Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1.Cl.[NH2:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(NC(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1cc(S(=O)(=O)NCCC(=O)OC(C)(C)C)ccc1NC(=O)c1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-(6-chloropyrimidine-4-carboxamido)-3-methylbenzene-1-sulfonyl chloride (Intermediate 30, 1.2 g; 3.47 mmol) in THF (100 ml) was treated with tert-butyl 3-aminopropanoate hydrochloride (800 mg; 4.4 mmol) and diisopropylamine (2 ml; 14.3 mmol). After stirring at RT for 18 hours the solvent was removed in vacuo and the residue redissolved in DCM and washed with water. The organic extracts were passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc. The title product was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:18])=[N:6][C:5]=2[N:19]=1.Cl[C@@H:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27])[CH3:22]>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@@H:11]([CH2:12][OH:13])[CH2:14][CH:15]([CH3:16])[CH3:17])=[N:8][C:7]([S:18][C@H:21]([C:23]3[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=3)[C:26]#[N:27])[CH3:22])=[N:6][C:5]=2[N:19]=1
Reactant: C[C@@H](Cl)c1cccc(C#N)c1
Reactant: CC(C)C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Product: CC(C)C[C@H](CO)Nc1nc(S[C@@H](C)c2cccc(C#N)c2)nc2nc(N)sc12
Yield: 31 %

Procedure:
The title compound was prepared in 31% yield from (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (200 mg, 0.67 mmol) and 3-[(1R)-1-chloroethyl]benzonitrile (166 mg, 1.0 mmol) according to general method A.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.[H-].[Na+].[C:19]([O:23][C:24](=[O:27])[CH2:25]Br)([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:25][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:27])=[CH:11][CH:10]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (440 mg, 2.00 mmol) in anhydrous THF (40 mL) was added NaH (160 mg, 4.00 mmol). The reaction was stirred for 10 minutes at room temperature. Then, tert-butyl-bromoacetate was added and the mixture was stirred for 18 h at room temperature. Then, extracted with ethyl acetate (4×20 mL) and the organic layers were washed with an aqueous saturated solution of NaCl (3×20 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. Flash chromatography of the residue on silica gel (SiO2, hexane:ethyl acetate, 9:1) afforded 96.3 mg of tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetate as a white solid (74% yield). RMN1H (CDCl3, 400 MHz): δ: 7.86-7.59; (m, 2H), 6.95-6.78; (m, 2H), 4.53; (s, 2H), 1.33; (s, 12H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[CH:13]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14]1.CC1C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+].Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([NH:18][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc2C1
Reactant: NC1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: Brc1ccc2c(c1)CCC(NC1CCCC1)C2
Yield: 33 %

Procedure:
Charged 50 mL round bottomed flask with 6-bromo-2-tetralone (0.750 g., 3.33 mmoles., 1.0 eq.), cylcopentylamine (0.567 g., 0.648 mL., 6.66 mmoles., 2.0 eq.) and catalytic amount of tosic acid. Fitted flask with a Dean-Stark trap and heated reaction mixture overnight at 155° C. The next day, removed remaining solvent from reaction mixture using reduced pressure. Added 25 mL of methanol and placed reaction mixture on an ice bath. Added sodium borohydride (0.630 g, 16.6 mmoles, 5.0 eq.). Removed ice bath and allowed to stir for several hours. Partitioned reaction mixture between ethyl acetate and 1.0 N HCl aqueous solution. Extracted organic layer two times more with 1.0 N HCl solution. Combined acidic extractions and basified with 5.0 N NaOH. Extracted basic aqueous with methylene chloride three times. Combined organic extracts and dried over Na2SO4. Removed solvents using reduced pressure to obtain 0.429 g. (crude yield=43%). Purified using a reverse phase column and acetonitrile:TFA buffer solvent gradient. Collected TFA salt of 6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-cyclopentyl-amine. Partitioned the product between methylene chloride and 2.0N sodium carbonate solution. Washed organic layer with 2.0N sodium carbonate a second time and then with brine. Dried organic layer over sodium sulfate and removed solvent via reduced pressure to obtain 0.324 g. (yield=33%). Mass spectrum (APCI): 294 (M++1).
Reaction SMILES: [CH3:1][C:2](=[CH:5][CH2:6][C:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]=1[CH3:15])[CH:3]=[O:4].[CH2:16](O)[CH2:17][CH2:18][OH:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH3:1][CH:2]([CH:3]1[O:19][CH2:18][CH2:17][CH2:16][O:4]1)[CH:5]=[CH:6][C:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]=1[CH3:15]
Reactant: OCCCO
Reactant: CC(C=O)=CCC1=C(C)CCCC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=C(C=CC(C)C2OCCCO2)C(C)(C)CCC1

Procedure:
103 g (0.5 mol) of 2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-butenal, 38 g (0.5 mol) of 1,3-propanediol and 1 g of p-toluenesulfonic acid are heated with 200 g of toluene for 2.5 hours in a water separator. After cooling, the mixture is washed with soda solution and dried over sodium sulfate. 3 g of sodium carbonate are added and the mixture is distilled on a 30 cm packed column. At 122-126° C./1.6-0.82 mbar this yields 81 g of product comprising 66% of 2-[1-methyl-3-(2,6,6-trimethyl-1-cyclohexen-1-yl)allyl]-1,3-dioxane and also containing other isomers with double bonds.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[F:16][C:12]1[C:13]([F:15])=[CH:14][C:6]2[NH:5][C:1](=[O:2])[O:9][C:8](=[O:10])[C:7]=2[CH:11]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cc(F)c(F)cc2c(=O)o1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of phosgene (45 g) in toluene (160 ml) was added during 20 minutes to a stirred solution of 2-amino-4,5-difluorobenzoic acid (26 g) in aqueous sodium carbonate (20.7 g anhydrous sodium carbonate in 350 ml water), keeping the temperature below 40°. The mixture was stirred at room temperature for 15 hours. The solid product was collected by filtration, washed with water and dried to give the novel compound 6,7-difluoro-1H-3,1-benzoxazine-2,4-dione, m.p. 223°-226° (dec.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:9]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCc1ccccc1
Reactant: OCC1CCCCN1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: OCC1CCCCN1Cc1ccccc1
Yield: 52.8 %

Procedure:
A mixture of 12.9 g of 2-piperidine methanol, 13.2 g of benzyl chloride, 10.5 g of triethylamine and 50 ml of toluene was stirred at reflux for 4 hours. The reaction mixture was filtered, the filtrate was concentrated, and the concentrate was distilled under reduced pressure to obtain 11.3 g of 1-benzyl-2-piperidine methanol (yield: 52.9%). b.p.: 107° C./2 mmHg
Reaction SMILES: [CH2:1]([C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=2)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(-c2csc(Cc3ccccc3)n2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(-c2csc(Cc3ccccc3)n2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
To a stirred solution of 2-benzyl-4-(3-methoxyphenyl)thiazole (1.0 g, 3.55 mmol) in CH2Cl2 (20 ml) was added a solution of 1.0 M BBr3 in CH2Cl2 (4.26 ml) at −78° C. The resulting mixture was stirred at −78° C. for 30 min and then allowed to warm up to room temperature. The mixture was quenched with water and extracted with ether. The organic layer was washed with brine, dried (magnesium sulfate) and evaporated in vacuo. The residue was triturated with chloroform and dried under reduced pressure to give 3-(2-benzylthiazol-4-yl)phenol (760 mg, 80%).
Reaction SMILES: [N:1]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:50]1[CH:55]=[C:54]([O:56][CH3:57])[N:53]=[C:52]([S:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[C:62]([F:66])[C:61]=2[F:67])[N:51]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(O)(=O)C>[F:67][C:61]1[C:62]([F:66])=[CH:63][CH:64]=[CH:65][C:60]=1[CH2:59][S:58][C:52]1[N:51]=[C:50]([NH:8][S:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:6])[CH:55]=[C:54]([O:56][CH3:57])[N:53]=1
Reactant: NS(=O)(=O)N1CCC1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared according to the procedure outlined in example 1, step iv). A mixture of azetidine-1-sulfonamide (prepared according to patent WO 2004/011443, 0.15 g), tris(dibenzylideneacetone)dipalladium (0) (44 mg), 2-dicyclohexylphosphino-2′4′6′-tri-iso-propyl-1,1′biphenyl (44 mg), cesium carbonate (0.36 g) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product of step i) (0.23 g) in dioxane (7.2 mL). Acetic acid (0.67 mL) was added and the reaction mixture was extracted with EtOAc (×3). The combined organic layers were washed with H2O, dried (MgSO4), filtered and the solvent evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel using EtOAc/isohexane (3:7) as eluent. The resulting solid was further purified by trituration with iso-hexane and dried under high vacuum at 40° C. to give the title compound as a pale yellow solid. Yield: 0.29 g.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][N:10]1[C:16]2[CH:17]=[CH:18][N:19]=[CH:20][C:15]=2[N:14]=[CH:13][C:12]2=[CH:21][CH:22]=[CH:23][N:11]12>CCOCC.O1CCCC1>[CH3:9][N:10]1[C:16]2[CH:17]=[CH:18][N:19]=[CH:20][C:15]=2[NH:14][CH:13]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:12]2=[CH:21][CH:22]=[CH:23][N:11]12
Reactant: CN1c2ccncc2N=Cc2cccn21
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN1c2ccncc2NC(c2ccccc2)c2cccn21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 64 %

Procedure:
To 15 ml of a 3M solution of phenyl magnesium bromide in ether diluted with 15 ml of tetrahydrofuran was added a solution of 4.45 g of 5-methyl-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine in 75 ml of tetrahydrofuran. After stirring at ambient temperature for 45 minutes, the reaction mixture was quenched into an iced ammonium chloride solution. The aqueous layer was extracted with ethyl acetate (2×), and the combined organics were washed with water followed by a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The resultant solid was purified via flash chromatography (compound preadsorbed on silica; elution with diethyl ether) and recrystallized from toluene to yield 4.0 g (64%) of 10,11-dihydro-5-methyl-10-phenyl-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine, mp 200°-203° C.
Reaction SMILES: O=[C:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:3]([N:5]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1)[C:6]1[CH:7]=[N:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1)=[O:4].Cl.[NH2:35][OH:36].N1C(C)=CC=CC=1C>CCO>[OH:36][N:35]=[C:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:3]([N:5]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][CH:19]=1)[C:6]1[CH:7]=[N:8][C:9]([C:12]([F:15])([F:13])[F:14])=[CH:10][CH:11]=1)=[O:4]
Reactant: NO
Reactant: O=C(C(=O)N(CCc1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)nc1)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: Cc1cccc(C)n1
Product: O=C(C(=NO)c1ccccc1)N(CCc1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 45.7 %

Procedure:
To a solution of 2-oxo-2-phenyl-N-[2-(4-trifluoromethyl-phenyl)-ethyl]-N-(6-trifluoromethyl-pyridin-3-yl)-acetamide (46 mg, 0.1 mmol) in EtOH (2 mL) was added hydroxylamine hydrochloride (14 mg, 0.2 mmol) and 2,6-lutidine (32 mg, 0.3 mmol) and the mixture stirred at ambient temperature for 36 h then concentrated and redissolved in EtOAc (5 mL), washed with 10% aqueous citric acid (3×5 mL), dried over Na2SO4, filtered, then purified by chromatography (SiO2, heptane:ethyl acetate=95:5 to 50:50) to afford the title compound (22 mg, 46%) as a white solid. MS m/e: 480.3 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:16][C:17]1[C:22]([C:23]([OH:26])([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=1)[CH2:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][N:9]=1.Cl.N1C=CC([C:33]([NH2:35])=[NH:34])=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:14][C:13]1[C:8]([CH2:7][N:6]([CH2:16][C:17]2[C:22]([C:23]([OH:26])([CH3:24])[CH3:25])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:33]([NH2:35])=[NH:34])=[N:9][CH:10]=[C:11]([CH3:15])[CH:12]=1
Reactant: Cc1cnc(CN(CCCCN)Cc2ncccc2C(C)(C)O)c(C)c1
Reactant: N=C(N)c1cc[nH]n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cnc(CN(CCCCNC(=N)N)Cc2ncccc2C(C)(C)O)c(C)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 122.5 %

Procedure:
To a solution of 2-(2-{[(4-Amino-butyl)-(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-methyl}-pyridin-3-yl)-propan-2-ol (0.1423 g, 0.28 mmol) in DMF (3 mL) was added 1H-pyrazole-carboxamidine hydrochloride (0.0440 g, 0.28 mmol) and DIPEA (0.29 mL, 1.68 mmol) and stirred at room temperature for 20 hours. The reaction mixture was concentrated, and purification of the crude material by column chromatography on silica gel (5:1:1 CH2Cl2-MeOH—NH4OH) followed by radial chromatography on silica gel (10:2:1 CH2Cl2-MeOH—NH4OH) provided 0.1367 g (41%) of COMPOUND 197 as a white solid. 1H NMR (CDCl3) δ 1.43-1.48 (m, 8H), 1.68-1.70 (m, 2H), 2.21 (s, 3H), 2.25 (s, 3H), 2.71-2.73 (m, 4H), 3.15-3.17 (m, 3H), 3.47 (s, 2H), 3.91 (s, 2H), 4.32 (s, 2H), 7.18-7.21 (m, 1H), 7.59-7.63 (m, 1H), 7.92-7.93 (m, 1H), 8.17 (s, 1H), 8.37-8.39 (m, 1H). 13C NMR (CDCl3) δ 18.31, 18.65, 22.77, 26.67, 31.59, 41.57, 54.09, 56.32, 61.95, 72.43, 123.57, 132.52, 132.92, 135.02, 139.67, 144.31, 146.94, 147.10, 150.68, 153.40, 158.00. ES-MS m/z 400 (M+H). Anal. Calcd. for C22H34N6O.1.9CH2Cl2.1.5H2O: C, 48.91; H, 7.01; N, 14.32. Found: C, 48.68; H, 6.83; N, 14.68.
Reaction SMILES: C([O:4][C@H:5]1[O:17][C@@H:16]([CH3:18])[C@H:11]([O:12]C(=O)C)[C@@:7]([O:9][CH3:10])([CH3:8])[CH2:6]1)(=O)C>Cl>[OH:4][C@H:5]1[O:17][C@@H:16]([CH3:18])[C@H:11]([OH:12])[C@@:7]([O:9][CH3:10])([CH3:8])[CH2:6]1
Reactant: CO[C@]1(C)C[C@@H](OC(C)=O)O[C@@H](C)[C@@H]1OC(C)=O
Agent: Cl
Product: CO[C@]1(C)C[C@@H](O)O[C@@H](C)[C@@H]1O
Reaction time: 1 h
Yield: 126 %

Procedure:
1,4-Di-O-actyl-β-L-cladinose (2.18 g) was dissolved in 0.1N aqueous hydrochloric acid (245 mL) and the mixture was allowed to remain at 25° C. for 1 h. The mixture was extracted with diethyl ether and the ether layer was retained. The aqueous acid layer was neutralized and extracted with dichloromethane. The latter was combined with the ether extract and dried (MgSO4), filtered and evaporated to dryness to give 4-O-acetyl-α- and β-L-cladinose (1.86 g, 100%) as a colorless gum that was used without further purification.
Reaction SMILES: B.[C:2]([N:12]1[CH2:19][CH:18]([OH:20])[CH2:17][C@H:13]1[C:14](O)=[O:15])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].O>C1COCC1>[OH:15][CH2:14][C@@H:13]1[CH2:17][C@@H:18]([OH:20])[CH2:19][N:12]1[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: O=C(O)[C@@H]1CC(O)CN1C(=O)OCc1ccccc1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1C[C@H](O)C[C@H]1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.9 %

Procedure:
To 200 ml (0.2 mol) of borane. THF complex was added 27.8 g (0.1 mol) of 1-(carbobenzyloxy)-4-hydroxy-L-proline in 50 ml of THF at 0° C. After 16 hours of stirring at room temperature, 100 ml of water was added carefully followed by 12 ml of 6N aqueous HC1 solution and the mixture was extracted with 3 x 100 ml of methylene chloride. The combined organic extracts were dried over MgSO4 and evaporated to yield 22.6 g of the product (oil, 90% yield). NMR(CDC13) 7.40 (m,5H), 5.10 (m,2H), 4.90 (m,1H), 4.65 (m,1H), 4.35 (m,1H), 4.17 (m,1H), 3.60 (m,3H), 2.05 (m,1H), 1.70 (m,1H).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[C:22]2[N:21]=[CH:20][CH:19]=[N:18][C:17]=2[C:16]([C:23]([OH:25])=O)=[CH:15][CH:14]=1.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[N:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1>>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[N:39]=[CH:38][C:37]([NH:40][C:23]([C:16]3[C:17]4[N:18]=[CH:19][CH:20]=[N:21][C:22]=4[C:13]([C:3]4[C:2]([F:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=4[F:12])=[CH:14][CH:15]=3)=[O:25])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1
Reactant: COc1cc(OC)c(F)c(-c2ccc(C(=O)O)c3nccnc23)c1F
Reactant: CN1CCN(Cc2ccc(N)cn2)CC1
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)nc3)c3nccnc23)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (Step 88.1), 6-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-ylamine (Step 39.1), and stirring the reaction mixture for 16 h at rt. The crude product was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1) followed by trituration in Et2O. Title compound: ESI-MS: 535.1 [M+H]+; tR=3.15 min (System 1); TLC: Rf=0.13 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[NH:21][C:22]3[CH:23]=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[N:12]=[C:11]([CH3:30])[N:10]=2)=CC=1>C(O)(C(F)(F)F)=O.FC(F)(F)S(O)(=O)=O>[CH3:29][O:28][C:25]1[N:24]=[CH:23][C:22]([NH:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:13]2[N:12]=[C:11]([CH3:30])[N:10]=[C:9]([NH2:8])[N:14]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3ccccc3Nc3ccc(OC)nc3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ccccc2-c2nc(C)nc(N)n2)cn1
Temperature: 80 °C
Yield: 21.4 %

Procedure:
A solution of N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)phenyl)-6-methyl-1,3,5-triazin-2-amine (0.38 g, 0.70 mmol) in TFA (3 mL) was treated with several drops of trifluoromethane sulfonic acid and heated at 80° C. for 3 h. The solvent was removed in vacuo and the residue was purified by reverse phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in MeCN/H2O gradient to give 4-(2-(6-methoxypyridin-3-ylamino)phenyl)-6-methyl-1,3,5-triazin-2-amine (47 mg, 0.15 mmol, 22% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 10.92 (s, 1H); 8.44 (dd, J=8.12, 1.66 Hz, 1H); 8.12 (d, J=2.74 Hz, 1H); 7.68 (dd, J=8.80, 2.74 Hz, 2H); 7.53 (br. s., 1H); 7.28 (ddd, J=8.46, 6.99, 1.57 Hz, 1H); 6.88 (dd, J=12.81, 8.51 Hz, 2H); 6.69-6.82 (m, 1H); 3.86 (s, 3H); 2.38 (s, 3H). m/z (ESI, +ve ion) 309.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[C:16]([Mg]Br)([CH3:18])=[CH2:17]>>[CH3:18][C:16]1[NH:1][C:4]2=[C:5]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:6]=[CH:7][CH:8]=[C:9]2[CH:17]=1
Reactant: O=[N+]([O-])c1cccnc1-c1ccccc1
Reactant: C=C(C)[Mg]Br
Product: Cc1cc2ccnc(-c3ccccc3)c2[nH]1
Yield: 37 %

Procedure:
In accordance with the same procedures as in Example 242, except for using 3-nitro-2-phenylpyridine prepared in Preparation 15 and isopropenylmagnesium bromide, the titled compound was obtained as a white solid. (Yield: 37%)
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[O:10]1[CH2:12][CH:11]1[CH2:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1>CN(C)C=O>[O:7]([CH2:12][CH:11]([OH:10])[CH2:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1cncc(CCC2CO2)c1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC(CCc1cccnc1)COc1ccccc1
Yield: 16.4 %

Procedure:
Prepared according to the method described in Example 1a) from phenol (0.15 g), sodium hydride (0.075 g) and 3-(2-oxiranylethyl)pyridine (0.15 g) in dimethylformamide at 100° C. for 30 minutes to give the title compound as an oil (0.04 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)=[O:14].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:10][C:9]([F:12])([F:11])[O:8][C:5]1[CH:6]=[CH:7][C:2]([C:18]2[CH:19]=[CH:20][C:15]([CH:13]=[O:14])=[CH:16][CH:17]=2)=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 92.3 %

Procedure:
A mixture of 1-bromo-4-(trifluoromethoxy)-benzene (1.53 g, 6.35 mmol), 4-formylbenzeneboronic acid (1 g, 6.67 mmol), tetrakis(triphenylphosphine)-palladium (147 mg, 0.13 mmol), and potassium phosphate (2.02 g, 9.53 mmol) in DMF (10 ml) was stirred at 100° C. for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate, and the extract was washed with water three times and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/methylene chloride=3/1) to afford 4′-trifluoromethoxybiphenyl-4-carbaldehyde (1.56 g, yield 92%) as a white powder.