Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)C(OC(C)(C)C)=O.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>>[CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)[S:46]([CH3:45])(=[O:48])=[O:47]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)S(C)(=O)=O)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 31 in Step A and methylsulfonyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=O)[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][NH2:36].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([NH:36][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])=[O:19])[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: COc1ccc(CN(c2cccc(C(=O)O)c2)c2cc(Cl)nn3c(C#N)cnc23)cc1
Reactant: CN(C)CCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2cccc(C(=O)NCCN(C)C)c2)c2cc(Cl)nn3c(C#N)cnc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
A stirred solution of 253C (55 mg, 0.127 mmol) in DMF (1.0 mL) was treated with N1,N1-dimethylethane-1,2-diamine (0.021 mL, 0.190 mmol), BOP (72.9 mg, 0.165 mmol) and TEA (0.035 mL, 0.254 mmol), and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated, triturated with water, and the resulting white solid was collected by filtration to yield 253D (60.0 mg, 93.7% yield). HPLC: Rt=3.47 min. (PHENOMENEX® Luna C18 4.6×30 mm 3 u, A10-90% aqueous methanol containing 0.1% TFA in 2 min; 4 mL/min flow). MS (ES): m/z=504.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([NH:15][C:16]([NH:18][NH2:19])=[O:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:20](O)(=O)C.C(=N)N>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([N:15]3[CH:20]=[N:19][NH:18][C:16]3=[O:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCN(NC(=O)NN)CC2)cc1
Reactant: CC(=O)O
Agent: N=CN
Solvent: O
Product: COc1ccc(N2CCN(n3cn[nH]c3=O)CC2)cc1
Yield: 68 %

Procedure:
6.5 Parts of N-[4-(4-methoxyphenyl)-1-piperazinyl]-hydrazinecarboxamide and 6.5 parts of methanimidamide acetate (1:1) are melted together for 1 hour at 140° C. Water is added to the melt. The solid product is filtered off and crystallized from 1-butanol, yielding 4.5 parts (68%) of 2,4-dihydro-4-[4-(4-methoxyphenyl)-1-piperazinyl]-3H-1,2,4-triazol-3-one.
Reaction SMILES: [CH3:1][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.C[O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[NH:34][N:35]=[C:36]([CH:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[N:37]=2)=[CH:29][N:28]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C1COCC1.O.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH3:1][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:17]=[CH:18][C:19]([CH2:20][N:41]4[CH2:42][CH2:43][CH:38]([C:36]5[N:37]=[C:33]([C:30]6[CH:31]=[CH:32][C:27]([OH:26])=[N:28][CH:29]=6)[NH:34][N:35]=5)[CH2:39][CH2:40]4)=[CH:22][CH:23]=3)[C:8]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:9][N:4]2[N:3]=1
Reactant: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Reactant: COc1ccc(-c2nc(C3CCNCC3)n[nH]2)cn1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccc(O)nc6)n5)CC4)cc3)c(-c3ccccc3)cn2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(2-methyl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzaldehyde (293 mg, 1 mmol) and 2-methoxy-5-(5-piperidin-4-yl-2H-[1,2,4]triazol-3-yl)-pyridine (0.58 g) in CH2Cl2 (5 mL) and THF (23 mL) was treated with Ti(OiPr)4 (0.82 mL) and stirred overnight at rt. The mixture was treated with NaBH(OAc)3 (395 mg) and stirred for 2 hours at rt. The reaction was diluted with CH2Cl2 and water and filtered through Celite. The phases were separated and the organic phase was washed with brine. The Celite pad was washed with MeOH and the combined organic portions were concentrated in vacuo. Purification was achieved by preparative HPLC to give the title compound.
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[C:15]2[O:14][CH:13]=[CH:12][C:11]=2[CH:10]=[C:9]([C:16]2[CH:20]=[N:19][NH:18][N:17]=2)[CH:8]=1.[OH-].[Na+]>Cl.O1CCCC1>[N:19]1[NH:18][N:17]=[C:16]([C:9]2[CH:8]=[C:7]([CH:2]=[O:1])[C:15]3[O:14][CH:13]=[CH:12][C:11]=3[CH:10]=2)[CH:20]=1
Reactant: c1cc2cc(-c3cn[nH]n3)cc(C3OCCCO3)c2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=Cc1cc(-c2cn[nH]n2)cc2ccoc12
Yield: 95.4 %

Procedure:
A solution of 4-(7-[1,3]dioxan-2-yl-benzofuran-5-yl)-2H-[1,2,3]triazole (80 mg) in hydrochloric acid (2M; 10 ml) and tetrahydrofuran was heated at reflux for 0.5 h. The cooled reaction mixture was treated with sodium hydroxide (25 ml; 2M) and extracted with ethyl acetate (3×50 ml). The combined organic extracts were dried, and evaporated in vacuo to give the title compound as a yellow/orange solid (60 mg).
Reaction SMILES: [ClH:1].[CH:2]1([CH2:5][N:6]2[CH2:11][CH2:10][C:9]3[N:12]([C@@H:22]4[C:30]5[C:25](=[C:26]([F:32])[CH:27]=[C:28]([F:31])[CH:29]=5)[CH2:24][C@H:23]4[OH:33])[N:13]=[C:14]([C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[C:8]=3[CH2:7]2)[CH2:4][CH2:3]1>CC#N>[ClH:1].[CH:2]1([CH2:5][N:6]2[CH2:11][CH2:10][C:9]3[N:12]([CH:22]4[C:30]5[C:25](=[C:26]([F:32])[CH:27]=[C:28]([F:31])[CH:29]=5)[CH2:24][CH:23]4[OH:33])[N:13]=[C:14]([C:15]4[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=4)[C:8]=3[CH2:7]2)[CH2:3][CH2:4]1
Reactant: O[C@@H]1Cc2c(F)cc(F)cc2[C@H]1n1nc(-c2ccc(F)cc2)c2c1CCN(CC1CC1)C2
Agent: Cl
Solvent: CC#N
Product: OC1Cc2c(F)cc(F)cc2C1n1nc(-c2ccc(F)cc2)c2c1CCN(CC1CC1)C2

Procedure:
The examples in the following table 8 were obtained according to Scheme 12 by following a reaction according to the synthesis of (18a). Sometimes, CH3CN was used instead of DMF and the temperature was decreased to 50° C.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Br:8])=[C:5]([Br:7])[N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.O1CCOCC1>CN(C)C=O>[CH2:15]([N:3]1[C:4]([Br:8])=[C:5]([Br:7])[N:6]=[C:2]1[Br:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Brc1nc(Br)c(Br)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Brc1nc(Br)n(Cc2ccccc2)c1Br
Temperature: -20 °C
Yield: 90 %

Procedure:
Combine 2,4,5-tribromoimidazole (15.29 g, 0.050 mol), cesium carbonate (18.0 g, 0.055 mol), benzyl bromide (6.3 mL, 0.053 mol) and dimethylformamide (100 mL) and stir at 20° C. for 18 hours. Filter solids and concentrate under reduced pressure. Suspend in dichloromethane, filter through 2 cm pad silica gel and wash with dichloromethane (1 L). Concentrate filtrates under reduced pressure. Redissolve in dichloromethane (15 mL), add 4 M HCl in dioxane (12.5 mL, 0.050 mol), cool to −20° C. and filter solids. Concentrate filtrate, dissolve in ethyl ether, add 1 M HCl/ether (20 mL) and hexane (40 mL), cool −20° C. and filter. Combine solids and dry under reduced pressure to give 19.6 g (90%, 0.045 mol) of the title compound. MS(ES+): m/z=393.0 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][O:36][C:35]1=[O:39]>C1C=CC=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:12][CH2:13][N:14]([CH2:32][CH2:33][N:34]4[CH2:38][CH2:37][O:36][C:35]4=[O:39])[CH2:15][CH2:16]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1OCCN1CCCl
Reactant: Brc1ccc2c(c1)CC(N1CCNCC1)c1ccccc1S2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: O=C1OCCN1CCN1CCN(C2Cc3cc(Br)ccc3Sc3ccccc32)CC1
Temperature: 0 °C

Procedure:
12.5 g of 1-(2-bromo- 10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-piperazine are treated, together with 13 g of powdered potassium carbonate, 0.2 g of potassium iodide and 1 litre of toluene, with 13.2 g of N-(β-chloroethyl)-oxazolidinone and the mixture is heated under reflux for 25 hours. Then the mixture is poured on to ice-water and diluted with benzene. The benzene solution is washed neutral with water and extracted with 2-N hydrochloric acid. The aqueous phase is made alkaline with sodium hydroxide and extracted with benzene. The organic phase is washed with water, dried over magnesium sulphate and concentrated under reduced pressure. There is obtained crude 3-[2-[4-(2-bromo- 10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone which is converted into the maleate of melting point 170°-172° C by treatment with maleic acid.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:13][C:14]1[C:22]([Cl:23])=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([O:24][CH3:25])[CH:15]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39][NH2:40])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39][NH:40][C:18]([C:17]2[CH:21]=[C:22]([Cl:23])[C:14]([NH2:13])=[CH:15][C:16]=2[O:24][CH3:25])=[O:20])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80 %

Procedure:
1,1′-Carbonyldiimidazole (1.61 g, 9.91 mmol) was added to a solution of 4-amino-5-chloro-2-methoxybenzoic acid (2.0 g, 9.91 mmol) in dimethylformamide (5 ml). After stirring for 5 min. at room temperature, solution of N-tert-butyloxycarbonyl-4-(aminomethyl)piperidine (1.77 g, 8.26 mmol) in dimethylformamide (5 ml) was added and the reaction mixture was heated at 55° C. After 23 h, the product was extracted into ethyl acetate and the organic layer was washed with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated. Flash chromatography of the crude product with 2:1, ethyl acetate/hexanes as the eluant gave N-tert-butyloxycarbonyl-4-(4-amino-5-chloro-2-methoxyphenylcarbonylaminomethyl)piperidine (2.63 g) as a foam.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[OH:12].[NH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH2:22])=[C:16]([Cl:30])[CH:15]=1.P(Cl)(Cl)Cl>>[Cl:30][C:16]1[CH:15]=[C:14]([NH:13][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([I:11])[CH:10]=[C:2]([I:1])[C:3]=2[OH:12])[CH:19]=[C:18]([CH3:20])[C:17]=1[C:21]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)=[CH2:22]
Reactant: O=C(O)c1cc(I)cc(I)c1O
Reactant: C=C(c1ccc(Cl)cc1)c1c(C)cc(N)cc1Cl
Solvent: ClP(Cl)Cl
Product: C=C(c1ccc(Cl)cc1)c1c(C)cc(NC(=O)c2cc(I)cc(I)c2O)cc1Cl

Procedure:
Using the reaction sequence of Example 4, 3,5-diiodosalicylic acid is reacted with 1-(4-amino-2-chloro-6-methylphenyl)-1-(4-chlorophenyl)ethylene in the presence of phosphorus trichloride to give N-[3-chloro-5-methyl-4-[1-(4-chlorophenyl)ethenyl]phenyl]-3,5-diiodo-2-hydroxybenzamide. The benzophenone used as starting material for the Wittig reaction was prepared by reacting 4-chlorobenzyl cyanide with 3-chloro-5-methyl-1-nitrobenzene followed by oxidation with alkaline peroxide as known in the literature.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]#[C:26][Si](C)(C)C)[CH:22]=[CH:21][C:20]=1[CH3:31])=[O:18].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O.O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]#[CH:26])[CH:22]=[CH:21][C:20]=1[CH3:31])=[O:18]
Reactant: Cc1ccc(C#C[Si](C)(C)C)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: C#Cc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1

Procedure:
A solution of compound 406 (426 mg, 0.94 mmol) and K2CO3 (195 mg, 1.41 mmol) in methanol (4.0 mL) were stirred at RT for 5 h. The reaction mixture was poured into a mixture of EtOAc/water. The organic phase was washed with water, brine and then dried (MgSO4), filtered and concentrated in vacuo to give the crude title compound. The product was used without any further purification.
Reaction SMILES: [CH3:1][C:2]1(C)[C@]2(CS(O)(=O)=O)C(C[CH:3]1CC2)=O.[F:16][C:17]1[CH:22]=[C:21]([CH2:23][OH:24])[C:20]([OH:25])=[C:19]([CH2:26][OH:27])[CH:18]=1.COC(OC)(C)C.C([O-])(O)=O.[Na+]>CC(C)=O.C(OCC)(=O)C>[F:16][C:17]1[CH:18]=[C:19]([CH2:26][OH:27])[C:20]2[O:25][C:2]([CH3:3])([CH3:1])[O:24][CH2:23][C:21]=2[CH:22]=1
Reactant: OCc1cc(F)cc(CO)c1O
Reactant: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)OC
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC1(C)OCc2cc(F)cc(CO)c2O1
Temperature: 55 °C
Yield: 91 %

Procedure:
D(+)-10-Camphorsulfonic acid (5.1 g, 22 mmol), 4-fluoro-2,6-bis(hydroxymethyl)phenol (74.5 g, 432 mmol), and 2,2-dimethoxypropane (90 mL, 734 mmol) were dissolved in acetone. To the solution was added 45 g of 4 Å molecular sieves. The resulting suspension was heated to 55° C. for 1 h and then cooled to rt. The mixture was neutralized with aqueous NaHCO3 (sat) and diluted with ethyl acetate. Solids were removed by filtration. The solvent volume was reduced in vacuo. Ethyl acetate and aqueous NaHCO3 (sat) were added, and the layers were partitioned. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Crude (6-fluoro-2,2-dimethyl-4H-1,3-benzodioxin-8-yl)methanol was isolated as an orange oil (91.7 g, 432 mmol, 100%). (17.2 g, 86.6 mmol, 91% yield). 1H NMR (400 MHz, CDCl3): δ 7.01 (dd, 1H), 6.79 (dd, 1H), 5.20 (t, 1H), 4.77 (s, 2H), 4.40 (d, 2H), 1.42 (s, 6H); GCMS for C11H13FO3: 212 (M+)
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([CH3:14])[N:5]=[C:4]([NH2:15])[CH:3]=1.[Cl:16][C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:18]=1[C:19]([N:21]=[C:22]=[O:23])=[O:20]>C(OCC)(=O)C>[Cl:16][C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:18]=1[C:19]([NH:21][C:22]([NH:15][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([CH3:14])[N:5]=1)=[O:23])=[O:20]
Reactant: Cc1cc(N)nc(C)c1-c1ccccc1
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Solvent: CCOC(C)=O
Product: Cc1cc(NC(=O)NC(=O)c2c(Cl)cccc2Cl)nc(C)c1-c1ccccc1

Procedure:
4,6-Dimethyl-5-phenyl-2-pyridylamine (500 mg) and 2,6-dichlorobenzoyl isocyanate (650 mg) were reacted in 25 ml ethyl acetate. A precipitate formed which was filtered, dried, and identified by NMR analysis as the desired product, m.p. 230°-235° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:23]([C:24]3[C:25](=O)[NH:26][C:27](=[O:31])[N:28]([CH3:30])[CH:29]=3)[C:10]3[N:11]=[C:12]([NH:14][CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[S:13][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:33]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:23]([C:24]3[C:25](=[S:43])[NH:26][C:27](=[O:31])[N:28]([CH3:30])[CH:29]=3)[C:10]3[N:11]=[C:12]([NH:14][CH2:15][CH2:16][N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)[S:13][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:33]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(NCCN4CCOCC4)nc32)c(=O)[nH]c1=O
Product: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(NCCN4CCOCC4)nc32)c(=S)[nH]c1=O

Procedure:
The title product was prepared from the product of step (i) (0.162 g) and Lawesson's reagent (0.7 g) according to the method of example 34 step (iv). Purification was by chromatography eluting with dichloromethane/ethanol/triethylamine mixtures to give the title product as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH2:20]([N:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[CH2:27][NH:28][CH2:29][CH2:30][CH2:31][NH2:32])[CH3:21]>>[CH2:20]([N:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[CH2:27][NH:28][CH2:29][CH2:30][CH2:31][NH:32][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17])[CH3:21]
Reactant: CCN1CCCC1CNCCCN
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCCNCC3CCCN3CC)s2)c(C)[nH]c1=O
Yield: 19 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 3-[(1-ethyl-pyrrolidin-2-ylmethyl)-amino]-propyl amine as described in Step 5, Example 24 to give the title compound (19% yield). LC/MS: RT 2.19 min; m/e 467 (M+H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=O)[CH3:9])[CH:5]=[CH:4][CH:3]=1.[CH:11]([C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:15]=1[NH2:16])([CH3:13])[CH3:12].CC1C=CC(S(O)(=O)=O)=CC=1.[Cl-].[Cl-].[Ca+2]>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[N:16][C:15]2[C:17]([CH:21]([CH3:22])[CH3:23])=[CH:18][CH:19]=[CH:20][C:14]=2[CH:11]([CH3:13])[CH3:12])[CH3:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1cccc(Br)n1
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(=Nc1c(C(C)C)cccc1C(C)C)c1cccc(Br)n1
Temperature: 25 °C

Procedure:
In argon atmosphere, a mixture of 3.70 g (18.50 mmol) of 1-(6-bromopyridin-2-yl)ethanone, 3.27 g (18.50 mmol) of 2,6-diisopropylaniline, 50 mg of TsOH, and 150 ml of toluene was refluxed for 2-3 h using a Soxhlet apparatus with an extraction thimble filled with anhydrous CaCl2. The reaction mixture was cooled to ambient temperature, passed through a short layer of silica gel 60 (40-63 um), and then evaporated to dryness. The crude product was recrystallized from 30 ml of methanol. Yield 3.63 g (56%) of yellow crystalline solid. Anal. calc. for C19H23BrN2: C, 63.51; H, 6.45, N, 7.80. Found: C, 63.44; H, 6.40, N, 7.93. 1H NMR (CDCl3): δ 8.31 (dd, J=7.7 Hz, J=0.6 Hz, 1H, 3-H in pyridine), 7.66 (t, J=7.7 Hz, 1H, 4-H in pyridine), 7.57 (dd, J=7.7 Hz, J=0.6 Hz, 1H, 5-H in pyridine), 7.14-7.16 (m, 2H, 3, 5-H in 2, 6-iPr2C6H3), 7.08 (m, 1H, 4-H in 2, 6-iPr2C6H3), 2.68 (sep, J=6.7 Hz, 2H, CHMe2), 2.17 (s, 3H, MeC═N), 1.13 (d, J=6.7 Hz, 6H, CHMe2), 1.12 (d, J=6.7 Hz, 6H, CHMe2).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:24])[CH:5]([C:12](=[O:23])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][Cl:22])=[CH:15][CH:14]=1)[C:6]2=[O:11].[N+](C1C=CC([O:34][C:35](=O)[NH:36][N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=CC=1)([O-])=O>CC#N.CN(C)C1C=CN=CC=1>[Cl:22][CH2:21][CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]([CH:5]2[C:4](=[O:24])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:35]([NH:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[O:34])[C:6]2=[O:11])=[O:23])=[CH:14][CH:15]=1
Reactant: Nc1cccc2c1C(=O)C(C(=O)c1ccc(OCCCl)cc1)C2=O
Reactant: O=C(NN1CCOCC1)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: O=C(Nc1cccc2c1C(=O)C(C(=O)c1ccc(OCCCl)cc1)C2=O)NN1CCOCC1
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a suspension of 4-amino-2-[4-(2-chloroethoxy)benzoyl]indan-1,3-dione (36 g, 105 mmol) in CH3CN (600 mL) was added morpholin-4-ylcarbamic acid 4-nitrophenyl ester (40 g, 120 mmol) followed by 4-dimethylaminopyridine (640 mg, 5.2 mmol). The reaction was heated at reflux for 4 hours then cooled to room temp. and stirred overnight. The bright yellow solid is collected by filtration, rinsed with Et2O and dried under vacuum to give the desired semicarbazide (40.5 g, 82% yield).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH3:6])[CH:2]1[C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.[CH2:20](I)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:20]([O:19][C:16]1[CH:15]=[CH:14][C:13]([C@H:10]2[CH2:11][CH2:12][C@H:7]([CH:2]3[O:1][CH:3]3[CH2:4][CH2:5][CH3:6])[CH2:8][CH2:9]2)=[CH:18][CH:17]=1)[CH3:21]
Reactant: CCI
Reactant: CCCC1OC1[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCC1OC1[C@H]1CC[C@H](c2ccc(OCC)cc2)CC1
Reaction time: 24 h

Procedure:
A solution of 1.6 g of p-[trans-4-(1,2-epoxypentyl)cyclohexyl]phenol in 120 ml of acetone was treated with 1.89 ml of ethyl iodide and 3.24 g of powdered potassium carbonate while gassing with argon. The mixture was heated to reflux while stirring for 24 hours, then evaporated on a rotary evaporator and the residue was partitioned in diethyl ether/water. The aqueous phase was extracted three times with diethyl ether. The organic phases were washed twice with water, dried over magnesium sulphate, filtered and evaporated. Chromatographic separation of the resulting, yellowish oil (1.76 g) on silica gel with ethyl acetate/petroleum ether (vol. 5:95) gave 1.45 g (82%) of 4-ethoxy-1-[trans-4-(1,2-epoxypentyl)cyclohexyl]benzene as an oily liquid.
Reaction SMILES: [N:1]([CH:4]([CH3:27])[CH2:5][O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[O:14][C:15]3[CH:21]=[C:20]([O:22][CH2:23][CH:24]4[CH2:26][CH2:25]4)[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:9][CH2:8]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[CH:24]1([CH2:23][O:22][C:20]2[CH:19]=[CH:18][C:16]3[N:17]=[C:13]([C@H:10]4[CH2:11][CH2:12][C@H:7]([O:6][CH2:5][CH:4]([NH2:1])[CH3:27])[CH2:8][CH2:9]4)[O:14][C:15]=3[CH:21]=2)[CH2:26][CH2:25]1
Reactant: CC(CO[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1)N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(N)CO[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1
Temperature: 25 °C

Procedure:
A solution of 2-[trans-4-(2-azidopropoxy)cyclohexyl]-6-(cyclopropylmethoxy)-1,3-benzoxazole (249 mg) and triphenylphosphine (353 mg) in THF (4 mL)/water (2 mL) was stirred at 60° C. overnight. The reaction mixture was allowed to cool to room temperature, and extracted with ethyl acetate and water. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate/methanol) to give the title compound (172 mg).
Reaction SMILES: [OH:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]([CH2:11][CH2:12][CH3:13])[C:5]=2[O:4][N:3]=1.CI.[C:24](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:24][O:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:10]([CH2:11][CH2:12][CH3:13])[C:5]=2[O:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCCc1c(OCc2ccccc2)ccc2c(O)noc12
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCCc1c(OCc2ccccc2)ccc2c(OC)noc12

Procedure:
A solution of 3-hydroxy-6-benzyloxy-7-propyl benz[4,5]isoxazole (195 mg) in acetone (3 mL) was treated with methyl iodide (0.067 mL) and potassium carbonate (100 mg). The mixture was refluxed for 8 hours. The reaction was partitioned between isopropyl acetate and pH 4 buffer. The organic was dried over magnesium sulfate, filtered and concentrated to a solid, which was chromatographed over silica gel to afford the product.