Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[N:11]([CH3:16])[C:10]([CH3:18])([CH3:17])[CH2:9]1.[C:19]([C:21]1[N:26]=[CH:25][C:24]([C:27]2[C:39]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]([C:40]4[CH:52]=[CH:51][C:43]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[C:42](F)[CH:41]=4)[C:31]=3[CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)#[N:20]>CS(C)=O.O>[C:19]([C:21]1[N:26]=[CH:25][C:24]([C:27]2[C:39]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]([C:40]4[CH:41]=[CH:42][C:43]([C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])=[C:51]([NH:7][CH:8]5[CH2:9][C:10]([CH3:18])([CH3:17])[N:11]([CH3:16])[C:12]([CH3:14])([CH3:15])[CH2:13]5)[CH:52]=4)[C:31]=3[CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)#[N:20]
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Reactant: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN1C(C)(C)CC(Nc2cc(-n3c4ccccc4c4c(-c5ccc(C#N)nc5)cccc43)ccc2C(=O)OC(C)(C)C)CC1(C)C
Temperature: 90 °C

Procedure:
0.95 g of potassium carbonate and 7.8 ml of 4-amino-1,2,2,6,6-pentamethylpiperidine are successively added to a solution of 1.06 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-fluorobenzoate, obtained in stage 1 of Example 49, in 8 ml of dimethyl sulphoxide. The reaction mixture is heated at 90° C. for 2 hours and 15 minutes in a microwave, and then diluted with distilled water. The aqueous phase is extracted twice with ethyl acetate and the combined organic phases are washed with water and a saturated solution of sodium chloride and dried over magnesium sulphate. The residue is purified by silica gel chromatography, elution being carried out with a mixture of dichloromethane and methanol (97/3 by volume), so as to give 0.8 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]benzoate in the form of a yellow oil, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([O:26][CH3:27])[C:11]([O:24][CH3:25])=[C:12]([C:14](=[O:23])[CH2:15][C:16](=[O:22])[C:17]([O:19]CC)=[O:18])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[OH-].[Na+]>[CH2:1]([C:8]1[CH:9]=[C:10]([O:26][CH3:27])[C:11]([O:24][CH3:25])=[C:12]([C:14](=[O:23])[CH2:15][C:16](=[O:22])[C:17]([OH:19])=[O:18])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1cc(Cc2ccccc2)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(Cc2ccccc2)cc(C(=O)CC(=O)C(=O)O)c1OC

Procedure:
To a solution of ethyl 4-(5-benzyl-2,3-dimethoxyphenyl)-2,4-dioxobutyrate (0.59 g) in ethanol (8 mL), aq. NaOH (1 M, 6.4 mL) was added. The resultant mixture was stirred at room temp for 2 h. The product mixture was concentrated under vacuum. The residue was partitioned between ethyl acetate and aq. HCl. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was triturated with a mixture of diethyl ether and hexane. Filtration of the resultant solid provided the title acid. 1H NMR (CDCl3) δ7.4-7.2 (m, 7H), 6.92 (br s, 1H), 3.97 (s, 2H), 3.89 (s, 3H), 3.84 (s, 3H).
Reaction SMILES: C([N:8]([CH2:40][C@@H:41]([C:50]1[CH:59]=[CH:58][C:57]([O:60]CC2C=CC=CC=2)=[C:56]2[C:51]=1[CH:52]=[CH:53][C:54](=[O:68])[NH:55]2)[O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25](=[O:39])[NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:20][CH2:19]1)C1C=CC=CC=1>CO>[Si:43]([O:42][C@H:41]([C:50]1[CH:59]=[CH:58][C:57]([OH:60])=[C:56]2[C:51]=1[CH:52]=[CH:53][C:54](=[O:68])[NH:55]2)[CH2:40][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:19][CH2:20][CH:21]([O:24][C:25](=[O:39])[NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:22][CH2:23]1)([C:46]([CH3:49])([CH3:47])[CH3:48])([CH3:45])[CH3:44]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN(CCCCCCCCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)Cc1ccccc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCCCCCCCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)c1ccc(O)c2[nH]c(=O)ccc12
Yield: 114.5 %

Procedure:
To a 500-mL round-bottomed flask was added a sample of the crude solution of biphenyl-2-yl-carbamic acid 1-(9-{benzyl-[(R)-2-(8-benzyloxy-2-oxo-1,2-dihydro-quinolin-5-yl)-2-(tert-butyldimethyl-silanyloxy)ethyl]amino}nonyl)piperidin-4-yl ester (50 mL containing about 17.5 g, 18.5 mmol) and methanol (150 mL) and the resulting mixture was stirred until homogeneous (if necessary, any undissolved solids can be removed by filtration through a pad of Celite). The flask was then purged with hydrogen gas for 5 minutes and then palladium hydroxide (3.5 g, 20% Pd (dry basis) on carbon, 60% water) was added. The resulting mixture was stirred at room temperature while hydrogen gas was slowly bubbled through the mixture for about 5 hours (>98% conversion by HPLC). The reaction mixture was then filtered through a pad of Celite and the solvent was removed under reduced pressure to give crude biphenyl-2-yl-carbamic acid 1-{9-[(R)-2-(tert-butyldimethylsilanyloxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]nonyl}piperidin-4-yl ester as a yellow solid (16 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[CH:40][C:6]([CH2:7][N:8]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=4)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=3)[N:10]=2)=[CH:5][CH:4]=1.CCN(CC)CC.Cl[C:50]([O:52][CH3:53])=[O:51].O>C(Cl)Cl>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:41][CH:40]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([NH:30][C:50](=[O:51])[O:52][CH3:53])=[N:28][CH:29]=4)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=3)[N:10]=2)=[CH:37][CH:36]=1
Reactant: COC(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(N)nc3)n2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)Nc1ccc(Nc2ncc(Cl)cc2-c2nc(C)nc(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)n2)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 4.4 %

Procedure:
A solution of N5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-yl)pyridine-2,5-diamine (Example 194, Step 2, 0.152 g, 0.266 mmol) and Et3N (0.111 mL, 0.799 mmol) in DCM (3 mL) was treated with methyl chloroformate (Aldrich) (0.025 mL, 0.319 mmol) and the mixture was stirred at rt for 2 days during which time solvent was lost due to evaporation. The residue was taken into the mixed solvent (1:1 DCM/THF, 5 mL) and Et3N (0.5 mL) and methyl chloroformate (0.1 mL) were added. The mixture was stirred at rt for 2 h. The resulting solid was collected and transferred to an Erlenmeyer flask using MeOH and DMSO. Water was added and the mixture was sonicated. The resulting orange solid was collected and this mixture was heated in TFA (2 mL) in the presence of trifluoromethanesulfonic acid (TCI) (0.2 mL) at rt for 30 min, then at 60° C. overnight. Solid sodium carbonate was added until effervescence subsided. Sodium bicarbonate was added slowly until no more effervescence was observed. The resulting solid was collected by filtration. The crude product was purified by preparative HPLC using Phenomenex, Gemni 5 micron C18 100×30 mm column (1%-90% CH3CN w/0.1% TFA/H2O w/0.1% TFA in 15 min). The fractions containing product were collected and lyophilized to give an orange fluffy solid, which was taken into water and the resulting yellow precopitate was collected, washed with water and dried to give methyl 5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-ylamino)pyridin-2-ylcarbamate (0.0074 g, 7% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 11.84 (s, 1H); 10.10 (s, 1H); 8.74 (d, J=2.74 Hz, 1H); 8.64 (d, J=2.54 Hz, 1H); 8.37 (d, J=2.74 Hz, 1H); 8.19 (dd, J=9.00, 2.74 Hz, 1H); 7.98 (br. s., 1H); 7.82-7.90 (m, 1H); 7.80 (d, J=8.80 Hz, 1H); 3.68 (s, 3H); 2.45 (s, 3H). m/z (ESI, +ve ion) 386.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])[CH:5]=[C:4]([Cl:13])[N:3]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>O1CCCC1>[CH3:14][S:15]([O:11][CH2:10][C@@H:9]([NH:8][C:6]1[CH:5]=[C:4]([Cl:13])[N:3]=[C:2]([Cl:1])[N:7]=1)[CH3:12])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](CO)Nc1cc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](COS(C)(=O)=O)Nc1cc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-2-((2,6-dichloropyrimidin-4-yl)amino)propan-1-ol (2.10 g, 9.46 mmol), MsCl (1.19 g, 10.4 mmol) and triethylamine (2.87 g, 28.4 mmol) in tetrahydro-furan (THF) (60 mL) was added dropwise methanesulfonyl chloride (1.19 g, 10.4 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 h, then filtered and concentrated. The crude was used into next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[C:16]([CH:19]3[CH2:24][CH2:23][NH:22][NH:21][CH2:20]3)[S:17][CH:18]=2)[CH2:10]1.[CH3:25][C:26]1[N:30]([CH2:31][C:32](O)=[O:33])[N:29]=[C:28]([C:35]([F:38])([F:37])[F:36])[CH:27]=1>ClCCl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:32](=[O:33])[CH2:31][N:30]4[C:26]([CH3:25])=[CH:27][C:28]([C:35]([F:38])([F:37])[F:36])=[N:29]4)[NH:21][CH2:20]3)[S:17][CH:18]=2)[CH2:10]1
Reactant: Fc1cccc(F)c1C1CC(c2csc(C3CCNNC3)n2)=NO1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C3=NOC(c4c(F)cccc4F)C3)cs2)CN1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]hexahydropyridazine (i.e. the product of Step H) (0.29 g, 0.83 mmol), 5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-acetic acid (0.19 g, 0.91 mmol) and N,N-dicyclohexylcarbodiimide (0.19 g, 0.91 mmol) in dichloromethane (5 mL) was stirred at room temperature for 48 h. More dichloromethane was added to the reaction mixture, the mixture was filtered, washing thoroughly with dichloromethane. The filtrate was concentrated under reduced pressure and loaded onto a chromatotron plate (4 mm). The plate was eluted with dichloromethane, followed by a gradient of 0.5% to 2% methanol in dichloromethane. Fractions containing product material were further purified by HPLC using an Alltima C18 column (250×22 mm), monitored at wavelength 225 nm and eluted with 60% methanol and 0.1% 2,2,2-trifluoroacetic acid in water to provide the title compound (69 mg), a compound of the present invention.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.Cl[S:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>N1C=CC=CC=1>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:1]2[C:13](=[O:14])[C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[S:10]2)[CH:7]=1
Reactant: Cc1ccnc(N)c1
Reactant: O=C(Cl)c1ccccc1SCl
Solvent: c1ccncc1
Product: Cc1ccnc(-n2sc3ccccc3c2=O)c1
Temperature: 50 °C
Yield: 37.1 %

Procedure:
Using the method of Fischer and Hurni (Arzneimittel Forsch., 1964;14:1301) 5.4 g (0.05 mol) of 2-amino-4-methylpyridine in 50 mL of pyridine at 10° C. was reacted with 10.3 g (0.05 mol) of 2-chlorosulfenylbenzoyl chloride. The mixture was heated to 50° C. and maintained at that temperature for 2 hours. The mixture was cooled to 25° C. and filtered. The solid was recrystallized from benzene to give 4.5 g of the title compound, mp 195°-196.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]#[N:8])=[N:4][O:5][N:6]=1.C[Si]([N:13]=[N+:14]=[N-:15])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[NH:13]1[C:7]([C:3]2[C:2]([NH2:1])=[N:6][O:5][N:4]=2)=[N:8][N:15]=[N:14]1
Reactant: N#Cc1nonc1N
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: Nc1nonc1-c1nnn[nH]1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
To a solution of 4-amino-furazan-3-carbonitrile (0.10 g, 0.90 mmol) and trimethylsilyl azide (0.21 g, 1.82 mmol) in toluene (10 mL) was added dibutyl tin oxide (0.227 g, 0.91 mmol) and the mixture was heated for 20 hours at 130° C. until complete consumption of nitrile was observed by LC-MS. The reaction mixture was allowed to cool to ambient temperature and concentrated in vacuo. The residue was dissolved in methanol and partitioned between ethyl acetate and 10% sodium bicarbonate solution and the organic portion was washed with a further portion of 10% sodium bicarbonate solution. The combined aqueous extracts were acidified to pH 2 with 10% HCl solution and re-extracted into ethyl acetate (2×30 mL). The combined organics were dried over MgSO4, filtered and concentrated in vacuo to yield 4-(1H-tetrazol-5-yl)-furazan-3-ylamine as a white solid (0.122 g, 87%).
Reaction SMILES: C([O:5][C:6](=[O:46])[C:7]([O:10]/[N:11]=[C:12](/[C:33]1[N:34]=[C:35]([NH:38]C(OC(C)(C)C)=O)[S:36][CH:37]=1)\[C:13]([NH:15][C@H:16]1[C@@H:19]([CH2:20][N:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]2=[O:27])[N:18]([S:28]([OH:31])(=[O:30])=[O:29])[C:17]1=[O:32])=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:38][C:35]1[S:36][CH:37]=[C:33](/[C:12](=[N:11]/[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:46])=[O:5])/[C:13](=[O:14])[NH:15][C@H:16]2[C@@H:19]([CH2:20][N:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]3=[O:27])[N:18]([S:28]([OH:31])(=[O:29])=[O:30])[C:17]2=[O:32])[N:34]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2ccccc2=O)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1ccccc1=O)c1csc(N)n1)C(=O)O
Yield: 20.4 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (3S,4R)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-oxo-4-((2-oxopyridin-1(2H)-yl)methyl)azetidine-1-sulfonic acid (61 mg, 0.089 mmol), DCM (891 μL) and TFA (412 μl, 5.35 mmol). The crude residue purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (9.6 mg, 19%) as a white powder. LCMS: Rt=0.57 min, m/z=529.1 (M+1) Method 2m_acidic_polar; 1H NMR (400 MHz, D2O) δ 7.59 (d, J=6.7 Hz, 1H), 7.56-7.48 (m, 1H), 7.05 (s, 1H), 6.50 (d, J=9.0 Hz, 1H), 6.39 (t, J=6.7 Hz, 1H), 5.30 (d, J=5.9 Hz, 1H), 4.47 (dd, J=14.5, 2.7 Hz, 1H), 4.07 (dd, J=14.5, 8.6 Hz, 1H), 1.37 (s, 3H), 1.36 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[CH:14][C:13]=2[F:29])[CH:8]=[CH:7][N:6]=1)=[O:4].O.[OH-].[Li+].Cl>CO.CN(C)C=O>[CH2:22]([O:21][C:19]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=2)=[C:13]([F:29])[CH:14]=1)=[O:20])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1cc(Oc2ccc(NC(=O)OCc3ccccc3)cc2F)ccn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccnc(C(=O)O)c2)c(F)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
4-(4-Benzyloxycarbonylamino-2-fluorophenoxy)pyridine-2-carboxylic acid methyl ester (10.7 g) was dissolved in methanol (450 ml) and N,N-dimethylformamide (150 ml), and water (75 ml) and lithium hydroxide (1.36 g) were added thereto, followed by stirring at room temperature for 1 hr. 1N hydrochloric acid (100 ml) was added thereto, then the reaction mixture was concentrated under reduced pressure and liquid-liquid separation was carried out after addition of ethyl acetate (500 ml), and the precipitated solid was collected by filtration. The resultant solid was washed with water and hexane, and dried under aeration. The organic layer of the filtrate obtained above was washed with water (100 ml×2) and brine (200 ml) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resultant solid was washed with water and hexane and dried under aeration. This solid was combined with the solid obtained above, and dried at 60° C. overnight to provide the titled compound as white powder (9.53 g, 92.3%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[C:29]([S:30][CH3:31])=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=[CH:26][C:15]=1[C:16]([O:18][C:19]1[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[CH:20]=1)=[O:17].S([O-])(O)=O.[Na+]>ClCCl>[CH3:12][O:13][C:14]1[C:29]([S:30]([CH3:31])=[O:9])=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=[CH:26][C:15]=1[C:16]([O:18][C:19]1[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[CH:20]=1)=[O:17]
Reactant: COc1c(C(=O)OC2=CC(=O)CCC2)ccc(C(F)(F)F)c1SC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(C(=O)OC2=CC(=O)CCC2)ccc(C(F)(F)F)c1S(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
68 mg (70% by weight, 0.28 mmol) of meta-chloroperbenzoic acid were added to 100 mg (0.28 mmol) of 3-(2-methoxy-3-methylthio-4-(trifluoromethyl)benzoyloxy)-cyclohex-2-enone in 10 ml of dichloromethane. The mixture was stirred at RT for 1 h. For work-up, 3 ml of 10 percent strength aqueous sodium hydrogensulfite solution were added. After confirmation that no peroxides were present, the organic phase was washed twice with in each case 5 ml of saturated aqueous NaHCO3 solution. After phase separation, the solvent was removed. This gave 90 mg of 3-(2-methoxy-3-methylsulfinyl-4-(trifluoromethyl)benzoyloxy)cyclohex-2-enone.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1>>[CH:9]1([C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[CH3:1])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C1=CCCCC1
Reactant: Cc1ccc(C)cc1
Product: Cc1ccc(C)c(C2CCCCC2)c1
Temperature: 141 °C

Procedure:
p-Xylene (50 g, 0.47 moles), 2 g (0.024 moles) of cyclohexene and 1 g of Y-20 zeolite catalyst were placed in a 100 M1, 3-neck flask bottle with a stirrer and water condenser. The flask was purged with nitrogen and the reaction mixture heated until refluxing began at 126° C.. Cyclohexene was added in 2 g increments and the reflux temperature gradually increased to 141° C. A total of 12 g of cyclohexene was added during a total reaction time of 7 hours.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][CH:9]=[O:10].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([SH:19])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([S:19][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[CH2:8][CH:9]=[O:10])[CH:16]=[CH:17][CH:18]=1
Reactant: O=CCC1CCCCC1Br
Reactant: COc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cccc(SC2CCCCC2CC=O)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 85.8 %

Procedure:
The mixture of 2-bromocyclohexylacetaldehyde 1.14 g, 3-methoxythiophenol 779 mg, potassium carbonate 1.54 g and acetone 20 ml is stirred at a room temperature for 21 hours. The solvent is distilled off under reduced pressure, and water 10 ml is added. Then, extraction is carried out twice with ethyl ether 20 ml. The organic layer is washed with saturated brine 5 ml and then dried on magnesium sulfate anhydrous. The solvent is distilled off under reduced pressure, and the residue is subjected to silica gel chromatography (hexane: chloroform=9:1), whereby colorless oily 2-(3-methoxyphenylthio)cyclohexylacetaldehyde 1.26 g is obtained. The yield: 86%.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][C:13]=1[C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][NH:32][C:33](=[O:35])[CH3:34].[H-].[Na+]>O1CCCC1>[C:33]([N:32]([CH2:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=1)[C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[C:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:14]=1)(=[O:35])[CH3:34]
Reactant: CCCCCCCCCCOc1ccc(C(=O)Cl)cc1C(C)(C)C
Reactant: CC(=O)NCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ccc(C(=O)N(Cc2ccccn2)C(C)=O)cc1C(C)(C)C
Yield: 45.4 %

Procedure:
The title compound is prepared by the procedure of Example 27, using 2.9 g of product from Example 132, 1.3 g of product from Example 12, 0.433 g of 50% sodium hydride and 60 ml of dry tetrahydrofuran. The residue is purified by chromatography to give 1.74 g of the desired product as a yellow oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.C(N(CC)CC)C.[CH3:17][CH:18]([CH3:22])[CH2:19][C:20]#[CH:21].O>O1CCCC1.[Cu]I.CCOCC>[CH3:17][CH:18]([CH3:22])[CH2:19][C:20]#[C:21][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1
Reactant: CSc1nccc(I)n1
Reactant: C#CCC(C)C
Agent: [Cu]I
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O
Product: CSc1nccc(C#CCC(C)C)n1
Reaction time: 72 h
Yield: 91.5 %

Procedure:
To a cold (0° C.) solution of 4-iodo-2-(methylthio)pyrimidine (4.73 g, 21.2 mmol) in tetrahydrofuran (70 mL) was added copper (I) iodide (404 mg, 2.12 mmol), dichlorobistriphenylphosphine palladium (II) (744 mg, 1.06 mmol), and triethylamine (8.8 mL, 63.8 mmol). 4-Methyl-pentyne (5.0 mL, 42.5 mmol) was added dropwise to the reaction mixture and the resultant solution was stirred at 0° C. for 30 minutes and then at room temperature for 72 hours. Water and ether were added and the layers separated. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration followed flash chromatography on silica gel (4:1 hexane-ether) provided 4-(4-methylpent-1-ynyl)-2-(methylthio)pyrimidine (4.0 g, 92%) as a clear oil. 1H NMR (CDCl3) δ 8.44 (d, 1H), 6.96 (d, 1H), 2.56 (s, 3H), 2.35 (d, 2H), 1.97 (M, 1H), 1.05 (d, 6H); MS m/z 207 (M+1).
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@H:7]([NH:16]C(=O)C(F)(F)F)[CH2:6]1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].CO>O>[CH2:1]([O:4][C@@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@H:7]([NH2:16])[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@H]1C[C@@H](NC(=O)C(F)(F)F)c2cc(OC)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C=CCO[C@H]1C[C@@H](N)c2cc(OC)ccc21
Yield: 99.6 %

Procedure:
Step C (3): cis-N-(3-(Allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoroacetamide (650 mg, 2.06 mmol) from stepC (2), potassium carbonate (1.42 g, 10.3 mmol) and MeOH (70 mL)/H2O (4.4 mL) were heated at reflux for 7 h. The reaction mixture was concentrated in vacuo. Added water to the residue, extracted with EtOAc, washed the organic layers with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford 450 mg (99% yield) of cis-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-amine as a light brown oil: LC-MS (M+H)+=220.2; 1H NMR (500 MHz, DMSO-d6) δ 7.19 (d, J=8.24 Hz, 1H), 6.97 (d, J=2.14 Hz, 1H), 6.78 (dd, J=8.24, 2.44 Hz, 1H), 5.81-6.07 (m, 1H), 5.30 (dd, J=17.09, 1.83 Hz, 1H), 5.15 (dd, J=10.53, 1.68 Hz, 1H), 4.72 (t, J=6.87 Hz, 1H), 4.02-4.21 (m, 2H), 3.96 (t, J=7.48 Hz, 1H), 3.73 (s, 3H), 2.64-2.88 (m, 1H), 1.39-1.58 (m, 1H).