Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10].[C:11](Cl)(=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C1(C)C=CC=CC=1>[C:11]([N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10])(=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: O=C1CCCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC(=O)N1CCCCCC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride [5.14 g (50% oil dispersion); 0.107 mol] in 100 ml of dry toluene was added to a 500 ml, 3-necked flask fitted with a mechanical stirrer. Azacycloheptan-2-one (10.07 g; 0.089 mol) was dissolved in 50 ml of dry toluene with slight warming and added to the sodium hydride suspension dropwise at room temperature. The suspension was stirred at room temperature for 1 hour. n-Dodecanoyl chloride (19.39 g; 0.089 mol) in 10 ml of dry toluene was added dropwise to the mixture and after the addition was complete, the mixture was stirred overnight at room temperature. The mixture was then washed with water, and the organic layer separated, dried with MgSO4, and concentrated. The resulting yellow oil was distilled 160° C./0.35mm to yield 1-n-dodecanoylazacycloheptan-2-one as clear oil.
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][N:16]=1)[C:11]([OH:13])=[O:12].CO>C(Cl)Cl.CN(C=O)C>[CH3:1][O:12][C:11](=[O:13])[C:10]1[C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][N:16]=[C:8]([Cl:7])[CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(Cl)ncc1C(F)(F)F
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Oxalyl chloride (0.5 ml) was added to a solution of 2-chloro-5-(trifluoromethyl)isonicotinic acid (CAS Reg. No. 505084-58-2, 68 mg) in DCM (5 ml). DMF (1 drop) was added and the resulting mixture was stirred overnight at room temperature. Methanol (5 ml) was added and the mixture was concentrated to dryness. The crude product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][N:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[O:30][C:29]([CH3:32])([CH3:31])[O:28][C:27](=[O:33])[C:26]=2[CH:34]=1>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[N:14]=[CH:15][C:16]([CH2:17][NH:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][C:29]([CH3:31])([CH3:32])[O:28][C:27](=[O:33])[C:26]=4[CH:34]=3)=[CH:19][CH:20]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(C=O)cn2)cc1
Reactant: CC1(C)OC(=O)c2cc(N)ccc2O1
Product: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cn2)cc1

Procedure:
The titled compound was prepared following the procedure A using 6-[(4-butylphenyl)ethynyl]nicotinaldehyde and 6-amino-2,2-dimethyl-benzo[1,3]dioxin-4-one as a yellow powder (22%). 1H NMR (CDCl3, 300 MHz) δ 8.61 (s, 1H), 7.66 (m, 1H), 7.48 (m, 3H), 7.16 (m, 3H), 6.87-6.76 (m, 2H), 4.36 (s, 2H), 2.61 (t, J=7.7 Hz, 2H), 1.69 (s, 6H), 1.66-1.54 (m, 2H), 1.41-1.28 (m, 2H), 0.92 (t, J=7.2 Hz, 3H). M− (ESI): 439.1; M+ (ESI): 441.4. HPLC, Rt: 4.55 min (Purity: 85.3%).
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:20][C:19]2[C@H:14]([CH2:15][CH2:16][C:17](=O)[CH:18]=2)[C@@H:13]2[C@@H:4]1[C@H:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C@@H:8]([OH:22])[CH2:7][CH2:6]1)=[CH2:2].Cl.[NH2:24][OH:25].O>N1C=CC=CC=1>[CH:1]([C@@H:3]1[CH2:20][C:19]2[C@H:14]([CH2:15][CH2:16]/[C:17](=[N:24]\[OH:25])/[CH:18]=2)[C@@H:13]2[C@@H:4]1[C@H:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C@@H:8]([OH:22])[CH2:7][CH2:6]1)=[CH2:2].[CH:1]([C@@H:3]1[CH2:20][C:19]2[C@H:14]([CH2:15][CH2:16]/[C:17](=[N:24]/[OH:25])/[CH:18]=2)[C@@H:13]2[C@@H:4]1[C@H:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C@@H:8]([OH:22])[CH2:7][CH2:6]1)=[CH2:2]
Reactant: NO
Reactant: C=C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]21
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: C=C[C@@H]1CC2=C/C(=N/O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]21
Product: C=C[C@@H]1CC2=C/C(=N\O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]21
Temperature: 80 °C
Reaction time: 0.83 h

Procedure:
To a solution of (7α,17β)-7-ethenyl-17-hydroxyestr-4-en-3-one (Example 4; 1.63 g) in pyridine (9.4 ml) was added hydroxylamine hydrochloride (4.15 g). The reaction mixture was stirred at 80° C. for 50 min. After cooling, the mixture was poured into water (118 ml). The product was extracted into ethyl acetate; the combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography afforded (3E,7α,17β)-7-ethenyl-3-(hydroxyimino)estr-4-en-17-ol (0.60 g), [α]D20=−4.8° (c=1.00, dioxane), and (3Z,7α,17β)-7-ethenyl-3-(hydroxyimino)estr-4-en-17-ol (0.65 g), m.p. 206-224° C.
Reaction SMILES: [Na+].[CH:2]1([N:5]2[C:9]([C:10]([O-:12])=O)=[C:8]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:7]=[C:6]2[C:19]2[CH:24]=[CH:23][C:22](OC(F)(F)F)=[CH:21][CH:20]=2)[CH2:4][CH2:3]1.C(OC(=O)CN(C1CC1)C(=O)C1C=CC=C([O:43][C:44]([F:47])([F:46])[F:45])C=1)C.[N:53]1([CH:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH2:57][CH2:56][CH2:55][CH2:54]1>>[CH:2]1([N:5]2[C:9]([C:10]([N:61]3[CH2:62][CH2:63][CH:58]([N:53]4[CH2:57][CH2:56][CH2:55][CH2:54]4)[CH2:59][CH2:60]3)=[O:12])=[C:8]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:7]=[C:6]2[C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([O:43][C:44]([F:47])([F:46])[F:45])[CH:24]=2)[CH2:3][CH2:4]1
Reactant: O=C([O-])c1c(-c2cccnc2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: CCOC(=O)CN(C(=O)c1cccc(OC(F)(F)F)c1)C1CC1
Agent: [Na+]
Product: O=C(c1c(-c2cccnc2)nc(-c2cccc(OC(F)(F)F)c2)n1C1CC1)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 2, the title compound has been obtained by coupling of 3-cyclopropyl-5-pyridin-3-yl-2-(3-trifluoromethoxy-phenyl)-3H-imidazole-4-carboxylic acid sodium salt (prepared in analogy to the sequence described for the preparation of intermediate 8, but using [cyclopropyl-(3-trifluoromethoxy-benzoyl)-amino]-acetic acid ethyl ester instead of [cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-acetic acid ethyl ester in step 8A) with 4-pyrrolidin-1-yl-piperidine to give the title compound as a colorless amorphous solid. MS: 526.4 (MH+).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:21][O:22][C:23](=[O:45])[C:24]1[C:29]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])=[CH:28][N:27]=[CH:26][C:25]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[F:44]>>[CH3:21][O:22][C:23](=[O:45])[C:24]1[C:29]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([I:1])=[CH:33][C:32]=2[F:37])=[CH:28][N:27]=[CH:26][C:25]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[F:44]
Reactant: COC(=O)c1c(Nc2ccccc2F)cncc1-c1ccccc1F
Reactant: O=C1CCC(=O)N1I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
N-iodosuccinimide (400 mg, 1.76 mmol) and p-toluenesulfonic acid monohydrate (670 mg, 3.53 mmol) were added to a solution of 3-(2-fluoro-phenyl)-5-(2-fluoro-phenylamino)-isonicotinic acid methyl ester (480 mg, 1.41 mmol), and stirred overnight at 60° C. The reaction mixture was quenched with Na2S2O3 (1 mL, 10% aqueous solution), diluted with CH2Cl2, and filtered through an Extrelut column. The column was washed with CH2Cl2, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 0 to 55% EtOAc in hexanes to afford the desired product (516 mg, 78%). LC-MS (M+H=467, obsd.=467).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][NH:12][CH2:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[C:17]([O:20][C@@H:21]([C:23]1[N:28]=[C:27](Cl)[CH:26]=[CH:25][N:24]=1)[CH3:22])(=[O:19])[CH3:18].C(N(CC)CC)C>C(O)(C)C>[C:17]([O:20][C@@H:21]([C:23]1[N:24]=[C:25]([N:12]2[CH2:11][CH2:10][C:9]3[C:14](=[CH:15][C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:16])[CH3:1])=[CH:7][CH:8]=3)[CH2:13]2)[CH:26]=[CH:27][N:28]=1)[CH3:22])(=[O:19])[CH3:18]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CNCC2
Reactant: CC(=O)O[C@H](C)c1nccc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(=O)O[C@H](C)c1nccc(N2CCc3ccc(S(=O)(=O)N(C)C)cc3C2)n1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 92 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-isoquinoline-7-sulfonic acid dimethylamide (prepared according to the method of Example 247, Step B, 210 mg, 0.88 mmol) in isopropanol (5 mL) was added (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl acetate (prepared according to the method of Preparation Five, 175 mg, 0.88 mmol) followed by triethylamine (0.24 mL, 1.75 mmol). This mixture was stirred at room temperature for 1.75 h then heated to reflux for 1.5 h, cooled to room temperature, evaporated, and purified by flash column chromatography (1% methanol/chloroform) to give 327 mg (92%) of the title compound of Example 247, Step C as a white solid. 1H NMR (CDCl3, 250 MHz) δ8.28 (d, 1H), 7.68-7.58 (c, 2H), 7.47 (d, 1H), 6.44 (d, 1H), 5.72 (q, 1H), 4.86 (s, 2H), 3.92 (t, 2H), 3.05 (t, 2H), 2.73 (s, 6H), 2.19 (s, 3H), 1.62 (d, 3H); MS (TS) 431 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1C=CC=CC=1.BrC1[CH:18]=[N:19][CH:20]=[N:21]C=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[OH:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:1]2[CH:2]=[N:21][CH:20]=[N:19][CH:18]=2)=[CH:14][CH:13]=1
Reactant: Brc1cncnc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc(Oc2cncnc2)cc1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To 1.00 g (4.99 mmol) 4-(benzyloxy)phenol and 794 mg (4.99 mmol) 5-bromo-pyrimidine in 5 mL DMF are added 3.25 g (9.99 mmol) Cs2CO3 and the reaction mixture is stirred at 120° C. for 6 h in a microwave oven. Then the reaction mixture is diluted with water and extracted with EtOAc. The organic layer is dried with Na2SO4 and the solvent is removed in vacuo. The residue is purified by HPLC (MeOH/H2O/NH3).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[C:7]([C:11]1[N:15]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19][CH2:18]2)[C:14]2[CH:25]=[CH:26][C:27]([S:29]([N:32]3[CH2:35][CH:34]([NH2:36])[CH2:33]3)(=[O:31])=[O:30])=[CH:28][C:13]=2[N:12]=1)([CH3:10])([CH3:9])[CH3:8].CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[C:7]([C:11]1[N:15]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20]([F:23])([F:24])[CH2:19][CH2:18]2)[C:14]2[CH:25]=[CH:26][C:27]([S:29]([N:32]3[CH2:33][CH:34]([NH:36][C:4]([CH:1]4[CH2:3][CH2:2]4)=[O:5])[CH2:35]3)(=[O:31])=[O:30])=[CH:28][C:13]=2[N:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(N)C3)ccc2n1CC1CCC(F)(F)CC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(NC(=O)C4CC4)C3)ccc2n1CC1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.3 %

Procedure:
Cyclopropane carbonylchloride (16 uL, 19 mg, 0.18 mmol) was added to a solution of 1-({2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)azetidin-3-amine (52 mg, 0.12 mmol) (see Example 102 for preparation) and DIPEA (41 uL, 31 mg, 0.24 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred for 4 h at room temperature, diluted with EtOAc (50 mL), washed with NaHCO3 (2×10 mL) and dried over Na2SO4. The crude product was purified by MPLC using Hex/EtOAc (1:4) on silica gel to give 60 mg (99%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.66-0.71 (m, 2 H), 0.71-0.77 (m, 2 H), 1.38-1.48 (m, 1 H), 1.51-1.64 (m, 2 H), 1.65 (s, 9 H), 1.68-1.86 (m, 4 H), 1.99-2.13 (m, 2 H), 2.19-2.35 (m, 1 H), 3.67 (dd, J=8.69, 6.15 Hz, 2 H), 4.00 (dd, J=8.8, 7.8 Hz, 2 H), 4.23-4.37 (m, 1 H), 4.53 (d, J=7.62 Hz, 2 H), 7.90 (dd, J=8.79, 1.76 Hz, 1 H), 8.03 (d, J=8.59 Hz, 1 H), 8.16 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=509.3; Anal. Calcd for C25H34F2N4O3S+1.20 TFA+0.1H2O (647.26): C, 50.85; H, 5.51; N, 8.66. Found: C, 50.81; H, 5.52; N, 8.43.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]1([CH2:18][CH2:19][CH:20]=[CH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[S:7]([O:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=[CH:20][CH2:19][CH2:18][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: OCCCCCCCC=CCCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCCCCC=CCCc2ccccc2)cc1
Reaction time: 16 h

Procedure:
4-Toluenesulphonyl chloride (1.3 g) was added in portions to a stirred solution of the product of step (c) (1.5 g) in pyridine at 0°-5° C. The mixture was stirred for 16 hours at 0°-5° C. then poured onto ice-hydrochloric acid and extracted with ether. The extract was washed with sodium bicarbonate and sodium chloride solutions, dried and evaporated to give the title compound as a pale oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[NH2:14].[N:15]([O-])=O.[Na+].[ClH:19]>O>[ClH:19].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[NH:14][NH2:15]
Reactant: Nc1cc(-c2ccccc2)ccc1Br
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(-c2ccccc2)ccc1Br
Temperature: 0 °C

Procedure:
To 4 g of 4-bromo-[1,1'-biphenyl]-3-amine were added 25 ml of water and 50 ml of concentrated HCl with stirring. The solution was cooled to 0° C. A solution of 1.1 g of sodium nitrite in 6 ml of water was then added dropwise while maintaining a temperature of 0° C. After this addition, the mixture was stirred at 0° C. for one hour. A solution of 20 g of stannous chloride in 20 ml of concentrated HCl cooled to -20° C. was added to the reaction mixture and again the mixture was stirred for one hour.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:8][C:9]1[CH:14]=[CH:13][C:12](F)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1>CS(C)=O>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CC(C)(C)N
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of t-butylamine (1.3 mL, 13 mmol) in DMSO (15 mL) was added sodium hydride (60% wt. in mineral oil, 0.53 g, 14 mmol) at RT. After the reaction mixture was stirred for 10 min, it was treated with 1-bromo-4-fluoro-3-nitrobenzene (2.0 mL, 9.1 mmol). The reaction mixture was stirred at RT for 1 h the 70° C. for 3 h. After cooling to RT, it was quenched with 50 mL of water and extracted with DCM (3×40 mL). The combined organic phases were washed with 2 N HCl followed by brine. The resulting organic solution was then dried over magnesium sulfate and concentrated under reduced pressure to give 4-bromo-N-tert-butyl-2-nitrobenzenamine as a red crystalline solid. The crude product was used without further purification. MS (ESI, pos. ion) m/z: 273.9 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1)=[O:7].[N:16]1([C:22]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:19]2[CH2:20][CH2:21][N:16]([C:22](=[O:23])[C:24]3[C:25]([F:31])=[CH:26][CH:27]=[CH:28][C:29]=3[F:30])[CH2:17][CH2:18]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: O=C(c1c(F)cccc1F)N1CCNCC1
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3c(F)cccc3F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (3-methylbutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2,6-difluorophenyl)methanone, the title compound was obtained as a white powder (42.2% yield). 1H NMR (400 MHz, CDCl3) δ 8.07, 7.85, 7.44-7.38, 7.03-6.97, 4.0-3.99, 3.86-3.83, 3.52-3.48, 1.73-1.67, 1.51, 0.94.
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([N+:20]([O-])=O)[CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H][H]>[Pd].O1CCCC1>[CH2:1]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([NH2:20])[CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1ccc(O)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1ccc(O)c(N)c1
Yield: 99.5 %

Procedure:
5.80 g of the 4-dodecyl-2-nitrophenol obtained in (2) above was mixed with 500 mg of 5% active carbon-supported palladium, and 150 ml of tetrahydrofuran and the resulting mixture was contacted with hydrogen at room temperature for 7 hours to reduce the nitro group. The reaction mixture was filtered, and then the solvent was distilled off to obtain 5.21 g of 4-dodecyl-2-aminophenol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.II.[C:10]1([C:20]#N)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.Cl.C([O:25]CC)C>[Mg].C(Cl)Cl.O>[C:20]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)(=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: Brc1ccccc1
Reactant: N#Cc1cccc2ccccc12
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
To 10.3 g (65 mMol) of bromobenzene in 50 mL of diethyl ether, magnesium turnings were added. The reaction was initiated by adding a few crystals of iodine to about 5 mL of the bromobenzene solution, and warming gently. The remainder of the bromobenzene was then added at such a rate as to maintain a mild reflux. When the reaction had abated, 1-naphthonitrile was added slowly in 50 mL of diethyl ether. The mixture was allowed to stir at room temperature overnight. Water was added, and the mixture acidified to pH 1 with concentrated hydrochloric acid. Methylene chloride was added and the mixture was heated under reflux overnight. The layers were separated, and the organic layer was washed with brine and dried over magnesium sulfate. The subtitled product was crystallized from methylene chloride/hexane, then further purified by medium pressure column chromatography on silica gel, eluting with ethyl acetate:hexane/5:95. The desired product was obtained as a white crystalline solid (4.38 g; 29% yield).
Reaction SMILES: CN([C:4]([O:8]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[C:39]([CH2:40][N:41]2[CH2:60][CH2:59][C:44]3([O:49][CH2:48][CH2:47][N:46]([C:50]([C:52]4[N:53]=[C:54]([CH2:57][CH3:58])[S:55][CH:56]=4)=[O:51])[CH2:45]3)[CH2:43][CH2:42]2)=[CH:38][CH:37]=[CH:36][C:27]=1[CH2:28][CH2:29][O:30][CH2:31][CH2:32]C(O)=O.CCN(C(C)C)C(C)C.[CH2:70]([NH:72][CH2:73][CH:74]([O:77][CH3:78])[O:75][CH3:76])[CH3:71]>CN(C=O)C>[Cl:25][C:26]1[C:39]([CH2:40][N:41]2[CH2:60][CH2:59][C:44]3([O:49][CH2:48][CH2:47][N:46]([C:50]([C:52]4[N:53]=[C:54]([CH2:57][CH3:58])[S:55][CH:56]=4)=[O:51])[CH2:45]3)[CH2:43][CH2:42]2)=[CH:38][CH:37]=[CH:36][C:27]=1[CH2:28][CH2:29][O:30][CH2:31][CH2:32][C:4]([N:72]([CH2:73][CH:74]([O:77][CH3:78])[O:75][CH3:76])[CH2:70][CH3:71])=[O:8]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)O)c4Cl)CC3)C2)cs1
Reactant: CCNCC(OC)OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)N(CC)CC(OC)OC)c4Cl)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HATU (1.06 g) was added to a solution of 3-(2-chloro-3-((4-(2-ethylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanoic acid [Example 26, step e] (0.75 g), Hunig's base (1.22 mL) and N-ethyl-2,2-dimethoxyethanamine [U.S. Pat. No. 2,707,186] (0.37 g) in DMF (5 mL). The resulting dark solution was stirred overnight at RT. The reaction mixture was partitioned between ethyl acetate (25 mL) and 20% brine (25 mL). The organic layer was separated and washed with 20% brine (2×25 mL). The organic solution was evaporated and the residue purified by silica gel chromatography, gradient elution isohexane:triethylamine 95:5 to ethyl acetate:triethylamine 95:5. The fractions containing the product were combined and evaporated to give the subtitled compound as an oil. Yield 0.70 g.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=3)[C:9]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:32][C:33]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36].C(=O)(O)[O-].[Na+]>ClCCl>[F:32][C:33]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:34]=1[C:35]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=3)[C:9]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:8]2)=[CH:23][CH:24]=1)=[O:36]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: CCOC(=O)Cc1nn(Cc2ccc(N)cc2)c2cc(F)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc(F)cc3F)cc2)c2cc(F)ccc12
Yield: 45.6 %

Procedure:
The crude ethyl 2-[1-(4-aminobenzyl)-6-fluoro-1H-indazol-3-yl]acetate (about 1.0 mmol) obtained in the last step and triethylamine (0.5 mL) were dissolved in dichloromethane (15 mL), and in an ice bath dichloromethane solution (10 mL) of 2,4-difluorobenzoyl chloride (177 mg, 1.0 mmol) was added dropwise slowly. Upon completion of the dropwise addition, it was reacted at room temperature for 16 hours. An aqueous solution of sodium bicarbonate was added to quench, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduce pressure, chromatographed on a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain a white solid 213 mg, at a total yield over two steps of reactions of 45.6%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[O:20][N:19]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14](=[O:16])[NH:17][C:18]2[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[O:20][N:19]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: CC(C)(C)c1cc(N)no1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)Nc2cc(C(C)(C)C)on2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (5° C.) solution of piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (1 g; 4.362 mmol) and 3-amino-5-t-butylisoxazole (589 mg; 4.2 mmol) in anhydrous pyridine (12 mL) is added phosphorus oxychloride (0.393 mL; 4.362 mmol). The reaction mixture is stirred at room temperature for 30 minutes. The mixture is quenched with saturated NH4Cl aqueous solution and extracted with ethyl acetate 3 times. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica using methanol/methylene chloride provides the title compound, m/z 352 [M+H+].