Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]#[N:8].[CH2:9]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[C:19]([O:25][CH3:26])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH:27]1([N+:32]#[C-:33])[CH2:31][CH2:30][CH2:29][CH2:28]1.Cl(O)(=O)(=O)=O>CO>[CH2:9]([O:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]2[NH:1][C:2]3[N:6]([C:33]=2[NH:32][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[N:5]=[CH:4][C:3]=3[C:7]#[N:8])=[C:19]([O:25][CH3:26])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1cc(OCc2ccccc2)ccc1C=O
Reactant: N#Cc1cn[nH]c1N
Reactant: [C-]#[N+]C1CCCC1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CO
Product: COc1cc(OCc2ccccc2)ccc1-c1[nH]c2c(C#N)cnn2c1NC1CCCC1
Reaction time: 15 h
Yield: 41.8 %

Procedure:
To a mixture of 5-amino-1H-pyrazole-4-carbonitrile (193 mg, 1.79 mmol) and 4-(benzyloxy)-2-methoxybenzaldehyde (433 mg, 1.79 mmol) in a vial under nitrogen atmosphere were added methanol (10 mL) followed by cyclopentyl isonitrile (172 mg, 200 μL, 1.79 mmol) and perchloric acid (35.9 mg, 32.1 μL, 0.358 mmol) at RT. Then, the resulting brown solution was stirred for 15 h by which time lot of solids precipitated. These solids were collected by filtration and washed with methanol. After air drying, 320 mg of (42%) 2-(4-benzyloxy-2-methoxyphenyl)-3-(cyclopentylamino)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile, the desired product was isolated as a white solid. LC/MS calcd. for C25H25N5O2 (m/e) 427.5, obsd. 428.1 (M+H, ES+).
Reaction SMILES: [Mg].I[CH3:3].[C:4]1(=[O:19])[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=[CH:5]1.[Cl-].[NH4+]>CCOCC>[CH3:3][CH:17]1[CH2:18][C:4](=[O:19])[CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C1C=CCCCCCCCCCCC=C1
Reactant: CI
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1CCCCCCCCCCC=CC(=O)C1
Reaction time: 0.5 h

Procedure:
To the Grignard reagent prepared from 72 mg (3 mg-atoms) of magnesium and 0.25 ml (4 mMole) of iodomethane in 5 ml of ether was added 50 mg of cuprous iodide, and the mixture was heated at reflux for 5 min. Cyclopentadeca-2,14-dien-1-one (0.44 g; 2 mMole) in 5 ml of ether was then added over a period of 10 min without cooling, and stirring was continued for 30 min at room temperature. The reaction mixture was poured into cold ammonium chloride solution and extracted with ether. The organic layer was washed with water, dried over sodium sulphate, evaporated and distilled to give 0.33 g (69%) of dehydromuscone having b.p. 110°/0.1 Torr;
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Cl:27])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=O)(C)(C)C.C([O:32]C(NC1CCN(S(C2C3C(Br)=CN=CC=3C=CC=2)(=O)=O)C1)=O)(C)(C)C>>[NH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Cl:27])=[CH:20][N:21]=[C:22]([OH:32])[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1.[ClH:27]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Cl)c23)C1
Product: Cl
Product: N[C@H]1CCN(S(=O)(=O)c2cccc3c(O)ncc(Cl)c23)C1

Procedure:
Intermediate 16a was used in the method of Example 6, Step A instead of Intermediate 1, then the resultant was used in the method of Step B in a similar manner, and then the title compound was obtained as hydrochloride according to the method described in Example 7.
Reaction SMILES: [CH3:1][C@@H:2]([NH2:11])[C@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH3:1][C@H:2]1[C@H:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:10][C:13](=[O:15])[NH:11]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@@H](N)[C@H](O)c1ccccc1
Solvent: ClCCl
Product: C[C@@H]1NC(=O)O[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 224 %

Procedure:
To a solution of (1S,2S)-(+)-Norpseudoephedrine (2.00 g, 13.2 mmol) in CH2Cl2 (60 mL) was added under argon Et3N (4.61 mL, 33.1 mmol) at 0° C. Then, triphosgene (1.57 g, 5.29 mmol) dissolved in 20 mL of CH2Cl2 was added slowly, and the temperature was allowed to warm from 0° C. to room temperature. The reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was then quenched by addition of aqueous NH4Cl. The organic layers were separated, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography using EtOAc in heptane from 0% to 100% in order to give the desired product (2.10 g, 89%). LC-MS: [M+H] 178.1; Rt 0.67 min; (LCMS method 2). 1H NMR (400 MHz, DMSO-d6) 7.88 (br s, 1H), 7.50-7.32 (m, 5H), 5.09 (d, 1H), 3.78-3.62 (m, 1H), 1.26 (d, 3H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[NH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[NH2:27]>N1C=CC=CC=1>[NH2:20][C@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[NH:27][C:11]1[CH:12]=[C:13]2[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]2[CH:1]2[CH2:3][CH2:2]2)=[CH:9][C:10]=1[F:15]
Reactant: N[C@@H]1CCCC[C@@H]1N
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Solvent: c1ccncc1
Product: N[C@H]1CCCC[C@H]1Nc1cc2c(cc1F)c(=O)c(C(=O)O)cn2C1CC1
Temperature: 115 °C
Yield: 60.5 %

Procedure:
A mixture of 1.33 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 1.73 g of cis-1,2-diaminocyclohexane in 10 ml of pyridine was heated in an oil bath of 115° C. for 1 hour then filtered while hot. Cooling the filtrate afforded 1.09 g of the desired product, m.p. 270°-274° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]([N+:11]#[C-:12])([CH3:10])([CH3:9])[CH3:8].[Cl:13][C:14]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O>Cl(O)(=O)(=O)=O>[C:7]([NH:11][C:12]1[N:6]2[C:2]([S:3][CH:4]=[CH:5]2)=[N:1][C:16]=1[C:15]1[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:14]=1[Cl:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: [C-]#[N+]C(C)(C)C
Reactant: Nc1nccs1
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)(C)Nc1c(-c2cccc(Cl)c2Cl)nc2sccn12

Procedure:
Compound 28 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 2-aminothiazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) tert-butylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) 2,3-dichlorobenzaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH2:12])=[CH:4][CH:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O.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>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([NH2:12])=[CH:4][CH:3]=2)=[CH:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Nc1ccc(Br)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(N)c3ccccc23)CC1
Temperature: 100 °C

Procedure:
A mixture of 4-bromonaphthalen-1-amine (1.0 g, 4.5 mmol), tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.7 g, 5.4 mmol), Pd(PPh3)4 (26.01 mg, 0.02 mmol) and Na2CO3 (3.34 g, 31.5 mmol) in 10 mL of DMF and 5 mL of water was degassed and purged with nitrogen. The reaction was heated at 100° C. for 5 h, and cooled to room temperature. The reaction mixture was partitioned between EtOAc and water. The combined organic extracts were dried (Na2SO4), concentrated in vacuo and purified by silica gel chromatography (MeOH/DCM: 5/95) to afford tert-butyl-4-(4-aminonaphthalen-1-yl)-5,6-dihydropyridine-1(2H)-carboxylate.
Reaction SMILES: [ClH:1].[OH:2][C@H:3]1[CH2:7][CH2:6][NH:5][C@@H:4]1[C:8]([OH:10])=[O:9].[CH3:11]O>>[ClH:1].[CH3:11][O:9][C:8]([C@@H:4]1[C@@H:3]([OH:2])[CH2:7][CH2:6][NH:5]1)=[O:10]
Reactant: O=C(O)[C@H]1NCC[C@@H]1O
Reactant: CO
Agent: Cl
Product: COC(=O)[C@H]1NCC[C@@H]1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.7 %

Procedure:
Part A. Hydrogen chloride gas was bubbled into a stirred suspension of trans-3-hydroxy-L-proline (25 g, 190 mmol) in MeOH (250 mL) at 0° C. for 10 min. The resulting clear solution was capped and stirred at room temperature for 6 h. It was concentrated under reduced pressure. The resulting white solids were triturated with either, filtered, and dried under vacuum to give (2S,3S)-3-hydroxy-pyrrolidine-2-carboxylic acid methyl ester hydrochloride salt (32.5 g, yield: 93.7%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19]3=[C:20]([CH2:22][O:23][CH2:24][CH2:25][N:18]3[C@H:17]3[CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][C@@H:16]23)[CH:21]=1.[OH-].[NH4+]>>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([NH:12][C:13]2[CH:14]=[C:15]3[C:19]4=[C:20]([CH2:22][O:23][CH2:24][CH2:25][N:18]4[C@H:17]4[CH2:26][CH2:27][NH:28][CH2:29][C@@H:16]34)[CH:21]=2)[CH:3]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Agent: [NH4+]
Agent: [OH-]
Product: c1ccc2ncc(Nc3cc4c5c(c3)[C@@H]3CNCC[C@@H]3N5CCOC4)cc2c1

Procedure:
Using 3-bromoquinoline and following the procedures described in EXAMPLE 56, Part C, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)Carboxylate from EXAMPLE 56, Part B was converted into (7bR,11aS)-N-(3-quinolinyl)-1,2,7b,8,9,10,11,11a-octahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indol-6-amine, bis-trifluoroacetic acid salt. This material was free-based with aq ammonium hydroxide, extracted with chloroform, washed with brine, dried (K2CO3) and concentrated to afford the title compound of EXAMPLE 114. 1H NMR (CDCl3) δ: 8.60 (d, 1H, J=2.9 Hz), 7.95 (d, 1H, J=1.9 Hz), 7.60-7.55 (m, 1H), 7.50-7.38 (m, 3H), 6.88 (d, 1H, J=1.9 Hz), 6.81 (s, 1H), 5.99 (s, 1H4), 5.85 (broad s, 1H), 4.61 (ABq, 2H, JAB=14.7 Hz), 4.23 (app d, 1H, J=12.4 Hz), 3.74 (app t, 1H), 3.43 (broad s, 1H), 3.30-3.00 (m, 4H), 2.75 (app t, 1H), 2.65-2.55 (m, 1H), 2.20-1.90 (m 3H). LRMS (ES)+: 373.4 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[NH:14][C@@H:13]([CH:15]([CH2:17][CH3:18])[CH3:16])[CH2:12][S:11]2)=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].[CH2:23](Br)[CH:24]([CH3:26])[CH3:25]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[N:14]([CH2:23][CH:24]([CH3:26])[CH3:25])[C@@H:13]([CH:15]([CH2:17][CH3:18])[CH3:16])[CH2:12][S:11]2)=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2]
Reactant: CC(C)CBr
Reactant: CCC(C)[C@H]1CSC(=Nc2ccc(C#N)c(C(F)(F)F)c2)N1
Product: CCC(C)[C@H]1CSC(=Nc2ccc(C#N)c(C(F)(F)F)c2)N1CC(C)C

Procedure:
(1S)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 4-Cyano-3-(trifluoromethyl)aniline was converted to 4-cyano-3-(trifluoromethyl)phenyl isothiocyanate according to A2a, Step 3. The isothiocyanate was reacted with (1S)-1-(chloromethyl)-2-methylbutanammonium chloride according to Method C1a to give (4S)-2-(4-cyano-3-(trifluoromethyl)phenylimino)-4-(2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(4-cyano-3-(trifluoromethyl)phenylimino)-4-(2-butyl)-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: [N:1]1[C:10]2[C@H:9]([NH:11]C(=O)C)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>Cl.C(Cl)Cl>[NH2:11][C@H:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1
Reactant: CC(=O)N[C@@H]1CCCc2cccnc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: N[C@@H]1CCCc2cccnc21
Yield: 79.7 %

Procedure:
A stirred solution of (R)-(−)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-acetamide (230 mg, 1.21 mmol, 97% ee) in 6 N aqueous HCl (4.0 mL) was heated to 130° C. for 2 h. At this time, the reaction mixture was cooled to room temperature and cautiously rendered basic with a minimum amount of saturated aqueous NaOH, then diluted with CH2Cl2 (10 mL). The phases were separated and the aqueous phase was washed with CH2Cl2 (5×20 mL), then the combined organic phases were dried (MgSO4) and concentrated. Flash chromatography through a plug of silica gel (elution with 20:2:1 CH2Cl2—MeOH—NH4OH) afforded 143 mg (80%) of (R)-(−)-8-amino-5,6,7,8-tetrahydroquinoline in 96% ee (separated by chiral GC, J&W CycloSil B column, initial temperature: 160° C., initial time: 0 min, rate: 1° C./min, final temperature: 130° C., final time: 0 min, (S)-(+)-enantiomerrt=12.43 min, (R)-(−)-enantiomerrt=13.13 min). [α]D=−125.7 (c 0.56, CHCl3); 1H NMR (CDCl3) δ 1.52-1.62 (m, 2H), 1.78-1.85 (m, 1H), 1.91 (br s, 2H), 2.02-2.06 (m, 1H), 2.60-2.65 (m, 2H), 3.83-3.87 (m, 2H), 6.91 (dd, 1H, J=8, 5 Hz), 7.21 (dd, 1H, J=8, 1 Hz), 8.26 (d, 1H, J=5 Hz); 13C NMR (CDCl3) δ 19.6, 28.7, 31.7, 51.0, 121.3, 131.2, 136.4, 146.7, 159.2. ES-MS m/z 149 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Cl)[N:3]=1.[CH2:10]([O:12][C:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21](=[S:23])[NH2:22])[CH2:17][CH2:16]1)=[O:14])[CH3:11].[CH2:24](N(CC)CC)C>C(O)C>[CH2:10]([O:12][C:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[S:23][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[N:3]=3)=[CH:24][N:22]=2)[CH2:17][CH2:16]1)=[O:14])[CH3:11]
Reactant: ClCc1cccc(Br)n1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)C1CCN(C(N)=S)CC1
Solvent: CCO
Product: CCOC(=O)C1CCN(c2ncc(-c3cccc(Br)n3)s2)CC1
Temperature: 25 °C
Yield: 65.4 %

Procedure:
2-Bromo-6-chloromethylpyridine obtained in Step 1 of Example 1 (2.90 g, 14.0 mmol) was dissolved in ethanol (30 ml) and 1-thiocarbamoylpiperidine-4-carboxylic acid ethyl ester (3.00 g, 13.9 mmol) obtained in Step 1 was added, and the mixture was heated to reflux for 2 hours. The reaction solution was cooled to room temperature, dimethylormamide dimethylacetal (2.8 ml, 21.1 mmol) and triethylamine (5.9 ml, 42.3 mmol) were added, and the mixture was heated at reflux for 1 hour. After concentration, water was added and the reaction solution was extracted with ethyl acetate and washed with a saturated brine. The organic layer was dried over magnesium sulfate and the residue obtained by vacuum concentration was purified by silica gel chromatography (n-hexane:ethyl acetate=50:50 to 0:100) and the title compound (3.60 g, 65%) was obtained.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]#[N:14].C(OCC)(=O)C.Cl.O1CCCC1.CCOP(S)(OCC)=[S:31]>O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13](=[S:31])[NH2:14]
Reactant: CCOP(=S)(S)OCC
Reactant: N#CCN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: NC(=S)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 51 %

Procedure:
To a mixture of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetonitrile (15 g), 4 mol/L hydrogen chloride-ethyl acetate solution (40 mL) and tetrahydrofuran (50 mL) was added O,O-diethyldithiophosphate (15 mL), and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and tetrahydrofuran. The extract was washed twice with water, and then washed with saturated brine and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as white crystals (yield 9.0 g, 51%).
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[C:30](=[O:36])[NH:31][CH:32]2[CH2:35][CH2:34][CH2:33]2)=[O:24])[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:17]=1)=[O:15])[C:10](O)=[O:11])(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:77]([O:79][C:80]([N:82]1[CH2:87][CH2:86][NH:85][C@@H:84]([CH3:88])[CH2:83]1)=[O:81])[CH3:78]>CN(C=O)C>[CH2:77]([O:79][C:80]([N:82]1[CH2:87][CH2:86][N:85]([C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30](=[O:36])[NH:31][CH:32]3[CH2:33][CH2:34][CH2:35]3)=[O:24])[N:18]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:17]=2)=[O:15])[CH2:8][CH2:7][C:6]([OH:43])=[O:5])[C@@H:84]([CH3:88])[CH2:83]1)=[O:81])[CH3:78]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Reactant: CCOC(=O)N1CCN[C@@H](C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)[C@@H](C)C1
Reaction time: 36 h

Procedure:
To a solution of 100 mg (S)-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester in 5 ml DMF were added 28 μl DIPEA, 63 mg HATU and 28 mg (S)-3-Methyl-piperazine-1-carboxylic acid ethyl ester. After stirring for 36 h the solution was concentrated, the residue dissolved in 1.5 ml dichloromethane and treated with 360 μl TFA. After stirring for 4 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:25]([C:26]4[N:30](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:29]=[N:28][N:27]=4)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:50]([O:52][CH:53]([O:55][C:56]([O:58][CH:59]2[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]2)=[O:57])[CH3:54])=[O:51])[N:5]=1.C1(C)C=CC=CC=1.CO>O>[CH3:1][CH2:2][O:3][C:4]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[N:27]=[N:28][NH:29][N:30]=3)=[CH:16][CH:15]=2)[C:11]2[C:10]([C:50]([O:52][CH:53]([O:55][C:56]([O:58][CH:59]3[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64]3)=[O:57])[CH3:54])=[O:51])=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1

Procedure:
A mixture of trityl candesartan cilexetil (20 g, 23.45 mmol), toluene (60 ml), methanol (60 ml), and water (1 ml) was gently refluxed for about 12 h. The reaction was monitored by HPLC. The solution volume was reduced by evaporation under reduced pressure (30 mbar) at a temperature of about 55° C. 60° C. to obtain viscous oil of candesartan cilexetil as a residue (36.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH2:22]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C:28]1=O)=[O:26])[CH3:23].FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>O1CCOCC1>[C:7]([O:6][C:4]([C:3]1[CH:11]=[CH:12][C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[CH:14][C:2]=1[NH:1][CH:30]1[CH2:31][CH2:32][N:27]([C:25]([O:24][CH2:22][CH3:23])=[O:26])[CH2:28][CH2:29]1)=[O:5])([CH3:10])([CH3:9])[CH3:8]
Reactant: CCOC(=O)N1CCCCC1=O
Reactant: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c(N)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CCOC(=O)N1CCC(Nc2cc(N3CCN(C)CC3)ccc2C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
tert-Butyl 2-amino-4-(4-methylpiperazin-1-yl)benzoate (1.5 g, 5.15 mmol) was dissolved in dry dioxane (25 mL) under a nitrogen atmosphere. N-ethoxycarbonylpiperidone (1.06 g, 0.932 mL, 6.18 mmol, 1.2 eq) was added, followed by trifluoroacetic acid (1.03 mL, 13.39 mmol, 2.6 eq) and sodium triacetoxyborohydride (1.72 g, 7.73 mmol, 1.5 eq). The mixture was stirred at room temperature for 4 hours. A saturated aqueous solution of NaHCO3 was then added, the mixture was concentrated under reduced pressure and extracted with dichloromethane (3×40 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. After purification by chromatography over silica gel (DCM/EtOH 93:7) 2.187 g of title compound were obtained as a white solid (95% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH2:8].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14](B(O)O)[CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[N+:9]([C:6]1[C:7]([NH2:8])=[C:2]([C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[CH:3]=[N:4][CH:5]=1)([O-:11])=[O:10]
Reactant: Nc1c(Br)cncc1[N+](=O)[O-]
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1c(-c2cccnc2)cncc1[N+](=O)[O-]
Yield: 88.8 %

Procedure:
A solution of 3-bromo-5-nitropyridin-4-amine (LVIII) (6 g, 26 mmol), pyridin-3-ylboronic acid (3.54 g, 29 mmol), 1 N Na2CO3 solution (78 ml) and 1,4-dioxane (150 mL) was degassed with argon thrice. Pd(PPh3)2C12 (927 mg, 5 mmol %) was added to the reaction and the solution was refluxed for 15 h until TLC showed the reaction was complete. The reaction was passed through a pad of Celite® and then concentrated under reduced pressure. The reaction mixture was concentrated and the residue was taken up in EtOAc. The organic extract was washed with water, dried and concentrated under vacuum. The crude product was purified on a silica gel column (100% EtOAc→2:98 MeOH:DCM) to give 5-nitro-3,3′-bipyridin-4-amine (LIX) as a yellow solid (5 g, 23.1 mmol, 87% yield). 1H NMR (CDCl3, 500 MHz,) δ ppm 9.31 (s, 1H), 8.80-8.79 (m, 1H), 8.70 (s, 1H), 8.23 (s, 1H), 7.80-7.73 (m, 1H), 7.52-7.48 (m, 1H). ESIMS found C10H8N4O2 m/z 216.95 (M+H).
Reaction SMILES: Cl.[C:2]([C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].C1CCN2C(=NCCC2)CC1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([NH:36][C:37](=O)[O:38]CC)=[N:28]1>CS(C)=O>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([NH:36][C:37]([N:7]2[CH2:6][CH2:5][C:4]([C:2]#[N:3])([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)=[O:38])=[N:28]1
Reactant: CCOC(=O)Nc1n[nH]c2ccccc12
Reactant: N#CC1(c2ccccc2)CCNCC1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: N#CC1(c2ccccc2)CCN(C(=O)Nc2n[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
4-Cyano-4-phenylpiperidine hydrochloride (Aldrich Co., 217 mg) was dissolved in dimethyl sulfoxide (3 ml) and DBU (0.16 ml) was added thereto. The mixture was stirred at room temperature for 30 min, and ethyl 1H-indazol-3-ylcarbamate (200 mg) and potassium fluoride-alumina (40 wt %, 200 mg) were added to the mixture. By the following operation as in Example 1, 4-cyano-4-phenyl-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide (253 mg, yield 75%) was obtained.