Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.F[C:24]1[C:25]([O:34][C:35]2[CH:36]=[N:37][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:39][CH:40]=2)=[CH:26][C:27]([N+:31]([O-:33])=[O:32])=[C:28]([NH2:30])[CH:29]=1>O>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[O:1][C:24]1[C:25]([O:34][C:35]2[CH:36]=[N:37][C:38]([S:41]([CH3:44])(=[O:42])=[O:43])=[CH:39][CH:40]=2)=[CH:26][C:27]([N+:31]([O-:33])=[O:32])=[C:28]([NH2:30])[CH:29]=1)#[N:5]
Reactant: N#Cc1ccccc1O
Reactant: CS(=O)(=O)c1ccc(Oc2cc([N+](=O)[O-])c(N)cc2F)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2cc([N+](=O)[O-])c(N)cc2Oc2ccccc2C#N)cn1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
60 mg of 2-hydroxy-benzonitrile and 70 mg of potassium carbonate were added to an N-methylpyrrolidinone (2 ml) solution of 150 mg of 5-fluoro-4-(6-methanesulfonyl-pyridin-3-yloxy)-2-nitro-phenylamine obtained in (step 3), and the reaction liquid was stirred at 90° C. for 5 hours. Water was added to the reaction liquid, and the deposit was taken out through filtration to obtain the entitled compound.
Reaction SMILES: C[O:2][C:3](=[O:18])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10].[Li+].[OH-]>CO>[C:12]1([S:9]([N:5]2[CH2:6][CH2:7][CH2:8][C@H:4]2[C:3]([OH:18])=[O:2])(=[O:11])=[O:10])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1
Yield: 95.8 %

Procedure:
To a solution of 38.2 g (0.142 mol) of the above methyl ester 7 in 500 mL methanol was added 140 mL (0.28 mol) of freshly-prepared 2 M aqueous LiOH with stirring to give a colorless solution. This was stirred overnight, after which HPLC showed no starting material. The solution was reduced by 50% in vacuo and partitioned between 1 N HCl and CH2Cl2 (˜200 mL each). The phases were separated and the aqueous layer was washed again with CH2Cl2. The organic phases were combined, dried (MgSO4), and concentrated to a white solid. This was recrystallized twice from ethyl acetate/hexanes to give 34.7 g (0.136 mol, 96%) of 8 as fine white needles. M/z=256.2 (M+H+).
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:30])([F:29])[CH2:5][N:6]=[C:7]([NH2:28])[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([S:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH:26][CH3:27])=[N:21][S:22]([CH3:25])(=[O:24])=[O:23])[N:10]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:14]1[C:9]([NH:8][C:7]([NH2:28])=[N:6][CH2:5][C:4]([F:29])([F:3])[F:30])=[N:10][C:11]([S:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH:26][CH3:27])=[N:21][S:22]([CH3:25])(=[O:23])=[O:24])=[N:12][CH:13]=1
Reactant: CNC(=NS(C)(=O)=O)NCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Reactant: BrBr
Solvent: ClCCl
Solvent: c1ccncc1
Product: CNC(=NS(C)(=O)=O)NCCCSc1ncc(Br)c(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.9 %

Procedure:
A solution of bromine (0.064 g.) in methylene chloride (2 ml.) was added dropwise over 15 minutes to a stirred solution of 4-[2-(2,2,2-trifluoroethyl)-guanidino]-2-[3-(2-methylsulphonyl-3-methylguanidino)-propylthio]pyrimidine (0.176 g.) and pyridine (0.2 ml.) in methylene chloride (10 ml.), and the mixture stirred at room temperature for one hour. The solution was evaporated to dryness, and the residue purified by preparative thin layer chromatography using ethyl acetate/methanol/ammonia 6:1:0.5 v/v/v as developing solvent to give 5-bromo-4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(2-methylsulphonyl-3-methylguanidino)propylthio]-pyrimidine (0.12 g.), m.p. 166°-167° after recrystallisation from ethanol.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][NH:10][C:11](=O)[C@H:12]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([C:27]#[N:28])=[CH:19][CH:18]=2)[C@H:13]([OH:15])[CH3:14])=[O:8])=[CH:5][CH:4]=1)#[N:2].C(NP1(N(CC)CC)N(C)CCCN1C)(C)(C)C>C1COCC1>[C:1]([C:3]1[CH:31]=[CH:30][C:6]([C:7]2[O:8][C:11]([C@H:12]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([C:27]#[N:28])=[CH:19][CH:18]=3)[C@H:13]([OH:15])[CH3:14])=[N:10][N:9]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2ccccc12)C(=O)NNC(=O)c1ccc(C#N)cc1
Agent: CCN(CC)[PH]1(NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2ccccc12)c1nnc(-c2ccc(C#N)cc2)o1
Reaction time: 1.25 h
Yield: 2.9 %

Procedure:
To a solution of 4-cyano-N′-((2R,3R)-2-(4-cyanonaphthalen-1-ylamino)-3-hydroxybutanoyl)benzohydrazide (900 mg, 2.18 mmol) in anhydrous THF (90 mL) at room temperature was added 2-tert-butylamino-2-diethylamino-1,3-dimethyl perhydro-1,3,2-diazaphosphorine on polystyrene (2.2 mmol base/g) (2.97 g, 6.53 mmol) followed by p-TSCl (498 mg, 2.60 mmol) and the mixture was stirred for 75 minutes. The mixture was filtered and the residue washed with acetone (3×100 mL) followed by MeOH (3×150 mL). The filtrate was concentrated under reduced pressure to provide an off white solid, which was purified by flash chromatography over silica gel (30-50% EtOAc in hexanes) to provided the title compound as a brown oil (25 mg, 3%): 1H NMR (400 MHz, CDCl3, δ in ppm) 8.19 (d, J=8.4 Hz, 2H), 8.18 (d, J=8.4 Hz, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.84 (d, J=8.6 Hz, 2H), 7.77 (d, J=8.2 Hz, 1H), 7.68 (t, J=7.4 Hz, 1H), 7.59 (t, J=7.2 Hz, 1H), 6.67 (d, J=8.2 Hz, 1H), 5.69 (d, J=9.6 Hz, 1H), 5.47 (d, J=3.7 Hz, 1H), 4.71 (dqd, J=3.7, 6.5, 9.9 Hz, 1H), 1.65 (d, J=6.4 Hz, 3H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[N:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21]O)=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]1(=[O:52])[NH:46][C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12>C1COCC1>[N:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][N:46]2[C:45](=[O:47])[C:44]3=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]3[C:42]2=[O:52])=[CH:17][CH:18]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCCc1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCc1ccncc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 53.5 %

Procedure:
Diethyl azodicarboxylate (4.4 g, 25.4 mmol) was dissolved in dry THF and added dropwise to a solution of 3-(4-pyridyl)propanol (3.18 g, 23.18 mmol), triphenylphosphine (12.3 g, 46.9 mmol) and phthalimide (3.6 g, 24.5 mmol) in dry THF (50 mL). The mixture was stirred at RT for 3.5 h, concentrated and the residue taken up in ether and filtered. The filter cake was taken up in hexane/ethyl acetate/chloroform (40:30:30) and flash chromatographed (silica gel, 30:35:35 hexane:ethyl acetate:chloroform) (3 L) to yield the title compound (3.3 g, 54%). 1H NMR (90 MHz, CDCl3) δ8.44 (m, 2H), 7.71 (m, 4H), 7.13 (d, 2H), 3.70 (t, 2H), 2.65 (t, 2H), 2.05 (m, 2H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8](Cl)=[N:7][C:6]=12.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(C(C)C)CC)(C)C>C(O)(C)C.O>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:22]3[CH2:21][CH2:20][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:24][CH2:23]3)=[N:7][C:6]=12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ccn2ncc(Br)c2n1
Solvent: CC(C)O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
3-bromo-5-chloropyrazolo[1,5-a]pyrimidine (10 g, 43 mmol) taken up in isopropanol. T-butylpiperazine carboxylate (9.61 g, 51.6 mmol), diisopropylethylamine (22.4 mL, 129 mmol) added and stirred at 65° C. overnight. Reaction was cooled to room temperature, diluted with water and solid product filtered off. The solid was washed with water, dried to obtain 15.84 g crude product for further reaction, as is. LRMS (ESI) m/z 382/384 [(M+H)]+, calc'd for C15H20BrN5O2: 382.2.
Reaction SMILES: O[C@H:2]1[CH2:12][C@@:11]2([CH3:14])[O:13][C@@:3]31[C@@H:15]1[C@@H:7]([N:8]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=4)[C:9](=[O:16])[C@H:10]21)[O:6][CH2:5][CH2:4]3.[CH3:29][O:30][C:31](=[O:52])[CH:32]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([N:8]2[C@@H:7]3[C@@H:15]4[C@@H:10]([C@:11]5([CH3:14])[O:13][C@@:3]4([CH2:4][CH2:5][O:6]3)/[C:2](=[CH:32]/[C:31]([O:30][CH3:29])=[O:52])/[CH2:12]5)[C:9]2=[O:16])=[CH:18][C:19]=1[C:25]([F:26])([F:27])[F:28])#[N:22]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@@]12C[C@H](O)[C@]3(CCO[C@H]4[C@@H]3[C@@H]1C(=O)N4c1ccc(C#N)c(C(F)(F)F)c1)O2
Solvent: C1CCOC1
Product: COC(=O)/C=C1\C[C@@]2(C)O[C@@]13CCO[C@H]1[C@@H]3[C@@H]2C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 72 h
Yield: 70.6 %

Procedure:
To a solution of Example 3 (50 mg, 0.128 mmol) in THF (2 mL) was added methyl(triphenylphosphoranylidene)acetate (51 mg, 0.153 mmol). The reaction mixture was stirred for 3 days and then concentrated in vacuo. The resulting residue was purified by ISCO column (4.0 g column, EtOAc/hexane=0-80%, 10 mL/min) to give Example 103 (40.5 mg, 71%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:27][CH2:28][CH2:29][NH2:30])[N:15]=[C:14]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:27][CH2:28][CH2:29][NH:30][S:38]([CH3:37])(=[O:40])=[O:39])[N:15]=[C:14]([C:31]3[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=3)[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccncc2)nc1OCCN
Reactant: CS(=O)(=O)Cl
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccncc2)nc1OCCNS(C)(=O)=O

Procedure:
According to the procedure described in Example 4a) 107 mg 5-methyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was reacted with methanesulfonylchloride to give 100 mg 5-methyl-N-[6-(2-(methanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=3.72 min, [M+1]+=587.46, [M−1]−=585.50.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][CH:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([CH2:20][C:21]([NH:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=3)=[O:22])[CH:14]=[CH:13][C:12]=2[CH2:11]1)(=[O:8])=[O:7].CO.[OH-].[Na+]>O1CCCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][CH:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([CH2:20][C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[O:22])[CH:14]=[CH:13][C:12]=2[CH2:11]1)(=[O:7])=[O:8]
Reactant: COC(=O)c1ccc(NC(=O)Cc2ccc3c(c2)CCC(NS(=O)(=O)c2cccs2)C3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Cc1ccc2c(c1)CCC(NS(=O)(=O)c1cccs1)C2)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
A mixture of 1.45 g of methyl 4-{[6-(2-thienyl)sulfonylamino-5,6,7,8-tetrahydronaphthalene-2-yl]acetylamino}benzoate, 10 ml of methanol, 9 ml of a 2N aqueous sodium hydroxide solution and 4 ml of tetrahydrofuran is stirred at room temperature overnight. Methanol and tetrahydrofuran are distilled off, and the residual mixture is washed and acidified. The precipitated crystals are collected by filtration, washed, dired and recrystallized from a mixture of tetrahydrofuran and isopropyl ether to give 1.33 g of 4-{[6-(2-thienyl)sulfonylamino-5,6,7,8-tetrahydronaphthalene-2-yl]acetylamino}benzoic acid as colorless crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[C:8]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]([O:20]C)=[O:19].[OH-].[Na+]>O.C(O)(=O)C>[CH3:22][N:2]([CH3:1])[C:3]1[C:8]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: COC(=O)Cc1cccc(C(=O)c2ccccc2)c1N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CN(C)c1c(CC(=O)O)cccc1C(=O)c1ccccc1

Procedure:
A mixture of 500 mg. (1.85 mmole) of methyl 2-dimethylamino-3-benzoylphenylacetate and 15 ml. of 3N sodium hydroxide was refluxed for 1.5 hr. under nitrogen. The cooled filtered reaction mixture was diluted with an equal volume of water and neutralized with glacial acetic acid. The precipitate which formed could not be recrystallized and was therefore dissolved in benzene and placed on a magnesium silicate column. The column was eluted with benzene-acetone to give 300 mg. of product which melted at 144°-146° C. after recrystallization from benzene-isooctane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:6](Cl)=[O:7].[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH:34][C:35](=[O:37])[CH3:36]>>[C:35]([N:34]([CH2:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=1)[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:37])[CH3:36]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1OC
Reactant: CC(=O)NCc1ccccn1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2ccccn2)C(C)=O)cc1OC
Yield: 27.7 %

Procedure:
The title compound is prepared by the procedure of Example 27 using 1.09 g product from Example 48, 0.450 g of product from Example 12, 0.144 g of 50% washed sodium hydride and 12 ml of dry tetrahydrofuran. The residue is purified by column chromatography (silica gel:35% ethyl acetate/hexane) to give 0.391 g of the desired product as yellow crystals.
Reaction SMILES: [C:1]([CH2:6][C:7]([N:9]([CH3:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-])=O)=[O:8])([O:3][CH2:4][CH3:5])=[O:2].Cl>[Zn]>[C:1]([CH2:6][C:7]([N:9]([CH3:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16])=[O:8])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CC(=O)N(C)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [Zn]
Product: CCOC(=O)CC(=O)N(C)c1ccccc1N
Temperature: 0 °C
Reaction time: 8 h

Procedure:
11 g. of N-carbethoxy acetyl N-methyl o-nitro aniline are admixed with 16.2 g. of powdered zinc, and 100 g. of cracked ice are added, whilst agitating; 62 cc. of concentrated hydrochloric acid, diluted with 250 cc. of ice water, are then added, and this is cooled to -5°-10° C. for 10 to 15 minutes; the temperature is allowed to raise again to +5° C. within 30 minutes, this is filtered, the filtrate is alkalinized with ammonium hydroxide and extracted with chloroform; the chloroformic phases are washed with water, dried over sodium sulfate and evaporated under reduced pressure; the residue is dissolved in 30 cc. of xylene and the solution is kept overnight at -10° C.; the formed precipitate is washed with ether and recrystallized in xylene, to obtain N-carbethoxy acetyl N-methyl o-phenylene diamine, melting at 63°-64° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([O:34]C(OC)=O)[CH2:20][C@@H:21]3[O:29][C:30]([O:32][CH3:33])=[O:31])=[CH:16][CH:15]=4)[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1.COC(O[C@@H]1[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C=O)C)C[C@@H](OC(OC)=O)C1)=O>>[CH3:39][C:2]1([CH3:1])[CH2:3][O:4][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([OH:34])[CH2:20][C@@H:21]3[O:29][C:30]([O:32][CH3:33])=[O:31])=[CH:16][CH:15]=4)[CH2:12][CH2:11]2)[CH3:9])[O:6][CH2:7]1
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Agent: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Product: COC(=O)O[C@H]1C[C@H](O)CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@]21C
Yield: 95.1 %

Procedure:
The reaction and workup procedures of Example 164 were repeated except that 100 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene was used in lieu of 100 mg of 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carbaldehyde to give 85 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α-(methoxycarbonyl)oxypregna-5,7-dien-3β-ol showing the following physical properties.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7]2)[CH2:3][CH2:2]1.BrCCCC[C:20]12[CH:30]=[CH:29][CH:28]=[CH:27][CH:21]1[C:22]([NH:24][C:25]2=[O:26])=[O:23]>>[N:1]1([CH2:2][CH2:3][CH2:4][CH2:5][C:27]2[CH:28]=[CH:29][CH:30]=[C:20]3[C:25]([NH:24][C:22](=[O:23])[C:21]=23)=[O:26])[CH2:6][CH2:5][C:4]2([CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7]2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CC1(CCNCC1)O2
Reactant: O=C1NC(=O)C2(CCCCBr)C=CC=CC12
Product: O=C1NC(=O)c2c(CCCCN3CCC4(CC3)Cc3ccccc3O4)cccc21

Procedure:
From spiro[benzofuran-2(3H),4'-piperidine] prepared as described by R. C. Effland, et al. J. Heterocyclic Chem. 1981, 18, 81 1, and 2-(4-bromobutyl)-phthalimide using the procedure described for Example 15, Step 5 there was obtained a white solid: mp 255°-7° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][NH:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.Cl[C:23]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C.O>O1CCOCC1.CN(C)C(=O)C>[CH3:32][S:29]([C:28]1[C:23]([N:17]2[CH2:18][CH2:19][C:11]3[C:10]([NH:9][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:20])[F:21])=[CH:8][CH:7]=4)=[N:15][CH:14]=[N:13][C:12]=3[CH2:16]2)=[N:24][CH:25]=[CH:26][CH:27]=1)(=[O:31])=[O:30]
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cc1
Reactant: CS(=O)(=O)c1cccnc1Cl
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CS(=O)(=O)c1cccnc1N1CCc2c(ncnc2Nc2ccc(C(F)(F)F)cc2)C1
Temperature: 150 °C
Yield: 49 %

Procedure:
N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine prepared as described in Example 1.D. (0.100 g, 0.34 mmol) was dissolved in a mixture of dioxane/N,N-dimethylacetamide (10:1) (1.1 mL). To the solution was added 2-chloro-3-(methylsulfonyl)pyridine (Ponticello et al, J. Org. Chem., 44(17), 1979) (0.128 mg, 0.67 mmol) and N,N-diisopropylethylamine (0.09 mL, 0.51 mmol). The mixture was heated via microwave (Emrys Optimizer model, Personal Chemistry) at 150° C. for 20 min. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated to leave a solid. The solid was purified by silica gel chromatography using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as an white solid (75 mg, 49%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:29]=[CH:28][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]([C:20]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])=[C:13]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:30][NH:31][CH3:32].C1COCC1>>[CH3:30][N:31]([CH2:2][C:3]1[CH:29]=[CH:28][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]([C:20]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])=[C:13]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[O:8])=[CH:5][CH:4]=1)[CH3:32]
Reactant: CNC
Reactant: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1)c1ccc(CCl)cc1
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(C(=O)Nc2nc(-c3ccco3)c(C(=O)C3CCOCC3)s2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
Compound 478 (340 mg, 0.789 mmol) was added to a 2 mol/L solution of dimethylamine in THF (20 mL, 39.5 mmol), followed by stirring overnight at 60° C. The solvent was distilled away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (chloroform:methanol=19:1), followed by reslurrying with a mixed solvent of ethanol and diethyl ether to afford the entitled Compound 479 (153 mg, 44%) as a yellow solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]3[N:14]=[CH:13][N:12]([C:15]4[CH:16]=[C:17](OS(C(F)(F)F)(=O)=O)[CH:18]=[CH:19][CH:20]=4)[C:9]3=[N:10][CH:11]=2)=[CH:2]1.[CH:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O)=[O:30].FC(F)(F)C([O-])=O>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]3[N:14]=[CH:13][N:12]([C:15]4[CH:16]=[C:17]([C:32]5[C:31]([CH:29]=[O:30])=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH:18]=[CH:19][CH:20]=4)[C:9]3=[N:10][CH:11]=2)=[CH:2]1
Reactant: O=S(=O)(Oc1cccc(-n2cnc3cc(-c4ccoc4)cnc32)c1)C(F)(F)F
Reactant: O=Cc1ccccc1B(O)O
Agent: O=C([O-])C(F)(F)F
Product: O=Cc1ccccc1-c1cccc(-n2cnc3cc(-c4ccoc4)cnc32)c1

Procedure:
The title compound was prepared from trifluoromethanesulphonic acid 3-[6-(furan-3-yl)imidazo[4,5-b]pyridin-3-yl]phenyl ester and 2-formylphenylboronic acid as described in Example 6. Trifluoroacetate salt (cream-coloured powder): δH (400 MHz, d6-DMSO) 7.10-7.11 (1H, m), 7.49 (1H, dt, J 8 and 1), 7.59-7.62 (2H, m), 7.70 (1H, t, J 8), 7.75-7.79 (2H, m), 7.93-7.95 (1H, m), 8.08-8.11 (2H, m), 8.33-8.34 (1H, m), 8.48 (1H, d, J 2), 8.76 (1H, d, J 2), 8.99 (1H, s), 9.99 (1H, s); m/z (ES+) 366 (M++H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][C:11]([CH3:13])=[O:12].[OH-].[Na+].O>C(O)C>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:10][C:11](=[O:12])[CH:13]=[CH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH3:4]
Reactant: Cc1ccccc1C=O
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccccc1C=CC(=O)C=Cc1ccccc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.3 %

Procedure:
2-Methylbenzaldehyde (1ac, 1.45 ml, 12.5 mmol) and acetone (19, 0.46 ml, 6.3 mmol) were combined in ethanol (20 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (2.61 g, 65.3 mmol) and water (25 ml) was added and the mixture stirred for 3 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was recrystallized from ethanol to give 0.71 g (43%) of a yellow solid: mp 98-100° C. [expected mp 94-96° C.]; 1H NMR: δ 2.47 (s, 6H), 6.98 (d, 2H, J=15.9 Hz), 7.24 (m, 6H), 7.64 (d, 2H, J=7.2 Hz), 8.03 (d, 2H, J=15.9 Hz); 13C NMR: δ 19.7, 126.1, 126.2, 126.5, 129.9, 130.7, 133.6, 137.9, 140.5, 188.5.
Reaction SMILES: C1([C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:8])C=CC=CC=1.C=CC=C.C(O)(=[O:22])C=C>C1C=CC=CC=1>[CH:9]1([C:7]([OH:22])=[O:8])[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10]1
Reactant: O=C(c1ccccc1)C1CCCCC1
Reactant: C=CC(=O)O
Agent: C=CC=C
Solvent: c1ccccc1
Product: O=C(O)C1CC=CCC1

Procedure:
The present invention relates to a method for preparing a cyclohexyl phenyl ketone from a 1,3 butadiene and acrylic acid without a purification or separation step and, more particularly, to a synthesis method of cyclohexyl phenyl ketone that includes carrying out a [2+4] Diels-Alder reaction of 1,3-butadiene and acrylic acid in the presence or absence of benzene or a non-aromatic organic solvent to yield 3-cyclohexene-1-carboxylic acid, a hydrogenation reaction to yield cyclohexanecarboxylic acid, a chlorination reaction to prepare a cyclohexanecarbonyl chloride; and a Friedel-Crafts reaction in the same reactor without purifying or separating the cyclohexanecarboxylic acid to prepare a cyclohexyl phenyl ketone with a high yield.