Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][C@H:5]1[CH2:16][CH2:15][C:14]2[S:13][C:12]3[N:11]=[CH:10][N:9]=[C:8]([O:17][CH:18]4[CH2:23][CH2:22][CH:21]([N:24](C)[C:25](=O)OC(C)(C)C)[CH2:20][CH2:19]4)[C:7]=3[C:6]1=2)(=[O:3])[NH2:2].Cl>ClCCl>[CH3:25][NH:24][CH:21]1[CH2:22][CH2:23][CH:18]([O:17][C:8]2[C:7]3[C:6]4[C@@H:5]([CH2:4][C:1]([NH2:2])=[O:3])[CH2:16][CH2:15][C:14]=4[S:13][C:12]=3[N:11]=[CH:10][N:9]=2)[CH2:19][CH2:20]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Agent: Cl
Solvent: ClCCl
Product: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.2 %

Procedure:
Into a 50-mL round-bottom flask placed a solution of tert-butyl N-(4-[[(3R)-3-(carbamoylmethyl)-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (170 mg, 0.37 mmol, 1.00 equiv) in dichloromethane (4 mL) was added hydrochloric acid (12 M, 0.5 mL) at 0° C. and the resulting solution was stirred for 4 hr at 25° C. The reaction was then quenched with saturated aqueous sodium bicarbonate, extracted with 3×50 mL of DCM. The organic layers were combined and concentrated under vacuum. The crude product (150 mg) was purified by preparative HPLC under the following conditions (SHIMADZU): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with 100 mM NH4HCO3 and CH3CN (6.0% CH3CN up to 60% in 20 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 2-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetamide (83 mg, 62%) as a white solid. MS (ES): m/z 361 [M+H]+. 1H NMR (300 MHz, CD3OD): δ 8.43 (1H, s), 5.28 (1H, m), 3.76 (1H, m), 3.00-3.28 (1H, m), 2.97-2.99 (2H, m), 2.66-2.73 (1H, m), 2.42-2.49 (1H, m), 2.36 (3H, s), 2.29-2.18 (4H, m), 2.00-2.03 (2H, m), 1.65-1.57 (2H-m), 1.26-1.35 (2H, m).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:21][CH2:22][CH2:23]Br.O>CC(=O)CC>[Br:21][CH2:22][CH2:23][O:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1
Reactant: Oc1ccc2c(c1)[nH]c1ccccc12
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: BrCCOc1ccc2c(c1)[nH]c1ccccc12
Reaction time: 28 h

Procedure:
A mixture of 2-hydroxycarbazole (30 g; mfd. by Aldrich), potassium carbonate (113.1 g; mfd. by KANTO CHEMICAL) and 1,2-dibromoethane (211 mL; mfd. by TOKYO KASEI KOGYO) in 2-butanone (165 mL; mfd. by Wako Pure Chemical Industries) was stirred vigorously at a reflux temperature for 28 hours. The reaction solution was poured into water (1050 mL) all at once and stirred. The precipitated crystal obtained by filtration was washed with water (1 L) and 2-propanol (250 mL), and then dried under reduced pressure at room temperature to give the title compound (43.43 g) as a white solid.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:16][C:17]([F:27])([F:26])[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10](=[O:12])[NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([O:18][C:17]([F:16])([F:26])[F:27])[CH:20]=1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1cccc(OC(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a mixture of Boc-L-proline (5 g, 23.23 mmol), 3-(trifluoromethoxy)aniline (3.73 mL, 27.88 mmol) and HBTU (13.2 g, 34.8 mmol) in DMF (60 mL) was added DIPEA (7.95 mL, 46.5 mmol) and the resulting yellow solution was stirred at RT under nitrogen. The solvent was concentrated under vacuum and the residue dissolved in EtOAc and washed with HCl 1N. The combined organic layers were neutralized by addition of an aqueous saturated solution of NaHCO3. The layers were separated and the aqueous one back-extracted twice with CH2Cl2. The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 3:1 to 2:1) to give the desired compound. TLC, Rf (c-hexane/EtOAc 1:1)=0.57; MS (LC/MS): 397.1 [M+Na]+, 275.2 [MH−Boc]+, 373.3 [M−H]−; tR (HPLC conditions a) 3.81 min.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1.Cl>[Pd].CO>[F:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1
Reactant: CN1CC=C(c2cccc(C(F)(F)F)c2F)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN1CCC(c2cccc(C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 2: 4-[2-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1,2,3,6-tetrahydropyridine (0.59 g, 2.28 mmol), methanol (30 ml), palladium on carbon (0.07 g) and hydrochloric acid (0.1 ml, conc). Yield: 0.43 g. The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 260-261° C. MS m/z (relative intensity, 70 eV) 261 (M+, 69), 260 (bp), 242 (9), 97 (12) 70 (37).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)([O-:3])=[O:2].[Br:13]N1C(C)(C)C(=O)N(Br)C1=O>S(=O)(=O)(O)O>[Br:13][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[CH:7]=1
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 87 %

Procedure:
To a solution of 1,3-dinitrobenzene (25 g, 0.149 mol) in concentrated sulfuric acid (100 ml) at 0° C. was added 1,3-dibromo-5,5-dimethylhydantoin (31.75 g, 0.111 mol, 0.75 eq) portionwise over a period of 30 min. The mixture was stirred for 12 at RT and quenched by the addition of crushed ice. The precipitate formed was filtered and was washed repeatedly with water to obtain white solid. The solid was dried under vacuum to give the product in 87% yield (32 g).
Reaction SMILES: [C:1]([CH2:3][C:4]1([CH3:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#[N:2]>[Ni].CO>[NH2:2][CH2:1][CH2:3][C:4]1([CH3:17])[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CC1(CC#N)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Ni]
Solvent: CO
Product: CC1(CCN)CCN(C(=O)OC(C)(C)C)CC1
Yield: 94.9 %

Procedure:
The process is performed according to the procedure described in Example 12 (step 12.2.) Starting with 1.40 g (5.87 mmol) of tert-butyl 4-cyanomethyl-4-methylpiperidine-1-carboxylate (WO 2006/001 752) and 1.72 g (29.37 mmol) of Raney nickel in 20 mL of methanol under a hydrogen atmosphere (70 psi) at 45° C., 1.35 g of expected product are obtained in the form of a wax.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].CCN(C(C)C)C(C)C.[C:25]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[C:25]([C:29]1[CH:30]=[CH:31][C:32]([C:33]([NH:1][C@@H:2]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[CH:12][CH:13]=2)[C:3]([O:5][CH3:6])=[O:4])=[O:34])=[CH:36][CH:37]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(C#N)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(C#N)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 2 h
Yield: 87.6 %

Procedure:
Prepared using General Procedure 3: To the solution of (S)-methyl 2-amino-3-(4-cyanophenyl)propanoate (789.2 mg, 3.32 mmol) in DCM (15 mL) and DIEA (1.29 g, 9.96 mmol) was added 4-(tert-butyl)benzoyl chloride (981.3 mg, 4.99 mmol) at RT. The reaction was stirred for 2 h and the reaction was partitioned between DCM and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by chromatography (EA/hexanes) to afford 1.06 g (88%) of (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-cyanophenyl)propanoate. LCMS-ESI (m/z) calculated for C22H24N2O3: 364.2. found 365.3 [M+H]+, tR=3.55 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J=8.0 Hz, 1H), 7.85-7.60 (m, 4H), 7.49 (dd, J=15.1, 8.4 Hz, 4H), 4.85-4.60 (m, 1H), 3.65 (s, 3H), 3.30-3.23 (m, 1H), 3.18 (dd, J=13.7, 10.6 Hz, 1H), 1.29 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.N>O.S(C1C=CC(C)=CC=1)(O)(=O)=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1ncnc2c1ncn2C1CCCCO1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
Ethyl acetate (300 ml) was added to 6-chloropurine (25 g, 162 mmol) and tosylic acid monohydrate (460 mg, 2.43 mmol) and the resulting mixture was heated at 60° C. Dihydropyrane (16 ml, 178 mmol) was added and the resulting mixture was stirred at the same temperature for 30 minutes. The reaction mixture was cooled to room temperature followed by the addition of 28% aqueous ammonia solution (15 ml) and the organic layer was fractionated, washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (35 g, 91%) as a pale yellow solid.
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([CH2:9][OH:10])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH:11]1[C:16](O)=[CH:15][CH:14]=[C:13]([CH3:18])[CH:12]=1>>[CH3:2][C:1]([N:5]1[CH2:8][CH:7]([CH2:9][O:10][C:16]2[CH:15]=[CH:14][C:13]([CH3:18])=[CH:12][CH:11]=2)[CH2:6]1)([CH3:4])[CH3:3]
Reactant: Cc1ccc(O)cc1
Reactant: CC(C)(C)N1CC(CO)C1
Product: Cc1ccc(OCC2CN(C(C)(C)C)C2)cc1

Procedure:
Following the procedures of Example 8, the title compound is prepared from 1-t-butyl-3-azetidinemethanol and p-cresol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)(=O)C.[BH4-].[Na+]>O1CCCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1cccc(NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (3-amino-phenyl)-carbamic acid tert-butyl ester (1 g, 4.8 mmol), benzaldehyde (0.54 ml, 5.3 mmol) and acetic acid (0.41 ml, 7.2 mmol) in dry tetrahydrofuran (30 ml) were stirred at room temperature for 2 hrs. Sodium borohydride (0.172 g, 4.5 mmol) was added and the reaction stirred at room temperature overnight. The reaction mixture was quenched with water (50 ml) and extracted with dichloromethane (3×50 ml). The combined organics were dried (magnesium sulphate), concentrated in vacuo and the crude residue purified by flash column chromatography (SiO2) eluting with ethyl acetate to afford the title compound as an off white solid (1.27 g, 89%) HPLC retention time 6.4 min. Mass spectrum (ES+) m/z 198 (M+H-BOC)
Reaction SMILES: Cl.[CH3:2][S:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)(=[O:5])=[O:4].[CH3:22][C:23]1[N:28]=[C:27]([CH:29]=[CH2:30])[CH:26]=[CH:25][CH:24]=1.C([O-])(=O)C.[Na+].CO>O>[CH3:22][C:23]1[N:28]=[C:27]([CH2:29][CH2:30][N:19]2[CH2:20][CH2:21][CH:16]([S:13]([C:10]3[CH:11]=[CH:12][C:7]([NH:6][S:3]([CH3:2])(=[O:4])=[O:5])=[CH:8][CH:9]=3)(=[O:15])=[O:14])[CH2:17][CH2:18]2)[CH:26]=[CH:25][CH:24]=1
Reactant: CS(=O)(=O)Nc1ccc(S(=O)(=O)C2CCNCC2)cc1
Reactant: C=Cc1cccc(C)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cccc(CCN2CCC(S(=O)(=O)c3ccc(NS(C)(=O)=O)cc3)CC2)n1
Yield: 63.9 %

Procedure:
0.60 g (1.86 mmol) of 4-(4-methylsulfonylaminophenylsulfonyl)piperidine hydrochloride obtained in Example 5, 0.44 g (3.72 mmol) of 6-methyl-2-vinylpyridine and 0.31 g of sodium acetate were suspended in 10 ml of a mixture of methanol with water (1:1) and the suspension was refluxed for 2 h. The reaction liquid was filtered and the filtrate was concentrated to give a residue. After extraction with dichloromethane followed by washing with water, the organic layer was concentrated to precipitate white crystals. The crystals were collected by filtration and recrystallized from ethyl acetate to give 0.52 g (yield: 64%) of the intended compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])=[CH:5]2.[OH-].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH2:18]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:11](=[O:15])[CH:12]([CH3:13])[CH3:14])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)C(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(=O)c1cc2cc(Cl)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(5-chloro-1H-indole-2-yl)-2-methylpropan-1-one (1 mmol) in 15 mL of DMF, was added KOH (2 mmol) at 0° C. The mixture was stirred for 30 min., followed by adding benzyl bromide (2 mmol) slowly. The mixture was warmed up to room temperature and stirred for additional 1 h. The solution was poured into water, and extracted with EtOAc (×3). The organic layers were combined, washed with H2O (×3), brine (×3), dried (Na2SO4), filtered, and the filtrate was concentrated. The material was purified by flash chromatography (10% EtOAc:hexane) to yield 1-(1-benzyl-5-chloro-1H-indole-2-yl)-2-methylpropan-1-one.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH:7][CH2:8][C:9]1[N:10]=[C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]2[CH:21]=1.[F:22][C:23]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[C:24]=1[C:25]([C:27]1[CH:28]=[C:29]([C:32](O)=[O:33])[NH:30][CH:31]=1)=[O:26].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CCOC(C)=O.CN(C=O)C>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[CH2:6][N:7]([CH2:8][C:9]1[N:10]=[C:11]2[CH:16]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:14]=[CH:13][N:12]2[CH:21]=1)[C:32]([C:29]1[NH:30][CH:31]=[C:27]([C:25](=[O:26])[C:24]2[C:23]([F:22])=[CH:38][C:37]([F:39])=[CH:36][C:35]=2[F:40])[CH:28]=1)=[O:33]
Reactant: FC(F)(F)c1ccn2cc(CNCC3OCCO3)nc2c1
Reactant: O=C(O)c1cc(C(=O)c2c(F)cc(F)cc2F)c[nH]1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=C(c1c[nH]c(C(=O)N(Cc2cn3ccc(C(F)(F)F)cc3n2)CC2OCCO2)c1)c1c(F)cc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.9 %

Procedure:
To a DMF 10 mL solution of 1-(1,3-dioxolan-2-yl)-N-{[7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]methyl}methanamine (1.13 g, 3.75 mmol) were added 4-(2,4,6-trifluorobenzoyl)-1H-pyrrole-2-carboxylic acid (1.06 g, 3.94 mmol), EDC (1.08 g, 5.63 mmol), HOBt (862 mg, 5.63 mmol) and triethyl amine (1.57 mL, 11.25 mmol). The mixture was stirred at room temperature overnight. The resulting suspension was diluted with EtOAc. The organic phase was washed with sat. ammonium chloride aq., sat. aq. sodium bicarbonate aq. and brine, dried over anhydrous Na2SO4, filtered, concentrated and chromatographed on silica gel eluting with a gradient solvent mixture (100% DCM to 5% MeOH-DCM) to give the title compound as foam (744 mg). LC/MS: m/z 533(M+H).
Reaction SMILES: [O-2].[O-2].[Ti+4:3].P(=O)(O)(O)O.[O:9]=[P:10]12[O:21]P3([O:22][P:12]([O:14]P(O3)([O:17]1)=O)(=[O:13])[O:11]2)=O>>[O-:17][P:10]([O:11][P:12]([O-:22])([O-:14])=[O:13])(=[O:9])[O-:21].[Ti+4:3]
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Ti+4]
Agent: O=P(O)(O)O
Agent: [O-2]
Product: O=P([O-])([O-])OP(=O)([O-])[O-]
Yield: 90 %

Procedure:
thermally reacting titanium dioxide and phosphoric acid at a temperature of about 400° C. to about 500° C. in a reaction mixture having a phosphorus pentoxide to titanium dioxide mole ratio of about 1.20 to about 1.25 to form a fine titanium pyrophosphate powder with greater than 90% of said fine titanium pyrophosphate powder having a particle size less than 1 micron in diameter; and
Reaction SMILES: [H-].[Na+].C(O[C:6](=[O:27])[CH2:7][CH2:8][N:9]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10](=[O:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C.CCO>CCOCC>[CH2:19]([N:9]1[CH2:8][CH2:7][C:6](=[O:27])[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10]1=[O:18])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)CCN(CCc1ccccc1)C(=O)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: O=C1CCN(CCc2ccccc2)C(=O)C1c1ccccc1
Yield: 37.1 %

Procedure:
Sodium hydride (1.1 g, 50% in mineral oil) was suspended in ether (40 ml) under argon at RT. 3-(Phenethyl-phenylacetyl-amino)-propionic acid ethyl ester (2.5 g) was added in portions followed by addition of abs. EtOH (0.5 ml). The resulting mixture was refluxed for 2 hours, cooled and poured into water/ice/1 N HCl. The aqueous layer was extracted with ethyl acetate and the organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (ethyl acetate/hexanes 1:1 and then DCM/MeOH 95:5) to give the desired product as a light yellow foam (801 mg). MS (ESI: 294.4 (MH+).
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:6]=[C:7]([N:16]([CH3:18])[CH3:17])[C:8]([O:14][CH3:15])=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1.[Cl-].[NH4+]>CCOCC>[Br:4][C:5]1[CH:6]=[C:7]([N:16]([CH3:18])[CH3:17])[C:8]([O:14][CH3:15])=[C:9]([C:11]([OH:13])([CH3:1])[CH3:12])[CH:10]=1
Reactant: COc1c(C(C)=O)cc(Br)cc1N(C)C
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1c(N(C)C)cc(Br)cc1C(C)(C)O
Temperature: -70 °C

Procedure:
A solution of methylmagnesium bromide in ether was added to a solution of 1-[5-bromo-3-(dimethylamino)-2-methoxyphenyl]-1-ethanone (4 g) in diethyl ether while stirring at −70° C. After stirring at the same temperature for 30 minutes, saturated aqueous ammonium chloride was added, extraction was performed with ethyl acetate, and the organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to yield the title compound (3.4 g) as an oil.
Reaction SMILES: C1(N([C@H]2CC[C@H](CC)CC2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)CCCC1.[CH:28]1([NH:35][CH:36]2[CH2:41][CH2:40][CH:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:38][CH2:37]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:28]1([N:35]([C@H:36]2[CH2:41][CH2:40][C@H:39]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:38][CH2:37]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Reactant: c1ccc(C2CCC(NC3CCCCCC3)CC2)cc1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: O=C(O)CSc1cnc(NC(=O)N(C2CCCCCC2)[C@H]2CC[C@H](c3ccccc3)CC2)s1

Procedure:
Prepared in a similar manner to {2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via cycloheptyl-(4-phenyl-cyclohexyl)-amine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:4][N:3]=1.[CH2:29](N)[CH2:30][NH2:31].CC1C=CC(S(O)(=O)=O)=CC=1.O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[NH:26]1[CH2:29][CH2:30][N:31]=[C:25]1[C:24]1[CH:23]=[CH:22][C:21]([S:18]([C:5]2[C:6]([NH:8][C:9]3[C:10]([CH3:17])=[CH:11][C:12]([CH3:16])=[CH:13][C:14]=3[CH3:15])=[N:7][C:2]([CH3:1])=[N:3][CH:4]=2)(=[O:20])=[O:19])=[CH:28][CH:27]=1
Reactant: NCCN
Reactant: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(C#N)cc2)c(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(C3=NCCN3)cc2)c(C)c1
Temperature: 25 °C
Yield: 15.3 %

Procedure:
A mixture of 4-[2-methyl-4-(2,4,6-trimethyl-phenylamino)-pyrimidine-5-sulfonyl]-benzonitrile (83 mg, 0.21 mmol), prepared by the method described in Example 22, ethylenediamine (0.042 mL, 0.63 mmol), p-TsOH.H2O (59 mg, 0.31 mmol) and toluene (4 mL) was heated at reflux under N2 overnight and then cooled to room temperature. Saturated aqueous NaHCO3 was added, and the mixture was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (75:25 EtOAc/MeOH) to provide the target compound (14 mg, 15%) as a white solid: mp 240–242° C.; 1H NMR (300 MHz, CDCl3) δ 8.78 (s, 1H), 8.27 (br s, 1H), 8.00 (d, J=8.5 Hz, 2H), 7.95 (d, J=8.5 Hz, 2H), 6.92 (s, 2H), 4.80 (br s, 1H), 3.83 (s, 4H), 2.40 (s, 3H), 2.30 (s, 3H), 2.01 (s, 6H); ESI MS m/z 436 [(M+H)+, calcd for C23H26N5O2S, 436.2].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[F:12][C:13]([F:25])([F:24])[C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[N:18][CH:19]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:20]([C:16]2[CH:17]=[N:18][CH:19]=[C:14]([C:13]([F:25])([F:12])[F:24])[CH:15]=2)(=[O:22])=[O:21])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc2cccnc12
Reactant: O=S(=O)(Cl)c1cncc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc2cccnc12)c1cncc(C(F)(F)F)c1
Yield: 17.7 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (70 mg, 0.48 mmol), 5-trifluoromethyl-pyridine-3-sulfonyl chloride (Intermediate 442) (153 mg, 0.63 mmol), DMAP (cat.), pyridine (1.5 ml) and DCM (2 ml) gave the title compound (30 mg, 11%) after purification by column chromatography with n-hexane/EtOAc (85:15) as the eluent.
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:11]1C=CC=CC=1.S(=O)(=O)(O)O>CO>[OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:11])=[O:5]
Reactant: c1ccccc1
Reactant: O=C(O)c1cccnc1O
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cccnc1O
Reaction time: 8 h
Yield: 22 %

Procedure:
2-Hydroxynicotinic acid (6.95 g, 50 mmol) was dissolved in 125 mL of methanol, 75 mL of benzene, and 0.75 mL of concentrated sulfuric acid under nitrogen and heated at reflux for 2.5 hours. A Dean-Stark trap was added to the apparatus and heating was continued overnight. The volatiles were removed under reduced pressure and the resulting solid was suspended in cold water (150 mL) and filtered to remove unreacted starting material. The filtrate was extracted with methylene chloride and chloroform. The combined organic extracts were concentrated in vacuo to afford 2.5 g. Recrystallization from hot benzene afforded 1.7 g (22%) of the title compound. 1H NMR (CD3OD, 300 MHz) δ 3.83 (s, 3H), 6.45 (t, 1H), 7.68 (dd, 1H), 8.29 (dd, 1H). MS (DCl/NH3) m/e 154 (M+H)+.