Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:21])[C:11](=[O:20])[C:12]([CH3:19])=[CH:13][C:14]=2[C:15]([O:17]C)=O)=[C:4]([F:22])[CH:3]=1.[CH:23]([O:25][CH2:26][CH2:27][O:28][NH2:29])=[CH2:24].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:21])[C:11](=[O:20])[C:12]([CH3:19])=[CH:13][C:14]=2[C:15]([NH:29][O:28][CH2:27][CH2:26][O:25][CH:23]=[CH2:24])=[O:17])=[C:4]([F:22])[CH:3]=1
Reactant: C=COCCON
Reactant: COC(=O)c1cc(C)c(=O)n(C)c1Nc1ccc(Br)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=COCCONC(=O)c1cc(C)c(=O)n(C)c1Nc1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 95.1 %

Procedure:
To a solution of methyl 2-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (0.060 g, 0.16 mmol) in THF (2 mL) was added O-(2-vinyloxy-ethyl)-hydroxylamine (0.042 ml, 0.41 mmol). The solution was cooled to 0° C. and lithium bis(trimethylsilyl)amide (0.81 ml, 0.81 mmol, 1 M solution in hexanes) was added dropwise. The reaction mixture was warmed to room temperature. After stirring for 35 minutes the reaction mixture was quenched by the addition of saturated NaHCO3 and partitioned between EtOAc and saturated NaCl. The layers were separated and the organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/MeOH, 20:1) gave 0.067 g (94%) pure desired product as an off-white crystalline solid.
Reaction SMILES: [CH2:1]([NH:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][NH2:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH:22]([CH2:24][CH:25]([CH3:30])[C:26](OC)=[O:27])=O>>[CH2:1]([NH:15][CH2:16][CH2:17][N:18]1[C:26](=[O:27])[CH:25]([CH3:30])[CH2:24][CH:22]=[N:21][CH2:20][CH2:19]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCNCCNCCN
Reactant: COC(=O)C(C)CC=O
Product: CCCCCCCCCCCCCCNCCN1CCN=CCC(C)C1=O

Procedure:
Into an apparatus similar to that in Example 1, where charged 299.5 g (1 mole) of N-tetradecyldiethylenetriamine and 130.1 g (1 mole) of methyl 3-formyl-2-methylpropionate. At 145° to 150° C., 18 g of water and 32 g of methanol were distilled off to obtain 4-tetradecylaminoethyl-6-methyl-2,3,6,7-tetrahydro-1,4-diazocin-5-one.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[CH3:7][N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9](Cl)=[O:10]>CCOC(C)=O.CCCCCCC>[N:2]1([O:1][C:9](=[O:10])[N:8]([CH3:7])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[N:3]1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: On1cccn1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(C(=O)On1cccn1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxypyrazole and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (Quad flash 25, EtOAc-heptane) (79%, oil which slowly crystallizes). HPLC-MS m/z=218.1 (M+1), Rt: 2.82 min. Mp 63–67° C.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:16]=[CH:15][C:14]3[CH2:13][CH2:12][C:11]4[C:17]([C:21]([O-])=[O:22])=[N:18][N:19]([CH3:20])[C:10]=4[C:9]=3[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[K+].C([N:27](C(C)C)C(C)C)C.N1(C([O-])=O)C2C=CC=CC=2N=N1.[NH4+]>CN(C)C=O.O1CCCC1.O>[CH:1]1([NH:6][C:7]2[N:16]=[CH:15][C:14]3[CH2:13][CH2:12][C:11]4[C:17]([C:21]([NH2:27])=[O:22])=[N:18][N:19]([CH3:20])[C:10]=4[C:9]=3[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cn1nc(C(=O)[O-])c2c1-c1nc(NC3CCCC3)ncc1CC2
Agent: O=C([O-])n1nnc2ccccc21
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: Cn1nc(C(N)=O)c2c1-c1nc(NC3CCCC3)ncc1CC2
Temperature: 0 °C
Yield: 90 %

Procedure:
A suspension of potassium 8-(cyclopentylamino)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (180 mg, 0.51 mmol) in anhydrous dimethylformamide (3.0 mL) and anhydrous tetrahydrofuran (3.0 mL) was treated with N-ethyl-N,N-diisopropylamine (0.175 mL, 2 eq.) and N-ethyl-N′,N′-diisopropyl carbodiimide hydrochloride (EDCI) (195 mg, 2 eq). The mixture was then cooled to 0° C. and treated with ammonium 1H-1,2,3-benzotriazol-1-ate (137 mg, 2 eq). After 5 minutes the reaction was warmed to room temperature and kept at this temperature overnight. The reaction was diluted with water and the resulting precipitate was collected by filtration to afford the title compound (143 mg, 90% yield),
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>>[C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc2ncc(Br)cn2n1
Reactant: C#C[Si](C)(C)C
Product: CC(C)(C)c1cc2ncc(C#C[Si](C)(C)C)cn2n1

Procedure:
The title compound, brown solid, MS: m/e=272.3 (M++H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and trimethylsilylacetylene.
Reaction SMILES: [CH:1]([C:3]1[CH2:4][C@H:5]2[C@@H:12]([CH:13]=1)[C:7]1(OCC[O:8]1)[CH2:6]2)=[CH2:2].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(#N)C.O>[CH:1]([C:3]1[CH2:4][C@H:5]2[C@@H:12]([CH:13]=1)[C:7](=[O:8])[CH2:6]2)=[CH2:2]
Reactant: C=CC1=C[C@@H]2[C@H](C1)CC21OCCO1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: C=CC1=C[C@H]2C(=O)C[C@H]2C1
Temperature: 25 °C

Procedure:
(±)-(1R,5S)-3-vinylspiro[bicyclo[3.2.0]hept-3-ene-6,2′-[1,3]dioxolane] (990 mg, 5.55 mmol) was dissolved in a mixed solvent of acetonitrile (16 mL) and water (7 mL). To the solution, 2 M sulfuric acid (2.60 mL) was added with stirring at room temperature. The mixture was stirred at room temperature for 7 hours, and the reaction solution was then neutralized by the addition of a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure. Then, the compound of interest was obtained as an oil substance (710 mg, 55%, Major/Minor=2/1) in the same way as in Example (11-e) from the obtained (1R,5S)-3-vinylbicyclo[3.2.0]hept-3-en-6-one.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[N:42]=[N:43][CH:44]=[CH:45][CH:46]=1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:39]([C:41]2[N:42]=[N:43][CH:44]=[CH:45][CH:46]=2)=[O:40])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Reactant: CON(C)C(=O)c1cccnn1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3cccnn3)c(F)c2F)C[C@H](C)O1

Procedure:
Starting material: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3) and N-methoxy-N-methylpyridazine-3-carboxamide
Reaction SMILES: C([O:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])CCC.[Se](=O)=O>>[CH2:6]([O:5][C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:7]([CH:6]=[O:5])=[O:8])[CH2:7][CH2:9][CH3:10]
Reactant: CCCCOCC(=O)c1ccccc1
Agent: O=[Se]=O
Product: CCCCOc1ccccc1C(=O)C=O
Yield: 186.4 %

Procedure:
2 g of 2-n-butoxyacetophenone and 1.7 g of selenium dioxide are treated in the same manner as described in Example 6-(1). 2 g of 2-n-butoxyphenylglyoxal thus obtained are dissolved in 6 ml of dimethylsulfoxide, and 1.8 g of 3,4-dimethoxyphenethylamine are added thereto. The solution is stirred at room temperature for 30 minutes. Then, 12 ml of ethanol are added to the solution. After ice-cooling, 0.55 g of sodium borohydride is added gradually to the solution, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is evaporated to remove solvent. Water is added to the thus obtained residue, and the aqueous mixture is extracted with ethyl acetate. The extract is washed with water, dried and then evaporated to remove solvent. The oily residue thus obtained is treated with hydrochloric acid and recrystallized from a mixture of ethanol and ether. 2.6 g of α-(3,4-dimethoxyphenethylaminomethyl)-2-n-butoxybenzylalcohol hydrochloride are obtained. M.p. 128°-129° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[C:21]=2[CH:20]=1)[C:4]([NH:6][C:7]1[CH:18]=[CH:17][C:10]([C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])=[CH:9][CH:8]=1)=[O:5].Br[CH2:34][CH2:35][CH2:36][OH:37]>>[OH:37][CH:36]([O:1][N:2]=[C:3]([C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[C:21]=2[CH:20]=1)[C:4]([NH:6][C:7]1[CH:18]=[CH:17][C:10]([C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])=[CH:9][CH:8]=1)=[O:5])[CH2:35][CH3:34]
Reactant: OCCCBr
Reactant: C=CCOC(=O)c1ccc(NC(=O)C(=NO)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Product: C=CCOC(=O)c1ccc(NC(=O)C(=NOC(O)CC)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
Following the basic procedure of Example 1 (f), 3.4 g (7.8 mmol) of allyl 4-[α-hydroxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido]benzoate were reacted with 710 μl (7.8 mmol) of 3-bromo-1-propanol. 1.4 g (36%) of the syn allyl ester and 710 mg (18%) of the trans allyl ester were recovered after purification by chromatography on a silica column, eluted with dichloromethane.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[C:14]1([O:20][CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([SiH](CC)CC)C>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:17]1[CH:18]=[CH:19][C:14]([O:20][CH3:21])=[CH:15][CH:16]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)CCCCCBr
Agent: CC[SiH](CC)CC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(CCCCCCBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.8 %

Procedure:
A solution of 6-bromohexanoyl chloride (50 g, 0.2 mol) in dry dichloromethane (40 ml) was added dropwise over 5 minutes to a suspension of aluminium chloride (31 g, 0.2 mol) in dry dichloromethane (100 ml), keeping the temperature between 20-23° C. The mixture was stirred for 30 minutes at room temperature to give a yellow solution. Anisole (23 g, 0.2 mol) in dry dichloromethane (30 ml) was added and stirred for 20 hours at room temperature. Triethylsilane (59.9 g, 0.515 mol) was added over 10 minutes, maintaining the temperature between 25° C.-35° C. The solution was stirred for 60 minutes at room temperature and poured onto ice/water (200 g). The organic layer was washed with brine and water until the pH of the solution was neutral. Drying (MgSO4) and evaporation under reduced pressure gave a yellow oil which was distilled under reduced pressure at 90-110° C./0.5 mbar. Produce containing fractions were combined and purified by flash chromatography on silica gel using hexane as eluant to give a colourless oil (18.33 g, 33%).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=O)=O.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CO>[CH2:20]([N:8]1[CH2:9][CH2:10][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][C@@H:7]1[CH2:6][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)OC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: Nc1ccccc1
Solvent: CO
Product: c1ccc(CN2CCN(Cc3ccccc3)[C@@H](CNc3ccccc3)C2)cc1
Temperature: 140 °C
Yield: 73.2 %

Procedure:
A 20-mL vial was charged ((2R)-1,4-dibenzyl-2-piperazinyl)methyl methanesulfonate (1.01 g, 2.70 mmol, Example 184, Step 1), aniline (1.30 mL, 14.3 mmol, Alfa Aesar, Ward Hill, Mass.) and MeOH (12 mL). The reaction mixture was sealed and heated at 140° C. for 30 min in an Initiator microwave reactor (Biotage AB, Inc., Uppsala, Sweden). The mixture was allowed to cool to room temperature and then concentrated in vacuo. The crude product was purified by column chromatography (50 g of silica gel, (2 M NH3 in MeOH) in CH2Cl2 0 to 5%) to afford N-(((2S)-1,4-dibenzyl-2-piperazinyl)methyl)aniline (0.734 g) as an orange oil.
Reaction SMILES: CC([CH:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16](=O)[CH2:17]/[C:18](=[N:20]/[N:21]([C:23](OC(C)(C)C)=O)C)/[CH3:19])=[CH:15][C:10]=2[CH2:9][CH2:8][N:7](C([O-])=O)[CH2:6]1)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:23][N:21]1[C:16]([C:14]2[CH:13]=[CH:12][C:11]3[CH2:5][CH2:6][NH:7][CH2:8][CH2:9][C:10]=3[CH:15]=2)=[CH:17][C:18]([CH3:19])=[N:20]1
Reactant: C/C(CC(=O)c1ccc2c(c1)CCN(C(=O)[O-])CC2C(C)(C)C)=N\N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc3c(c2)CCNCC3)n(C)n1
Yield: 98.8 %

Procedure:
A solution of 1,1-dimethylethyl-7-{(3E)-3-[{[(1,1 dimethylethyl)oxy]carbonyl}(methyl)hydrazono]butanoyl}-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (0.5 g) (intermediate 2) in dichloromethane (5 ml) was added dropwise to trifluoroacetic acid (10 ml) under vigorous stirring. After 1 h the reaction mixture was concentrated in vacuo and sodium hydroxide (1N) was added until pH ˜12, then the mixture was extracted twice with dichloromethane. The organic phase was dried with sodium sulphate and evaporated to give the title compound (0.26 g).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[C:8]([CH2:18][CH3:19])=[N:9][N:10]3[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[N:12][C:11]=23)=[CH:4][CH:3]=1.[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24].C1(N(C2CCCCC2)C)CCCCC1>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:27][O:26][C:22](=[O:25])/[CH:23]=[CH:24]/[C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[C:8]([CH2:18][CH3:19])=[N:9][N:10]3[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[N:12][C:11]=23)=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(Br)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(/C=C/C(=O)OC)cc1
Temperature: 130 °C

Procedure:
3-(4-Bromo-benzyl)-2-ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidine (3) (525 mg, 1.47 mmol) was dissolved in 15 ml of dioxane and after addition of methyl acrylate (264 ul, 2.93 mmol), dicyclohexyl-methylamine (622 ul ml, 2.93 mmol) and Pd(PtBu3)2 (15 mg, 0.03 mmol) the mixture was heated for 5 min at 130° C. in a microwave oven. Then the mixture was evaporated under reduced pressure. The residue was diluted with ethyl acetate, washed with sat. NaHCO3— and NaCl-solution, and dried over Na2 SO4. Evaporation gave a yellow solid. The crude product was purified by recrystallization from diethylether to give a colorless solid.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[C:9]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:10]([CH3:16])=[N:11]2.C(O)C.[OH-].[Li+]>O>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][C:9]2[C:10]([CH3:16])=[N:11][C:12]3[C:7]([CH:8]=2)=[C:6]([O:5][CH2:4][C:3]([OH:25])=[O:2])[CH:15]=[CH:14][CH:13]=3)=[CH:23][CH:22]=1
Reactant: COC(=O)COc1cccc2nc(C)c(Cc3ccc(Cl)cc3)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc2cccc(OCC(=O)O)c2cc1Cc1ccc(Cl)cc1

Procedure:
A solution of [3-(4-chlorobenzyl)-2-methylquinolin-5-yloxy]acetic acid methyl ester (0.11 g), ethanol (6.0 mL), water (2.0 mL) and saturated aqueous lithium hydroxide solution (2.0 mL) was stirred at room temperature for 5 hours. The ethanol was removed under reduced pressure and the pH of the residue adjusted to 4 by the addition of glacial acetic acid. The resulting precipitate was collected by filtration, washed with water and purification by preparative reverse-phase HPLC using a gradient over 37 minutes of acetonitrile in water (20% to 95% of organic modifier) gave title compound as a yellow gum, 0.028 mg.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([C:16](=[S:18])[NH2:17])[C:9]=2[CH3:19])[CH2:5][C:4](=[O:20])[C:3]=1[C:21](=O)[CH2:22][CH3:23].Cl.[CH2:26]([O:28][NH2:29])[CH3:27]>>[CH2:26]([O:28][N:29]=[C:21]([C:3]1[C:4](=[O:20])[CH2:5][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([C:16](=[S:18])[NH2:17])[C:9]=2[CH3:19])[CH2:7][C:2]=1[OH:1])[CH2:22][CH3:23])[CH3:27]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(C(N)=S)c2C)CC1=O
Agent: Cl
Product: CCON=C(CC)C1=C(O)CC(c2c(C)cc(C)c(C(N)=S)c2C)CC1=O

Procedure:
The reaction of 3-hydroxy-5-(3-thiocarbamoyl-2,4,6-trimethylphenyl)-2-propionylcyclohex-2-en-1-one with ethoxyamine hydrochloride was carried out following the same procedure as that described in Example 1 part (v) to give 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(3-thiocarbamoyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (24) as a tan oil. The compound was characterized by its proton nuclear magnetic resonance spectrum and the data are recorded in Table 3, Example 11.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[CH3:10][N:11]([CH3:17])[CH2:12][CH2:13][CH2:14][CH:15]=O>O.Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:14]([CH2:13][CH2:12][N:11]([CH3:17])[CH3:10])[CH3:15])=[CH:4][CH:3]=1
Reactant: NNc1ccc(I)cc1
Reactant: CN(C)CCCC=O
Agent: Cl
Solvent: O
Product: CC(CCN(C)C)=NNc1ccc(I)cc1

Procedure:
A solution of 4-iodophenylhydrazine (2 g) in water (70 ml) and 2N hydrochloric acid (4 ml) was stirred at room temperature with 4-dimethylaminobutanal, diethyl acetal (2.6 g) for 3 h. The resulting solution was partitioned between sodium bicarbonate (50 ml) and ethyl acetate (2×50 ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil (2.3 g), which was used directly in the next stage.
Reaction SMILES: [ClH:1].Cl.Cl.C1(NC(C2C3C=C(C4C([Cl:25])=CN=C([NH:26][CH2:27][CH2:28][CH2:29][N:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)N=4)SC=3C=CC=2)=O)CC1.[Cl:36][C:37]1[N:42]=[C:41]([C:43]2[S:47][C:46]3[CH:48]=[C:49]([C:52]([N:54]4[CH2:59][CH2:58][O:57][CH2:56][CH2:55]4)=[O:53])[CH:50]=[CH:51][C:45]=3[CH:44]=2)[C:40]([Cl:60])=[CH:39][N:38]=1.C(OC(N1CCN(CCCN)CC1)=O)(C)(C)C>>[ClH:25].[ClH:36].[ClH:1].[Cl:60][C:40]1[C:41]([C:43]2[S:47][C:46]3[CH:48]=[C:49]([C:52]([N:54]4[CH2:59][CH2:58][O:57][CH2:56][CH2:55]4)=[O:53])[CH:50]=[CH:51][C:45]=3[CH:44]=2)=[N:42][C:37]([NH:26][CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:38][CH:39]=1
Reactant: O=C(c1ccc2cc(-c3nc(Cl)ncc3Cl)sc2c1)N1CCOCC1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCCN4CCNCC4)ncc3Cl)cc12
Agent: CC(C)(C)OC(=O)N1CCN(CCCN)CC1
Agent: Cl
Product: O=C(c1ccc2cc(-c3nc(NCCCN4CCNCC4)ncc3Cl)sc2c1)N1CCOCC1

Procedure:
Using the method of 2-[5-chloro-2-(3-piperazin-1-ylpropylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide tri-hydrochloride, the title compound is synthesized from [2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophen-6-yl]-morpholin-4-yl-methanone and 4-(3-aminopropyl)-piperazine-1-carboxylic acid tert-butyl ester and isolated as a yellow solid. ES+(m/z) 501 (35Cl) and 503 (37Cl) [M+H].
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][C:6]=2[F:14])[CH2:3][CH2:2]1>CO>[CH:1]1([NH:4][C:5]2[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:6]=2[F:14])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cccc(F)c1NC1CC1
Solvent: CO
Product: Nc1cccc(F)c1NC1CC1
Reaction time: 6 h

Procedure:
To a solution of N-cyclopropyl-2-fluoro-6-nitroaniline (650 mg, 3.31 mmol) in MeOH (15 mL) palladium 10 wt % on carbon (176 mg, 0.166 mmol) was added under N2. After flushing the flask with N2 for two minutes, the solution was stirred under a H2 balloon. After 6 h, the mixture was filtered through a celite pad rinsed with MeOH, and concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column using EtOAc:DCM (1:1) as eluent to give N1-cyclopropyl-6-fluorobenzene-1,2-diamine: LC-MS (ESI) m/z 167.1 [M+H]+.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH:12]([F:14])[F:13].[C:15]([Cu])#[N:16].[Li+].[Br-]>O1CCCC1.C1(C)C=CC=CC=1>[F:13][CH:12]([F:14])[O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[C:15]#[N:16]
Reactant: N#C[Cu]
Reactant: O=[N+]([O-])c1cccc(OC(F)F)c1Br
Agent: [Br-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#Cc1c(OC(F)F)cccc1[N+](=O)[O-]
Temperature: 200 °C
Yield: 84.6 %

Procedure:
A mixture of 2-bromo-1-difluoromethoxy-3-nitro-benzene (1 g, 3.7 mmol), CuCN (0.40 g, 4.5 mmol) and LiBr (0.32 g, 3.7 mmol) in tetrahydrofuran (10 ml) are heated in a microwave oven at 200° C. for 40 minutes. The reaction mixture is cooled to ambient temperature, diluted with toluene and washed with aqueous sodium bromide (1M) and aqueous sodium hydrogen sulfite (saturated). The organic phase is dried over sodium sulfate and concentrated. The residue is purified by HPLC to give 2-difluoromethoxy-6-nitrobenzonitrile (0.67 g, 84% yield). 1H-NMR (CDCl3, 400 MHz): 8.20 (d, 1H), 7.85 (t, 1H), 7.75 (d, 1H), 6.75 (t, 1H) ppm.
Reaction SMILES: C(OC(C1C(B2OC(C)(C)C(C)(C)O2)=C(C)SC=1C)C(OCC)=O)(C)(C)C.[C:28]([O:32][CH:33]([C:39]1[C:43]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[Cl:50])=[C:42]([CH3:51])[S:41][C:40]=1[CH3:52])[C:34]([O:36]CC)=[O:35])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][CH:33]([C:39]1[C:43]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[Cl:50])=[C:42]([CH3:51])[S:41][C:40]=1[CH3:52])[C:34]([OH:36])=[O:35])([CH3:31])([CH3:30])[CH3:29]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(C)c1-c1ccccc1Cl
Agent: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(C)c1B1OC(C)(C)C(C)(C)O1
Product: Cc1sc(C)c(C(OC(C)(C)C)C(=O)O)c1-c1ccccc1Cl

Procedure:
Using the procedure described in example 29, step 2, ethyl tert-butoxy-[4-(2-chloro-phenyl)-2,5-dimethyl-thiophen-3-yl]-acetate (28f) (110 mg, 0.29 mmol) is converted, after purification by flash chromatography on silica gel (dichloromethane/methanol 95/5), to tert-butoxy-[4-(2-chloro-phenyl)-2,5-dimethyl-thiophen-3-yl]-acetic acid (example 51) (67 mg, 0.19 mmol, 67%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[N:9]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[CH:12]=[C:8]2[C:7](=[O:20])[NH:6][CH2:5]1.[S:21](Cl)([CH3:24])(=[O:23])=[O:22].O>C(Cl)Cl>[CH3:24][S:21]([O:1][CH2:2][CH2:3][CH:4]1[N:9]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[CH:12]=[C:8]2[C:7](=[O:20])[NH:6][CH2:5]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1NCC(CCO)n2cc(-c3cccc(Cl)c3)cc21
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1CNC(=O)c2cc(-c3cccc(Cl)c3)cn21
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To a solution of 4-(2-hydroxyethyl)-7-(3-chlorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (128 mg, 0.44 mmol) in DCM (10 ml), mesyl chloride (58 ul, 0.748 mmol) and TEA (200 ul, 1.48 mmol), were added. The resulting solution was stirred at room temperature, after 1 h the reaction mixture was portioned between DCM and water. The organic layers were washed with brine, dried over Na2SO4 and concentrated. The crude was triturated with diethyl ether and filtered to give 2-[1-oxo-7-(3-chlorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl]ethyl methanesulfonate as a solid 157 mg (97%).