Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([NH:13][S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:5][C:6]1([OH:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C([O-])([O-])=O.[K+].[K+].[C:30]([O:39]N1C(=O)CCC1=O)([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=O>C1COCC1.O>[OH:12][C:6]1([CH2:5][CH:4]([NH:13][S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:3][N:2]([CH3:1])[C:30](=[O:39])[O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:37])[CH3:38])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CNCC(CC1(O)CCCCC1)NS(=O)(=O)c1ccc(C)cc1
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(CN(C)C(=O)OCC[Si](C)(C)C)CC2(O)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a solution of 1-(3-(methylamino)-2-(tosylamino)propyl)cyclohexanol in 3:1 THF/H2O v/v (4 mL) was added K2CO3 (240 mg, 1.74 mmol), followed by Teoc-OSu (248 mg, 0.96 mmol). The resulting solution was stirred at rt for 30 min and the organic solvent was removed under reduced pressure. The residue was extracted with EtOAc (2×). The combined organic phases were washed with brine, dried, filtered and concentrated under vacuum. The residue was chromatographied on silica gel to give 2-(trimethylsilyl)ethyl 3-(1-hydroxycyclohexyl)-2-(tosylamino)propylmethylcarbamate (300 mg, 74% for two steps). MS m/z 469 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][C:11]1[S:12][C:13]2[CH2:19][C@@H:18]([NH:20]C(OC(C)(C)C)=O)[CH2:17][CH2:16][C:14]=2[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>C(Cl)Cl>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[CH2:1]([O:8][C:9](=[O:28])[NH:10][C:11]1[S:12][C:13]2[CH2:19][C@@H:18]([NH2:20])[CH2:17][CH2:16][C:14]=2[N:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2nc(NC(=O)OCc3ccccc3)sc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CCc2nc(NC(=O)OCc3ccccc3)sc2C1
Reaction time: 1 h

Procedure:
Dissolved ((S)-6-tert-butoxycarbonylamino-4,5,6,7-tetrahydro-benzothiazol-2-yl)-carbamic acid benzyl ester in 20 mL of CH2Cl2. Added 20 mL of TFA. Stirred for 1 h. LC-MS analysis indicated complete deprotection of BOC group. Concentrated to give 46.0 g of ((S)-6-amino-4,5,6,7-tetrahydro-benzothiazol-2-yl)-carbamic acid benzyl ester trifluoroacetate as pale yellow solid.
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14]3([CH2:23][CH2:22][CH:21]([CH:24]([F:26])[F:25])[CH2:20][CH2:19]3)[C:15]2=O)=[CH:11][CH:10]=1.C([O-])(O)=O.[Na+]>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC.CCOC(C)=O>[Br:8][C:9]1[CH:17]=[C:16]2[C:12](=[CH:11][CH:10]=1)[CH2:13][C:14]1([CH2:23][CH2:22][CH:21]([CH:24]([F:25])[F:26])[CH2:20][CH2:19]1)[C:15]2=[N:7][S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6]
Reactant: CC(C)(C)S(N)=O
Reactant: O=C1c2cc(Br)ccc2CC12CCC(C(F)F)CC2
Agent: [Ti+4]
Agent: CC[O-]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2CC12CCC(C(F)F)CC2
Temperature: 90 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
Titanium ethoxide (0.893 mL, 4.33 mmol), 2-methylpropane-2-sulfinamide (0.315 g, 2.60 mmol) and 6′-bromo-4-(difluoromethyl)spiro[cyclohexane-1,2′-inden]-1′(3′H)-one (Intermediate 91, 0.713 g, 2.17 mmol) were dissolved in 2-Me THF (5 mL) and heated to 90° C. overnight. 2-Methylpropane-2-sulfinamide (0.315 g, 2.60 mmol) and titanium ethoxide (0.893 mL, 4.33 mmol) were added and the reaction was refluxed for 7 h. Another portion of reagents was added and the mixture was refluxed overnight. The reaction was allowed to attain r.t. EtOAc (50 mL) was added followed by dropwise addition of NaHCO3 (10 mL). The mixture was stirred at r.t. for 2 h. The crude product was purified using flash chromatography (40 g SiO2, 0-40% EtOAc in heptane) to give the title compound (564 mg, 60% yield): MS (ES+) m/z 432 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[C:4]([CH3:11])=[N:3]1.[Li]CCCC.[I:17]I>O1CCCC1.CCCCC>[I:17][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([CH3:11])[C:5]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: II
Reactant: COC(=O)c1cn(C)nc1C
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: COC(=O)c1c(C)nn(C)c1I
Temperature: -45 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a solution of methyl 1,3-dimethyl-1H-pyrazole-4-carboxylate (154 mg, 1 mmol) in dry tetrahydrofuran (10 mL) at −78° C., 2 M solution of BuLi (0.550 mL, 1.100 mmol) in pentane was added dropwise. The reaction mixture was then warmed to −45° C. and stirred for 1 h. It was then cooled to −78° C. and a solution of IODINE (279 mg, 1.100 mmol) in THF (2 mL) was added. The reaction mixture was warmed to RT and stirred for 1 h. It was then quenched with saturated NH4Cl solution and extracted with ethyl acetate (2×25 mL). The organic layers were combined, washed with brine, dried over MgSO4, and then concentrated in vacuo. The crude product was obtained as a brown thick oil. This material was then purified by preparative HPLC using CH3CN/H2O/TFA as solvent system. Homogeneous fractions were combined and concentrated in vacuo. The concentrate was then extracted with ethyl acetate and the extracts combined and dried over MgSO4. The suspension was then filtered and the filter and evaporated under reduced pressure to give the title compound as a white solid, (137 mg, 0.460 mmol, 46.0% yield). MS m/z 281 (MH+), Retention time: 1.107 min. (basic). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 2.45 (s, 3H) 3.84 (s, 3H) 3.91 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:21])[C:12]3[S:19][C:18](I)=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:24]([OH:27])[C:25]#[CH:26]>CN(C=O)C.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:21])[C:12]3[S:19][C:18]([C:26]#[C:25][CH2:24][OH:27])=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(I)cc21
Reactant: C#CCO
Agent: Cl[Pd]Cl
Solvent: CN(C)C=O
Solvent: N#Cc1ccccc1
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(C#CCO)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-iodo-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (0.20 g, 0.44 mmol), Pd(PhCN)2Cl2 (10 mg) CuI (7 mg) Et3N (1 mL) and propargyl alcohol (0.036 g, 0.66 mmol) in DMF was stirred at ambient temperature overnight. The solvent was removed and the residue partitioned between H2O and CH2Cl2 (100 mL each). The layers were shaken, the organic layer separated and dried over MgSO4. The solvents were removed in vacuo and the residue purified via flash column chromatography (eluant 5% MeOH/CH2Cl2) to afford 0.117 g title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:22]([O:24]CC)=O)[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.Cl.[CH3:28][NH:29][CH3:30].C(N(CC)CC)C>C(O)C.C(OCC)(=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:22](=[O:24])[N:29]([CH3:30])[CH3:28])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: CNC
Reactant: CCOC(=O)c1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)s1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc(C(=O)N(C)C)sc2-c2ccc(OC)cc2)cc1
Temperature: 100 °C
Yield: 24.1 %

Procedure:
A mixture of 4,5-bis(4-methoxyphenyl)-2-ethoxycarbonylthiazole (1.50 g), dimethylamine hydrochloride (6.62 g) and triethylamine (11.32 ml) in ethanol (15 ml) was heated at 100° C. for 85 hours in a sealed tube. After allowing to cool to ambient temperature, the mixture was dissolved in ethyl acetate and water. The separated organic layer was washed with water and brine, dried over magnesium sulfate and treated with activated charcoal. After filtration, the filtrate was evaporated in vacuo. The residue was subjected to column chromatography on silica gel (75 g) and eluted with chloroform. The fractions containing the object compound were combined and evaporated in vacuo, to give a oily compound of 4,5-bis(4-methoxyphenyl)-2-(N,N-dimethylcarbamoyl)thiazole (0.36 g).
Reaction SMILES: [K].[NH:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.Cl[C:8]([O:10][CH3:11])=[O:9].CS(C)=O>C1CCCCC1>[C:8]([N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1)([O:10][CH3:11])=[O:9]
Reactant: c1cc[nH]c1
Reactant: COC(=O)Cl
Agent: [K]
Solvent: CS(C)=O
Solvent: C1CCCCC1
Product: COC(=O)n1cccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
Potassium (5.85 g, 0.15 mol) was added to a solution of 10 ml pyrrole (0.145 mol) in 80 ml hot cyclohexane in several portions. The mixture was refluxed for 1 hour. To this cold solution was added 15 g (0.16 mol) methyl chloroformate slowly. After addition, the mixture was stirred at room temperature for 30 minutes. During this period, 2.5 ml dimethyl sulfoxide was added for catalysis. After quenching with ice-water, the organic layer was separated and the aqueous layer extracted with ether. The combined organic layer was washed with 10% sodium bicarbonate, sat. sodium chloride and dried over magnesium sulfate. Removal of solvent yielded 17.4 g of a liquid. Bulb to bulb distillation gives 16.5 g N-carbomethoxy pyrrole 21 as a colorless liquid, yield 91%. The product requires storage at −20° C.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.[Cl:12][CH2:13][C:14](Cl)=[O:15]>C1(C)C=CC=CC=1>[Cl:12][CH2:13][C:14]([N:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]1[CH3:1])=[O:15]
Reactant: O=C(Cl)CCl
Reactant: CC1NCCc2ccccc21
Solvent: Cc1ccccc1
Product: CC1c2ccccc2CCN1C(=O)CCl

Procedure:
A reaction vessel was charged with 50 ml toluene and 2 g 1-methyl-1,2,3,4-tetrahydroisoquinoline (prepared by procedure of Example 1,--Method A). Then, 2 ml 2-chloroacetyl chloride was added gradually to the mixture. The reaction mixture was stirred and heated until a homogeneous solution appeared. The mixture was filtered, stripped of solvent, and subjected to Kugelrohr distillation 130° C. @ 0.2 mm Hg) to provide 2.7 g of an amber oil product having the elemental analysis reported in Table I.
Reaction SMILES: [O:1]=[C:2]1[N:13]2[C:14]3[C:10]([CH:11]=[CH:12]2)=[CH:9][C:8]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=2)=[CH:7][C:6]=3[CH2:5][NH:4][CH2:3]1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>O>[N:23]1([CH2:19][C:18]2[CH:17]=[CH:16][C:15]([C:8]3[CH:9]=[C:10]4[C:14]5=[C:6]([CH2:5][NH:4][CH2:3][C:2](=[O:1])[N:13]5[CH:12]=[CH:11]4)[CH:7]=3)=[CH:22][CH:21]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCNC1
Reactant: O=Cc1ccc(-c2cc3c4c(ccn4C(=O)CNC3)c2)cc1
Solvent: O
Product: O=C1CNCc2cc(-c3ccc(CN4CCCC4)cc3)cc3ccn1c23
Yield: 76 %

Procedure:
Using the reductive amination procedure described in Example 82, the title compound was synthesized from 4-(1-oxo-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-6-yl)-benzaldehyde and pyrrolidine in 76% yield as a pale-yellow solid: mp 146-148° C.; 1H NMR (DMSO-d6) δ 1.71 (br s, 4H), 2.49 (br s, 4H), 3.48 (br s, 2H), 3.64 (br s, 2H), 4.30-4.33 (m, 2H), 6.69 (s, 1H), 7.16 (t, 1H, J=9.0 Hz), 7.43 (d, 2H, J=9.0 Hz), 7.55 (d, 2H, J=9.0 Hz), 7.77 (d, 1H, J=9.0 Hz), 7.80 (d, 1H, J=9.0 Hz), 8.38 (t, 1H, J=6.0 Hz). HRMS calcd. for 345.1841 (M+), found 345.1835. Anal. (C22H23N3O.0.25 H2O) C, H, N.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][N:12]2[C:18](=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:20](O)(=[O:29])/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1(/[CH:22]=[CH:21]/[C:20]([N:15]2[CH2:16][CH2:17][C:18](=[O:19])[N:12]([CH2:11][CH2:10][CH2:9][N:3]3[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]3)[CH2:13][CH2:14]2)=[O:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1CCNCCN1CCCN1CCCCC1
Reactant: O=C(O)/C=C/c1ccccc1
Agent: Cl
Product: O=C(/C=C/c1ccccc1)N1CCC(=O)N(CCCN2CCCCC2)CC1

Procedure:
In analogy to the procedure described in example 11A, 4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one-dihydrochloride (intermediate 4B) and (E)-cinnamic acid gave the title compound as off-white solid. MS: 370.2 (MH+).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:21]=[CH:20][C:9]3[CH2:10][CH:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:12][O:13][C:8]=3[CH:7]=2)[CH2:2]1.[CH3:22][CH:23]([NH2:25])[CH3:24]>C(O)C>[C:14]1([CH:11]2[CH2:10][C:9]3[CH:20]=[CH:21][C:6]([O:5][CH2:4][CH:3]([OH:1])[CH2:2][NH:25][CH:23]([CH3:24])[CH3:22])=[CH:7][C:8]=3[O:13][CH2:12]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)N
Reactant: c1ccc(C2COc3cc(OCC4CO4)ccc3C2)cc1
Solvent: CCO
Product: CC(C)NCC(O)COc1ccc2c(c1)OCC(c1ccccc1)C2

Procedure:
5.0 g 1,2-epoxy-3-(3-phenyl-3,4-dihydro-2H-1-benzopyrane-7-yloxy)-propane and 2.5 cm3 2-propylamine were boiled in 40 cm3 ethanol for 2 hours. After evaporating the mixture and triturating the residue with water, the base 1-(3-phenyl-3,4-dihydro-2H-1-benzopyrane-7-yloxy)-3-(1-methylethylamino)-2-propanol was obtained, from which forming salt following the process of example 5 (a) 5.5 g of the maleate was obtained (m.p. 171°-173° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH3:11])[C:5]2=[N:6][CH:7]=1.[NH2:12][C:13]1[C:22]2[C:17](=[C:18](Br)[C:19]([CH3:23])=[CH:20][CH:21]=2)[N:16]=[N:15][C:14]=1[C:25]([NH2:27])=[O:26]>>[NH2:12][C:13]1[C:22]2[C:17](=[C:18]([C:2]3[CH:3]=[C:4]4[N:10]=[CH:9][N:8]([CH3:11])[C:5]4=[N:6][CH:7]=3)[C:19]([CH3:23])=[CH:20][CH:21]=2)[N:16]=[N:15][C:14]=1[C:25]([NH2:27])=[O:26]
Reactant: Cc1ccc2c(N)c(C(N)=O)nnc2c1Br
Reactant: Cn1cnc2cc(Br)cnc21
Product: Cc1ccc2c(N)c(C(N)=O)nnc2c1-c1cnc2c(c1)ncn2C

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 96 using 6-bromo-3-methyl-3H-imidazo[4,5-b]pyridine and 4-amino-8-bromo-7-methylcinnoline-3-carboxamide. 1H NMR (400 MHz, CD3OD) δ ppm 2.34 (s, 3 H), 4.03 (s, 3 H), 7.75 (d, J=8.59 Hz, 1 H), 8.04 (d, J=1.77 Hz, 1 H), 8.28 (d, J=8.59 Hz, 1 H), 8.35 (d, J=1.77 Hz, 1H), 8.45 (s, 1 H); ESI-MS m/z [M+H]+ 334.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11].[CH:14](OC)=[O:15].[H-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](=[CH:14][OH:15])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC=O
Reactant: COC(=O)Cc1c(F)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=CO)c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A mixture of methyl (2-chloro-6-fluorophenyl)acetate (5.20 g) and methyl formate (31.4 ml) in dry DMF (40 ml) was added dropwise to a stirred suspension of sodium hydride (1.23 g) in dry DMF (40 ml) at a temperature between 0° and 5° C. Vigorous evolution of gas was observed. The reaction mixture was stirred at room temperature for 3.5 hours, then poured into a mixture of ice and aqueous sodium carbonate, and washed with ether. The resulting aqueous mixture was acidified with concentrated hydrochloric acid and extracted with ether. The extracts were washed with water, dried and concentrated to give methyl 2-(2-chloro-6-fluorophenyl)-3-hydroxypropenoate (3.44 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:23]([C@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1)([CH3:25])[CH3:24].Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH:23]([C@H:26]1[CH2:30][O:29][C:28](=[O:31])[N:27]1[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1)([CH3:25])[CH3:24]
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(Br)c1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CC(C)[C@H]1COC(=O)N1c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 79.9 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (600 mg, 1.7 mmol), (S)-4-isopropyl-2-oxazolidinone (322 mg, 2.5 mmol), copper(I) iodide (96 mg, 0.5 mmol), N,N-dimethylglycine hydrochloride (140 mg, 1.0 mmol) and potassium carbonate (923 mg, 6.7 mmol) in dimethyl sulfoxide (5 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-((S)-4-isopropyl-2-oxo-oxazolidin-3-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (555 mg, 80%) as a white solid: LC/MS m/e calcd for C24H28N2O4 (M+H)+: 409.50, observed: 409.1.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[N:31]=[C:30]([CH3:32])[C:29]([C:33]([OH:35])=O)=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.[CH3:45][C@@H:46]1[NH:51][CH2:50][CH2:49][N:48]([S:52]([C:55]2[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][CH:56]=2)(=[O:54])=[O:53])[CH2:47]1>CN(C=O)C>[Cl:25][C:26]1[N:31]=[C:30]([CH3:32])[C:29]([C:33]([N:51]2[CH2:50][CH2:49][N:48]([S:52]([C:55]3[CH:56]=[CH:57][C:58]([C:61]([F:64])([F:62])[F:63])=[CH:59][CH:60]=3)(=[O:53])=[O:54])[CH2:47][C@@H:46]2[CH3:45])=[O:35])=[CH:28][CH:27]=1
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Reactant: Cc1nc(Cl)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[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: Cc1nc(Cl)ccc1C(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
HATU (460 mg, 1.21 mmol) was added to a solution of 6-chloro-2-methyl-3-pyridinecarboxylic acid (commercially available, e.g. from Anichem, or may be prepared according to known methods) (173 mg, 1.01 mmol) in DMF (4 ml) and the mixture was treated with DIPEA (0.440 ml, 2.52 mmol). This mixture was stirred for ca. 10 min at ambient temperature. (3S)-3-Methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Description 2) (371 mg, 1.20 mmol) was then added and stirring was continued for one hour. The reaction mixture was partitioned between DCM and sat aq. NaHCO3 solution (20 ml each). The layers were separated and the aqueous was washed with further DCM (2×20 ml). The combined organic layers were concentrated to leave a dark brown gum. Purification by silica chromatography (Biotage SP4, 25S cartridge), eluting with 12-100% ethyl acetate in isohexane, gave the title compound (456 mg) as a pale yellow gum.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].[OH:13][C:14]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:13][C:14]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:19][CH2:18][N:17]([C:2]2[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=2[N+:10]([O-:12])=[O:11])[CH2:16][CH2:15]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: Cc1nc(Br)c([N+](=O)[O-])c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N2CCC(O)(c3ccccc3)CC2)c([N+](=O)[O-])c(=O)[nH]1

Procedure:
In analogy to the procedure described in example 1, the 6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one (as prepared in Eur. Pat. Appl. EP 1 074 549 A2) was treated with the 4-hydroxy-4-phenylpiperidine in N,N-dimethylformamide in the presence of potassium carbonate at room temperature to yield the 6-(4-hydroxy-4-phenyl-piperidin-1-yl)-2-methyl-5-nitro-3H-pyrimidin-4-one as yellow solid; m.p.>250° C. (decomposition); MS: [M+H]+=331.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[C:19](Cl)[N:18]=[C:17]([NH:22]C)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.CN.C([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])C>C(O)C>[CH2:19]([NH:18][C:17]1[N:16]=[C:15]([NH:14][S:11]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:10][CH:9]=2)(=[O:13])=[O:12])[CH:33]=[C:32]([NH:29][CH2:30][CH3:31])[N:22]=1)[CH3:20]
Reactant: CCN(CC)CC
Reactant: CNc1nc(Cl)cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1
Agent: CN
Agent: Cl
Solvent: CCO
Product: CCNc1cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(NCC)n1
Temperature: 140 °C
Reaction time: 18 h
Yield: 30.6 %

Procedure:
0.47 g (0.0013 mol) of 4-tert-butyl-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide was dissolved in 10 ml of ethanol, treated with 1.3 g (0.019 mol) of methylamine hydrochloride and 4.7 ml (0.034 mol) of triethylamine and stirred in an autoclave at 140° C. for 18 hours. The mixture was freed completely from solvent, the residue was partitioned in ethyl acetate/water and the insoluble constituents were filtered off under suction. The filtered cake was recrystallized in methanol/diethyl ether. There was obtained 0.15 g (33%) of N-(2,6-bis-ethylamino-pyrimidin-4-yl)-4-tert-butyl-benzenesulfonamide as white crystals; m.p. 316-318° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:15][C:16]([N:18]2[CH2:27][CH2:26][C:25]3[CH:24]=[N:23][C:22]([NH:28][CH:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[N:21][C:20]=3[CH2:19]2)=[O:17])[C:9]([NH:11][NH:12][CH:13]=O)=[O:10])=[CH:4][C:3]=1[F:35].CCN(C(C)C)C(C)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:9]2[O:10][CH:13]=[N:12][N:11]=2)[NH:15][C:16]([N:18]2[CH2:27][CH2:26][C:25]3[CH:24]=[N:23][C:22]([NH:28][CH:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[N:21][C:20]=3[CH2:19]2)=[O:17])=[CH:4][C:3]=1[F:35]
Reactant: O=CNNC(=O)C(NC(=O)N1CCc2cnc(NC3CCOCC3)nc2C1)c1ccc(Cl)c(F)c1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(NC(c1ccc(Cl)c(F)c1)c1nnco1)N1CCc2cnc(NC3CCOCC3)nc2C1
Reaction time: 0.08 h

Procedure:
To a solution of 48 (119 mg, 0.212 mmol) and MeCN (2 mL) was added DIPEA (164 mg, 1.27 mmol) and PPh3 (99.9 mg, 0.381 mmol) and the solution was stirred for 5 min. Perchloroethane (65.1 mg, 0.275 mmol) was added and the reaction was stirred for 3 h. The reaction mixture was concentrated and partitioned between EtOAc and H2O. The organic layer was separated and the aqueous phase was extracted with EtOAc. The organic layers were combined and concentrated. The crude product was purified by reverse phase chromatography (SP4) eluting with a MeCN/H2O gradient (5-95% MeCN) to afford 50.0 mg (48.4%) of I-9: 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 8.08 (s, 1H), 7.41 (t, 1H), 7.21 (dd, 1H), 7.14 (d, 1H), 6.35 (d, 1H), 5.83 (d, 1H), 4.90 (d, 1H), 4.43 (s, 2H), 4.05-3.95 (m, 3H), 3.77-3.60 (m, 2H), 3.55 (t, 2H), 2.70 (m, 2H), 2.03 (d, 2H), 1.53 (m, 2H); LCMS (ACPI-pos) m/z 488.2 (M+H)+.