Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CCN(C(C)C)C(C)C.C[Al](C)C.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH:31]=[C:30]([O:32][CH3:33])[C:29](=[O:34])[C:28]([C:35]([O:37]C)=O)=[N:27]1.Cl.[Na+].[Cl-]>C(Cl)Cl>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH:31]=[C:30]([O:32][CH3:33])[C:29](=[O:34])[C:28]([C:35]([N:3]([O:4][CH3:5])[CH3:2])=[O:37])=[N:27]1
Reactant: COC(=O)c1nn(-c2ccccc2F)cc(OC)c1=O
Reactant: CNOC
Agent: C[Al](C)C
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cn(-c2ccccc2F)nc(C(=O)N(C)OC)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (4.74 g, 48.6 mmol) and iPr2NEt (8.47 mL, 48.6 mmol) in CH2Cl2 (50 mL) was added AlMe3 (1.8 M solution in toluene, 27 mL, 48.6 mmol) dropwise at 0° C. under Ar atmosphere. After stirring for 1 h, a solution of methyl 1-(2-fluorophenyl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (4.51 g, 16.2 mmol) in CH2Cl2 (50 mL) was added dropwise, and the mixture was stirred for 1 h at 0° C. The reaction mixture was poured into ice-water, acidified with 1 M HCl aqueous solution, saturated with NaCl, and extracted with AcOEt five times. The combined extracts were dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from AcOEt to give the title compound (3.23 g, 65% yield) as colorless crystals: mp 152-154° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.39 (3H, s), 3.71 (3H, s), 3.91 (3H, s), 7.25-7.33 (2H, m), 7.41-7.48 (1H, m), 7.65 (1H, dt, J=1.9, 7.9 Hz), 7.81 (1H, d, J=2.3 Hz). Anal. Calcd for C14H14FN3O4: C, 54.72; H, 4.59; N, 13.67. Found: C, 54.85; H, 4.54; N, 13.86.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@H:16]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:17]([OH:19])=[O:18].[CH:24]([C:26]1[CH:31]=[CH:30][N:29]=[C:28]2[N:32]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:33]=[C:34]([C:35]([O:37][CH3:38])=[O:36])[C:27]=12)=O>C(Cl)Cl>[C:42]([O:41][C:39]([N:32]1[C:28]2=[N:29][CH:30]=[CH:31][C:26]([CH2:24][NH:15][C@H:16]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:17]([OH:19])=[O:18])=[C:27]2[C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33]1)=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)[C@@H](N)C(=O)O
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@@H](C(=O)O)C(C)(C)C)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 10 mL round bottom flask was added sodium triacetoxyborohydride (104 mg, 0.493 mmol), (R)-2-amino-3,3-dimethylbutanoic acid (43.1 mg, 0.329 mmol) and DCM (2 mL). The reaction mixture were stirred at room temperature in for 30 min after which was added 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (50 mg, 0.164 mmol) in DCM (2 mL). The reaction was stirred at room temperature for 2 h and then quenched with MeOH (3 drops). The mixture was concentrated to afford the title compound, which was used in the next step without further purification. [M+H] calc'd for C21H29N3O6, 420; found, 420.3.
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[C:13]([C:18]2[O:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:21][N:22]=2)[C:14]([NH2:17])=[N:15][CH:16]=1)([CH3:3])[CH3:2].ClC1C=C(C(OO)=[O:37])C=CC=1>ClCCl>[CH:1]([S:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[C:13]([C:18]2[O:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:21][N:22]=2)[C:14]([NH2:17])=[N:15][CH:16]=1)=[O:37])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)Sc1ccccc1-c1cnc(N)c(-c2nnc(-c3ccccc3)o2)n1
Solvent: ClCCl
Product: CC(C)S(=O)c1ccccc1-c1cnc(N)c(-c2nnc(-c3ccccc3)o2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 30.9 %

Procedure:
5-(2-isopropylsulfanylphenyl)-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine (50 mg, 0.1284 mmol) was dissolved in dichloromethane (10 mL) and cooled to 0° C. in an ice-bath. 3-Chlorobenzenecarboperoxoic acid (26.59 mg, 0.1541 mmol) was added in one portion with rapid stirring. The mixture was stirred at 0° C. for 15 min, washed with saturated aqueous NaHCO3 solution (1×5 mL) and brine (1×5 mL), dried over MgSO4 and concentrated in vacuo to leave a solid which was purified by column chromatography on silica eluting with ether/ petroleum ether to yield the product as a yellow solid (16.1 mg, 31% yield); 1H NMR (400.0 MHz, CDCl3) d 1.2 (d, 3H), 1.35 (d, 3H), 3.5-3.6 (m, 1H), 7.5-7.75 (m, 2H), 7.5-7.65 (m, 7H), 8.25 (d, 2H) and 8.55 (s, 1H) ppm; MS (ES+) 406.1
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.C([N:15](CC)CC)C.[O:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>CCOCC>[O:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.[N-:15]=[C:5]=[O:11].[CH3:22][CH2:21][O:20][CH2:24][CH3:23]
Reactant: CCN(CC)CC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: [N-]=C=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In reaction 1 of Scheme 1, the compounds of formula A-1 or A-2 are converted to the corresponding compounds of Formula II, wherein f is 1 to 8, or III, respectively, by adding triphosgene to a suspension of C-1 or C-2 and triethylamine in a aprotic solvent, such as tetrahydrofuran. The reaction is stirred at room temperature for a time period between about 5 minutes to about 20 minutes, preferably about 15 minutes, and a small amount of ether was added. The triethylammonium salt generated is filtered off. Separately, sodium hydride is added to a suspension of A-1 or A-2, wherein X is OH or NH, in an aprotic solvent, such as tetrahydrofuran, at 0° C. or room temperature. The reaction is stirred at room temperature for a time period between about 5 minutes to about 20 minutes, preferably about 15 minutes, and the isocyanate tetrahydrofuran/ether solution so formed above is added dropwise. Alternatively, the compounds of Formula II and III may be formed by reacting the compounds of D3 or D4 with A-1 and A-2 in presence of a base such triethylamine and diphenylphosphoryl azide in aprotic solvent such toluene as described in procedure discussed above in reaction 4 of Preparation D.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:39])[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:39])[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1ccnc(C#N)c1

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example H10) according to the general procedure K. Obtained as a white solid (151 mg).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)=[O:4].C(OC([N:23]1[C:28]([CH3:30])([CH3:29])[CH2:27][CH2:26]OS1(=O)=O)=O)(C)(C)C>>[NH2:23][C:28]([CH3:30])([CH3:29])[CH2:27][CH2:26][N:10]1[C:11]2[C:7](=[CH:6][C:5]([C:3](=[O:4])[C:2]([F:1])([F:14])[F:15])=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: CC(C)(C)OC(=O)N1C(C)(C)CCOS1(=O)=O
Reactant: O=C(c1ccc2[nH]ccc2c1)C(F)(F)F
Product: CC(C)(N)CCn1ccc2cc(C(=O)C(F)(F)F)ccc21

Procedure:
Prepared analogously to Component V by alkylation of 2,2,2-trifluoro-1-(1H-indol-5-yl)-ethanone with N-tert-butoxycarbonyl-4,4-dimethyl-[1,2,3]oxathiazinane-2,2-dioxide (Component XI) and subsequent cleaving of the acid protecting group.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[N:8]=1)=O.[C:22]1([NH:28]N)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[CH3:20][C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1
Reactant: NNc1ccccc1
Reactant: Cc1cccc(-n2ccc(=O)c(C(=O)C=CN(C)C)n2)c1
Solvent: CO
Product: Cc1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)c1
Yield: 7.3 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(3-methylphenyl)pyridazin-4(1H)-one (crude, 650 mg, 2.29 mmol) in 20 mL of methanol was added phenylhydrazine (370 mg, 3.44 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-(3-methylphenyl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (55 mg, 7% for two steps) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11]([NH:13][C:14]1[C:15]([NH:24][CH2:25][CH2:26][OH:27])=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])=S.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11]1[N:24]([CH2:25][CH2:26][OH:27])[C:15]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=[CH:23][C:14]=2[N:13]=1
Reactant: COC(=O)c1cccc(NC(=S)Nc2c(C)cc(Cl)cc2Cl)c1NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cccc2nc(Nc3c(C)cc(Cl)cc3Cl)n(CCO)c12
Temperature: 50 °C
Reaction time: 14 h
Yield: 75.7 %

Procedure:
To a solution of methyl 3-{[(2,4-dichloro-6-methylphenyl)carbamothioyl]amino}-2-[(2-hydroxyethyl)amino]benzoate (300 mg, 0.70 mmol) in tetrahydrofuran (7.0 mL) was added 1-ethyl-3-(3 dimethylaminopropyl)carbodiimide hydrochloride (148 mg, 0.77 mmol) and triethylamine (0.108 mL, 0.77 mmol) at room temperature. The mixture was stirred at 50° C. for 14 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with, water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give methyl 2-[(2,4-dichloro-6-methylphenyl)amino]-1-(2-hydroxyethyl)-1H-benzimidazole-7-carboxylate (210 mg, 0.53 mmol, 76%) as a pale yellow solid. To a solution of methyl 2-[(2,4-dichloro-6-methylphenyl)amino]-1-(2-hydroxyethyl)-1H-benzimidazole-7-carboxylate (200 mg, 0.507 mmol) and triethylamine (0.28 mL, 3.8 mmol) was added methanesulfonyl chloride (0.079 mL, 1.02 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hr and at room temperature for 14 hr. Then the mixture was warmed to 45° C. and stirred at 45° C. for 8 hr. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 25-70% ethyl acetate/n-hexane gradient mixture to give the title compound (170 mg, 0.45 mmol, 89%) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][CH:17]4[CH2:22][CH2:21][CH2:20][N:19](C([O-])=O)[CH2:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][CH:17]4[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cnc3nnn(CC4CCCN(C(=O)[O-])C4)c3n2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(-c2cnc3nnn(CC4CCCNC4)c3n2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)piperidine-1-carboxylate (0.45 g, 0.89 mmol) was dissolved in CH2Cl2 (5 ml), and then TFA (5 ml) was added, followed by stirring at room temperature overnight. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the next reaction was advanced without purification.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:21]2[CH:26]=[CH:25][C:24]([NH:27]C(=O)OC(C)(C)C)=[C:23]([F:35])[CH:22]=2)=[C:6]2[N:11]([C:12]=1[CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[N:10]=[CH:9][N:8]=[C:7]2[NH2:20])(=[O:3])[CH3:2].FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:20][C:7]1[C:6]2=[C:5]([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([F:35])[CH:22]=3)[C:4]([C:1](=[O:3])[CH3:2])=[C:12]([CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]2[N:10]=[CH:9][N:8]=1
Reactant: CC(=O)c1c(-c2ccc(NC(=O)OC(C)(C)C)c(F)c2)c2c(N)ncnn2c1CN1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)c1c(-c2ccc(N)c(F)c2)c2c(N)ncnn2c1CN1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
To a solution of CH2Cl2 (50 mL) was added of tert-butyl {4-[6-acetyl-4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2 fluorophenyl}-carbamate (291 mg, 0.60 mmol) followed by trifluoroacetic acid (5 mL). The solution was allowed to stir for 30 min at rt. Aq saturated NaHCO3 was added to the solution until bubbling stopped. Additionally CH2Cl2 was added and the solution was then transferred to a separatory funnel. The organic layer was isolated while the aqueous layer was back extracted with CH2Cl2 (2×25 mL). The combined organic layers were collected, dried (MgSO4), filtered, and concentrated to dryness yielding 214 mg of the above compound as a white solid (0.56 mmol, yield 93%). 1H-NMR (DMSO-d6) δ 7.95 (s, 1H), 7.08 (dd, J=1.7 Hz, 10.3 Hz, 1H), 6.92 (dd, J=1.8 Hz, 7.9 Hz, 1H), 6.86 (t, J=8.7 Hz, 1H), 5.47 (s, 2H), 4.05 (s, 2H), 3.49 (m, 4H), 2.41 (m, 4H), 2.06 (s, 3H); MS [M+H]+=385.1; LCMS RT=1.16 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](O)=[O:6].CN(C=O)C.C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([Cl:20])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Cl)c(Br)c1
Reaction time: 1 h

Procedure:
To 3-bromo-4-chloro-benzoic acid (9.4 g, 40 mmol) in dry DCM (100 mL), was added DMF (0.5 mL) followed by addition of oxalyl chloride (22.5 mL, 55 mmol, 2M in DCM) slowly. The mixture was stirred for 1 hr, then concentrated to yield 3-bromo-4-chloro-benzoyl chloride as an off-white solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)#[N:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:1][CH2:2][CH:3]([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])=[O:21])=[CH:18][CH:17]=1)#[N:15]
Reactant: CC(CN)CNC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CC(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(C#N)cc1
Yield: 92.5 %

Procedure:
A solution of tert-butyl (3-amino-2-methylpropyl)carbamate (200 mg, 1.06 mmol), 4-cyanobenzoic acid (156 mg, 1.06 mmol), HATU (525 mg, 1.38 mmol) and TEA (0.444 mL, 3.19 mmol) in DMF (5 mL) was stirred at room temperature for 16 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 50% ethyl acetate/hexane) to give tert-butyl (3-(4-cyanobenzamido)-2-methylpropyl)carbamate (311 mg, 0.980 mmol, 92%) as a white powder.
Reaction SMILES: C[C@H]1[C@](C[CH2:11][C:12]2[C:16](=O)[O:15][CH:14]([OH:18])[CH:13]=2)(C)C(=C)C=CC1.[CH3:19][C:20]1[CH2:25][CH2:24][CH2:23][C:22]([CH3:27])([CH3:26])[C:21]=1/[CH:28]=[CH:29]/[C:30](O)([CH:32]=[CH2:33])[CH3:31].Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[K+]>C(O)C.O>[CH3:19][C:20]1[CH2:25][CH2:24][CH2:23][C:22]([CH3:27])([CH3:26])[C:21]=1/[CH:28]=[CH:29]/[C:30](/[CH3:31])=[CH:32]/[CH:33]=[CH:11]/[C:12](/[CH3:16])=[CH:13]\[C:14]([OH:18])=[O:15]
Reactant: C=CC(C)(O)/C=C/C1=C(C)CCCC1(C)C
Reactant: C=C1C=CC[C@@H](C)[C@@]1(C)CCC1=CC(O)OC1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C\C(=O)O)C(C)(C)CCC1

Procedure:
43 g of the mixture of retinoic acids from the condensation of hydroxy butenolide, vinyl beta-ionol and triphenylphosphine hydrochloride in 10 ml of ethanol are treated with 15 g of a 50% potassium hydroxide aqueous solution, subsequently diluted to 200 mL with water, added with 30 mg of Bengal rose, then irradiated with a 18 Watt lamp for 12 hours.
Reaction SMILES: [OH:1][C:2]1[C:3]([Se:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[C:28]([O:31][CH2:32][CH2:33]Br)(=[O:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+]>CCC(C)=O>[C:28]([O:31][CH2:32][CH2:33][O:1][C:2]1[C:3]([Se:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)=[CH:4][C:5]2[C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OCCBr
Reactant: CCOC(=O)c1ccc([Se]c2cc3c(cc2O)C(C)(C)CCC3(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1ccc([Se]c2cc3c(cc2OCCOC(C)=O)C(C)(C)CCC3(C)C)cc1

Procedure:
In a manner similar to that of Example 51, by reaction of 400 mg (0.93 mmol) of ethyl 4-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanyl)benzoate with 334 mg (2.2 mmol) of 2-bromoethyl acetate and 257 mg of potassium carbonate in MEK (10 ml), 333 mg (69%) of a yellow oil are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[NH:14][CH:15]=[C:16]([CH3:18])[N:17]=1.[Cl:19][S:20](O)(=[O:22])=[O:21].S(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[NH:14][C:15]([S:20]([Cl:19])(=[O:22])=[O:21])=[C:16]([CH3:18])[N:17]=1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1c[nH]c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Solvent: O=S(Cl)Cl
Product: Cc1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]c1S(=O)(=O)Cl
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2-(2,6-Dichloro-4-trifluoromethylphenyl)-4-methyl-imidazole (1.0 g, 0.0034 mol) was added portionwise to chlorosulphonic acid (3 ml) and the mixture was stirred and heated at 100° C. for 2 hours. After cooling thionyl chloride (0.2 ml) was added and the mixture was reheated to 100° C. for 2 hours. The mixture was added cautiously to ice (20 g), and extracted with ethyl acetate (2×20 ml). The combined extracts were washed with water (20 ml) dried over anhydrous sodium sulphate and evaporated to dryness. Recystallisation from a mixture of ethyl acetate and petroleum spirit (bp 60°-80° C.) (1:3) gave 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylimidazole-5-sulphonyl chloride (0.21 g), m.p. 227°-230° C. as an off-white solid.
Reaction SMILES: [OH:1][C:2]1([CH3:12])[C:7](=O)[CH2:6][CH:5]2[CH2:9][CH:3]1[C:4]2([CH3:11])[CH3:10].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][NH2:20])[CH:14]=1.B(F)(F)F>C1C=CC=CC=1>[CH3:12][C:2]1([OH:1])[C:7](=[N:20][CH2:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)[CH2:6][CH:5]2[CH2:9][CH:3]1[C:4]2([CH3:11])[CH3:10]
Reactant: NCc1cccnc1
Reactant: CC1(O)C(=O)CC2CC1C2(C)C
Agent: FB(F)F
Solvent: c1ccccc1
Product: CC1(O)C(=NCc2cccnc2)CC2CC1C2(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.4 %

Procedure:
To a stirring solution of (−)-2-hydroxy-3-pinanone (10.00 g, 59.4 mmol) in benzene (500 mL) was added 3-pyridylmethylamine (6.66 mL, 65.4 mmol) in one portion. Boron trifluoride diethyletherate (0.7 mL, 5.9 mmol) was added in one portion and the reaction was refluxed under N2 for 5 h, then stirred at room temperature for an additional 16 h. The benzene was removed by rotary evaporation and the resulting residue was stirred in saturated NaHCO3 solution (100 mL) for 1 h. This was then extracted with chloroform (3×100 mL), and the combined extracts dried (Na2SO4), filtered and concentrated by rotary evaporation. The resulting dark brown oil was purified by column chromatography, using a chloroform:methanol gradient (5:1 to 1:1, v/v) as eluent. The light yellow oil was crystallized by dissolving in hot ethyl acetate (50 mL) and placed in a freezer at −4° C. for 16 h. After warming to room temperature, the crystals were filtered, washed with ice-cold ethyl acetate, and dried on a hi-vacuum pump to yield off-white crystals (8.04 g, 52.4% yield).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:32][S:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=O)OC(C)(C)C)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[CH2:41]Cl>C(O)(C(F)(F)F)=O>[CH3:41][N:24]([CH3:25])[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([NH:18][C:16](=[O:17])[O:15][CH2:14][CH: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)[CH2:32][S:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](CSc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCCC[C@H](CSc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 0.5 h

Procedure:
A solution of Example 124B (1.36 g, 2.4 mmol) in dichloromethane (5 mL) and TFA (5 mL) was stirred at room temperature for 30 minutes, and concentrated. The concentrate was dissolved in acetic acid (1 mL) and 37% aqueous formaldehyde (5 mL), treated with 1M NaCNBH3 in THF (10 mL), stirred for 30 minutes, adjusted to pH 7 with aqueous NaHCO3, and extracted with ethyl acetate (3×100 mL). The combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 48:48:4 ethyl acetate/dichloromethane/methanol to provide the desired product. MS (ESI) m/e 475 (M+H)+.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[N:17]([CH3:21])[CH:18]=[N:19][CH:20]=3)[S:15][C:8]=12.[CH3:22][C:23]([CH3:25])=[O:24]>O1CCCC1.O>[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[N:17]([CH3:21])[C:18]([C:23]([OH:24])([CH3:25])[CH3:22])=[N:19][CH:20]=3)[S:15][C:8]=12
Reactant: Cn1cncc1-c1cc2nccc(Cl)c2s1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(-c2cc3nccc(Cl)c3s2)cnc1C(C)(C)O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 31 %

Procedure:
In a 50 mL round-bottomed flask 7 mL of tetrahydrofuran and n-butyllithium (0.88 mL, 2.5M in hexane) were cooled to −40° C. A suspension of 7-chloro-2-(3-methyl-3H-imidazol-4-yl)-thieno[3,2-b]pyridine (500 mg, 2.00 mmol) in 9 mL of tetrahydrofuran was added dropwise to the solution and stirred for 40 minutes. Acetone (0.79 mL, 3.00 mmol) was added to the anion and the reaction mixture was allowed to warm to room temperature overnight. The mixture was diluted with water and extracted with chloroform (3×50 mL). The combined extracts were dried over NaSO4, filtered, and concentrated. Chromatography on 50 g of silica gel with 5% methanol:methylene chloride afforded 191 mg (31%) of 2-[5-(7-chloro-thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-2-yl]-propan-2-ol. 1H NMR (400 MHz, CDCl3) δ8.58 (d, 1H), 7.51 (s, 1H), 7.28 (d, 1H), 7.24 (s, 1H), 4.02 (s, 3H), 1.77 (s, 6H). LC-MS: 308.1, 310.1 (MH+); HPLC RT: 4.18 min.