Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[N:11]([C:12]2[S:13][C:14]([CH2:26][CH3:27])=[CH:15][C:16]=2[C:17](=[O:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:10]([CH3:28])=[N:9][N:8]=1.O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:3][CH2:6][C:7]1[N:11]([C:12]2[S:13][C:14]([CH2:26][CH3:27])=[CH:15][C:16]=2[C:17](=[O:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:10]([CH3:28])=[N:9][N:8]=1
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CO)s1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CCl)s1
Reaction time: 2 h
Yield: 88.5 %

Procedure:
Four grams of thionyl chloride is added dropwise to a solution of 10 g of 3-hydroxymethyl-4-(3-o-chlorobenzoyl-5-ethyl-2-thienyl)-5-methyl-4H-1,2,4-triazole in 50 ml of dioxane. The mixture is stirred at 70° - 80°C for 2 hours. The reaction mixture is poured into 200 ml of water and made alkaline with potassium carbonate. The oil liberated is extracted with ethyl acetate. The extract is washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is treated with ligroin containing 5% ethyl acetate to cause crystallization. The crystals are collected by suction filtration and recrystallized from ligroin containing 5% ethyl acetate to give 9.3 g of 3-chloromethyl-4-(3-o-chlorobenzoyl-5-ethyl-2-thienyl)-5-methyl-4H-1,2,4-triazole as colorless pillars melting at 109° - 110°C.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[C:14](=[O:16])[NH:13][CH2:12]2)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:6]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[C:14](=[O:16])[NH:13][CH2:12]2)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1cccc2c1C(=O)NC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cccc2c1C(=O)NC2
Reaction time: 1.5 h
Yield: 76.3 %

Procedure:
To a solution of 7-((trimethylsilyl)ethynyl)isoindolin-1-one (160) (0.172 g, 0.634 mmol) in dry THF (8 mL) under an atmosphere of nitrogen was added TBAF (1.0 M in THF, 0.697 mL, 0.697 mmol) dropwise at 0° C. The solution was stirred at this temperature for 1.5 hours and then quenched by the addition of water (2 mL). The reaction mixture was concentrated in vacuo and diluted with DCM (100 mL) and sat. aq. NaHCO3 (70 mL). The layers were separated and the aqueous layer was extracted with DCM (70 mL), the combined organic layers were washed with water (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give a beige solid. The crude product was purified by silica gel chromatography (Biotage Isolera, 12 g Si Cartridge, 0-80% EtOAc in DCM) to give the title compound (I61) (0.076 g, 76% yield) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 8.59 (s, 1H), 7.61-7.50 (m, 3H), 4.39 (s, 1H), 4.33 (s, 2H). LCMS Method C: rt 4.56 min, m/z 158.1 [M+H]+.
Reaction SMILES: C(Cl)CCl.[C-:5]1([C:10]([OH:12])=O)[CH:9]=[CH:8][CH:7]=[CH:6]1.[CH-:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.[Fe+2:18].ON1C(=O)CCC1=O.[Cl-].[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34][S:35][CH2:36][CH2:37][NH3+:38].CCN(CC)CC>C(Cl)Cl>[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34][S:35][CH2:36][CH2:37][NH:38][C:10]([C:5]1[CH-:6][CH:7]=[CH:8][CH:9]=1)=[O:12].[CH-:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.[Fe+2:18]
Reactant: [NH3+]CCSSc1ccccn1
Reactant: O=C(O)[c-]1cccc1
Agent: [Fe+2]
Agent: O=C1CCC(=O)N1O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NCCSSc1ccccn1)c1ccc[cH-]1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
EDC (213 mg, 1.1 mmol) was added to a solution of ferrocenecarboxylic acid (232 mg, 1.0 mmol) and N-hydroxysuccinimide (128 mg, 1.1 mmol) dissolved in 20 mL of CH2Cl2. The solution was stirred at room temperature for 5 h and concentrated. The crude residue was dissolved in 8 mL of DMF and 2-(pyridin-2-yldisulfanyl) -ethyl-ammonium chloride (222 mg, 1.0 mmol) was added followed by Et3N (0.14 mL, 1.0 mmol). After stirring for 48 h, the solvent was evaporated in vacuo. The crude residue was purified by flash chromatography (gradient: hexanes/EtOAc, 1:1, v/v to EtOAc) to afford 113 mg (28% over 2 steps) of 12. 1H NMR 400 MHz (CDCl3) d 8.56 (m, 1H), 7.61 (m, 1H), 7.52 (m, 1H), 7.43 (t, J=6.8 Hz, 1H), 7.15 (m, 1H), 4.75 (m, 2H), 4.34 (m, 2H), 4.20 (s, 5H), 3.63 (q, J=6.0 Hz, 2H), 2.98 (t, J=6.0 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])=[C:6]([CH3:16])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:24](Cl)(Cl)=[S:25]>C(Cl)(Cl)Cl.ClCCl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:9][CH2:10][CH2:11][N:12]([CH:13]([CH3:14])[CH3:15])[C:24]2=[S:25])=[C:6]([CH3:16])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(Cl)c1NCCCNC(C)C
Reactant: S=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cccc(Cl)c1N1CCCN(C(C)C)C1=S
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To an ice-cold solution of the diamine of Step A (8.2 g) and triethylamine (9.09 mL) in dry chloroform (180 mL) under nitrogen was added thiophosgene (3.92 mL). After 10 minutes in the cold and 30 minutes at ambient temperature, the pH was adjusted to 8 with triethylamine and the reaction was quenched with water and extracted with dichloromethane. The combined extracts were dried over sodium sulfate, and concentrated in vacuo to give a brown oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with 11% ethyl acetate in hexane provided a white crystalline solid which was triturated with diethyl ether to give the title product (4.5 g, 46%), m.p. 135-136° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].Br[CH2:24][CH2:25][CH3:26].O>CN(C)C=O>[CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([N:17]([CH2:24][CH2:25][CH3:26])[C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: CC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(C(C)=O)c1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 1 h

Procedure:
To 10.0 g of N-[3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl) phenyl]acetamide in 500 ml of dry dimethylformamide under argon, was added 2.0 g of sodium hydride (50% in oil). This mixture was stirred for 1 hour, then 3.75 ml of 3-bromopropane was added. This mixture was stirred for 2.5 days, then poured into 1 liter of water and extracted with 150 ml portions of dichloromethane. The extracts were combined, dried and evaporated in vacuo. The residue was chromatographed as described in Example 1, giving 3.60 g of the desired product as yellow crystals, mp 145°-49° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH:13]2[C:21]([OH:23])=O)(=[O:11])=[O:10])=[CH:5][CH:4]=1.ClC(OCC)=O.CN1CCOCC1.C[Si](C)(C)[O:39][NH2:40].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C(=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH:13]2[C:21]([NH:40][OH:39])=[O:23])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3CC2C(=O)O)cc1
Reactant: C[Si](C)(C)ON
Agent: CCOC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)N2c3ccccc3CC2C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.3 g (3.9 mmol) of the 1-(4-methoxybenzenesulfonyl)indoline-2-carboxylic acid of Example 28a are dissolved in 10 ml of N,N-dimethylacetamide (DMA) and, at −20° C., admixed successively with 0.37 ml (1 equivalent) of ethyl chloroformate and 0.81 ml of N-methylmorpholine. After an activation time of 30 minutes (min), the mixture is admixed with 3.8 ml (19.5 mmol) of O-trimethylsilylhydroxylamine and stirred at RT for a further 4 h. The mixture is diluted with ethyl acetate, acidified with citric acid and, after removal of the aqueous phase, washed with saturated NaCl solution. The organic phase is dried over sodium sulfate, filtered off and concentrated under reduced pressure. The resulting oil is subjected to chromatography under pressure over silica gel 60 using dichloromethane/ethyl acetate/acetic acid 5.5/3.5/1 as mobile phase. Product fractions (showing positive iron(III) chloride-reaction) are pooled and concentrated. The crystalline product is subsequently admixed with diethyl ether and freed of residual solvent under reduced pressure.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5]C(=O)OC(C)(C)C)[CH2:2]1.[F:13][CH2:14][C:15](=O)[CH2:16][F:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:13][CH2:14][CH:15]([N:1]1[CH2:2][CH:3]([NH2:5])[CH2:4]1)[CH2:16][F:17]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: O=C(CF)CF
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: NC1CN(C(CF)CF)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl azetidin-3-ylcarbamate (0.256 g) and 1,3-difluoropropan-2-one (0.154 g) in dichloromethane (2 mL) was added sodium triacetoxyborohydride (0.473 g) and the reaction was allowed to stirred at room temperature. After 16 hours, the reaction was quenched with saturated NaHCO3 solution (10 mL) and extracted into dichloromethane (25 mL). The organic layer was dried and concentrated. Silica gel chromatography (GraceResolv 12 g) eluting with a gradient of 0.5% to 3.5% methanol/dichloromethane followed by treatment with HCl (4.0M in dioxane, 3 mL) and methanol (0.5 mL) for 2 hours gave the title compound after concentration.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:13])[C:5]([N:8]([CH2:10][CH2:11]Cl)[CH3:9])=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]([CH3:9])[CH2:10][CH2:11][NH:13]2
Reactant: CN(CCCl)c1ccc(Br)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCNc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101.1 %

Procedure:
A solution of 4-bromo-N′-(2-chloroethyl)-N′-methylbenzene-1,2-diamine (25D) (0.611 g, 2.3 mmol) and K2CO3 (0.634 g, 4.6 mmol) in DMF (7 mL) was heated to 80° C. for 1 hour and then at 100° C. for 1.5 hours, cooled to rt, diluted with water and extracted with EtOAc. The organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to provide 0.528 g (100%) of the desired product 6-bromo-1-methyl-1,2,3,4-tetrahydroquinoxaline (25E): 1H NMR (300 MHz, CDCl3) δ 6.72 (1H, dd), 6.56 (1H, d), 6.38 (1H, d), 3.74 (1H, bs), 3.47 (2H, t), 3.22 (2H, t), 2.82 (3H, s).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.[C:15]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[C:26](=O)[C:27](OC)=[O:28])#[N:16].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[C:15]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[C:26]1[C:27](=[O:28])[NH:14][C:12](=[O:13])[C:11]=1[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2)#[N:16]
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Reactant: COC(=O)C(=O)c1c[nH]c2ccc(C#N)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1ccc2cccc(C3=C(c4c[nH]c5ccc(C#N)cc45)C(=O)NC3=O)c21
Temperature: 50 °C
Yield: 10.1 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)acetamide (296 mg, 1.57 mmol) and methyl 2-(5-cyano-1H-indol-3-yl)oxoacetate (356 mg, 1.56 mmol) in DMF (6.5 mL) was added a 1.0 M solution of potassium tert-butoxide in THF (4.8 mL, 4.8 mmol) dropwise over 20 min at 4° C. under N2. The resulting dark red solution was heated up to 50° C. for 6 h. The mixture was cooled to 4° C. and quenched with 1.0 N hydrochloric acid (10 mL) and poured into EtOAc (100 mL). The organic layer was separated, washed with saturated NaHCO3 (60 mL), saturated NaCl (60 mL), dried (MgSO4), and concentrated to a red solid. Filtration from a slurry in CH2Cl2 (15 mL) afforded the first batch of the title compound (58 mg, 7.4%) as a red crystalline solid, mp 220° C. dec. Tritration of the concentrated filtrate with Et2O (8.0 mL) afforded a second batch of the title compound (288 mg, 36.9%). 1H NMR (DMSO-d6) δ 8.09 (s, 1H), 7.68 (m, 1H), 7.51 (m, 1H), 7.28–7.19 (m, 2H), 7.09–6.92 (m, 2H), 6.47 (m, 2H), 3.60 (s, 3H). MS (ESI): m/z=367 [C22H14N4O2+H]+
Reaction SMILES: [CH2:1]([O:11][CH:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].P(Br)(Br)[Br:21].CO.C(=O)([O-])O.[Na+]>C(OCC)C>[CH2:1]([O:11][CH:12]([Br:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCCCCCCCOC(O)c1ccccc1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: C=CCCCCCCCCOC(Br)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 223.9 %

Procedure:
First, 16.05 g (0.061 M) of 9-decenoxybenzyl alcohol (compound (23)) prepared in Synthetic example 1-2 was dissolved in 85 mL of diethyl ether, and the solution was cooled to 0° C. After cooling, 6.76 g (0.022 M) of phosphorus tribromide (compound (21)) was added dropwise thereto at 5° C. or less. The mixture was aged at 5° C. for 2 hours and then at 15° C. for 1.5 hours. After aging, the solution was cooled to 50° C. Then, 38 mL of methanol was added dropwise at 50° C. or less. After dropwise addition, 73.4 g of a sodium hydrogen carbonate aqueous solution (1 M) was added dropwise at 10° C. or less, and then phase separation was performed. After the separation, the separated organic layer was washed with 32 mL of deionized water and then concentrated. Thereby, 18.19 g of 9-decenoxybenzyl bromide (compound (24)) was produced (yield: 91.6%).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.Br[C:31]1[CH:32]=[N:33][CH:34]=[N:35][CH:36]=1.N[C@@H]1CCCC[C@H]1N.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Cu]I>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:31]3[CH:32]=[N:33][CH:34]=[N:35][CH:36]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: Brc1cncnc1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cncnc2)CC1

Procedure:
A mixture of (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1, 100 mg, 1.0 eq.), 5-bromopyrimidine (44 mg, 1.1 eq.), trans-1,2-diaminocyclohexane (18 mg, 0.65 eq.), copper(I) iodide (6 mg, 0.12 eq.) and potassium phosphate tribasic (110 mg, 2.1 eq.) in dioxan (2.0 mL) was stirred under reflux for 3 d. Potassium carbonate (72 mg, 2.1 eq.) was added and the mixture was refluxed for 1 d, evaporated to dryness and purified on silica gel, eluting with a 49:1:0 to 95:5:0.25 gradient of dichloromethane/methanol/ammonium hydroxide, to yield 121 mg (100%) from the desired product as orange oil. MS (m/e): 484.4 (MH+, 100%).
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][Si](C(C)C)(C(C)C)C(C)C)=[C:7]([F:23])[C:3]=1C(O)=O.C(Cl)(C(Cl)=O)=O.[N-:30]=[N+]=[N-].[Na+].[OH-].[K+].Cl>C(Cl)Cl.CN(C=O)C.CC(C)=O.O.O1CCOCC1>[NH2:30][C:3]1[C:7]([F:23])=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:2]=1[F:1]
Reactant: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c(C(=O)O)c1F
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(O)c(F)c(N)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of 2,6-difluoro-3-methyl-5-triisopropylsilyloxy-benzoic acid (1.08 g, 3.14 mmol, 1.0 eq) in CH2Cl2 (15 mL) was added (COCl)2 (1.19 g, 9.40 mmol, 3.0 eq) dropwise at 0° C. DMF (3 drops) was added and the mixture warmed to room temperature and stirred for 1 h. The reaction mixture was concentrated to dryness, and the residue obtained was dissolved in acetone (20 mL) and added dropwise to a cooled solution of NaN3 (815 mg, 12.5 mol, 4 eq) in a mixture of acetone (10 mL) and water (10 mL) at 0° C. The reaction was stirred for 1 h at 0° C., further water (20 mL) was then added and the reaction heated at 70° C. overnight. The reaction was partitioned between EtOAc and water and extracted with EtOAc, the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was dissolved in dioxane (25 mL), aqueous KOH (25% aqueous solution, 12 mL) was added and the reaction heated at reflux overnight. The reaction was then cooled to room temperature and acidified to pH 5-6 with 1M HCl. The aqueous layer was extracted with EtOAc and the combined organic extracts washed with water, brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum Ether: EtOAc, 50:1 to 20:1) to give the title compound as a white solid (270 mg, 87%).
Reaction SMILES: [P:1](Cl)([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])([O:3][CH2:4][CH:5]([CH3:7])[CH3:6])=[O:2].N1C=CC=CC=1.[CH2:20]([OH:24])[CH2:21][CH2:22][CH3:23]>ClCCl>[P:1]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])([O:3][CH2:4][CH:5]([CH3:7])[CH3:6])([O:24][CH2:20][CH2:21][CH2:22][CH3:23])=[O:2]
Reactant: CCCCO
Reactant: CC(C)COP(=O)(Cl)OCC(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCOP(=O)(OCC(C)C)OCC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of diisobutyl chlorophosphate (130.3 g, 0.57 mole) in 600 mL of dichloromethane and 55.37 g (0.70 mole) of pyridine was cooled to 0° C. n-Butanol (42.25 g, 0.57 mole) was added dropwise over 1 hour. The formation of a white precipitate was immediately observed. The reaction mixture was then stirred for 24 hours at room temperature. The pyridinium hydrochloride was filtered off and the solution washed with water (2×250 mL), aqueous 0.5 N HCl (2×250 mL) and water (2×250 mL). The organic phase was dried over anhydrous magnesium sulfate for 12 hours. Filtration of the drying agent, followed by the removal of the solvent using a Roto-vap, yielded n-butyl diisobutyl phosphate as a clear colorless liquid. Distillation of the crude product (68° C. at 0.02 torr) gave 125 g of 96% n-butyl diisobutyl phosphate (BDIBP).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[Cl:5][C:6]1[S:7][C:8]([CH:12]=O)=[C:9]([Cl:11])[N:10]=1>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:5][C:6]1[S:7][C:8]([CH:12]2[O:4][CH2:1][CH2:2][O:3]2)=[C:9]([Cl:11])[N:10]=1
Reactant: O=Cc1sc(Cl)nc1Cl
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1nc(Cl)c(C2OCCO2)s1
Yield: 96.2 %

Procedure:
Ethylene glycol (7.0 ml, 125.5 mmol) and p-toluenesulfonic acid monohydrate (0.56 g, 2.94 mmol) are added to a solution of 2,4-dichloro-thiazole-5-carboxaldehyde (7.88 g, 43.3 mmol) in toluene (100 ml). The reaction is heated at reflux and water removed via Dean-Stark for 4 h. The reaction is cooled, poured into 20% Na2CO3 (200 ml), and extracted with ethyl acetate (3×100 ml). The ethyl acetate is washed with aqueous saturated brine solution and dried over anhydrous Na2SO4. The solid is filtered off and the filtrate concentrated. The crude product is purified by flash chromatography on silica gel eluting with 10% ethyl acetate/hexanes to yield (9.42 g, 96%) of 2,4-dichloro-5-([1,3]dioxolan-2-yl)-thiazole: 1H NMR (CDCl3): δ=6.07 (1H, s), 4.18-3.99 (4H, m).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH2:10])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C[Al](C)C.CC[O:17][C:18]([C:20]1[N:21]([CH2:32][C:33]2[CH:37]=[C:36]([C:38]3[S:39][C:40]([Cl:43])=[CH:41][CH:42]=3)[O:35][N:34]=2)[CH:22]=[C:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[N:24]=1)=O>C(Cl)Cl>[C:28]([O:27][C:25]([C:23]1[N:24]=[C:20]([C:18](=[O:17])[NH:10][CH:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)[N:21]([CH2:32][C:33]2[CH:37]=[C:36]([C:38]3[S:39][C:40]([Cl:43])=[CH:41][CH:42]=3)[O:35][N:34]=2)[CH:22]=1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)N1CCC(N)CC1
Reactant: CCOC(=O)c1nc(C(=O)OC(C)(C)C)cn1Cc1cc(-c2ccc(Cl)s2)on1
Agent: C[Al](C)C
Solvent: ClCCl
Product: CC(C)N1CCC(NC(=O)c2nc(C(=O)OC(C)(C)C)cn2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28.9 %

Procedure:
To a solution of 1-isopropyl-piperidin-4-ylamine (142 mg) in DCM (4 mL) was added trimethyl aluminium (0.5 mL, 2M solution in hexanes) dropwise under an Ar atmosphere. The mixture was stirred for 15 min at RT. A solution of 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-imidazole-2,4-dicarboxylic acid 4-tert-butyl ester 2-ethyl ester [example 1, (i)] (438 mg) in DCM (4 mL) was added dropwise and stirring was continued for 17 h at RT and 3 h at 35° C. After cooling the reaction was quenched by dropwise addition of 1M aqueous KHSO4 solution, concentrated, taken up in 6N HCL and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC. The fractions containing the product were evaporated to provide 154 mg of 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-imidazole-4-carboxylic acid tert-butyl ester (example 2) as its trifluoroacetate salt. MS (ESI+): m/e=534, chloro pattern.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O>CN(C)C(=O)C>[CH2:17]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCBr
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCCCCn1c2ccccc2c2ccccc21
Temperature: 0 °C

Procedure:
20 g of carbazole was dissolved in 100 mL dry N,N-dimethyl acetamide (DMAc) in a 500 mL round bottomed flask. NaH (60% in mineral oil) was added into the flask slowly in nitrogen to form a mixture. The mixture was stirred for 20 minutes in ice/water bath. 30 g of 1-bromohexane was then added slowly to the flask and stirred for 6 hours in ice/water bath. The resulting solution was poured into 2L deionized water and extracted with ethyl acetate several times. The extract was re-extracted by deionized water. The final extract was concentrated by a rotary evaporator and further purified by column chromatography. A product of the following structure was obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:9]2[CH:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[CH2:11][CH:12]=[CH:13][C:8]2=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[H][H]>[Pd].C(O)C>[CH2:1]([C:5]1[N:9]2[CH:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[CH2:11][CH2:12][CH2:13][C:8]2=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CC=C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCc1nnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CCC2

Procedure:
A suspension of bicyclic olefin triazole 0.1 mmol, the title compound of Example 3257) and 20 mg (0.019 mmol) of 10% palladium on charcoal in 2 mL of absolute ethanol is agitated on a Parr apparatus under 50 psi of hydrogen gas at room temperature until the reaction is complete. The mixture is filtered through a pad of celite, concentrated in vacuo and purified to give the title compound of Example 3259.