Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH:12]1[CH:16]=[C:15]([CH2:17][CH2:18][NH2:19])[N:14]=[CH:13]1>CO.[BH4-].[Na+]>[NH:12]1[CH:16]=[C:15]([CH2:17][CH2:18][NH:19][CH:9]2[C:10]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH2:6][CH2:7][CH2:8]2)[N:14]=[CH:13]1
Reactant: O=C1CCCc2cccnc21
Reactant: NCCc1c[nH]cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1cnc2c(c1)CCCC2NCCc1c[nH]cn1

Procedure:
Using General Procedure B: Reaction of 6,7-dihydro-5H-quinolin-8-one in MeOH, 2-(1H-imidazol-4-yl)-ethylamine and NaBH4 gave [2-(1H-imidazol-4-yl)-ethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine. 1H NMR (CDCl3) δ 1.75 (m, 2H), 1.91 (m, 1H), 2.10 (m, 1H), 2.72 (q, 2H, J=8.6 Hz), 2.82 (q, 2H, J=10.0 Hz), 3.01 (t, 2H, J=6.6 Hz), 3.81 (t, 1H, J=6.1 Hz), 6.73 (s, 1H), 7.04 (q, 1H, J=4.3 Hz), 7.35 (d, 1H, J=7.6 Hz), 7.43 (s, 1H), 8.36 (d, 1H, J=4.0 Hz).
Reaction SMILES: I[C:2]1[NH:6][C:5]([CH2:7][O:8][CH3:9])=[N:4][C:3]=1[CH3:10].[CH3:11][C:12]1[CH:21]=[C:20]([CH3:22])[C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:9][O:8][CH2:7][C:5]1[NH:6][C:2]([C:19]2[C:20]([CH3:22])=[CH:21][C:12]([CH3:11])=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])=[C:3]([CH3:10])[N:4]=1
Reactant: COCc1nc(C)c(I)[nH]1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COCc1nc(C)c(-c2cc(C(=O)OC)c(C)cc2C)[nH]1
Temperature: 90 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
Into a 50-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 5-iodo-2-(methoxymethyl)-4-methyl-1H-imidazole (compound 222.3, 400 mg, 1.59 mmol) in 1,4-dioxane (15 mL). Methyl 2,4-dimethyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1, 510 mg, 1.76 mmol), a solution of potassium carbonate (662 mg, 4.79 mmol) in water (1 mL) and Pd(dppf)Cl2 (234 mg, 0.32 mmol) were added to the reaction. The reaction mixture was stirred overnight at 90° C. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography with dichloromethane/ethyl acetate (1:1) as eluent to furnish 220 mg (48%) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:10]=1N)=[O:5])[CH3:2].C(O)(=O)C.N(OC(C)(C)C)=O.[ClH:28]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:10]=1[Cl:28])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(CCCOC)c1N
Reactant: Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn(CCCOC)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
To a mixture of 5-amino-1-(3-methoxypropyl)-1H-pyrazole-4-carboxylic acid ethyl ester (5.22 g, 23.0 mmol) in dry acetonitrile (46 mL) was added anhydrous cuprous chloride (3.73 g, 37.7 mmol) and acetic acid (2.6 mL, 46.0 mmol). The mixture was cooled to 0° C. in an ice-water bath after which tert-butyl nitrite (4.9 mL, 36.8 mmol) was added over 10 minutes. The solution was allowed to warm to room temperature and stir for 4 h. To the solution was carefully added 6.0N hydrochloric acid (20 mL). The aqueous layer was extracted with methylene chloride (2×100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the crude material. The product was purified by column chromatography on silica gel (eluting with ethyl acetate/hexanes, 1:1) to provide 5-chloro-1-(3-methoxypropyl)-1H-pyrazole-4-carboxylic acid ethyl ester (1.71 g, 30%) as an orange oil. Mass spectrum: m/z: 247.3 (M+1).
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:13]1[CH:17]=[N:16][C:15]([CH3:18])=[N:14]1.[CH2:19]([OH:22])[CH:20]=[CH2:21]>CN(C=O)C>[CH2:19]([O:22][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:13]1[CH:17]=[N:16][C:15]([CH3:18])=[N:14]1)[CH:20]=[CH2:21]
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2F)n1
Reactant: C=CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cc([N+](=O)[O-])ccc1-n1cnc(C)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
A suspension of NaH (2.295 g 57.4 mmol, 60% dispersion in mineral oil) in DMF (85 mL) was cooled at 0° C. and a solution 1-(2-fluoro-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (8.50 g 38.3 mmol) was added dropwise. Allyl alcohol (2.67 g, 49.9 mmol) was added via syringe over 10 min. The reaction mixture was allowed to warm to room temperature. After 30 min, TLC showed completion of reaction. The reaction mixture was slowly quenched with water (20 mL), treated with 200 mL of brine and extracted with EtOAc (3×200 mL). The combined organic extracts were washed with water (3×200 mL) and brine solution (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude reaction mixture was purified using silica gel chromatography (20-80% EtOAc/hexane, linear gradient). Pure fractions were concentrated under reduced pressure to afford 1-(2-(allyloxy)-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (5 g, 19.21 mmol 50% yield) as a yellow colored solid. LC-MS (M+H)+=261.0. 1H NMR (400 MHz, CDCl3) δ ppm 8.906 (s, 1H), 8.09 (d, 1H, J=8.8 Hz), 7.99-7.94 (m, 2H), 6.13-6.03 (m, 1H), 5.50-5.54 (m, 2H), 4.80-4.79 (m, 2H), 2.497 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH:13]=[O:14]>C1COCC1>[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH:13]([OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1
Reactant: Fc1cccc(Br)c1
Reactant: COc1ccc(C=O)cc1F
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2cccc(F)c2)cc1F
Temperature: 25 °C
Yield: 94.6 %

Procedure:
A mixture of Mg° turnings (2.45 g, 101 mmol), 1-bromo-3-fluorobenzene (17.69 g, 100 mmol), and dry THF (200 mL) was carefully heated to reflux for 30 min. While still refluxing, 3-fluoro-p-anisaldehyde (15.3g, 99.3 mmol) in THF (100 mL) was added over a period of 5 min. The reaction temperature was maintained for 30 min. cooled to room temperature, and then the reaction was quenched with satd. aq. NH4Cl (200 mL). The organic layer was separated, washed with satd. aq. NaCl (2×200 mL), dried (anh. Na2SO4) and rotary evaporated to yield 23.5 g (94.4%) of product as an orange-brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[S:17](Cl)(=[O:19])=[O:18].Cl.CN.[CH2:24]([N:26](CC)CC)C.Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[S:17]([NH:26][CH3:24])(=[O:19])=[O:18]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)c(F)cc1OCC(F)(F)F
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cc([N+](=O)[O-])c(OCC(F)(F)F)cc1F
Temperature: -45 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
A mixture of 2-fluoro-5-nitro-4-[(2,2,2-trifluoroethyl)oxy]benzenesulfonyl chloride (15 g, crude) in THF (150 mL) at −45° C. was treated with methylamine hydrochloride (5.96 g, 89 mmol) and then treated dropwise with triethylamine (12.4 mL, 89 mmol). After stirring for 1 hour at −45° C., the mixture was adjusted to pH 3 by the addition of aqueous 3M HCl, warmed to room temperature, diluted with water, and extracted with EtOAc. The organic extract was dried (Na2SO4), concentrated, and subjected to flash chromatography (9-17% EtOAc-petroleum ether) to give 2-fluoro-N-methyl-5-nitro-4-[(2,2,2-trifluoroethyl)oxy]benzenesulfonamide (10 g, 72% for two steps) as a yellow solid. MS (m/z) 333.0 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]4[CH2:29][O:28]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:28])[CH2:29][NH:37][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C4CO4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CNCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 187, Step 2, using 1-[4′-(3-methyl-4-oxiranyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and benzyl amine.
Reaction SMILES: C(OC(N1CCC(N[C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[NH2:31][C@H:32]([CH2:40][OH:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([C@H:32]([NH:31][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15])[CH2:40][OH:41])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: O=C(N[C@H](CO)Cc1ccccc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using (S)-phenylalaninol instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 393 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (1H, br. s.) 10.13 (1H, s) 7.98 (1H, d, J=5.47 Hz) 7.72-7.82 (2H, m) 7.40 (1H, d, J=5.42 Hz) 7.28 (1H, dd, J=3.44, 2.32 Hz) 7.19 (4H, d, J=0.10 Hz) 7.10 (1H, td, J=5.93, 2.59 Hz) 6.73 (1H, d, J=5.52 Hz) 6.38 (1H, dd, J=3.42, 1.76 Hz) 4.82 (1H, t, J=5.66 Hz) 4.13 (1H, ddd, J=14.19, 5.60, 3.15 Hz) 3.42-3.51 (1H, m) 3.38 (1H, t, J=5.93 Hz) 2.84-2.93 (1H, m) 2.73 (1H, dd, J=13.64, 8.96 Hz)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1>[CH3:16][S:17]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2)(=[O:19])=[O:18]
Reactant: COC(=O)Cn1ccc2cc(N)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)Cn1ccc2cc(NS(C)(=O)=O)ccc21

Procedure:
To a solution of methyl 2-(5-amino-1H-indol-1-yl)acetate (730 mg, 3.54 mmol) in pyridine (15 ml), methanesulfonyl chloride (418 μl, 5.36 mmol) was added, and the mixture was reacted for 2 hours at room temperature. The solvent was evaporated and the resulting crude was partitioned between 1N HCl and ethyl acetate; the aqueous phase was extracted with ethyl acetate (3×30 ml) and dried over sodium sulfate. The solvent was removed obtaining crude methyl 2-(5-(methylsulfonamido)-1H-indol-1-yl)acetate that was used in the next step without any additional purification (1 g, 3.54 mmol, quantitative yield). MS/ESI+ 283.3 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C=O)C.C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:19])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccccc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of methylbenzoic acid (I-1) (0.41 mol, 1 eq) and DMF (0.5 mL) in DCM (500 mL) at RT, oxalyl chloride (0.45 mol, 1.1 eq) is added slowly over 5 min. The resulting mixture is stirred at RT for 2 h and then concentrated in vacuo to afford the product, methylbenzoyl chloride. The product is used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:12]([O:14]CC)=O)=[C:5]([CH:7]2[CH2:11][CH2:10][CH2:9][O:8]2)[N:6]=1.O1CCCC1C(Cl)=O.N[N:26]1C(C(OCC)=O)=C(C2CCCO2)[N:28]=[C:27]1C>>[CH3:1][C:2]1[N:3]2[C:4]([C:12](=[O:14])[NH:28][CH:27]=[N:26]2)=[C:5]([CH:7]2[CH2:11][CH2:10][CH2:9][O:8]2)[N:6]=1
Reactant: CCOC(=O)c1c(C2CCCO2)nc(C)n1N
Reactant: CCOC(=O)c1[nH]c(C)nc1C1CCCO1
Agent: O=C(Cl)C1CCCO1
Product: Cc1nc(C2CCCO2)c2c(=O)[nH]cnn12
Temperature: 25 °C

Procedure:
Ethyl 2-methyl-4-(tetrahydrofuran-2-yl)-1H-imidazole-5-carboxylate (C52) [prepared in an analogous manner to C63 in Preparation P2, by employing tetrahydrofuran-2-carbonyl chloride as starting material] (0.4 mol) was converted to ethyl 1-amino-2-methyl-4-(tetrahydrofuran-2-yl)-1H-imidazole-5-carboxylate (C53) using the general method for synthesis of C64 in Preparation P2. In this case, due to enhanced water-solubility, extraction was carried out with a mixture of ethyl acetate and tetrahydrofuran. The isolated material was judged by proton NMR analysis to be a 3:1 mixture of C53 and its regioisomer ethyl 1-amino-2-methyl-5-(tetrahydrofuran-2-yl)-1H-imidazole-4-carboxylate. The mixture was subjected to reaction with formamide and formamidine acetate, as described for the synthesis of P2 in Preparation P2. After the reaction was cooled to room temperature, it was partitioned between water and a mixture of ethyl acetate and tetrahydrofuran. The extracts were concentrated in vacuo, dissolved in a small volume of ethyl acetate, and the product was extracted into aqueous potassium carbonate solution. Adjustment of the aqueous layer to a mildly acidic pH resulted in precipitation of the product. Additional product was obtained by evaporating the aqueous layer to dryness, triturating the residue with methanol and filtering. The filtrate was treated with a small amount of water, and the methanol was removed in vacuo. Additional product precipitated from the aqueous residue. Combined yield: 13.5 g, 61 mmol, 15%. LCMS m/z 221.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 11.71 (br s, 1H), 7.81 (s, 1H), 5.33 (dd, J=6.8, 6.8 Hz, 1H), 3.87-3.93 (m, 1H), 3.70-3.76 (m, 1H), 2.46 (s, 3H), 2.04-2.18 (m, 3H), 1.85-1.96 (m, 1H).
Reaction SMILES: CC([N:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][C:18]2[CH:23]=[C:22]([CH:24]([F:26])[F:25])[CH:21]=[C:20]([C:27]#[N:28])[CH:19]=2)[C:11]=1[F:29])C(=O)[O-])(C)C.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[NH2:5][CH2:9][C:10]1[C:11]([F:29])=[C:12]([O:17][C:18]2[CH:19]=[C:20]([CH:21]=[C:22]([CH:24]([F:26])[F:25])[CH:23]=2)[C:27]#[N:28])[C:13]([Cl:16])=[CH:14][CH:15]=1
Reactant: CC(C)(C)N(Cc1ccc(Cl)c(Oc2cc(C#N)cc(C(F)F)c2)c1F)C(=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Oc2c(Cl)ccc(CN)c2F)cc(C(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a solution of 1,1-dimethylethyl[(4-chloro-3-{[3-cyano-5-(difluoromethyl)phenyl]oxy}-2-fluorophenyl)methyl]carbamate (210 mg, 0.492 mmol) in DCM (10 ml) was added TFA (3.0 mL, 38.9 mmol) and the reaction mixture was stirred at RT for 30 minutes. The solvent was removed and the crude material 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(difluoromethyl)benzonitrile trifluoroacetate (183 mg, 0.415 mmol, 84% yield) was used directly in the next step without purification. 1H NMR
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([CH2:12][NH2:13])[CH2:4][CH2:3]1.F[C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([CH2:12][NH:13][C:21]2[CH:20]=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=[CH:23][N:22]=2)[CH2:4][CH2:3]1
Reactant: O=C(O)c1ccncc1F
Reactant: CN1CCC(CN)c2ccccc21
Product: CN1CCC(CNc2cc(C(=O)O)ccn2)c2ccccc21
Yield: 18 %

Procedure:
The title compound was prepared in 18% yield from 1-(1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)methanamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 53. 1H NMR (400 MHz, DMSO-d6): δ 13.36 (br s, 1H), 8.35 (s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.72 (br s, 1H), 7.56 (d, 1H, J=5.0 Hz), 7.01-7.08 (m, 2H), 6.52-6.62 (m, 2H), 3.45-3.51 (m, 2H), 3.04-3.32 (m, 3H), 2.85 (s, 3H), 1.89-1.95 (m, 2H). [M+H] calc'd for C17H19N3O2, 298; found 298.
Reaction SMILES: [CH2:1]([CH:11]([CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:12]([OH:22])[CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl.[CH3:34][N:35]([CH3:42])[CH2:36][CH2:37][CH2:38][C:39](O)=[O:40].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:34][N:35]([CH3:42])[CH2:36][CH2:37][CH2:38][C:39]([O:22][CH:12]([CH:11]([CH2:1][CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:40]
Reactant: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)C(O)CC/C=C\CCCCC
Reactant: CN(C)CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)C(CC/C=C\CCCCC)OC(=O)CCCN(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To a solution of (6Z,15Z)-11-((Z)-dec-4-enyl)henicosa-6,15-dien-10-ol 17 (0.5 g, 1.1 mmol), 4-(dimethylamino)butanoic acid hydrochloride (0.3 g, 1.7 mmol), EDCI hydrochloride (0.3 g, 1.7 mmol), DIPEA (0.4 g, 3.4 mmol) in anhydrous dichloromethane (10 mL) was added DMAP (5 mg). The solution was stirred at room temperature overnight under a nitrogen atmosphere. The mixture is concentrated in vacuo to dryness then taken up in DCM (150 mL) and extracted with saturated sodium bicarbonate. The reaction mixture was purified by column chromatography on silica gel 60 (1:1 ethyl acetate/hexanes) to afford (6Z,15Z)-11-((Z)-dec-4-enyl)henicosa-6,15-dien-10-yl 4-(dimethylamino)butanoate 22 as a colorless oil (0.4 g, 67%). 1H NMR (400 MHz, CDCl3) δ 5.40-5.28 (m, 6H), 4.97-4.90 (m, 1H), 2.36-2.25 (m, 4H), 2.25-2.19 (m, 6H), 2.07-1.95 (m, 12H), 1.85-1.73 (m, 2H), 1.58-1.45 (m, 3H), 1.45-1.10 (m, 24H), 0.93-0.85 (m, 9H). Rf 0.4 (10% MeOH—CH2Cl2).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[Li]C1C=CC=CC=1.[Li]C(CC)C.CN([CH:38]=[O:39])C>C1COCC1>[CH3:22][O:21][C:13]1[CH:12]=[C:11]([C:7]2[CH:6]=[C:5]3[C:10]([C:2]([CH:38]=[O:39])=[N:3][NH:4]3)=[CH:9][CH:8]=2)[CH:16]=[CH:15][C:14]=1[O:17][CH2:18][O:19][CH3:20]
Reactant: COCOc1ccc(-c2ccc3c(I)n[nH]c3c2)cc1OC
Reactant: CN(C)C=O
Agent: [Li]C(C)CC
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Product: COCOc1ccc(-c2ccc3c(C=O)n[nH]c3c2)cc1OC
Temperature: -78 °C
Reaction time: 0.13 h
Yield: 71 %

Procedure:
In a 100-mL round-bottom flask, 3-iodo-6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole (921 mg, 2.245 mmol, 1.00 equiv) was dissolved in THF (36 mL) and cooled to −78° C. (allow 8 min at this scale). A solution of PhLi (2.5 mL, 1.8 M, 4.49 mmol, 2.00 equiv) was added and the mixture was allowed to stir for 30 min. A solution of s-BuLi (3.63 mL, 4.71 mmol, 2.1 equiv) was added and the reaction mixture was allowed to stir for 1 h at −78° C. Neat DMF (1.4 mL, 18 mmol, 8.0 equiv) was added. The cold bath was removed and the reaction was allowed to slowly warm to 0° C. in the air. As the ice melted saturated sodium bicarbonate (20 mL) was added. The product was extracted into ethyl acetate (200 mL) from saturated sodium bicarbonate (75 mL more), dried over sodium sulfate, decanted and concentrated under reduced pressure. Purification by silica gel chromatography (450 mL silica, 4:6 ethyl acetate/hexane) gave 6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole-3-carbaldehyde (498 mg, 71%)): Rf sm 0.30, p 0.14 (ethyl acetate-hexane 4:6); 1H NMR (CDCl3) δ 10.85 (bs, 1H), 10.25 (s, 1H), 8.37 (d, 1H, J=8.4 Hz), 7.67 (s, 1H), 7.60 (d, 1H, J=8.4 Hz), 6.26 (d, 1H, J=8.7 Hz), 7.19 (m, 2H), 5.30 (s, 2H), 3.99 (s, 3H), 3.55 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15](=[O:17])[CH3:16])[CH:6]=[C:7]([S:9]([F:14])([F:13])([F:12])([F:11])[F:10])[CH:8]=1.C(OC)(OC)OC.C1COCC1.[Br-:30].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>CO.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>[Br:30][CH2:16][C:15]([C:5]1[CH:6]=[C:7]([S:9]([F:10])([F:11])([F:12])([F:13])[F:14])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:17]
Reactant: [Br-]
Reactant: COc1cc(C(C)=O)cc(S(F)(F)(F)(F)F)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: C[N+](C)(C)c1ccccc1
Solvent: CO
Solvent: C1CCOC1
Solvent: COC(OC)OC
Product: COc1cc(C(=O)CBr)cc(S(F)(F)(F)(F)F)c1
Reaction time: 8 h
Yield: 68.5 %

Procedure:
1-[3-Methoxy-5-(pentafluorosulfanyl)phenyl]ethanone (34 mg) was dissolved in absolute methanol (3 ml). To this were added, while stirring, DL-camphorsulfonic acid (0.6 mg) and trimethyl orthoformate (40 mg). After stirring for 4 h, the mixture was left to stand overnight and then absolute THF (3 ml) and phenyltrimethylammonium tribromide (40 mg) were added while stirring. After stirring at RT for 2 h, the mixture was stirred at 50° C. for 3 h, left to stand over the weekend and, after adding further phenyltrimethylammonium tribromide (20 mg), stirred at 50° C. for another 5 h. The reaction mixture was concentrated, and the residue was taken up with acetonitrile and admixed with 5N sulfuric acid while stirring. After stirring for 2 h, the mixture was concentrated and the residue was purified by means of preparative HPLC. The product-containing fractions were combined, freed of the acetonitrile, admixed with saturated sodium hydrogencarbonate solution and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 15 mg of the desired compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][N:12]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.Cl[CH:19]([C:25](=O)[CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21].FC1C=NC=C(F)C=1C=O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][N:12]=2)[C:5]2[N:6]([C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:25]([CH3:26])[N:8]=2)[CH:7]=1
Reactant: Nc1ncc(Cl)cc1OCc1ncccc1F
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: O=Cc1c(F)cncc1F
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(OCc3ncccc3F)cc(Cl)cn12

Procedure:
3.00 g (11.83 mmol) of 5-chloro-3-[(3-fluoropyridin-2-yl)methoxy]pyridine-2-amine from Example 127A and 9.73 g (59.13 mmol) of ethyl 2-chloro-3-oxobutanoate were dissolved in 72 ml of ethanol and, together with 4.5 g of 3 A molecular sieve, stirred under reflux for 6 days. The mixture was cooled and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (mobile phase: cyclohexane/ethyl acetate gradient=4/1 to 2/1). This gave 2.0 g (46% of theory) of the target compound.