Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8](Br)[C:7]([NH2:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21].[C:23](N)(C)([CH3:25])[CH3:24]>C(O)(C)C.O.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([C:23]([CH3:25])=[CH2:24])[C:7]([NH2:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21]
Reactant: COC(=O)c1cc(Br)c(N)c(F)c1Nc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)N
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)O
Product: C=C(C)c1cc(C(=O)OC)c(Nc2ccc(Cl)cc2Cl)c(F)c1N
Yield: 49.5 %

Procedure:
A mixture of 4-amino-5-bromo-2-(2,4-dichlorophenylamino)-3-fluorobenzoic acid methyl ester (502 mg, 1.23 mmol), potassium isopropenyl trifluoroborate (218 mg, 1.47 mmol, Org. Lett. 2002, 4, 107), PdCl2(dppf)CH2Cl2 (101 mg, 0.122 mmol), and t-BuNH2 (0.39 mL, 3.67 mmol) in i-PrOH-H2O (2:1, 12 mL) was refluxed for 16 hours. The reaction mixture was diluted with EtOAc, washed with water, dried over MgSO4, filtered, and concentrated in vacuo to give the crude material which was purified by silica gel flash column chromatography (20% CH2Cl2 in hexanes) to give the desired product (225 mg, 49%).
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]([CH3:16])[S:8]([N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)(=[O:10])=[O:9].Cl[Si:18]([CH2:23][CH3:24])([CH2:21][CH3:22])[CH2:19][CH3:20].[Cl:25][C:26]1[CH:51]=[CH:50][C:29]([C:30]([C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[N:38]([CH3:42])[C:37](=[O:43])[CH:36]=[C:35]3[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:31])=[CH:28][CH:27]=1>O1CCCC1>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[N:38]([CH3:42])[C:37](=[O:43])[CH:36]=[C:35]3[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([OH:31])[C:14]2[N:13]=[C:12]([Si:18]([CH2:23][CH3:24])([CH2:21][CH3:22])[CH2:19][CH3:20])[N:11]([S:8]([N:7]([CH3:16])[CH3:6])(=[O:9])=[O:10])[CH:15]=2)=[CH:50][CH:51]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: Cn1c(=O)cc(-c2ccccc2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Reactant: CN(C)S(=O)(=O)n1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1nc(C(O)(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2ccccc2)cc(=O)n3C)cn1S(=O)(=O)N(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Butyllithium (30.1 ml) was added slowly at −78° C. to a solution of N,N-dimethyl-1H-imidazol-1-sulfonamide (8,4 g) in tetrahydrofuran (150 ml) and the mixture was stirred at −78° C. for 15 minutes. Chlorotriethylsilane (8.1 ml) was added and the mixture was stirred till the temperature reached 20° C. The mixture was cooled till −78° C., butyllithium (30.1 ml) was added, the mixture was stirred at −78° C. for 1 hour and allowed to reach −15° C. The mixture was cooled again till −78° C., a solution of 6-(4-chlorobenzoyl)-1-methyl-4-phenyl-2(1H)-quinolinone (15 g) in tetrahydrofuran (30 ml) was added and the mixture was stirred till the temperature reached 20° C. The mixture was hydrolized and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered off and evaporated till dryness. The product was used without further purification, yielding 26 g (100%) of (±)-4-[(4-chlorophenyl)(1,2-dihydro-1-methyl-2-oxo-4-phenyl-6-quinolinyl)hydroxymethyl]-N,N-dimethyl-2-(triethylsilyl)-1H-imidazole-1-sulfonamide (interm. 3-a).
Reaction SMILES: NC(N)=[S:3].Br[CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].Cl[CH2:22][C:23]([OH:25])=O>O>[CH:6]([CH2:22][C:23]([OH:25])=[S:3])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(N)=S
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: O=C(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OC(=S)CC(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 120.8 %

Procedure:
To a solution of thiourea (30.4 g, 0.399 mol) in water (200 mL) was added bromodiphenylmethane (98.8 g, 0.399 mol) at 42 degrees C. The mixture was heated gradually to reflux for 10 minutes. The reaction mixture was then cooled to 50 degrees C. and 5 N NaOH (200 mL) was subsequently added. The reaction mixture was then heated to reflux (101-102° C.) for 30 minutes and subsequently cooled to 60 degrees C. To this reaction mixture was slowly added a solution of chloroacetic acid (53.4 g, 0.565 mol) and NaOH (22.2 g) in water (150 mL) over 45 minutes. The reaction mixture was stirred for another 30 minutes. The reaction was then cooled to room temperature and washed with t-butylmethylether (200 ml) to remove any non carboxylic acid impurities. The aqueous layer was acidified (pH 2.0) using concentrated HCl (50 mL). The resulting precipitate was filtered, washed with water (2×200 mL) and heptane (200 mL) and allowed to air dry to give benzhydrylthioacetic acid (116.8 g, 100%) as a colorless solid. (See U.S. Pat. No. 4,066,686)
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([NH2:7])[NH:4][N:3]=1.[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11]>O>[O-:12][C:10]([C:9]([F:14])([F:13])[F:8])=[O:11].[NH2:1][C:2]1[NH:3][NH+:4]=[C:5]([NH2:7])[N:6]=1
Reactant: Nc1n[nH]c(N)n1
Reactant: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1nc(N)[nH+][nH]1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3,5-Diamino-1,2,4-triazole (1.50 g, 15.14 mmol) was dissolved in 5 ml of distilled water. Trifluoroacetic acid (1.12 ml, 15.14 mmol) was added via syringe at room temperature and the reaction was stirred at room temperature for 1 hour. The water was removed in vacuo with heating to approximately 90° C. for 4 hours.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:18]=4[O:19][CH2:20][C:21](=O)[CH3:22])=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:29].[CH3:30][NH:31][CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C1COCC1.ClCCCl.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:18]=4[O:19][CH2:20][CH:21]([N:31]([CH3:32])[CH3:30])[CH3:22])=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:29]
Reactant: CC(=O)COc1cc(F)ccc1C(=O)N1Cc2nn3c(C)c(Cl)c(C)nc3c2C1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1OCC(C)N(C)C)C3
Temperature: 70 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
A mixture of Example 164 (90 mg; 0.22 mmol; 1 eq.), a 2M solution of dimethylamine in THF and sodium triacetoxyborohydride (59 mg; 0.28 mmol; 1.3 eq.) in DCE (2 mL) was stirred at 50° C. for 1 hour whereupon triacetoxyborohydride (59 mg; 0.28 mmol; 1.3 eq.) was added. The resulting mixture was stirred at 70° C. for 3 hours then diluted with ethyl acetate. The solution was washed with 0.1M NaOH, dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography (EA to 10 MeOH in EA) afforded the title compound (27 mg, 28%) as a white solid. 1H NMR (DMSO-d6) δ 7.42-7.26 (m, 1H), 7.09 (d, J=11.5 Hz, 1H), 6.86 (t, J=8.2 Hz, 1H), 4.78 (d, J=7.9 Hz, 2H), 4.59 (d, J=15.0 Hz, 2H), 4.13-3.89 (m, 2H), 2.92-2.74 (m, 4H), 2.61 (s, 1.4H), 2.56 (s, 1.6H), 2.06 (s, 6H), 0.95-0.78 (m, 3H). HPLC (max plot) 99.9%, Rt 2.77 min. UPLC/MS: (MS+) 446.3 ([M+H]+).
Reaction SMILES: [C:1]([Cl:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:10]1([CH2:15][CH2:16][CH2:17][NH:18][C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])[CH:14]=[CH:13][N:12]=[CH:11]1.C(=O)(O)[O-].[Na+].[ClH:29]>ClCCl.CCOCC.C(N(CC)CC)C>[ClH:9].[ClH:29].[C:1]([O:21][CH2:20][C:19]([NH:18][CH2:17][CH2:16][CH2:15][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)([CH3:23])[CH3:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CO)NCCCn1ccnc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(COC(=O)c1ccccc1)NCCCn1ccnc1
Temperature: 0 °C

Procedure:
A solution of benzoyl chloride (0.36 g) in dichloromethane (1.5 ml) was added dropwise to a mixture of 2-[3-(imidazol-1-yl)propylamino]-2-methyl-1-propanol (0.5 g) and triethylamine (0.5 g) in dichloromethane (5 ml) with stirring under nitrogen at 0° C. The mixture was stirred at 0° C. for 1 hour and then allowed to warm up to ambient temperature and stirred at this temperature for 3 hours. Saturated aqueous sodium bicarbonate (5 ml) was added. The mixture was shaken and the organic layer separated. The aqueous layer was extracted with further dichloromethane. The combined organic extracts were dried, filtered and evaporated to give an oil which was dissolved in ether and treated with ethereal hydrogen chloride to give 2-[3-(imidazol-1-yl)propylamino]-2,2-dimethylethyl benzoate dihydrochloride, m.p. 198-199° C., after recrystallisation from ethanol.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH3:7])[CH:5]=[CH:4][N:3]=1.C([Li])CCC.[F:13][C:14]([F:24])([F:23])[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.[OH2:25]>C1COCC1>[OH:25][C:16]1([CH:19]=[CH:20][CH:21]=[CH:22][CH:15]1[C:14]([F:24])([F:23])[F:13])[CH2:17][C:5]1[N:6]([CH3:7])[C:2]([SH:1])=[N:3][CH:4]=1
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: O
Reactant: Cn1ccnc1S
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(CC2(O)C=CC=CC2C(F)(F)F)cnc1S
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-mercapto-3-methylimidazole in dry THF (100 ml) at 0° C. was added an n-butyl lithium solution (2.5M, 35.1 ml) over 10 minutes. The mixture was allowed to warm to room temperature and stirred for 3 hours. A white solid formed during this time. The temperature was brought down to 0° C. and 2-trifluoromethylbenzaldehyde (7.63 g) was added slowly over 15 minutes. The color turned dark brown. After 30 minutes, water (4 ml) was added to quench the reaction. The mixture was allowed to stir overnight. The 4-(1-hydroxy-2'-trifluoromethylbenzyl)-2-mercapto-3-methylimidazole formed (8.8 g) was collected by filtration, washed with 1:1 diethyl ether:hexanes and air dried.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]4)=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4].C([Cl:34])(=O)C>>[ClH:34].[CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[CH2:20][NH:19][CH2:18]4)=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)Cl
Reactant: CCCCNc1ccc2ncc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)C4)n2n1
Product: CCCCNc1ccc2ncc(-c3ccc4c(c3)CNC4)n2n1
Product: Cl
Temperature: 25 °C
Yield: 38.8 %

Procedure:
The solution of tert-butyl 5-(6-(butylamino)imidazo[1,2-b]pyridazin-3-yl)isoindoline-2-carboxylate (38 mg, 0.09 mmol) was cooled to 0° C. and treated with acetyl chloride (220 mg, 2.8 mmol). The reaction was maintained at room temperature for overnight. The resulting solution was concentrated under reduced pressure to afford N-butyl-3-(isoindolin-5-yl)imidazo[1,2-b]pyridazin-6-amine hydrochloride (12 mg, 35% yield) as a white solid: 1H NMR (METHANOL-d4) δ: 8.26 (s, 1H), 8.17-8.21 (m, 2H), 7.98 (d, J=10.1 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.27 (d, J=9.9 Hz, 1H), 4.76 (s, 4H), 3.36-3.45 (m, 2H), 1.63-1.81 (m, 2H), 1.40-1.56 (m, 2H), 1.00 (t, J=7.3 Hz, 3H); LRMS (ESI) m/e 308.4 [(M+H)+, calcd for C18H22N5 308.2].
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8](OC)=[O:9])=[CH:6][C:5]([NH:12][C:13]([NH:15][CH2:16][CH3:17])=[O:14])=[N:4][CH:3]=1.[NH3:18]>CO>[Br:1][C:2]1[C:7]([C:8]([NH2:18])=[O:9])=[CH:6][C:5]([NH:12][C:13]([NH:15][CH2:16][CH3:17])=[O:14])=[N:4][CH:3]=1
Reactant: N
Reactant: CCNC(=O)Nc1cc(C(=O)OC)c(Br)cn1
Solvent: CO
Product: CCNC(=O)Nc1cc(C(N)=O)c(Br)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 95 %

Procedure:
A solution of methyl 5-bromo-2-(3-ethylureido)isonicotinate (Intermediate 4, 261 g, 865 mmol) and 7N ammonia in methanol (1.7 L) was allowed to stir at room temperature for 3 d. The solid that precipitated was then collected by filtration, rinsed with methanol (2×500 mL), and then dried on a high vacuum pump overnight, yielding 237 g (95%) of 5-bromo-2-(3-ethylureido)isonicotinamide as a smooth white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19](/[CH:26]=[CH:27]/[C:28](=O)[CH2:29][CH3:30])=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O>C(O)(=O)C.C(O)C.[Fe]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3=[C:19]4[C:20](=[CH:21][CH:22]=[C:16]3[O:15][CH2:14]2)[N:23]=[C:28]([CH2:29][CH3:30])[CH:27]=[CH:26]4)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCC(=O)/C=C/c1c([N+](=O)[O-])ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCc1ccc2c3c(ccc2n1)OCC(COS(=O)(=O)c1ccc(C)cc1)O3

Procedure:
To a solution of {(2R)-7-nitro-8-[(E)-3-oxo-1-pentenyl]-2,3-dihydro-1,4-benzo-dioxin-2-yl}methyl 4-methylbenzenesulfonate (1.57 g, 3.50 mmole) in 100 mL of acetic acid/ethanol (1:1) was added 1.00 g (17.9 mmole) of iron powder and the mixture was heated at reflux under nitrogen for 8 hours. After the reaction was complete, 150 mL of water was added and the mixture filtered through a pad of celite. The filtrate was neutralized with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered and evaporated in vacuum. The residue was column chromatographed on silica gel using a gradient elution commencing with 20% ethyl acetate/hexane and ending with 70% ethyl acetate/hexane to give 0.94 g of the (R)-enantiomer of the title compound as a yellow oil. 1H-NMR (CDCl3): doublet 8.2 δ(1 H); doublet 7.8 δ(2 H); doublet 7.55 δ(1 H); 7.2-7.3 δ(4 H); multiplet 4.6 δ(1 H); multiplet 4.2-4.4 δ(3 H); multiplet 4.1 δ(1 H); quartet 3.0 δ(2 H); singlet 2.4 δ(3 H); triplet 1.4 δ(3 H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH3:17])[N:15]=[C:14]([C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[N:13]=2)=[CH:8][C:7]=1[Cl:26])(=O)C.[OH-].[Na+].C(OCC)(=O)C>C(O)C.O>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:18]=1[C:14]1[N:13]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][OH:4])=[C:7]([Cl:26])[CH:8]=2)[N:16]([CH3:17])[N:15]=1
Reactant: CC(=O)OCc1ccc(-c2nc(-c3c(F)cccc3Cl)nn2C)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CO)c(Cl)c1
Temperature: 25 °C
Yield: 67.6 %

Procedure:
5-(4-acetoxymethyl-3-chlorophenyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole (11.1 g) is dissolved in a mixed solvent of ethanol (50 ml) and water (20 ml), added with sodium hydroxide (2.3 g) and heated under reflux for 1 hour with stirring. After cooling to room temperature, the reaction mixture is added with ethyl acetate and washed with water. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain crude solid. The crude solid is washed with mixed solvent of hexane-ethanol to give 6.7 g of desired compound (melting point: 111°-113° C.).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.Cl.NCC(N[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(O)C)C1)=O.[NH2:41][C@@H:42]1[CH2:61][CH2:60][C@@:59]2([CH3:62])[C@@H:44]([CH2:45][CH2:46][C@@H:47]3[C@@H:58]2[CH2:57][CH2:56][C@@:55]2([CH3:63])[C@H:48]3[CH2:49][CH2:50][C@@H:51]2[CH:52]([OH:54])[CH3:53])[CH2:43]1.[C:64]([NH:71][C@H:72]([C:74](O)=[O:75])[CH3:73])([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:69][C:67]([CH3:70])([O:66][C:64]([NH:71][CH:72]([CH3:73])[C:74]([NH:41][C@@H:42]1[CH2:61][CH2:60][C@@:59]2([CH3:62])[C@@H:44]([CH2:45][CH2:46][C@@H:47]3[C@@H:58]2[CH2:57][CH2:56][C@@:55]2([CH3:63])[C@H:48]3[CH2:49][CH2:50][C@@H:51]2[C@@H:52]([OH:54])[CH3:53])[CH2:43]1)=[O:75])=[O:65])[CH3:68]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](NC(=O)CN)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(NC(=O)OC(C)(C)C)C(=O)N[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)O)CC[C@@H]32)C1
Reaction time: 0.83 h

Procedure:
1.14 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride were added with stirring under an inert atmosphere at 0° to 5° C. to a solution of 1.92 g of (20S) 3α-amino-5α-pregnan-20-ol, 2.27 g of tert.-butyloxycarbonyl-L-alaine (BOC-L-Alanine), 60 ml of chloroform and 12 ml of pyridine and the mixture was stirred for 75 minutes after which another 1.15 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride was added thereto. The mixture was stirred at 0° to 5° C. for 50 minutes and was evaporated to dryness. The residue was taken up in aqueous sodium bicarbonate solution and the solution was extracted with ethyl acetate. The organic phase was washed with aqueous saturated sodium chloride and then with aqueous N hydrochloric acid and then with aqueous saturated sodium chloride solution, dried and evaporated to dryness. The residue was crystallized from isopropyl ether and was vacuum filtered. The product was rinsed with isopropyl ether and dried at 60° C. under reduced pressure to obtain 2-[1,1-dimethylethoxycarbonylamino]-N-[(20S)-5α-pregnan-20-ol-3α-yl]-propanamide melting at 171° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[N:28][CH:29]=1.[F:33][C:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[CH:36][N:35]=1>>[F:23][C:24]1[CH:25]=[C:26]([C:2]2[CH:3]=[C:4]3[C@@:15]4([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]4)[C:14]4[CH:13]=[C:12]([C:38]5[CH:37]=[CH:36][N:35]=[C:34]([F:33])[CH:39]=5)[N:11]=[CH:10][C:9]=4[O:8][C:5]3=[CH:6][CH:7]=2)[CH:27]=[N:28][CH:29]=1
Reactant: NC1=N[C@@]2(CCO1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Reactant: OB(O)c1cncc(F)c1
Reactant: OB(O)c1ccnc(F)c1
Product: NC1=N[C@@]2(CCO1)c1cc(-c3cncc(F)c3)ccc1Oc1cnc(-c3ccnc(F)c3)cc12

Procedure:
The titled compound was synthesized by steps analogous to those described in method A1 above, but using intermediate 18B, 5-fluoropyridin-3-ylboronic acid and 2-fluoropyridin-4-ylboronic acid. MS m/z=458.0 [M+H]+. Calculated for C25H17F2N5O2: 457.43
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:13])([CH3:3])[CH3:2].C1N2CN3CN(C2)CN1C3.CCCCCC.FC(F)(F)[C:32](O)=[O:33]>>[CH:10]([C:6]1[CH:7]=[C:8]([CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[OH:13])[CH:32]=[O:33])([CH3:12])[CH3:11]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Solvent: CCCCCC
Product: CC(C)c1cc(C=O)cc(C(C)C)c1O
Yield: 26 %

Procedure:
18 g of 2,6-di isopropyl phenol and 1.8 g HMTA (hexamethylene tetraamine) in 60 ml TFA (trifluoro acetic acid) was refluxed 3.5 hours. Workup, chromatography on silica gel (CH2Cl2) and trituration with hexane gave 5.3 g, 26% yield, white solid, mp-103° C. (3,5,-di-iso-propyl 4 hydroxybenzaldehyde). NMR CDCl3 δ 9.87 (1H, S, CHO), 7.63 (2H, S), 3.19 (2H, septet, J=7.7 Hz), 1.30 (12H, d, J=7.7 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].Br[CH2:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[C:17]#[N:18]>CN(C)C=O>[ClH:11].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:13][C:14]2[CH:15]=[C:16]([C:17]#[N:18])[CH:19]=[CH:20][C:21]=2[Cl:22])[CH:9]=1
Reactant: N#Cc1ccc(Cl)c(CBr)c1
Reactant: NC(=O)c1cc(Cl)cnc1N
Solvent: CN(C)C=O
Product: Cl
Product: N#Cc1ccc(Cl)c(Cn2cc(Cl)cc(C(N)=O)c2=N)c1
Temperature: 100 °C
Reaction time: 14 h
Yield: 27.5 %

Procedure:
(Step 2) To a solution of 2-amino-5-chloronicotinamide (0.15 g) in N,N-dimethylformamide (3 ml) was added 3-(bromomethyl)-4-chlorobenzonitrile (0.31 g), and the mixture was stirred at 100° C. for 14 hr. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=3:2-19:1). 2N Hydrochloric acid-methanol solution (1 ml) was added to the obtained yellow oil at room temperature, and the obtained precipitate was recrystallized from methanol-ethyl acetate to give the title compound (43 mg).
Reaction SMILES: C[N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.[CH2:8]([C@H:11]1[CH2:16][CH2:15][C@H](C=CBr)[CH2:13][CH2:12]1)[CH2:9][CH3:10].[Cu](C#N)C#N>Cl>[CH2:8]([C@H:11]1[CH2:16][CH2:15][C@H:6]([CH:5]=[CH:4][C:3]#[N:2])[CH2:13][CH2:12]1)[CH2:9][CH3:10]
Reactant: CCC[C@H]1CC[C@H](C=CBr)CC1
Reactant: CN1CCCC1=O
Agent: N#C[Cu]C#N
Agent: Cl
Product: CCC[C@H]1CC[C@H](C=CC#N)CC1

Procedure:
To 30 ml of N-methylpyrrolidone was dissolved 3 g of 2-(trans-4-propylcyclohexyl)ethenyl bromide, 2 g of copper cyanide was added thereto, and then stirred under reflux by heating for 7 hours. A solution of ferric chloride in 6N hydrochloric acid was added to the reaction liquid, and extracted with toluene. The organic layer thus obtained was washed with water, dried, and then concentrated under a reduced pressure to obtain a brown oily product. This product was isolated and purified by using silica gel column chromatography to obtain 1.5 g of an oily product. As a result of various instrumental analysises, the product was confirmed to be the subject compound.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15].CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: OCCCCCCCBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: BrCCCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 849.9 %

Procedure:
Dihydropyran (5.20 g, 6.11 mmol) was added to a stirring 0° C. solution of 7-bromoheptane-1-ol (2) (11.0 g, 56.7 mmol) and a catalytic amount of PTSA in CH2Cl2. After stirring at rt for 12 h, the reaction mixture was diluted with CH2Cl2 (200 mL), washed with water (100 mL×2), brine (100 mL×3), dried over anhydrous sodium sulphate, and evaporated. The residue was purified by silica gel column chromatography using a gradient of 10-20% ethyl acetate/hexane as eluent to give 2-(7-bromoheptyloxy)tetrahydro-2H-pyran (3) (14.50 g, 92%) as a colorless oil. TLC: 10% EtOAc/hexanes, Rf≈0.55; 1H NMR (400 MHz, CDCl3) δ 4.58-4.56 (m, 1H), 3.84-3.88 (m, 1H), 3.68-3.77 (m, 1H), 3.46-3.51 (m, 1H), 3.33-3.43 (m, 3H), 1.80-1.81 (m, 2H), 1.30-1.62 (m, 14H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]2)[CH:5]=[C:4]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([OH:32])[CH:30]=3)[N:25]([S:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:24]=2)[CH:3]=1.N(C(OC(C)(C)C)=O)=NC(O[C:47](C)(C)[CH3:48])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]2)[CH:5]=[C:4]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([O:32][CH2:47][CH3:48])[CH:30]=3)[N:25]([S:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:24]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2cc(-c3cn(S(=O)(=O)c4ccccc4)c4ncc(O)cc34)cc(Cl)n2)CC1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1cnc2c(c1)c(-c1cc(Cl)nc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c1)cn2S(=O)(=O)c1ccccc1

Procedure:
A mixture of Example 224a (80.0 mg, 0.134 mmol), di-tert-butyl azodicarboxylate (77 mg, 0.334 mmol), triphenylphosphine on solid support (3 mmol/g, 112.0 mg, 0.427 mmol) and ethanol (0.039 mL, 0.669 mmol) in THF (3 mL) was stirred at room temperature overnight. The mixture was diluted with EtOac, filtered through celite, concentrated and purified on a 12 g column using the ISCO Companion flash system eluting with hexane/EtOAc (8:2 to 6:4) to give 76.1 mg of the title compound.