Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[F:9].[Li+].CC([N-]C(C)C)C.B(OC)(OC)[O:19]C.C(OO)(=O)C>O1CCCC1>[Br:1][C:2]1[C:3]([F:9])=[C:4]([OH:19])[C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: Fc1cc(Cl)ccc1Br
Reactant: COB(OC)OC
Agent: CC(=O)OO
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Oc1c(Cl)ccc(Br)c1F
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
To a stirred solution of 1-bromo-4-chloro-2-fluorobenzene (5 g, 23.87 mmol) in tetrahydrofuran (40 mL) cooled to −78° C. was added LDA (14.92 mL, 29.8 mmol) dropwise. The reaction mixture was stirred at this temperature for 30 min. then allowed to warm to −20° C. and stirred for 30 min. The reaction was then cooled to −78° C. and trimethyl borate (3.47 mL, 31.0 mmol) dissolved in THF (5 mL) was added dropwise. The reaction mixture was warmed to −20° C. and stirred for 1 h. The reaction mixture was then cooled to −78° C. and peracetic acid (16 mL, 84 mmol) as slowly added dropwise. The mixture was allowed to warm to rt and stirred for 12 h. The reaction mixture was again cooled to 0° C. and quenched with 5% ammonium chloride The solution was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 3-bromo-6-chloro-2-fluorophenol (4.99 g, 18.25 mmol, 76% crude yield) as a yellow oil. The material was carried forward without further purification. LC/MS (ESI) m/e 225.1 [(M+H)+, calcd for C6H4BrClFO 224.9]; LC/MS retention time (method E): tR=0.87 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:60]=[CH:59][C:6]([CH2:7][C:8]2[C:9]([Cl:58])=[C:10]([O:54][CH2:55][CH2:56]Cl)[C:11](Br)=[C:12]([CH:14]3[C@H:19]([O:20]CC4C=CC=CC=4)[C@@H:18]([O:28][CH2:29]C4C=CC=CC=4)[C@H:17]([O:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C@@H:16]([CH2:44][O:45][CH2:46]C4C=CC=CC=4)[O:15]3)[CH:13]=2)=[CH:5][CH:4]=1)[CH3:2].[CH2:61]([Li])[CH2:62][CH2:63][CH3:64]>C1COCC1>[CH2:61]([O:20][C@@H:19]1[C@@H:18]([O:28][CH2:29][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:17]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@@H:16]([CH2:44][O:45][CH2:46][C:60]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:59]=2)[O:15][CH:14]1[C:12]1[C:11]2[CH2:56][CH2:55][O:54][C:10]=2[C:9]([Cl:58])=[C:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:60][CH:59]=2)[CH:13]=1)[C:62]1[CH:17]=[CH:16][CH:44]=[CH:64][CH:63]=1
Reactant: CCc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(Br)c(OCCCl)c2Cl)cc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)OCC3)cc1
Reaction time: 18 h
Yield: 97.6 %

Procedure:
To a solution of compound 71 (1.16 g, 1.27 mmol) in THF (12.7 mL) was added dropwise n-butyllithium (2.5M in hexane, 1.27 mL, 3.17 mmol) at −78° C. under an atmosphere of nitrogen. The mixture was stirred for 18 hours at −78° C. to 5° C. The mixture was quenched with 1N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 72 (493 mg, 48%) as brown oil.
Reaction SMILES: [CH2:1]([C:6]1[CH:7]=[C:8]([CH:25]=[CH:26][CH:27]=1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=O)[O-:18])=[CH:12][C:11]=1[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:28][O:29][CH:30]([O:34][CH3:35])[CH2:31][NH:32][CH3:33]>C1(C)C=CC=CC=1>[CH2:1]([C:6]1[CH:7]=[C:8]([CH:25]=[CH:26][CH:27]=1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:32]([CH2:31][CH:30]([O:34][CH3:35])[O:29][CH3:28])[CH3:33])=[O:18])=[CH:12][C:11]=1[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1cccc(Oc2ccc(NC(=O)[O-])cc2CCCCC)c1
Reactant: CNCC(OC)OC
Solvent: Cc1ccccc1
Product: CCCCCc1cccc(Oc2ccc(NC(=O)N(C)CC(OC)OC)cc2CCCCC)c1

Procedure:
[4-(3-Pentylphenoxy)-3-pentylphenyl]carbamate (0.1 mole) and toluene (100 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer and condenser. N-(2,2-dimethoxyethyl)methanamine (0.15 mole) is added to the vessel and the mixture is refluxed for 16 hours. Solvent is then removed by mild warming under reduced pressure to yield the desired product N-[4-(3-pentylphenoxy)-3-pentylphenyl]-N'-(2,2-dimethoxyethyl)-N'-methylurea.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH:1][C:2]2[CH:18]=[CH:17][CH:16]=[C:4]([O:5][C:6]3[CH:11]=[CH:10][N:9]=[C:8]4[NH:12][C:13](=[O:15])[NH:14][C:7]=34)[CH:3]=2)=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: O=C=Nc1cccc(F)c1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: O=C(Nc1cccc(F)c1)Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Yield: 16 %

Procedure:
Method G was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 3-fluoro-phenylisocyanate to afford the title compound (10 mg, 16%). 1H-NMR (DMSO), δ (ppm), J (Hz): 6.40 (d, 1H, HPyr, J=5.9 Hz), 6.74-6.79 (m, 1H, Harom2′), 7.21 (d, 1H, Harom4 or 6, J=8.05 Hz), 7.27 (d, 1H, Harom6 or 4), 7.30-7.46 (m, 5H, Harom4′, Harom5′, Harom6′, Harom2, Harom 5), 7.79 (d, 1H, HPyr), 9.04 (s, 2H, NHurea), 11.17 (s, 1H, NHim), 11.37 (s, 1H, NHim); MS-LC, Rf=6.84 min, (C19H14FN5O3), m/z: 380.1 [M++H], 100.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:29]1([CH2:35][S:36](Cl)(=[O:38])=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:16]1([CH:4]([NH:3][S:36]([CH2:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:38])=[O:37])[C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O[C@H]1CN2CCC1CC2)C(NS(=O)(=O)Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 59.5 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (100 mg, 0.30 mmol) in DCM (4 ml) and triethylamine (65.8 μl, 0.90 mmol), was added phenylmethanesulfonyl chloride (68.6 mg, 0.36 mmol). The reaction was stirred at RT for 13 hours. DCM was evaporated, and the crude was taken up with EtOAc and washed 1M Na2CO3, water and brine. The organic phase was dried over Na2SO4, filtered and evaporated to obtain (R)-quinuclidin-3-yl 2-phenyl-2-(phenylmethylsulfonamido)-acetate (74 mg; 59.5% yield).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][C:4](=[O:12])[NH:3][C:2]1=[O:13].CC(C)([O-])C.[K+].Br[CH2:21][CH2:22][CH2:23][Cl:24]>CN(C)C=O>[CH2:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:1][C:2](=[O:13])[N:3]([CH2:21][CH2:22][CH2:23][Cl:24])[C:4]1=[O:12]
Reactant: ClCCCBr
Reactant: O=C1Cc2ccccc2CC(=O)N1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1Cc2ccccc2CC(=O)N1CCCCl

Procedure:
A quantity of 3.5 gm (0.020 mol) of 1,3,4,5-tetrahydro-2H-3-benzazepin-2,4-dione is suspended in 30 ml of dimethylformamide and mixed with 2.5 gm of potassium tert.butoxide with stirring. After ten minutes, the solution obtained is added dropwise to 3.5 ml of 1-bromo-3-chloropropane in 20 ml of dimethylformamide while being cooled with ice. After one hour the mixture is poured onto ice water. A short time later the greasy precipitate crystallizes. The precipitate is subjected to suction filtration, dissolved in acetone, precipitated again with water, suction filtered, and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH2:24])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:11][CH2:10]1.C(N(CC)CC)C.[CH3:32][C:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH:24][C:39]([C:33]2([CH3:32])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:40])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCN(C[C@H](N)Cc2ccccn2)CC1
Reactant: CC1(C(=O)Cl)CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C[C@@H](Cc2ccccn2)NC(=O)C2(C)CCCCC2)CC1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
To a solution of (1R)-2-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-1-pyridin-2-ylmethyl-ethylamine (1.06.; 3.2 mmol, from Example 13) in dichloromethane (40 mL) at 0° C. was added triethylamine (0.90 mL; 6.5 mmol) and a solution of 1-methyl-1-cyclohexanecarbonyl chloride (520 mg.; 3.2 mmol) in dichloromethane (6 mL). The reaction mixture was stirred while allowing to warm to ambient temperature over 1 hour, washed sequentially with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered, and the solvent removed in vacuo. The crude residue was purified by flash chromatography on silica gel (2% methanol/chloroform) to yield the free base of the title compound as a clear oil (1.0 g.; 70%). Treatment with an equimolar amount of fumaric acid in ethanol afforded the fumarate salt as a white amorphous solid, m.p. 135–139° C.; MS (+) FAB [M+H]+ @ m/z 451; 1H NMR, 400 MHz, DMSO-d6. Analysis for C27H38N4O2.C4H4O4 Calculated: C, 65.70; H, 7.47; N, 9.89 Found: C, 65.29; H, 7.69; N, 9.77
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.[NH2:71][CH2:72][CH2:73][C:74]#[N:75]>CN(C=O)C>[C:72]([CH2:73][CH2:74][NH:75][C:30](=[O:32])[C:29]1[CH:33]=[CH:34][C:35]([CH3:36])=[C:27]([C:10]2[C:11]3[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]4[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=4[F:26])[C:12]=3[N:13]=[C:8]([NH:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:37][CH3:38])[N:9]=2)[CH:28]=1)#[N:71]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: N#CCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NCCC#N)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.9 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and 3-aminopropanenitrile hydrochloride (9.3 mg, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (6 mg, 21%). LC-MS m/z 560 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1.[C:13]([O:17][C:18]([N:20]1[CH2:26][CH2:25][CH2:24][C@H:21]1[CH2:22]O)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:3]([O:12][CH2:22][CH:21]2[CH2:24][CH2:25][CH2:26][N:20]2[C:18]([O:17][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:19])=[N:4][CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1
Reactant: COC(=O)c1cnc(O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cnc(OCC2CCCN2C(=O)OC(C)(C)C)c(Cl)c1
Temperature: 70 °C
Reaction time: 13 h
Yield: 39.7 %

Procedure:
To a stirred solution of methyl 3-chloro-2-hydroxypyridine-5-carboxylate (300 mg, 1.599 mmol), N-tert-butoxycarbonylprolinol (321.9 mg, 1.599 mmol), and Ph3P (503 mg, 1.919 mmol) in THF (3 mL) was slowly added DIAD (378 μl, 1.919 mmol) at room temp, and the mixture was stirred for 13 hr at 70° C. The mixture was concentrated and the residue was chromatographed on silica-gel with n-hexane-EtOAc (3:1, v/v) as eluent to give 235.6 mg (40%) methyl 3-chloro-2-[[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy]pyridine-5-carboxylate as a pale yellowish oil. 1H-NMR (400 MHz, CDCl3) δ1.46 (s, 9H), 1.87 (m, 1H), 2.05 (br s, 3H), 3.43 (br s, 2H), 3.92 (s, 3H), 4.17, 4.26 (br s each, 1H), 4.45-4.51 (m, 1H), 4.50 (s, 1H), 8.21 (s, 1H), (s, 1H), 8.67 (d, J=2.0 Hz, 1H); MS (FAB) m/z 371 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:24])([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH2:16])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.C([O:29]O)(C)(C)C>C1C=CC=CC=1.[V]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:24])([C:15]2([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[O:29][CH2:16]2)[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OO
Reactant: C=C(c1ccc(F)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1
Agent: [V]
Solvent: c1ccccc1
Product: OC(Cn1cncn1)(c1ccc(F)cc1)C1(c2ccc(F)cc2)CO1
Temperature: 25 °C
Yield: 62 %

Procedure:
2,3-Bis(4-fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-butene-2-ol (1.0 g) was dissolved in 50 ml of anhydrous benzene and stirred under nitrogen. To this solution was added 0.012 g of vanadium acetonylacetonate. The solution was then refluxed and tert-butyl hydroperoxide (0.44 g dissolved in 5 ml of anhydrous benzene) was added dropwise over 10 minutes. The reaction was refluxed for one additional hour and then cooled to ambient temperature. The benzene was removed in vacuo and the residue chromatographed on silica gel (2% MeOH/CH2Cl2). This yielded a total of 650 mg of diastereomeric products in a 3:1 ratio. Further chromatography resulted in the separation of the diastereomers. The major isomer was a waxy white solid. NMR (CDCl3 /TMS) δ2.60 (d, J=6 Hz, 1H); 3.48 (d, J=6 Hz, 1H); 4.70 (q, J=7 Hz, 2H); 5.25 (s, 1H); 6.8-7.3 (m, 8H); 7.55 (s, 1H); 7.90 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][C:6](=[O:17])[N:7]([N:9]=[CH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:8]=1.Br[CH2:19][C:20](=[O:23])[CH2:21][CH3:22]>CN(C)C=O>[CH2:21]([C:20]([CH2:19][N:5]1[C:4]([CH3:3])=[CH:8][N:7]([N:9]=[CH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:6]1=[O:17])=[O:23])[CH3:22]
Reactant: CCC(=O)CBr
Reactant: Cc1cn(N=Cc2cccnc2)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(=O)Cn1c(C)cn(N=Cc2cccnc2)c1=O
Reaction time: 0.5 h

Procedure:
0.72 g of sodium hydride are added to a suspension of 4.1 g of 2,3-dihydro-4-methyl-2-oxo-1-pyrid-3-ylmethyleneamino-1H-imidazole in 80 ml of N,N-dimethylformamide. The mixture is heated to 50°, treated with a solution of 3.78 g of 1-bromo-2-oxo-butane in 20 ml of N,N-dimethylformamide, and stirred for 30 minutes. The N,N-dimethylformamide is then removed on a rotary evaporator. In a mixer, the residue is mixed intimately with water. The crystals are filtered off, yielding the title compound melting at 183°-184°.
Reaction SMILES: [O:1]1[C@H:7]2[C@@H:2]1[C:3]([CH3:18])([CH3:17])[O:4][C:5]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([O:15][CH3:16])=[CH:8][C:6]=12.O.[NH3:20]>C(O)C>[NH2:20][C@H:7]1[C:6]2[CH:8]=[C:9]([O:15][CH3:16])[C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:5]=2[O:4][C:3]([CH3:18])([CH3:17])[C@@H:2]1[OH:1]
Reactant: COc1cc2c(cc1[N+](=O)[O-])OC(C)(C)[C@@H]1O[C@H]21
Reactant: N
Solvent: CCO
Solvent: O
Product: COc1cc2c(cc1[N+](=O)[O-])OC(C)(C)[C@H](O)[C@H]2N
Temperature: 100 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of (3R*,4R*)-3,4-epoxy-6-methoxy-2,2-dimethyl-7-nitro-3,4-dihydro-2H-1-benzopyran (2.64 g, 10.5 mmol) in ethanol (26 mL), an ammonia water (26 mL) was added, and the resulting mixture was stirred in a sealed tube at 100° C. for 2 hours. Upon the completion of the reaction, the solvent was distilled off. An aqueous solution of saturated sodium carbonate was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and thereby the aimed product was obtained as red amorphous substance (yield: 84%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>O1CCCC1>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:24]([C:21]1[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:23][CH:22]=1)(=[O:26])=[O:25]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)Nc2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.8 %

Procedure:
A flask with a stirrer was charged with 8.18 g of 2-aminophenol, 7.58 g of triethylamine and 100 ml of tetrahydrofuran, and a solution of 15.50 g of 4-methoxybenzenesulfonyl chloride in 30 ml of tetrahydrofuran was dropwise added with cooling with ice over 10 minutes. After completion of the addition, the reaction mixture was stirred at room temperature for 2 hours and then poured into 500 ml of ice water. A precipitated crystal was recovered by filtration and washed with water. The obtained crystal was recrystallized from ethanol/n-hexane mixed solvents, to give 9.8 g of an end product. Melting point 89° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.Cl.[N:8]1([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][O:26][C:27]4[CH:31]=[CH:30][O:29][N:28]=4)[O:22][C:21]3=[O:32])=[CH:16][C:15]=2[F:33])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]([N:11]1[CH2:10][CH2:9][N:8]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][O:26][C:27]4[CH:31]=[CH:30][O:29][N:28]=4)[O:22][C:21]3=[O:32])=[CH:16][C:15]=2[F:33])[CH2:13][CH2:12]1)=[O:4]
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCNCC2)c(F)c1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Yield: 88.9 %

Procedure:
Chloroacetyl chloride (114 mg, 1 mmol) was added to a stirred solution of 3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one dihydrochloride (435 mg, 1 mmol) and triethylamine (302 mg, 3 mmol) in dichloromethane (10 ml) at ambient temperature. After 10 minutes the reaction was purified by direct chromatography on a 10 g silica Mega Bond Elut® column, eluting with dichloromethane. Relevant fractions were combined and evaporated to give the desired product (390 mg). MS (ESP): 439 (MH+) for C19H20ClFN4O5;
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[CH:11]=[CH:10][C:9](=[O:12])[N:8]([C@H:13]3[CH2:18][CH2:17][C@H:16]([O:19][CH3:20])[CH2:15][CH2:14]3)[C:6]=2[N:7]=1.[Br:22]N1C(=O)CCC1=O>CN(C)C=O.COC(C)(C)C>[NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[CH:11]=[C:10]([Br:22])[C:9](=[O:12])[N:8]([C@H:13]3[CH2:14][CH2:15][C@H:16]([O:19][CH3:20])[CH2:17][CH2:18]3)[C:6]=2[N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CO[C@H]1CC[C@H](n2c(=O)ccc3c(C)nc(N)nc32)CC1
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CO[C@H]1CC[C@H](n2c(=O)c(Br)cc3c(C)nc(N)nc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-8-(trans-4-methoxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (482 mg, 0.1.67 mmol) in dimethylformamide (15 mL) was added N-bromosuccinimide (300 mg, 1.69 mmol). After stirring for 1 hour at room temperature the solution was diluted with methyltertbutylether and washed with 50% sodium carbonate (2×) and brine. The combined aqueous layers were extracted with dichloromethane. The combined organics were dried (MgSO4) filtered and concentrated. The solids were triturated with diethyl ether to afford 2-amino-6-bromo-8-(trans-4-methoxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (594 mg, 97%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)[S:6][CH:7]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:21][O:20][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([O:16][CH3:17])[C:13]=1[O:18][CH3:19])[C:9]([NH:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][N:23]2[CH2:28][CH2:27][N:26]([CH2:2][C:3]3[N:4]=[C:5]([NH:8][C:9](=[O:22])[C:10]4[CH:11]=[C:12]([O:20][CH3:21])[C:13]([O:18][CH3:19])=[C:14]([O:16][CH3:17])[CH:15]=4)[S:6][CH:7]=3)[CH2:25][CH2:24]2)[N:4]=1)=[O:22]
Reactant: C1CNCCN1
Reactant: COc1cc(C(=O)Nc2nc(CCl)cs2)cc(OC)c1OC
Product: COc1cc(C(=O)Nc2nc(CN3CCN(Cc4csc(NC(=O)c5cc(OC)c(OC)c(OC)c5)n4)CC3)cs2)cc(OC)c1OC

Procedure:
4-Chloromethyl-2-(3,4,5-trimethoxybenzamido)-thiazole (140 mg) and piperazine (17 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [CH:1]1([C:10]([O:12]C)=O)[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O-:9])=[O:8])[CH2:2]1.Cl.[NH3:15]>>[C:10]([CH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=[O:8])[CH2:2]1)(=[O:12])[NH2:15]
Reactant: N
Reactant: COC(=O)C1CCCC(C(=O)[O-])C1
Agent: Cl
Product: NC(=O)C1CCCC(C(=O)O)C1
Reaction time: 408 h

Procedure:
In 70 ml of aqueous conc. ammonia were dissolved 6.7 g of monomethyl 1,3-cyclohexanedicarboxylate, and the resulting mixture was allowed to stand at room temperature for 17 days. The pH of the mixture was adjusted to 1 with conc. hydrochloric acid under ice-cooling and the mixture was extracted with ethyl acetate. The extracts were washed with an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 2.64 g of the desired compound as a colorless crystalline solid. m.p.: 102°-128° C.; NMR spectrum (d6 -DMSO) δ ppm: 1.00-2.70(10H,m), 6.69(1H,s), 7.20(1H,s)
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[C:20]2[C:11]=1[O:12][C:13]1[C:14]([CH2:30][C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])=[C:15]([O:28][CH3:29])[CH:16]=[CH:17][C:18]=1[C:19]2([CH3:27])[CH3:26])=O)(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>O>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[NH2:8][CH2:9][C:10]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[C:20]2[C:11]=1[O:12][C:13]1[C:14]([CH2:30][C:31]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[O:32])=[C:15]([O:28][CH3:29])[CH:16]=[CH:17][C:18]=1[C:19]2([CH3:27])[CH3:26]
Reactant: COc1ccc2c(c1CNC(=O)OC(C)(C)C)Oc1c(ccc(OC)c1CC(=O)OCc1ccccc1)C2(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1CN)Oc1c(ccc(OC)c1CC(=O)OCc1ccccc1)C2(C)C

Procedure:
2.9 g (5.29 mmol) of benzyl 5-[(1-tert-butoxyformamido)methyl]-3,6-dimethoxy-9,9-dimethylxanthene-4-acetate were taken up in a mixture of 10 ml of trifluoroacetic acid and 5 ml of water at 0°. After half an hour the solvents were removed, whereupon the residue was treated with 20 ml of ether. The resulting solid was filtered off, washed with ether and dried over magnesium sulphate, whereby 2.25 g of benzyl 5-aminomethyl-3,6-dimethoxy-9,9-dimethylxanthene-4-acetate trifluoroacetate were obtained as a colourless powder of m.p. 169.5°-171°; IR 1716, 1662, 1631, 1604, 1538, 1494 cm-1.