Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([NH:23][C:24](=O)[O:25]C2C=CC=CC=2)[N:16]=1.N12CCCN=C1CCCCC2.Cl>C(#N)C>[CH3:22][O:21][C:19]1[CH:20]=[C:15]([O:14][CH3:13])[N:16]=[C:17]([NH:23][C:24]([NH:12][S:9]([C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH2:3][O:2][CH3:1])(=[O:11])=[O:10])=[O:25])[N:18]=1
Reactant: COCc1ccsc1S(N)(=O)=O
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COCc1ccsc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 0.41 g of 3-(methoxymethyl)thiophene-2-sulfonamide and 0.55 g of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate in 20 mL of acetonitrile is added 0.3 mL of 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU). After being stirred for 2 hours at ambient temperature and pressure, the reaction mass is poured onto 25-50 g of ice and the resultant mixture acidified to pH 3 by the addition of hydrochloric acid. The desired solid product can be isolated by filtration. Alternatively, it can be extracted into methylene chloride which is then dried over magnesium sulfate, filtered and evaporated to dryness to yield the desired product in sufficiently pure form for the purposes of this invention.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[OH-].[Na+].[CH3:14]S(C)=O.Cl[CH2:19][CH2:20][CH2:21][Si:22](OC)([O:25][CH3:26])[O:23][CH3:24]>C1(C)C=CC=CC=1>[C:3]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:19][CH2:20][CH2:21][Si:22]([CH3:14])([O:25][CH3:26])[O:23][CH3:24])=[CH:6][CH:5]=1)([O:2][CH3:1])=[O:11]
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: CS(C)=O
Reactant: COC(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OCCC[Si](C)(OC)OC)cc1
Temperature: 115 °C
Yield: 92 %

Procedure:
Using the general procedure described in Example 1 a reactor was charged with 83.7 g (0.55 mole) of methyl-p-hydroxybenzoate, 43.28 g of a 50% by weight aqueous solution of sodium hydroxide (0.54 mole NaOH), 112 cc dimethylsulfoxide and 120 cc toluene. The resultant mixture was heated to the boiling point for six hours under a nitrogen atmosphere to remove all of the water present by azeotropic distillation. The reaction mixture was then allowed to cool to about 75° C. at which time 109 g (0.56 mole) of 3-chloropropyl trimethoxysilane were added dropwise while the reaction mixture was stirred. Following completion of the addition the reaction mixture was heated at 115° C. for about 16 hours, following which the mixture was allowed to cool and was filtered to remove any sold material. The solvents were then removed under a pressure of about 15 mm of mercury at a temperature of about 60° C. The pressure was then reduced to 2 mm of mercury and the material boiling from 230° to 235° C. was collected. The weight of this fraction was equivalent to a yield of 92% based on starting materials. Analysis by vapor phase chromatography indicated that the purity of the product was greater than 98%. The infrared and nuclear magnetic resonance spectra of the product was consistent with the proposed structure.
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[C:13]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14].[C@H:23]1([NH:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([NH2:43])[CH:39]=3)[N:34]=2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1>>[C@H:23]1([NH:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([NH:43][C:1]([N:20]4[CH2:21][CH2:22][N:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:18][CH2:19]4)=[O:12])[CH:39]=3)[N:34]=2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: CC(C)(C)N1CCNCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: CC(C)(C)N1CCN(C(=O)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate (44 mg, 0.16 mmol), commercially available N-tert-butylpiperazine (52 mg, 0.363 mmol) and (R)—N2-indan-1-yl-quinoline-2,6-diamine (100 mg, 0.363 mmol); obtained as a white solid (150 mg, 93%); MS: m/e=444.5 (M+H+).
Reaction SMILES: [C:1]([CH:4]1[CH:9]([CH3:10])[CH:8]=[CH:7][CH2:6][C:5]1([CH3:12])[CH3:11])(=[O:3])[CH3:2]>C(O)C.[Pd]>[C:1]([C@H:4]1[C@@H:9]([CH3:10])[CH2:8][CH2:7][CH2:6][C:5]1([CH3:11])[CH3:12])(=[O:3])[CH3:2]
Reactant: CC(=O)C1C(C)C=CCC1(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(=O)[C@H]1[C@@H](C)CCCC1(C)C

Procedure:
464 g 1-acetyl-2,2,6-trimethyl-4-cyclohexene (V, prepared according to K. S. Ayyar Chem.Comm. 1973, 161) (2.8 moles) in 800 ml of ethanol and 3 g 10% palladium on charcoal are hydrogenated in an autoclave under a pressure of 50 atm and at 50° C. After the uptake ceases, the reaction mixture is filtered and concentrated by distillation under reduced pressure. The product cis-1-acetyl-2,2,6-trimethylcyclohexane (VI, containing about 10% of the trans isomer) is collected at 83°-88° C/12 mm; yield 420 g (90%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:23]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([CH3:23])[CH2:25][CH2:26][CH3:27])=[CH:16][CH:15]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCC(C)CO
Reactant: COC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCC(C)COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.2 %

Procedure:
(R)-methyl 2-(tert-butoxycarbonylamino)-2-(4-hydroxyphenyl)acetate (23.00 g, 82 mmol), 2-methylpentan-1-ol (16.70 g, 163 mmol), and triphenylphosphine (36.46 g, 139 mmol) were combined in tetrahydrofuran (600 mL). After stirring 10 min, diethylazodicarboxylate (21.9 mL, 138 mmol) was added via syringe at room temperature. The reaction was mildly exothermic resulting in the temperature rising to the mid thirties ° C. during the addition. Intermittent cooling with a tap water bath was used to prevent the reaction mixture temperature from rising higher than this, but it was not cooled down to room temperature during the addition. After the addition was complete, the mixture was stirred at room temperature for 18 h. The reaction mixture was transferred to a separatory funnel containing water (400 mL). The aqueous layer was extracted with ether (3×400 mL). The combined organic layers were washed with brine (250 mL), dried over MgSO4, filtered and concentrated. The crude product was taken up in ether (ca. 800 mL) and was stirred for 30 min. The mixture was filtered through a pad of diatomaceous earth (Celite®) to remove most of the triphenylphosphine oxide and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (20% ethyl acetate in hexanes) to afford (2R)-methyl 2-(tert-butoxycarbonylamino)-2-(4-(2-methylpentyloxy)phenyl)acetate (29.43 g, 98% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.20-7.29 (m, 2H), 6.84 (d, J=8.6 Hz, 2H), 5.45 (d, J=6.5 Hz, 1H), 5.22 (d, J=7.3 Hz, 1H), 3.77 (dd, J=9.1, 5.8 Hz, 1H), 3.69 (s, 3H), 3.65-3.70 (m, 1H), 1.85-1.96 (m, 1H), 1.41 (s, 9H), 1.14-1.50 (m, 4H), 0.98 (d, J=6.8 Hz, 3H), 0.90 (t, J=7.1 Hz, 3H); LRMS (ESI) m/e 366.4 [(M+H)+, calcd for C20H32NO5 366.2].
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([CH2:17]C4C=CN=C(C5C=C(OC)C(OC)=C(OC)C=5)C=4)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:36][CH2:37][C:38]1[CH:39]=[CH:40][C:41]([C:44]2[CH:49]=[C:48]([O:50][CH3:51])[C:47]([O:52][CH3:53])=[C:46]([O:54][CH3:55])[CH:45]=2)=[N:42][CH:43]=1>>[ClH:36].[ClH:36].[ClH:36].[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]([CH:11]3[CH2:12][CH2:13][N:14]([CH2:17][C:38]4[CH:39]=[CH:40][C:41]([C:44]5[CH:49]=[C:48]([O:50][CH3:51])[C:47]([O:52][CH3:53])=[C:46]([O:54][CH3:55])[CH:45]=5)=[N:42][CH:43]=4)[CH2:15][CH2:16]3)[CH2:37][C:38]3[CH:39]=[CH:40][C:41]([C:44]4[CH:49]=[C:48]([O:50][CH3:51])[C:47]([O:52][CH3:53])=[C:46]([O:54][CH3:55])[CH:45]=4)=[N:42][CH:43]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1cc(-c2ccc(CCl)cn2)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CN3CCC(Nc4ccc5c(c4)CCC5)CC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2ccc(CN3CCC(N(Cc4ccc(-c5cc(OC)c(OC)c(OC)c5)nc4)c4ccc5c(c4)CCC5)CC3)cn2)cc(OC)c1OC
Product: Cl

Procedure:
4-(5-Indanylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (143 mg) and 5-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a trihydrochloride.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:19][C:20]1[C:39]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46](=[O:57])[NH:47][C:48]3([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[CH2:50][CH2:49]3)[CH:41]=2)=[CH:38][C:23]2[C:24]([C:34]([NH:36][CH3:37])=[O:35])=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[O:26][C:22]=2[CH:21]=1.N12CCCN=C1CCCCC2>C1COCC1.CO>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[O:26][C:22]3[CH:21]=[C:20]([NH:19][C:4](=[O:6])[CH2:3][O:2][CH3:1])[C:39]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([C:46](=[O:57])[NH:47][C:48]5([C:51]6[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=6)[CH2:50][CH2:49]5)[CH:41]=4)=[CH:38][C:23]=3[C:24]=2[C:34]([NH:36][CH3:37])=[O:35])=[CH:28][CH:29]=1
Reactant: COCC(=O)O
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3cccc(C(=O)NC4(c5ccccc5)CC4)c3)cc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CO
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NC(=O)COC)c(-c3cccc(C(=O)NC4(c5ccccc5)CC4)c3)cc12
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-methoxyacetic acid (10.40 mg, 0.115 mmol) in THF (3 mL) at r.t. under N2 was added 1,1′-carbonyldiimidazole (CDI) (28.1 mg, 0.173 mmol). The mixture was stirred at 55° C. for 1 hr. The mixture was then transferred to a flask containing 6-amino-2-(4-fluorophenyl)-N-methyl-5-(3-(1-phenylcyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide (30 mg, 0.058 mmol) at r.t. under N2. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (0.035 mL, 0.231 mmol) was then added and the mixture was stirred at 55° C. for 2 hr 35 min. The mixture was then left standing at r.t. overnight. The mixture was re-stirred at 55° C. for 3 hr. The mixture was cooled to r.t., diluted with MeOH and purified by Shimadzu-VP preparative reverse phase HPLC using the separation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, Fraction Collection: 7.28-7.84 min. (UV detection at 220 nm). 1H NMR (500 MHz, DMSO-d6) δ 9.29 (s, 1H), 9.04 (s, 1H), 8.49 (q, J=4.58, 1H), 8.31 (s, 1H), 8.03-8.00 (overlapping m, 3H), 7.98 (m, 1H), 7.59 (s, 1H), 7.63 (s, 1H), 7.625 (d, J=2.44, 1H), 7.40 (t, J=9.00, 2H), 7.28 (apparent t, J=7.63, 2H,), 7.23 (apparent d, 2H,), 7.17 (t, J=7.17, 1H,), 3.90 (s, 2H), 3.18 (s, 3H), 2.83 (appeared as d, J=4.58, 3H), 1.28 (s, 4H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)+=592.49, HPLC Rt=1.652 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:26][CH3:27])[C:14]([CH2:28][CH2:29][CH2:30][CH2:31]I)=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1.[CH3:33][NH:34][CH3:35].COC1C=CC2NC3C=C(C(OCC4C=CC=CC=4)=O)C4C(=O)NC(=O)C=4C=3C=2C=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:26][CH3:27])[C:14]([CH2:28][CH2:29][CH2:30][CH2:31][N:34]([CH3:35])[CH3:33])=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1
Reactant: CNC
Reactant: COc1cc2c(cc1CCCCI)[nH]c1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Agent: COc1ccc2[nH]c3cc(C(=O)OCc4ccccc4)c4c(c3c2c1)C(=O)NC4=O
Product: COc1cc2c(cc1CCCCN(C)C)[nH]c1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Reaction time: 6 h
Yield: 64 %

Procedure:
Reaction of the iodide (173) prepared as described in example 312 with aqueous dimethylamine using the procedure described in example 179 of Scheme 3 except that the reaction conditions were 6 h at room temperature gave (174) (64%) as an orange powder, mp 162–164° C. 1H NMR δ [(CD3)2SO] 11.85 (s, 1H), 11.04 (br s, 1H), 8.42 (s, 1H), 7.57 (dd, J=8.0, 2.2 Hz, 1H), 7.55 (s, 1H), 7.51–7.43 (m, 3H), 7.42 (s, 1H), 3.93 (s, 3H), 2.77 (t, J=7.4 Hz, 2H), 2.24 (t, J=7.3 Hz, 2H), 2.11 (s, 6H), 1.63 (m, 2H), 1.47 (m, 2H). EIMS found M+=475.1657, 477.1650. C27H26ClN3O3 requires 475.1663, 477.1633.
Reaction SMILES: C([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21](=[O:30])[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:19])=[C:13]([Cl:31])[CH:12]=2)[CH:7]=[CH:6][N:5]=1)(=O)N.C[N:33](C=O)C>>[NH2:33][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21](=[O:30])[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:19])=[C:13]([Cl:31])[CH:12]=2)[CH:7]=[CH:6][N:5]=1
Reactant: NC(=O)c1cc(Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)c(Cl)c2)ccn1
Reactant: CN(C)C=O
Product: Nc1cc(Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)c(Cl)c2)ccn1
Yield: 55 %

Procedure:
Prepared in a manner similar to that which is described for Example 91. 1-(4-(2-Carbamoylpyridin-4-yloxy)-2-chlorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea (18 mg, 0.04 mmol) in DMF (1.0 mL) was converted to 1-(4-(2-aminopyridin-4-yloxy)-2-chlorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea (10 mg, 55% yield). 1H NMR (DMSO-d6) δ 13.47 (s, 1H), 11.26 (s, 1H), 11.08 (s, 1H), 8.37 (d, 1H, J=8.5 Hz), 7.95 (d, 1H, J=7.5 Hz), 7.88 (s, 2H), 7.62 (s, 1H), 7.35 (m, 3H), 7.17 (m, 2H), 6.64 (d, 1H, J=7.5 Hz), 6.13 (s, 1H), 3.76 (s, 2H); MS(ESI+): m/z 415.18/417.17 (M+H)+.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:28]([OH:30])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:32]=[C:33]([NH2:38])[CH2:34][CH2:35][O:36][CH3:37]>>[CH3:37][O:36][CH2:35][CH2:34][C:33]1[N:38]=[C:28]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:21][CH:22]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]3)=[O:10])[CH2:12]2)[O:30][N:32]=1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1
Reactant: COCCC(N)=NO
Product: COCCc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(C#N)CC3)C2)n1

Procedure:
100 mg (about 0.153 mmol) of the compound from Example 108A and 36 mg (0.306 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted according to the General Method 2. Yield: 14 mg (18% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([CH3:25])=[CH2:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[C:4]([CH3:27])[CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:33]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]3([CH3:25])[CH2:24][O:33]3)([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:12][C:11]2=[O:26])[CH3:9])=[C:4]([CH3:27])[CH:3]=1
Reactant: C=C(C)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2C)C(=O)O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(Br)ccc1[C@H](C)N1CC[C@](CC2(C)CO2)(c2ccccc2)OC1=O
Temperature: 5 °C
Reaction time: 8 h

Procedure:
3-[(S)-1-(4-Bromo-2-methyl-phenyl)-ethyl]-(R)-6-(2-methyl-allyl)-6-phenyl-[1,3]oxazin-an-2-one (1.34 g) dissolved in dichloromethane (15 mL) was added to a solution of 3-chloroperoxybenzoic acid (77%, 0.81 g) in dichloromethane (15 mL) cooled to 5° C. The cooling bath was removed and the solution was stirred at room temperature overnight. Aqueous 10% Na2S2O3 solution (10 mL) and aqueous saturated NaHCO3 solution (25 mL) were added and the resulting mixture was stirred for further 30 min. The organic phase was separated and washed with aqueous Na2S2O3 solution combined with aqueous saturated NaHCO3 solution, water, and brine. The organic phase was dried (MgSO4) and concentrated to furnish the title compound. Yield: 1.55 g (ca. 85-90% pure); LC-MS (Method 4): tR=4.28 min; Mass spectrum (ESI+): m/z=444/446 (Br) [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:6]=2[N:7]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([S:12][C:8]2[C:6]3[N:7]=[C:2]([N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:3]=[C:4]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:5]=3[N:11]=[CH:10][N:9]=2)=[CH:14][CH:15]=1
Reactant: Clc1ccc(Sc2ncnc3c(N4CCOCC4)nc(Cl)nc23)cc1
Reactant: C1CNCCN1
Product: Clc1ccc(Sc2ncnc3c(N4CCOCC4)nc(N4CCNCC4)nc23)cc1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(4-chlorophenyl-thio)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 208°-210° C.) and piperazine.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[C:12]([F:22])=[CH:13][C:14]3[O:19][CH2:18][C:17](=[O:20])[NH:16][C:15]=3[CH:21]=2)[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.[H-].[Na+].[CH2:25](I)[CH3:26].O>CN(C)C=O>[Cl:1][C:2]1[N:3]([C:11]2[C:12]([F:22])=[CH:13][C:14]3[O:19][CH2:18][C:17](=[O:20])[N:16]([CH2:25][CH3:26])[C:15]=3[CH:21]=2)[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: O=C1COc2cc(F)c(-n3nc4c(c3Cl)CCCC4)cc2N1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)COc2cc(F)c(-n3nc4c(c3Cl)CCCC4)cc21
Reaction time: 3 h

Procedure:
To a solution of 3-chloro-2-[7-fluoro-2H-1,4-benzoxazin-3(4H)-on-6-yl]-4,5,6,7-tetrahydro-2H-indazole (1.0 g) in N,N-dimethylformamide (10 ml), sodium hydride (0.3 g) and ethyl iodide (0.5 g) were successively added, and the resultant mixture was heated at 50° to 60° C., followed by stirring for 3 hours. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration and purified by silica gel column chromatography using a mixture of ethyl acetate and hexane as an eluent to give Compound No. 1 (0.9 g), m.p., 101.5°-102.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:11]([N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[C:25]2=[O:40])[CH2:12][CH2:13][CH2:14][NH:15][S:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)(=[O:18])=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].ClC(Cl)C.[O:45]1[CH:49]=[CH:48][C:47]([CH:50]=O)=[CH:46]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:11]([N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[N:34]3[CH2:39][CH2:38][N:37]([CH2:50][C:47]4[CH:48]=[CH:49][O:45][CH:46]=4)[CH2:36][CH2:35]3)[C:25]2=[O:40])[CH2:12][CH2:13][CH2:14][NH:15][S:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)(=[O:18])=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc([C@@H](CCCNS(=O)(=O)c2cccs2)N2C(=O)c3cccc(N4CCNCC4)c3C2=O)cc1OC
Reactant: O=Cc1ccoc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: CC(Cl)Cl
Product: COc1ccc([C@@H](CCCNS(=O)(=O)c2cccs2)N2C(=O)c3cccc(N4CCN(Cc5ccoc5)CC4)c3C2=O)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.4 %

Procedure:
A 50-mL round bottom flask was charged with Compound 167 (20.0 mg, 0.032 mmol) and dichloroethane (4.0 mL). Trietheylamine (5.0 μL) was added followed by 3-furaldehyde (6.0 mg, 0.06 mmol) and tetramethylammonium triacetoxyborohydride (11.8 mg, 0.045 mmol). The mixture was stirred at room temperature for 3 h. The mixture quenched with saturated aqueous sodium bicarbonate (10 mL) and extracted with dichloromethane (50 mL). The organic layer was dried using Na2SO4, filtered through Celite®, and concentrated in vacuo. The crude oil was purified on a on a Gilson HPLC with a reversed phase Kromasil column (10μ, 100 Å C18, column length 250×50 mm, gradient 90:10-0:100 H2O:MeCN) to give 13.7 mg of Compound 170 as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.50-7.64 (m, 5 H), 7.43 (d, J=7.2 Hz, 1 H), 7.13 (d, J=8.2 Hz, 1 H), 7.00-7.06 (m, 3 H), 6.79 (d, J=8.0 Hz, 1 H), 6.56 (s, 1 H), 5.12-5.23 (m, 1 H), 4.61-4.74 (m, 1 H), 3.87 (s, 3 H), 3.84 (s, 3 H), 3.63-3.75 (m, 4 H), 3.41-3.51 (m, 2 H), 2.94-3.35 (m, 4 H), 2.53-2.65 (m, 1 H), 2.18-2.30 (m, 1 H), and 1.46-1.71 (m, 2 H); MS (ES+) 665 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[OH-].[Na+]>C(O)C>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]=1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:24])=[O:2])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Temperature: 25 °C
Yield: 4.5 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (200 mg, 1.06 mmol) was added sodium hydride (55% dispersion in mineral oil, 996 mg, 22.8 mmol). After stirring for 0.5 h at ambient temperature methyl 6-chloronicotinate (1.06 mmol) was added and the reaction mixture was stirred for 5 h at ambient temperature. It was diluted with ethyl acetate (10 mL), washed with aqueous citric acid (10%, 10 mL), water (10 mL) and aqueous sodium chloride (saturated, 10 mL). The combined aqueous layers were extracted with ethyl acetate (10 mL). After drying over sodium sulfate and concentration purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 70:30) afforded 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (191 mg, 42%) as a white solid. To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (3.89 g, 120 mmol) in ethanol (40 mL) was added aqueous sodium hydroxide (1 M, 36.0 mL, 36.0 mmol). After heating at reflux for 2 h it was cooled to ambient temperature and concentrated. Addition of aqueous sodium hydroxide (1 M, 50 mL) was followed by washing with tert-butylmethylether (100 mL). The aqueous phase was acidified with aqueous hydrogen chloride (conc.) to pH=1 and extracted with tert-butylmethylether (100 mL). The organic layer was washed with water (50 mL) and aqueous sodium chloride (saturated, 50 mL). Drying over sodium sulfate and concentration afforded the title compound (1.68 g, 45%) as an off white solid. MS: m/e=309.3 [M−H]−.