)=O.C(N(CC)CC)C.ClC(OCC)=O.CNN>O1CCCC1>[NH2:8][CH:9]1[C:40](=[O:41])[N:11]2[C:12]([C:24]([O:26][CH:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[C:13]([CH2:16][S:17][C:18]3[S:19][C:20]([CH3:23])=[N:21][N:22]=3)[CH2:14][S:15][C@H:10]12
Reactant: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)c4ccccc4C(=O)O)[C@H]3SC2)s1
Agent: CCOC(=O)Cl
Agent: CNN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3SC2)s1
Reaction time: 0.33 h

Procedure:
A solution of benzhydryl 7-(2-carboxybenzamido)-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate (2 mmol.) in 30 ml. of dry tetrahydrofuran is cooled in an ice-salt bath, and 0.28 ml. (2 mmol.) of triethylamine and 0.20 ml. (2 mmol.) of ethyl chloroformate are added. After cooling and stirring for 20 minutes, 0.106 ml. (2 mmol.) of N-methylhydrazine in 5 ml. of tetrahydrofuran is added. Stirring is continued for about 10 minutes. The Et3N.HCl salt is filtered, and the filtrate is evaporated to dryness. The residue is taken up in about 15 ml. of chloroform, and the mixture is allowed to stand at room temperature for about one hour during which time methylphthalhydrazide (m.p. 243°-245° C.) precipitates. Filtration and evaporation in vacuo of the filtrate gives crude benzhydryl 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH2:7])[CH3:2].Br[CH2:12][CH:13]1[O:17][CH2:16][CH2:15][O:14]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH:7][CH2:12][CH:13]1[O:17][CH2:16][CH2:15][O:14]1)[CH3:2]
Reactant: BrCC1OCCO1
Reactant: CCOC(CCN)OCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(CCNCC1OCCO1)OCC
Temperature: 25 °C

Procedure:
3,3-Diethoxypropylamine (0.11 mole), 2-bromomethyl-1,3-dioxolane (0.1 mole), triethylamine (20 ml) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction is heated at reflux for a period of about 12 hours. After this time the reaction mixture is allowed to cool to room temperature and is filtered. The reaction mixture is then stripped of solvent and unreacted starting materials under reduced pressure to yield the desired product N-(3,3-diethoxypropyl)-N-(1,3-dioxolan-2-ylmethyl)amine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9](P(OC)(OC)=O)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N12CCCN=C1CCCCC2.[C:31]([N:35]1[C:39](=[O:40])[CH2:38][CH:37]([C:41]2[CH:48]=[CH:47][C:44]([CH:45]=O)=[CH:43][C:42]=2[F:49])[S:36]1(=[O:51])=[O:50])([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8]/[C:9](=[CH:45]\[C:44]1[CH:47]=[CH:48][C:41]([CH:37]2[S:36](=[O:51])(=[O:50])[N:35]([C:31]([CH3:32])([CH3:34])[CH3:33])[C:39](=[O:40])[CH2:38]2)=[C:42]([F:49])[CH:43]=1)/[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)P(=O)(OC)OC
Reactant: CC(C)(C)N1C(=O)CC(c2ccc(C=O)cc2F)S1(=O)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)/C(=C/c1ccc(C2CC(=O)N(C(C)(C)C)S2(=O)=O)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
Methyl [(tert-butoxycarbonyl)amino](dimethoxyphosphoryl)acetate (3.53 g, 11.9 mmol) in methylene chloride (180 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.92 mL, 12.9 mmol). After five minutes 4-(2-tert-butyl-1,1-dioxido-3-oxoisothiazolidin-5-yl)-3-fluorobenzaldehyde (3.1 g, 9.9 mmol) was added and the solution stirred at rt for 1 h. The solution was diluted with methylene chloride (50 mL), washed with 1 N aqueous hydrochloric acid solution (250 mL), and the organic phase dried over sodium sulfate. Purification by silica gel chromatography (5–25% ethyl acetate:hexanes) afforded product as a white foam (3.7 g, 77%). 1H NMR (400 MHz, CDCl3): δ 7.35–7.29 (m, 3H), 7.17 (s, 1H), 5.04 (dd, J=9.0, 7.1 Hz, 1H), 3.87 (s, 3H), 3.29 (dd, J=17.2, 9.0 Hz, 1H), 3.17 (dd, J=17.2, 7.0 Hz, 1H), 1.65 (s, 9H), 1.39 (s, 9H). LCMS found for C22H30FN2NaO7S (M+Na)+: m/z=507.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([C:36](O)=[O:37])[CH2:32][CH2:31]1)=[O:28].[NH2:39][CH2:40][CH2:41][OH:42].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(=O)([O-])O.[Na+]>[OH:42][CH2:41][CH2:40][NH:39][C:36]([C@H:33]1[CH2:34][CH2:35][C@H:30]([NH:29][C:27]([C:4]2[N:5]([CH3:26])[C:6]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]([CH2:16][C:17](=[O:24])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:8](=[O:25])[C:7]=3[C:3]=2[O:2][CH3:1])=[O:28])[CH2:31][CH2:32]1)=[O:37]
Reactant: NCCO
Reactant: COc1c(C(=O)N[C@H]2CC[C@H](C(=O)O)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C(=O)N[C@H]2CC[C@H](C(=O)NCCO)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of the compound of Example 537 (215 mg, 0.417 mmol), 2-aminoethanol (32.5 μL, 0.542 mmol) and HOBt (84.6 mg, 0.626 mmol) in DMF (5 mL) was added WSCD (120 mg, 0.626 mmol) under ice-cooling, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted twice with ethyl acetate. The extract was combined, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate/methanol=10/0-8/2). Recrystallization of the obtained solid from ethyl acetate-THF gave the title compound (131 mg, 56%) as a white powder.
Reaction SMILES: Cl.[I:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:22][O:23][C:24](=[O:29])[CH2:25][CH2:26][CH2:27]Br>>[CH3:22][O:23][C:24](=[O:29])[CH2:25][CH2:26][CH2:27][N:17]1[CH2:16][CH2:15][N:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][C:6]3[CH:20]=[CH:21][C:3]([I:2])=[CH:4][CH:5]=3)=[CH:13][CH:12]=2)[CH2:19][CH2:18]1
Reactant: COC(=O)CCCBr
Reactant: Ic1ccc(Oc2ccc(N3CCNCC3)cc2)cc1
Agent: Cl
Product: COC(=O)CCCN1CCN(c2ccc(Oc3ccc(I)cc3)cc2)CC1
Yield: 94.6 %

Procedure:
The title compound (300 mg, 85%) was prepared from the compound from step 2 of Example 14 (300 mg, 0.66 mmol) and 4-bromo-butyric acid methyl ester (153 mg, 0.85 mmol) by the procedure described in step 3 of Example 4: MS (ESI) m/z 481 (M+H); 1H NMR (400 MHz, CDCl3) δ 1.86 (m, 2H), 2.36-2.44 (m, 4H), 2.60 (t, J=4.8 Hz, 4H), 3.15 (t, J=4.8 Hz, 4H), 3.68 (s, 3H), 6.70 (s, J=8.8 Hz, 2H), 6.92 (m, 4H), 7.55 (d, J=8.8 Hz, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.[NH2:27][CH:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:29]([OH:33])[C:30]([NH2:32])=[O:31].Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[NH2:32][C:30](=[O:31])[CH:29]([OH:33])[CH:28]([NH:27][C:14]([C@H:9]1[CH2:10][CH2:11][C:12](=[O:13])[N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:16])[CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To the solution of (R)-1-benzyl-5-oxopyrrolidine-2-carboxylic acid (475 mg, 2.167 mmol) in a mixture of 15 ml of THF and 0.5 ml of DMF at 5° C. were successively added 1-hydroxybenzotriazole (365 mg, 2.383 mmol), 3-amino-2-hydroxy-4-phenylbutanamide (421 mg, 2.167 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC; 457 mg, 2.383 mmol) and DIPEA (0.416 mL; 308 mg, 2.383 mmol). After stirring overnight at room temperature the solvent was evaporated under reduced pressure, water was added to the remaining residue and after stirring for 30 minutes at about 5° C. the precipitate was filtered off. Drying under reduced pressure gave the title compound as an off-white powder (786 mg; yield: 92%) which was used without further purification in the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][C:8](=[O:23])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:28][CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>CN(C)C=O>[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][C:8](=[O:23])[CH:7]([CH2:28][CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:24])=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)CC(=O)CCc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(CCO[Si](C)(C)C(C)(C)C)C(=O)CCc1ccc(-c2ccccc2)cc1
Temperature: 70 °C
Yield: 59.1 %

Procedure:
A solution of 5-biphenyl-4-yl-3-oxo-pentanoic acid tert-butyl ester (13.7 g, 42.4 mmol) in dimethylformamide (10 mL) was added dropwise over 20 min to a stirred suspension of sodium hydride (60% mineral oil suspension; 1.78 g, 44.4 mmol) in dimethylformamide (10 mL) at 0° C. under nitrogen. After stirring for 20 min (2-bromoethoxy)-t-butyldimethylsilane (10.0 g, 46.4 mmol) was added dropwise over 20 min at 0° C. then the reaction heated to 70° C. for 2.5 h. On cooling to room temperature the reaction was quenched by careful addition of water (5 mL) then the volatiles evaporated. The residue was partitioned between saturated aqueous ammonium chloride solution (200 mL) and dichloromethane (200 mL) and the phases separated. The aqueous phase was washed with dichloromethane (3×200 mL) then the organic phases combined, washed with brine (200 mL), dried (sodium sulfate) and the solvent evaporated. The residue was chromatographed on silica gel (10% diethyl ether:cyclohexane) to give the title compound (12.1 g, 59%) as colourless oil which was a mixture of diastereomers. LC/MS: 4.70 min; z/e 483, calcd (M+1) 483. 1H NMR (400 MHz: CDCl3): 7.55 (2H), 7.50 (2H), 7.40 (2H), 7.35 (1H), 7.25 (2H), 3.60 (2H), 2.95 (3H), 2.20 (1H minor) 2.0 (1H major), 1.55 (1H), 1.45 (11H), 0.85 (9H), 0.5 (6H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)[CH:4]=[N:3]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[N:16][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)cn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cn1cc(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
A mixture of 2-(1-methyl-1H-pyrazol-4-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine (11.88 g, 40.0 mmol) and NH4Cl (22.4 g, 419 mmol) in EtOH (200 mL) and water (200 mL) was treated portion-wise with iron powder (22.4 g, 401 mmol), stirred for 0.5 h, treated with additional NH4Cl (22.4 g, 419 mmol) and iron powder (22.4 g, 401 mmol) and stirred at RT for 3 h. The solids were removed via filtration through diatomaceous earth and washed with EtOAc and DCM. The filtrate was washed with water, the aqueous layer back-extracted with DCM (4×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (6.4 g, 60%). MS (ESI) m/z: 268.1 (M+H+).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:19](OC2C=CC([N+]([O-])=O)=CC=2)=[O:20])=[CH:5][CH:4]=1.[C:33]([N:40]1[CH2:45][CH2:44][CH2:43][C@@H:42]([NH2:46])[CH2:41]1)([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>CO>[F:31][C:2]([F:1])([F:32])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:19]([NH:46][C@@H:42]2[CH2:43][CH2:44][CH2:45][N:40]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:41]2)=[O:20])=[CH:7][CH:8]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)N2CCc3ccccc3C2c2ccc(C(F)(F)F)cc2)C1

Procedure:
A mixture of 4-nitrophenyl 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (350 mg, 0.79 mmol, example 15) and (R)-1-Boc-3-amino-piperidine (1.6 mL, 7.91 mmol) was subjected to a microwave irradiation at 120° C. for 45 min. Then, MeOH (2 mL) was added to the mixture and the mixture was filtered. The solution mixture was purified by preparative HPLC (10%-100% of MeCN (0.1% TFA)/H2O (0.1% TFA). All fractions of the product were combined, saturated NaHCO3 (1 mL) was added and the solvents were removed. Then, an additional amount of saturated NaHCO3 (10 mL) was added and the aqueous mixture was extracted with EtOAc (2×10 mL). The combined organic extracts were dried over MgSO4 and concentrated to give the title compound as a white solid. MS (ESI, positive ion) m/z: 504 (M+H).