Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[C@H:11]([CH2:23][OH:24])[O:10][C:9]2=[O:25])=[CH:4][CH:3]=1.[CH2:26](OC(=N)C(Cl)(Cl)Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.FC(F)(F)S(O)(=O)=O>ClCCl>[CH2:26]([O:24][CH2:23][C@@H:11]1[O:10][C:9](=[O:25])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C@H:12]1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: O=C1O[C@@H](CO)[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Cl)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1O[C@@H](COCc2ccccc2)[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
(4S,5R)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-5-(hydroxymethyl)-oxazolidin-2-one (0.08 mmol), prepared according to the method described for Example 64, in dichloromethane (1 mL) was treated with benzyltrichloroacetimidate (0.09 mmol) and catalytic trifluoromethane sulfonic acid. The reaction was stirred overnight, and was then purified on silica gel (10-30% ethyl acetate/hexanes) to give the title compound. 1H NMR (acetone-d6) δ (ppm) 7.82 (s, 1H), 7.74 (d, J=7.6 Hz, 1H) 7.68 (d, J=7.7 Hz, 1H), 7.65-7.61 (m, 1H), 7.54-7.52 (m, 2H), 7.37-7.28 (m, 6H), 5.72 (d, J=5.3 Hz, 1H), 4.71-4.62 (m, 3H), 3.95 (d, J=3.8 Hz, 2H); HPLC-MS calculated C24H19ClF3NO3 (M+H+): 462.1, found: 461.9.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]2[C:19]([CH3:20])=[C:18]3[C:13]([CH2:14][CH2:15][CH2:16][CH2:17]3)=[N:12]2)=[C:4]([F:21])[CH:3]=1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N:11]2[C:19]([CH3:20])=[C:18]3[C:13]([CH2:14][CH2:15][CH2:16][CH2:17]3)=[N:12]2)=[C:4]([F:21])[CH:3]=1
Reactant: Cc1c2c(nn1-c1cc([N+](=O)[O-])c(Cl)cc1F)CCCC2
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1c2c(nn1-c1cc(N)c(Cl)cc1F)CCCC2
Reaction time: 0.17 h
Yield: 99.6 %

Procedure:
A mixture of iron powder (3 g) and a 5% aqueous acetic acid solution (10 ml) was heated at 90° to 100° C. while stirring for 10 minutes. To the resulting mixture, there was dropwise added 2-(4-chloro-2-fluoro-5-nitrophenyl)-3-methyl-4,5,6,7-tetrahydro-2H-indazole (2 g) in acetic acid (10 ml) and ethyl acetate (10 ml), followed by stirring at the same temperature for 1 hour. After cooling, the iron powder was eliminated by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution, dried and concentrated. The crystallized residue was collected by filtration and washed with ether to obtain 1.8 g of 2-(4-chloro-2-fluoro-5-aminophenyl)-3-methyl-4,5,6,7-tetrahydro-2H-indazole, m.p., 107°-108° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][O:10][CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:4]=1)#[N:2].[C:20](OC)(=[O:28])[C:21]1[C:22](=[CH:24][CH:25]=[CH:26][CH:27]=1)[SH:23].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:28]=[C:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[S:23][C:1]([C:3]2[N:4]=[C:5]([CH2:9][O:10][CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=[CH:7][CH:8]=2)=[N:2]1
Reactant: CC(C)(C)OC(=O)CCOCc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CCOCc1cccc(-c2nc(=O)c3ccccc3s2)n1

Procedure:
tert-Butyl 3-[(2-cyano-6-pyridyl)]methoxypropanoate (2.62 g, 10 mmol) and methyl thiosalicylate (1.85 g, 11 mmol) were dissolved in toluene (30 ml), and triethylamine (1.70 ml, 12 mmol) were added thereto. The reaction mixture was refluxed under nitrogen atmosphere for 15 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The titled compound (2.92 g, 71%) was given from the fraction eluted with ethyl acetate-hexane (1:2, v/v) and recrystallized from ethyl acetate-isopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[N:10]2[C:5]([C:6](=[O:12])[NH:7][C:8]([CH3:11])=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCOCC1.O>[CH2:19]([N:7]1[C:6](=[O:12])[C:5]2=[CH:4][CH:3]=[C:2]([Cl:1])[N:10]2[N:9]=[C:8]1[CH3:11])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1nn2c(Cl)ccc2c(=O)[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a stirred mixture of 7-chloro-2-methyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (1.10 g, 5.99 mmol) and Cs2CO3 (2.25 g, 6.9 mmol) in dioxane (20 mL) was added benzyl bromide (0.76 mL, 6.16 mmol) and heated at 95° C. under nitrogen for 3 h. The reaction mixture was cooled to rt, diluted with water and stirred for 1 h. The precipitated solid was collected and washed with water, dried in vaccum over P2O5 at 35° C. to give the title compound (1.41 g, 87%): 1H NMR (CDCl3) δ 7.26 (m, 2H), 7.20 (m, 1H), 7.13 (m, 2H), 6.98 (d, 1H, J=4.4 Hz), 6.40 (d, 1H, J=4.4 Hz), 5.19 (s, 2H), 2.35 (s, 3H); 3C NMR (CDCl3) δ 154.0, 148.0, 135.8, 129.0, 127.8, 126.5, 117.7, 116.5, 109.7, 108.2, 45.7, 20.1; MS (ESI+) 274.04, 276.06 (M++H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:15])[CH2:10][CH2:11][N:12]([CH3:14])C.[Br:16][C:17]1[CH:18]=C([CH:21]=[CH:22][CH:23]=1)N>C(O)C.O>[Br:16][C:17]1[CH:18]=[C:14]([NH:12][CH2:11][CH2:10][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[Cl:2])=[O:15])[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(Br)c1
Reactant: CN(C)CCC(=O)c1ccccc1Cl
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(CCNc1cccc(Br)c1)c1ccccc1Cl
Temperature: 25 °C
Yield: 40 %

Procedure:
A solution of 1-(2-chlorophenyl)-3-(dimethylamino)propan-1-one HCl salt (5.17 g, 20.85 mmol) and 3-bromoaniline (2.27 mL, 1 equiv) in 1:1 ethanol/water (21 mL, 1.0M) was heated at reflux overnight. LC-MS found the starting material was gone. The reaction mixture was cooled to rt. The ethanol was removed in vacuo. The residue was partitioned between EtOAc and water. The organic layer was washed with 1% aq HCl (2×30 mL), satd aq NaHCO3 solution (20 mL), brine (20 mL), and dried over Na2SO4. After filtration and concentration, the residue (6.08 g) was purified by chromatography on a 120-g silica cartridge to afford 3-(3-bromophenylamino)-1-(2-chlorophenyl)propan-1-one (2.75 g, 40% yield) as an orange oil. LC-MS (3 min) tR=2.03 min, m/z=340, 341(M+1); 1H NMR (CDCl3) δ 7.47(d, 1H), 7.44-7.38 (m, 2H), 7.33 (td, 1H), 7.00 (m, 1H), 6.84 (m, 1H), 6.77 (s, 1H), 6.56 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][CH2:28][C:29]([NH:32][S:33]([C:36]1[S:40][C:39]([NH2:41])=[N:38][CH:37]=1)(=[O:35])=[O:34])([CH3:31])[CH3:30]>>[OH:27][CH2:28][C:29]([NH:32][S:33]([C:36]1[S:40][C:39]([NH:41][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:13])=[N:38][CH:37]=1)(=[O:35])=[O:34])([CH3:31])[CH3:30]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cnc(N)s1
Product: CC(C)(CO)NS(=O)(=O)c1cnc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 2-amino-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.13) according to general procedure II. Yellow solid. MS (ISP) 607.0 [(M−H)−]; mp 292° C.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:9](=[O:23])[NH:10][CH:11]2[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CO.[Pd]>[C:1]1([CH2:7][CH:8]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[C:9](=[O:23])[NH:10][CH:11]2[CH2:15][CH2:14][NH:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)NC1CCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)NC1CCNC1

Procedure:
A solution of 21.2 g (50 mmol) of [R-(R*,S*)]-[1-phenylmethyl-2-oxo-2-[(1-(phenylmethyl)-3-pyrrolidinyl)amino]ethyl]carbamic acid, 1,1-dimethylethyl ester in 200 ml of methanol was treated with 1.0 g of 20% palladium on carbon and shaken in a hydrogen atmosphere at pressures of 32.5-53.4 psi and temperatures of 23.0°-27.5° for 18 hours. The catalyst was removed by filtration and the solvent was removed in vacuo to give 16.3 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH:13]=O)=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:17])#[N:2].[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21].[BH4-].[Na+].CCOC(C)=O>CO>[C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13][NH:22][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:17])#[N:2]
Reactant: CCCCN
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCNCc1cncn1Cc1ccc(C#N)c(F)c1
Reaction time: 18 h

Procedure:
To a solution of the product from Step G (114 mg, 0.498 mmol) in 1 mL of methanol was added n-butylamine (0.059 mL, 0.60 mmol). After 18 hours, sodium borohydride was added (25 mg, 0.66 mmol) and the reaction was stirred for one hour. The solution was poured into EtOAc, washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled product as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[CH3:32][CH:33]([C:35]1[CH:40]=[CH:39][C:38]([S:41]([NH2:44])(=[O:43])=[O:42])=[CH:37][CH:36]=1)[CH3:34]>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:44][S:41]([C:38]3[CH:37]=[CH:36][C:35]([CH:33]([CH3:32])[CH3:34])=[CH:40][CH:39]=3)(=[O:43])=[O:42])=[O:24])=[CH:18][CH:19]=2)[N:3]=1
Reactant: CC(C)c1ccc(S(N)(=O)=O)cc1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(C(C)C)cc3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 4-(1-methylethyl)benzenesulfonamide: 1H-NMR (CDCl3) δ 7.75 (2H, d, J=8.4 Hz), 7.47-7.24 (11H, m), 6.44 (1H, br.s), 3.54-3.47 (2H, m), 3.02-2.84 (3H, m), 2.33 (3H, s), 2.26 (3H, s), 1.25 (6H, d, J=6.9 Hz).
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:17])=[C:6]([Cl:16])[CH:7]=[C:8]([O:10][CH2:11][CH:12]=[C:13]([Cl:15])[Cl:14])[CH:9]=1)(=[O:3])[CH3:2].[F:18][C:19]([F:32])([F:31])[C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][CH2:29]O)=[N:24][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([C:4]1[C:5]([O:17][CH2:29][CH2:28][CH2:27][O:26][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:32])([F:18])[F:31])=[CH:25][N:24]=2)=[C:6]([Cl:16])[CH:7]=[C:8]([O:10][CH2:11][CH:12]=[C:13]([Cl:15])[Cl:14])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: OCCCOc1ccc(C(F)(F)F)cn1
Reactant: CC(=O)c1cc(OCC=C(Cl)Cl)cc(Cl)c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1cc(OCC=C(Cl)Cl)cc(Cl)c1OCCCOc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an atmosphere of protective gas, 1.2 g of 3-acetyl-1-chloro-5-(3,3-dichloroprop-2-enyloxy)-2-hydroxybenzene, 0.9 g of 3-(5-trifluoromethylpyrid-2-yloxy)propan-1-ol and 1.12 g of triphenylphosphine were dissolved in 35 ml of dry tetrahydrofuran (THF). With ice-bath cooling, 0.74 g of diethyl azodicarboxylate was added dropwise. After about 30 minutes, the ice-bath was removed, and the mixture was stirred at room temperature for 15 hours. The mixture was then concentrated under reduced pressure and the residue was taken up in a mixture of ethyl acetate and water. After shaking, the organic phase was isolated, dried and concentrated under reduced pressure. The crude product was purified chromatographically. Yield: 1.52 g (74%)
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:19])=[C:4]([C:10]([CH3:18])=[C:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:39]([O:46][C:47]1[C:52]([CH2:53][N:54]([CH2:62][CH2:63]O)[C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[C:51]([CH3:65])[CH:50]=[C:49]([CH3:66])[N:48]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[CH2:39]([O:46][C:47]1[C:52]([CH2:53][N:54]([C:55]([O:56][C:57]([CH3:59])([CH3:58])[CH3:60])=[O:61])[CH2:62][CH2:63][O:19][C:3]2[C:2]([Br:1])=[CH:12][C:11]([O:13][S:14]([CH3:17])(=[O:15])=[O:16])=[C:10]([CH3:18])[C:4]=2[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:51]([CH3:65])[CH:50]=[C:49]([CH3:66])[N:48]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CCOC(=O)c1c(C)c(OS(C)(=O)=O)cc(Br)c1O
Reactant: Cc1cc(C)c(CN(CCO)C(=O)OC(C)(C)C)c(OCc2ccccc2)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)c(OS(C)(=O)=O)cc(Br)c1OCCN(Cc1c(C)cc(C)nc1OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
A solution of ethyl 3-bromo-2-hydroxy-6-methyl-5-((methylsulfonyl)oxy)benzoate (116d, 593 mg, 1.5 mmol), triphenylphosphine (0.50 g, 1.9 mmol), and tert-butyl ((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)(2-hydroxyethyl)carbamate (Cpd LL, 0.54 g, 1.5 mmol) in tetrahydrofuran (12 mL) was cooled to 0° C. then diisopropyl azodicarboxylate (0.40 mL, 1.9 mmol) was added drop wise. The reaction was slowly warmed to room temperature and stirred overnight. The reaction was diluted with water (15 mL) and extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with brine (15 mL), dried over magnesium sulfate, concentrated under vacuum, and purified by column chromatography (20% EtOAc/Heptane) to give ethyl 2-(2-(((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)(tert-butoxycarbonyl)amino)ethoxy)-3-bromo-6-methyl-5-((methylsulfonyl)oxy)benzoate (116e, 0.58 g, 52% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([I:9])=[CH:4][CH:3]=1.C1C(=O)N([Br:17])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>ClCCCl>[Br:17][CH2:8][C:6]1[C:5]([I:9])=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(Cl)ccc1I
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: Clc1ccc(I)c(CBr)n1
Temperature: 80 °C

Procedure:
To a stirred solution of 6-chloro-3-iodo-2-methyl-pyridine (20 g, 79 mmol, 1 eq) in 1,2-dichloroethane (200 mL) was added NBS (21.1 g, 118.6 mmol, 1.5 eq) followed by addition of AIBN (5.2 g, 31.6 mmol, 0.4 eq) at room temperature in dark. Resulting reaction mixture was heated at 80° C. for 16 hours. After maximum consumption of starting material, reaction mixture was cooled to room temperature and quenched with water (50 mL), extracted with DCM (3×50 mL). Combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get dark brown semi solid (20 g, crude). Crude of title compound was used as such for next reaction. 1H NMR not clean. LC-MS: No ionization.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]>C(O)C>[OH:1][CH2:2][C:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CCO
Product: O=C(CO)[C@@H](O)[C@@H](O)[C@H](O)CO

Procedure:
U.S. Pat. No. 6,057,135 discloses a process for manufacturing D-tagatose, wherein a lactose permeate is hydrolysed to obtain a lactose hydrolysate comprising D-galactose and glucose. The hydrolysate is fermented to convert the glucose to ethanol which is subsequently removed and the remaining solution of D-galactose is subjected to enzymatic isomerisation with an L-arabinose isomerase to obtain D-tagatose. The L-arabinose isomerase preparations used are crude biomass extracts of Lactobacillus pentosus, Bacillus amyloliquefaciens or Arthrobacter spp
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][NH:6][C:7]([C:9]1([CH2:22][CH2:23][CH2:24][CH2:25]Br)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:8].[N:31]1([C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][NH:6][C:7]([C:9]1([CH2:22][CH2:23][CH2:24][CH2:25][N:34]2[CH2:35][CH2:36][N:31]([C:37]3[CH:46]=[CH:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:38]=3)[CH2:32][CH2:33]2)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:8]
Reactant: O=C(NCc1ccc(F)c(F)c1)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Product: O=C(NCc1ccc(F)c(F)c1)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-3,4-difluoro-benzylamide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:25]5[C:26](Br)=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[O:33]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34]1>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:25]5[C:26]([C:35]6[CH:36]=[CH:37][O:33][CH:34]=6)=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5Br)ccc(F)c43)ccc21
Reactant: OB(O)c1ccoc1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5-c5ccoc5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-(2-bromo-pyridin-3-yl)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and furan-3-boronic acid following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 9): tR=1.04 min; Mass spectrum (ESI+): m/z=486 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][CH:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:35]([CH:33]([CH3:34])[CH3:32])(=[O:37])=[O:36])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: CC(C)S(=O)(=O)Cl
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)C(C)C)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and propane-2-sulfonyl chloride. Purity (ELSD, based on MW=527.6)=84%.
Reaction SMILES: [Na].[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][OH:6].Cl[C:9]1[C:18]2[C:19](=[O:29])[C:20]3[C:25]([C:17]=2[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=[CH:24][C:23]1[O:26][CH2:27][O:28][C:22]=1[CH:21]=3>>[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][O:6][C:9]1[C:18]2[C:19](=[O:29])[C:20]3[C:25]([C:17]=2[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=[CH:24][C:23]1[O:26][CH2:27][O:28][C:22]=1[CH:21]=3
Reactant: O=C1c2cc3c(cc2-c2c1c(Cl)nc1ccccc21)OCO3
Reactant: CN(C)CCO
Agent: [Na]
Product: CN(C)CCOc1nc2ccccc2c2c1C(=O)c1cc3c(cc1-2)OCO3
Temperature: 60 °C
Yield: 68.1 %

Procedure:
To a solution prepared with sodium (1.78 g, 77.4 mmol) and 2-dimethylaminoethanol (80 ml, 796 mmol) was added 6-chloro-9,10-methylenedioxy-7H-indeno[2,1-c]quinoline-7-on (8 g, 25.8 mmol) obtained in reference example 2, and the mixture was stirred with heat at 60° C. for 24 hours. The reaction mixture was poured into ice water and extracted with chloroform. The chloroform layer was dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol=10:1(v/v)) and crystallized from ethyl acetate to give 6.37 g (yield: 68.1%) of title compound. The physicochemical properties thereof are shown in table 2.
Reaction SMILES: Cl[CH:2]([CH2:6][CH:7]=O)[C:3](=[O:5])[CH3:4].[CH:9]([NH2:11])=[O:10]>C(O)=O>[CH3:7][C:6]1[N:11]=[CH:9][O:10][C:2]=1[C:3](=[O:5])[CH3:4]
Reactant: NC=O
Reactant: CC(=O)C(Cl)CC=O
Solvent: O=CO
Product: CC(=O)c1ocnc1C

Procedure:
Scheme IX illustrates the synthesis of compounds represented by Formula XVI. Reaction of a mixture of 3-chloro-2,5-pentanedione and formamide in refluxing formic acid yields 4-methyl-5-acetyloxazole. Reaction of the sodium salt of 4-methyl-5-acetyloxazole and diethyl oxalate in ethanol affords the corresponding ketoacetate. Reaction of the ketoacetate with hydrazine in refluxing ethanol yields 3-ethoxycarbonyl-5-[4-(methyl)oxazol-5-yl]pyrazole which is alkylated to yield isomers XXIIa and XXIIb. Substituting triethyl orthoacetate for triethyl orthoformate in the reaction described in Scheme V yields isomeric compounds represented by. Formula XVIIa and XVIIb ##STR12##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[C:16]1([C:22]2[O:23][CH:24]=[N:25][N:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:24]2[O:23][C:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:26][N:25]=2)[OH:15])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: c1ccc(-c2nnco2)cc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1nnc(-c2ccccc2)o1

Procedure:
Prepared according to the procedure described in Example 19, Step 1, using 5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 2-phenyl-[1,3,4]oxadiazole.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:4]3[NH:14][CH:7]([CH2:8][C:9]=2[CH:10]=[CH:11][C:12]=1[NH2:13])[CH2:6][CH2:5]3.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])[C:19]([Cl:33])=[CH:18][N:17]=1>>[Cl:33][C:19]1[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])=[N:21][C:16]([NH:13][C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][CH:7]4[NH:14][CH:4]([CH2:5][CH2:6]4)[C:3]=3[C:2]=2[Cl:1])=[N:17][CH:18]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1Cl)C1CCC(C2)N1
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2Cl)C2CCC(C3)N2)ncc1Cl
Yield: 48 %

Procedure:
Following a procedure analogous to 61e, 3-Chloro-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamine (140 mg, 0.67 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (200 mg, 0.67 mmol) were converted to the title compound as a yellow solid (151 mg, 49%). 1HNMR (400 MHz, CDCl3) δ 11.1 (s, 1H), 8.6 (d, 1H, J=8.6 Hz), 8.1 (s, 1H), 8.2 (d, 1H, J=8.3 Hz), 7.5-7.4 (m, 2H), 7.3 (s, 1H), 7.1 (t, 1H, J=7.6 Hz), 6.9 (d, 1H, J=8.3 Hz), 6.2 (bs, 1H), 4.7 (d, 1H, J=5.0 Hz), 3.9 (m, 1H), 3.1 (dd, 1H, J=16.5, 5.0 Hz), 3.0 (d, 3H, J=4.8 Hz), 2.5 (d, 1H, J=16.5 Hz), 2.2-2.1 (m, 2H), 1.9 (m, 1H), 1.7 (bs, 1H), 1.6 (m, 1H); MS (m/e) 438 (M−NCH3); mp 132-136° C.