Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC([N:5]1[CH2:9][CH:8]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH:7]2[N:20]([C:23](=[O:39])[CH:24]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:21][CH2:22][CH:6]12)=O.CCN(C(C)C)C(C)C.[CH3:49][S:50](Cl)(=[O:52])=[O:51]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:35]([O:34][C:32](=[O:33])[NH:31][CH:24]([CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)[C:23]([N:20]1[CH2:21][CH2:22][CH:6]2[N:5]([S:50]([CH3:49])(=[O:52])=[O:51])[CH2:9][CH:8]([C:10]3[C:18]4[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH:7]12)=[O:39])([CH3:38])([CH3:37])[CH3:36]
Reactant: COC(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2S(C)(=O)=O)C1CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 49.4 %

Procedure:
A solution containing 50 (200 mg, 0.41 mmol) and DIPEA (163 mg, 1.26 mmol) in anhydrous DCM (5 mL) was cooled to 0° C. A solution of MsCl (44 mg, 0.41 mmol) in DCM (0.5 mL) was added followed by the addition of DMAP (5 mg, cat.). After 2 h, the reaction mixture was diluted with DCM and washed successively with 1M HCl and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (1:1 hexanes/EtOAc) to afford 114 mg (49%) of 61 as a white solid. Mass spectrum, m/z [563] (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH3:10])=[N:4][CH:3]=1.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[S:19](Cl)(=[O:21])=[O:20]>>[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[S:19]([NH:8][C:6]1[C:5]([O:9][CH3:10])=[N:4][CH:3]=[C:2]([Cl:1])[N:7]=1)(=[O:21])=[O:20]
Reactant: COc1ncc(Cl)nc1N
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Product: COc1ncc(Cl)nc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 6-chloro-3-methoxy-2-pyrazinamine (0.24 g) and 2,3-dichlorobenzenesulphonyl chloride (0.32 g). Yield 0.24 g.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10]C)=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].B(Br)(Br)Br>ClCCl>[OH:1][C:2]1[C:9]([OH:10])=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1c([N+](=O)[O-])ccc(C=O)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1ccc([N+](=O)[O-])c(O)c1O
Temperature: 0 °C
Reaction time: 4 h
Yield: 95.1 %

Procedure:
17.2 g of 2-hydroxy-3-methoxy-4-nitrobenzaldehyde (J. Het. Chem. 33, (1996), 1171) in 350 ml of dichloromethane is slowly mixed at 0° C. with 175 ml of boron tribromide solution (1 M in dichloromethane), and it is stirred for another 4 hours. The batch is added to ice water, the organic phase is separated, and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with water, and the solvent is removed in a vacuum. 15.2 g of 2,3-dihydroxy-4-nitrobenzaldehyde is obtained as a red solid, flash point 122–126° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4](Br)=[N:5][N:6]=1.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>C(O)C>[NH2:1][C:2]1[S:3][C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:5][N:6]=1
Reactant: C1COCCN1
Reactant: Nc1nnc(Br)s1
Solvent: CCO
Product: Nc1nnc(N2CCOCC2)s1
Reaction time: 8 h
Yield: 43.6 %

Procedure:
A mixture of 9 g of 2-amino-5-bromo-1,3,4-thiadiazole (0.05 mole), 9.1 g of morpholine (0.105 mole) and 150 ml ethanol was refluxed for 6 hours. After standing overnight at room temperature the precipitate was filtered off, suspended in water, again filtered off and then dried. Thus 2-amino-5-morpholino-1,3,4-thiadiazole is obtained in a yield of 43.6% of the theoretical yield. Melting point: 186°-188° C.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:14]2[O:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[CH:11][C:10]=2[CH:9]=[C:8]([OH:22])[CH:7]=1)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:22][C:8]1[CH:7]=[C:6]([CH:4]=[O:5])[C:14]2[O:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=3)=[CH:11][C:10]=2[CH:9]=1
Reactant: CON(C)C(=O)c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Reaction time: 0.5 h
Yield: 50.9 %

Procedure:
To a cooled (0° C.) solution of 119 (0.18 g, 0.58 mmol) in THF (10 ml) was added LiAlH4 (1.5 ml of 1.0 M in THF) dropwise. After stirring for 30 min, the reaction was quenched with 2N HCl and partitioned between 2N HCl and EtOAc. The EtOAc was separated, dried, and concentrated. The product was purified by column chromatography on silica gel (30% Et OAc/Hex) to give 120 as a yellow solid (0.075 g, 51%); Mp=261–263° C.; 1H NMR (DMSO-6) δ 10.36 (s, 1 H), 9.79 (s, 1 H), 9.77 (s, 1 H), 7.76 (d, 2 H, J=8.5 Hz), 7.25 (d, 1 H, J=2.0 Hz), 7.17 (s, 1 H), 7.12 (d, 1 H, J=2.1 Hz), 6.88 (d, 2 H, J=8.5 Hz); MS 255 (M+H)+
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][NH2:14].[Br:15][C:16]1[C:21]([CH2:22][CH3:23])=[C:20](Br)[N:19]=[CH:18][N:17]=1>CC(N(C)C)=O.C(N(C(C)C)CC)(C)C>[Br:15][C:16]1[N:17]=[CH:18][N:19]=[C:20]([NH:14][CH2:13][CH2:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[CH2:6][CH2:7][CH2:8][NH:9][C:10]=3[N:1]=2)[C:21]=1[CH2:22][CH3:23]
Reactant: CCc1c(Br)ncnc1Br
Reactant: NCCCc1ccc2c(n1)NCCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCc1c(Br)ncnc1NCCCc1ccc2c(n1)NCCC2
Reaction time: 6 h

Procedure:
A mixture of 0.20 g (1 mmole) of 3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-ylpropylamine [prepared according to J. Org. Chem. 2004, 69, (1959-1966)] and 0.30 g (1.1 mmoles) of 4,6-dibromo-5-ethyl-pyrimidine in 20 ml of dimethylacetamide and 1 ml of diisopropylethylamine is taken to 120° C. for 6 hours. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent evaporated off under reduced pressure (2 kPa). The residue is chromatographed on silica gel eluting with a gradient of 100% heptane to 100% ethyl acetate. 0.21 g of expected product is obtained in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@H:10]2[CH:23]=[O:24])[CH:5]=[CH:6][C:7]=1[Cl:8].C[Si](C)(C)[C:27]([F:30])([F:29])[F:28].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:11][C@H:10]2[CH:23]([OH:24])[C:27]([F:30])([F:29])[F:28])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](C=O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](C(O)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a solution (2.6 mL) of tert-butyl (6R,7R)-7-(3,4-dichlorophenyl)-6-formyl-1,4-oxazepane-4-carboxylate (100 mg) in THF were added a solution (1.0 M, 0.534 mL) of trimethyl(trifluoromethyl)silane (190 mg) and tetrabutylammonium fluoride in THF under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1 M hydrochloric acid (0.5 ml), and the mixture was further stirred for 3 hr. Distilled water was added, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (91.7 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]=[C:8]3[C:15]([CH3:23])([CH3:22])[C:16]4[C:21]([C:7]3=[CH:6][C:5]2=1)=[CH:20][CH:19]=[CH:18][CH:17]=4.[H-].[Na+].Cl[C:27]1[N:32]=[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:30]=[C:29]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:28]=1>CN(C)C=O.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:27]1[N:32]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:30]=[C:29]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:28]=1)[C:10]1[CH:9]=[C:8]3[C:15]([CH3:23])([CH3:22])[C:16]4[C:21]([C:7]3=[CH:6][C:5]2=1)=[CH:20][CH:19]=[CH:18][CH:17]=4
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccc(Br)cc13
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC1(C)c2ccccc2-c2cc3c4cc(Br)ccc4n(-c4nc(-c5ccccc5)nc(-c5ccccc5)n4)c3cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
25.5 g (70.4 mmol) of 7-bromo-12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]fluorene are dissolved in 400 ml of dimethylformamide under a protective-gas atmosphere, and 3.1 g of 60% NaH in mineral oil (78 mol) are added. After 1 h at room temperature, a solution of 2-chloro-4,6-diphenyl-1,3,5-triazine (22.6 g, 84.5 mmol) in 100 ml of THF is added dropwise. The reaction mixture is stirred at room temperature for 12 h. After this time, the reaction mixture is poured onto ice and extracted three times with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is recrystallised from toluene. Yield: 40 g (67 mmol), 95% of theory.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:28])[NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:17]=1.[OH-].[Na+].C(OCC)(=O)C>CO>[CH3:1][C:2]1([CH3:29])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:28])[NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)NS(C)(=O)=O)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(C(=O)NS(C)(=O)=O)c1
Yield: 99.4 %

Procedure:
A mixture of methyl 3,3-dimethyl-2-(3-(methylsulfonylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (58 mg, 0.14 mmol, 1.0 eq.) in methanol (2.5 mL) and 1N sodium hydroxide aqueous solution (2.1 mL, 2.1 mmol, 15.0 eq.) was heated to reflux for 1 h. Thin layer chromatography (petroleum ether:ethyl acetate=1:1) and LC-MS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure and the residual was acidified with 1N hydrochloric acid solution to pH=5. The white solid precipitated was dissolved in ethyl acetate and separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate Removal of the solvent in vacuo gave 56 mg of 3,3-dimethyl-2-(3-(methylsulfonylcarbamoyl)-phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a yellow solid in quantitative yield. MS (ESI+APCI) M+1=403.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][C:21]=1[CH3:30].N12CCN(CC1)CC2>C1COCC1>[CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1)[S:26]([C:23]1[CH:24]=[CH:25][C:20]([F:19])=[C:21]([CH3:30])[CH:22]=1)(=[O:27])=[O:28]
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1F
Reactant: COc1ccc(CNc2ccncn2)c(OC)c1
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(F)c(C)c2)c(OC)c1
Yield: 59.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 14b by using the N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (590 mg, 2.40 mmol) prepared in Example 14a, 4-fluoro-3-methylbenzenesulfonyl chloride (WO 2010/079443; 1000 mg, 4.79 mmol), 1,4-diazabicyclo[2.2.2]octane (537 mg, 4.79 mmol) and THF (20 mL), to yield the title compound (598 mg, 50%) as a colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]#[N:16].[C:17]1([S:23][CH2:24][N:25]=[N+:26]=[N-:27])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CS(C)=O>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[N:27]=[N:26][N:25]([CH2:24][S:23][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:15]=1[NH2:16]
Reactant: [N-]=[N+]=NCSc1ccccc1
Reactant: N#CCc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1c(-c2ccccc2F)nnn1CSc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.7 %

Procedure:
To a stirred suspension of potassium carbonate (19.5 g, 141 mmol) in dry dimethylsulfoxide (100 ml) under nitrogen was added 2-fluorophenylacetonitrile (5.9 ml, 46 mmol). The reaction was stirred for 5 minutes at which time azidomethyl phenyl sulfide (5 ml, 35.3 mmol) was added dropwise. The resulting yellow reaction mixture was stirred at room temperature for 16 hours before slow addition to distilled water (2000 ml) with vigorous stirring. The aqueous mixture was extracted with ethyl acetate (4×500 ml) and the combined organic extracts were washed with brine (500 ml), dried (Na2SO4) and the solvent removed in vacuo. The resultant brown oil was purified by flash chromatography (25% EtOAc/isohexane) and the product crystallised from diethyl ether to furnish 5-(2-fluorophenyl)-3-phenylsulfenylmethyl-3H-1,2,3-triazol-4-ylamine (3.04 g, 29%) as a pale yellow solid. δH (400 MHz, CDCl3) 4.10 (2H, br s, NH2), 5.55 (2H, s, PhSCH2), 7.11 (1H, ddd, J=11.5, 8.2 and 1, ArH), 7.22-7.32 (5H, m, ArH), 7.39-7.41 (2 H, m, ArH), 7.89 (1H, td, J=7.5 and 2.0, ArH); m/z (ES+) 301 (M+H+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N:14]([CH3:23])[CH:13]=1.[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CS(C)=O>[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([O:31][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH3:23])[CH:13]=2)[CH2:27][CH2:26]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Cn1cc(-c2cc(S(C)(=O)=O)ccc2F)c2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2O[C@H]2CC[C@H](N)CC2)c2ccccc2c1=O
Temperature: 120 °C
Reaction time: 12 h

Procedure:
A mixture of 4-(2-fluoro-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one (200 mg, 0.60 mmol), trans-4-aminocyclohexan-1-ol (278 mg, 2.42 mmol) and Cs2CO3 (591 mg, 1.81 mmol) in DMSO (4 mL) was stirred at 120° C. for 12 hrs. Water (20 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to give the title compound (103.15 mg, 36.9%) as its hydrochloride salt. 1H NMR (DMSO-d6, 400 MHz) δ 8.28 (d, J=8.0 Hz, 1H), 8.10 (s, 3H), 7.95 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.80 (d, J=2.4 Hz, 1H), 7.63 (t, J=7.2 Hz, 1H), 7.51-7.49 (m, 3H), 7.14 (d, J=8.0 Hz, 1H), 4.50-4.44 (m, 1H), 3.56 (s, 3H), 3.22 (s, 3H), 2.95-2.85 (m, 1H), 2.00-1.94 (m, 2H), 1.84 (d, J=11.2 Hz, 2H), 1.47-1.41 (m, 2H), 1.20-1.12 (m, 2H). LCMS (M+H)+=427.1 (M+H)+
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[CH3:30][O:31][C:32](=[O:41])[C:33]1[CH:38]=[C:37]([OH:39])[CH:36]=[CH:35][C:34]=1[OH:40].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:30][O:31][C:32](=[O:41])[C:33]1[CH:38]=[C:37]([O:39][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:36]=[CH:35][C:34]=1[OH:40]
Reactant: COC(=O)c1cc(O)ccc1O
Reactant: ICCCCCCc1cccc(OCc2ccccc2)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)ccc1O
Yield: 38.9 %

Procedure:
A mixture of 1.00 g of 1-(6-iodohexyl)-2,3-bis(phenylmethoxy)benzene, 0.34 g of 2,5-dihydroxybenzoic acid methyl ester and 1.0 g of potassium carbonate in 30 mL of acetone was stirred at reflux for 17 hours. Workup as in Example 16 and chromatography on 60 g of silica gel using 1% ethyl acetatetoluene gave 0.42 g (39% yield) of 2-hydroxy-5-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid methyl ester as an oil.
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([O:12][CH3:13])[N:5]=[C:4]([CH3:14])[N:3]=1.O.[NH2:16][NH2:17]>C(O)C>[NH:16]([C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([O:12][CH3:13])[N:5]=[C:4]([CH3:14])[N:3]=1)[NH2:17]
Reactant: COc1nc(C)nc(F)c1C(F)(F)F
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1nc(C)nc(NN)c1C(F)(F)F

Procedure:
Next, a reaction flask was loaded with 4-fluoro-6-methoxy-2-methyl-5-(trifluoromethyl)-pyrimidine (22 g) and ethanol (40 ml), followed by dropwise addition of hydrazine monohydrate (10.5 g) to the flask in one hour with stirring. Then, after stirring for one hour, the reaction mixture was filtrated to give 4-hydrazino-6-methoxy-2-methyl-5-(trifluoromethyl)pyrimidine. By GC/MS analysis, a molecular ion peak of 222 was confirmed for this compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1.[CH:13]([Mg]Br)=[CH2:14]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]2[C:3]=1[CH:13]=[CH:14][NH:10]2
Reactant: C=C[Mg]Br
Reactant: COc1ccc(Br)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: COc1ccc(Br)c2cc[nH]c12
Reaction time: 2 h
Yield: 8 %

Procedure:
To a −60° C. solution of 4-bromo-2-nitroanisole (7.89 g, 33.3 mmol) in THF (300 was added vinylmagnesium bromide (1 M in THF, 100 ml, 0.1 mol) while maintaining the reaction temperature below −40° C. The resulting mixture was stirred allowing the temperature to rise to −40° C. in 2 hours. The reaction mixture was then quenched with a saturated solution of NH4Cl (700 ml) and extracted with Et2O (200 ml). The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated, and purified through flash chromatography affording 4-bromo-7-methoxyindole LII (594 mg, 8% yield).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[N:17]=[C:16]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7].[C:30]1(=[O:36])[O:35][C:33](=[O:34])[CH2:32][CH2:31]1>C1C=CC=CC=1>[C:33]([CH2:32][CH2:31][C:30]([N:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[C:18]([N:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)[N:17]=[C:16]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[N:15]=2)[CH2:12][CH2:13]1)=[O:7])=[O:36])([OH:35])=[O:34]
Reactant: O=C(C1CCCN1)N1CCN(c2cc(N3CCCC3)nc(N3CCCC3)n2)CC1
Reactant: O=C1CCC(=O)O1
Solvent: c1ccccc1
Product: O=C(O)CCC(=O)N1CCCC1C(=O)N1CCN(c2cc(N3CCCC3)nc(N3CCCC3)n2)CC1
Yield: 120 %

Procedure:
A solution of 2 g of (-)-N'-[(pyrrolidin-2-yl)carbonyl]-N-[2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine in 20 ml of anhydrous benzene is added with 0.56 g of succinic anhydride and 0.05 g of N,N-dimethylaminopyridine, then the reaction mixture is refluxed for 2 hours. After that, solvent is evaporated off under reduced pressure, to give 3 g of (-)-N'-[(1-(carboxyethylcarbonyl)pyrrolidin-2-yl)carbonyl]-N-[2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH:22]1[CH2:27][CH2:26][S:25][CH2:24][CH2:23]1)[O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1.[C:28]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:31])[CH:29]=[CH2:30].CCN(C(C)C)C(C)C>CO>[C:33]([O:32][C:28](=[O:31])[CH2:29][CH2:30][N:16]1[CH2:15][CH2:14][CH:13]([C:10]2[CH:9]=[CH:8][C:7]([CH2:6][O:5][C:4]3[CH:19]=[CH:20][C:21]([CH:22]4[CH2:27][CH2:26][S:25][CH2:24][CH2:23]4)=[C:2]([CH3:1])[CH:3]=3)=[CH:12][CH:11]=2)[CH2:18][CH2:17]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: Cc1cc(OCc2ccc(C3CCNCC3)cc2)ccc1C1CCSCC1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCc2ccc(C3CCN(CCC(=O)OC(C)(C)C)CC3)cc2)ccc1C1CCSCC1
Temperature: 60 °C

Procedure:
Crude 4-{4-[3-Methyl-4-(tetrahydro-thiopyran-4-yl)-phenoxymethyl]-phenyl}-piperidine is dissolved in MeOH (8 mL) and treated with t-butyl acrylate (1.777 mmol, 228 mg, 0.26 mL) and DIEA (4.442 mmol, 574 mg, 0.77 mL). The resulting mixture is heated at 60° C. for 45 minutes. After concentration, the residue is partially purified by silica gel chromatography (0 to 10% MeOH in DCM) to give crude 3-(4-{4-[3-Methyl-4-(tetrahydro-thiopyran-4-yl)-phenoxymethyl]-phenyl}-piperidin-1-yl)-propionic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:23][C:24]1[CH:40]=[CH:39][C:27]([O:28][C:29]([CH3:38])([CH3:37])[C:30]([O:32]C(C)(C)C)=[O:31])=[CH:26][CH:25]=1)[CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][C:11]=1[C:19]([F:22])([F:21])[F:20])=[O:8].[ClH:41].C(OCC)C>C(OCC)(=O)C>[ClH:41].[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:28][C:29]([CH3:38])([CH3:37])[C:30]([OH:32])=[O:31])=[CH:39][CH:40]=1)[CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][C:11]=1[C:19]([F:22])([F:21])[F:20])=[O:8]
Reactant: COCCN(CC(=O)Nc1ccc(C(C)C)cc1C(F)(F)F)Cc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COCCN(CC(=O)Nc1ccc(C(C)C)cc1C(F)(F)F)Cc1ccc(OC(C)(C)C(=O)O)cc1
Reaction time: 1 h

Procedure:
0.4 g (0.78 mmol) of the compound from Example 3-7 are dissolved in 4 ml of ethyl acetate. At 40° C., first 8 ml of 1N hydrochloric acid (in diethyl ether) and then 12 ml of diethyl ether are added. The mixture is allowed to stand at 4° C. for one hour. The precipitated crystals are filtered off with suction, washed with a mixture of ethyl acetate and diethyl ether (ratio 1: 1) and then dried at 40° C. under reduced pressure for 20 hours. This gives 0.362 g (84.5% of theory) of the title compound.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C@H:4]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:5](=[O:13])[NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:13]=[C:5]1[C@@H:4]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:3][CH2:2][S:1][C@H:7]2[CH2:8][CH2:9][CH2:10][CH2:11][N:6]12
Reactant: O=CCCCCNC(=O)[C@H](CCS)NC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@H]1CCS[C@H]2CCCCN2C1=O)OCc1ccccc1
Temperature: 50 °C
Yield: 80.8 %

Procedure:
To a solution of (S)-benzyl 4-mercapto-1-oxo-1-(5-oxopentylamino)butan-2-ylcarbamate (150 mg, 0.426 mmol) in DCM (5 mL) at rt was added a couple drops of TFA (by pipette). The mixture was stirred at 50° C. (gentle refluxing) for 1.5 hr. The reaction mixture was cooled to rt and concentrated. The residue was diluted with EtOAc. The EtOAc solution was washed with saturated aqueous NaHCO3, saturated aqueous NaCl (2×), dried over Na2SO4, filtered and concentrated. The residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-70% EtOAc/Hex to give benzyl (4S,10aS)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (115 mg, 0.344 mmol, 81% yield). Anal. Calcd. for C12H22N2O3S m/z 334.3. found: 335.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.43-7.26 (m, 5H), 6.25 (d, J=6.5 Hz, 1H), 5.28 (dd, J=7.7, 3.0 Hz, 1H), 5.10 (d, J=2.5 Hz, 2H), 4.86 (ddd, J=10.3, 6.8, 3.3 Hz, 1H), 4.28 (d, J=13.8 Hz, 1H), 3.19 (ddd, J=14.1, 11.0, 2.7 Hz, 1H), 3.07-2.87 (m, 1H), 2.70 (ddd, J=14.4, 6.1, 3.0 Hz, 1H), 2.44-2.25 (m, 1H), 2.06-1.89 (m, 2H), 1.86-1.60 (m, 3H), 1.60-1.39 (m, 2H).