Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[OH:14])([O-:3])=[O:2].[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18]O.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOC(C)=O>[C:10]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:18][CH2:17][N:16]([CH3:20])[CH3:15])=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=1)([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc(O)c([N+](=O)[O-])c1
Reactant: CN(C)CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-nitro-4-tert-butylphenol (2 g) and N,N-dimethylethanolamine (1.3 g) and PPh2 (4 g) in THF (50 ml) was added DEAD (2.6 ml). The reaction was stirred at RT for 1 h, diluted with EtOAc (50 ml) and washed with 1 N HCl twice. The aqueous layer was basified with NaHCO3, extracted with EtOAc twice and washed with H2O and brine. The organic layer was dried over Na2SO4 and evaporated to give {2-[4-(tert-butyl)-2-nitrophenoxy]-ethyl}dimethylamine, was used in next step without further purification.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([S:10][CH2:11][CH:12]2[O:16][CH2:15][CH2:14][O:13]2)[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18]([CH3:22])[C:19](Cl)=[O:20].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:17][N:18]([CH3:22])[C:19]([N:7]1[C:8]([S:10][CH2:11][CH:12]2[O:16][CH2:15][CH2:14][O:13]2)=[N:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6]1)=[O:20]
Reactant: CC(C)(C)c1n[nH]c(SCC2OCCO2)n1
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)n1nc(C(C)(C)C)nc1SCC1OCCO1

Procedure:
3-t-Butyl-5-(1,3-dioxolan-2-yl-methylthio)-1H-1,2,4-triazole (7 g, 28.8 mmole), 2.8 ml (30.5 mmole) of dimethylcarbamoyl chloride, 8 ml (57 mmole) of triethylamine and 0.5 g (4.1 mmole) of 4-dimethylaminopyridine were dissolved in 50 ml of tetrahydrofuran (THF). The mixture was refluxed for four hours, concentrated in vacuo and partitioned between methylene chloride and dilute hydrochloric acid. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated. Chromatography on silica gel using ethyl ether/hexane gave 1-dimethylcarbamoyl-3-t-butyl-5-(1,3-dioxolan-2-yl-methylthio)-1H-1,2,4triazole, an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Br:13]N1C(=O)CCC1=O.Br>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:13][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1cccc(F)c1
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(Br)c1cccc(F)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
Methyl 2-(3-fluorophenyl)acetate (1.90 g, 11.3 mmol) and N-bromo succinimide (2.01 g, 11.3 mmol) were dissolved in CCl4 (80 ml). HBr (64 ul, 0.56 mmol) was added, and the mixture was stirred under reflux overnight. The mixture was cooled at room temperature, diluted with DCM, and washed with sat. NaHCO3, water and brine. The organic layer was dried (Na2SO4), filtered, and evaporated obtaining intermediate I15 (2.68 g, 96% yield).
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].Cl[S:6]([N:9]=[C:10]=[O:11])(=[O:8])=[O:7].[NH2:12][CH2:13][C:14]1[N:15]2[CH:21]=[N:20][CH:19]=[C:16]2[S:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.C(N(CC)CC)C.ClCCl>[CH2:1]([O:4][C:10]([NH:9][S:6]([NH:12][CH2:13][C:14]1[N:15]2[CH:21]=[N:20][CH:19]=[C:16]2[S:17][CH:18]=1)(=[O:8])=[O:7])=[O:11])[CH:2]=[CH2:3]
Reactant: C=CCO
Reactant: O=C=NS(=O)(=O)Cl
Reactant: NCc1csc2cncn12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C=CCOC(=O)NS(=O)(=O)NCc1csc2cncn12

Procedure:
Under an argon atmosphere, 0.68 ml of allyl alcohol was added dropwise to a dry dichloromethane solution containing 0.87 ml of chlorosulfonyl isocyanate at -43° C. with stirring, and the mixture was then stirred at -43 to -37° C. for 30 minutes. This mixed solution was added dropwise to 50 ml of a dry dichloromethane solution containing 766 mg of 3-aminomethylimidazo[5,1-b]thiazole and 1.40 ml of triethylamine at -60° C. under an argon atmosphere, followed by stirring at the same temperature for 1.5 hours. After the addition of distilled water, the solution was adjusted to pH 6.0 with a 15% aqueous potassium carbonate solution and 2N hydrochloric acid, and after salting-out, extraction was carried out five times with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was separated by a silica gel column chromatograph, and then recrystallized from ethanol-diethyl ether to obtain 1135 mg of 3-[(N-allyloxycarbonylamino)sulfonyl]aminomethylimidazo[5,1-b]thiazole as a milky white powder.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:27]=[C:28]([S:32]([NH:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[C:28]([S:32]([NH:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])(=[O:33])=[O:34])[CH:29]=[CH:30][CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: CN(C)CCNS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CN(C)CCNS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 3-bromo-N-(2-dimethylamino-ethyl)-benzenesulfonamide (example B.35) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (340 mg, 59%). MS (ISP) 564.3 [(M+H)+]; mp 160-162° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:18]2[N:19]([CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[C:20]([CH3:27])=[C:21]([S:23](=[O:26])(=[O:25])[NH2:24])[CH:22]=2)[CH:17]=1)[C:8]([O:10]C(C)(C)C)=[O:9])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:18]2[N:19]([CH2:28][CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[C:20]([CH3:27])=[C:21]([S:23](=[O:26])(=[O:25])[NH2:24])[CH:22]=2)[CH:17]=1)[C:8]([OH:10])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(S(N)(=O)=O)cc(-c2cc(C(=O)OC(C)(C)C)cc(C(C)(C)C)c2)n1CC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(S(N)(=O)=O)cc(-c2cc(C(=O)O)cc(C(C)(C)C)c2)n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
Compound 13a (180 mg, 0.37 mmol) was treated with a mixture of TFA (0.5 mL) and DCM (5 mL) and stirred at rt overnight. After the reaction was complete (monitored by LC-MS), the mixture was concentrated to give compound 13b (145 mg, 91%). 1H-NMR (400 MHz, CDCl3) δ: 8.12 (s, 1H), 7.88 (s, 1H), 7.58 (s, 1H), 6.51 (s, 1H), 4.77-4.75 (m, 2H), 3.76 (m, 2H), 2.56 (s, 3H), 1.53 (s, 3H), 1.37-1.35 (m, 12H), 1.00-0.99 (m, 3H), 0.64-0.63 (m, 2H). MS Found: 433 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH3:24])[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[C:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]1=[O:23])[O:9][CH2:8]2.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.O>CN(C=O)C>[CH3:24][N:4]([CH2:3][CH2:2][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[C:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]1=[O:23])[O:9][CH2:8]2
Reactant: C1COCCN1
Reactant: CN(CCCl)c1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCN1CCOCC1)c1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Temperature: 110 °C

Procedure:
A mixture of 3-{5-[(2-chloro-ethyl)-methyl-amino]-3H-isobenzofuran-1-ylidene}-1,3-dihydro-indol-2-one (1.20 g, 3.52 mmol) and morpholine (3 ml, 34.4 mmol) in DMF (5 ml) was heated at 110° C. under nitrogen for 16 hours. The mixture was cooled to room temperature and was then poured into water (100 ml). The solid was filtered, washed with water and dried under vacuum to give a crude product. Purification of the crude product by silica gel column chromatography, eluted with a gradient of MeOH in CHCl3, resulted in 3-{5-[methyl-(2-morpholin-4-yl-ethyl)-amino]-3H-isobenzofuran-1-ylidene}-1,3-dihydro-indol-2-one as a yellow solid (0.57 g, 41%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:14][N:13]3[C:9]([S:10][CH2:11][CH2:12]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15][CH2:16][C:17]([OH:19])=[O:18].[CH3:20]C(C)=O>>[Br-:15].[C:1]1([CH:7]2[CH2:14][N+:13]3[CH2:12][CH2:11][S:10][C:9]=3[N:8]2[CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2CN3CCSC3=N2)cc1
Reactant: O=C(O)CBr
Reactant: CC(C)=O
Product: COC(=O)CN1C2=[N+](CCS2)CC1c1ccccc1
Product: [Br-]
Reaction time: 12 h
Yield: 81 %

Procedure:
2 g (0.01 mol) of 2,3,5,6-tetrahydro-6-phenylimidazo-[2,1-b]-thiazole are dissolved in 20 ml of acetone and added with 1.53 g (0.01 mol) of methyl ester of monobromacetic acid. After 12 hours the residue is filtered-off and washed with acetone to give 2.86 g (81%) of 2,3,5,6-tetrahydro-6-phenyl-7-methoxycarbonylmethylimidazo-[2,1-b]-thiazolium bromide melting at 81°-82° C. (from dioxane).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([S:12](=[O:16])(=[O:15])[NH:13][CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:17][C:18]([F:32])([F:31])[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[F:11][C:10]1[CH:9]=[C:8]([S:12]([NH:13][CH3:14])(=[O:16])=[O:15])[CH:7]=[C:3]([C:4]([N:28]2[CH2:27][CH2:26][N:25]([C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:31])([F:32])[F:17])=[CH:24][CH:23]=3)[CH2:30][CH2:29]2)=[O:6])[C:2]=1[F:1]
Reactant: CNS(=O)(=O)c1cc(F)c(F)c(C(=O)O)c1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Product: CNS(=O)(=O)c1cc(F)c(F)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1

Procedure:
The title compound was prepared in analogy to Example BO by reaction of 2,3-Difluoro-5-methylsulfamoyl-benzoic acid and 1-(4-trifluoromethylphenyl)piperazine (ABCR F07741NB, [30459-17-7]) to yield the title compound as a light yellow amorpous solid. (m/e): 462.1 (M−H, 100%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][C:4]([CH2:7][OH:8])=[N:3]1.[H-].[Na+].Cl[C:12]1[C:13]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:14][C:15]2[N:16]([C:18]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)=[N:19][N:20]=2)[N:17]=1>CN(C)C=O>[CH3:1][N:2]1[CH:6]=[N:5][C:4]([CH2:7][O:8][C:12]2[C:13]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:26]=[N:25][CH:24]=[CH:23][N:22]=4)=[N:19][N:20]=3)[N:17]=2)=[N:3]1
Reactant: Clc1nn2c(-c3cnccn3)nnc2cc1-c1ccccc1
Reactant: Cn1cnc(CO)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cnc(COc2nn3c(-c4cnccn4)nnc3cc2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1-methyl-1H-1,2,4-triazol-3-yl)methanol (prepared using the conditions described in EP-A-421210; 0.044 g, 0.39 mmol) in dimethyl formamide (10 ml) was added sodium hydride (0.016 g of a 60% dispersion in oil, 0.390 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 0.5 h. After this time, the product from Example 1 step e) (0.1 g, 0.325 mmol) was added and the reaction mixture stirred for 2.5 h. The solvent was removed under high vacuum. Water (5 ml) was added to the residue and the solid produced was collected by filtration. The solid was recrystallised from ethyl acetate/ethanol to give the required product (0.049 g, m.p. 256.9-257.8° C.). 1H NMR (360 MHz, CDCl3) δ 3.94 (3H, s), 5.62 (2H, s), 7.47 (3H, m), 7.67 (2H, m), 8.04 (1H, s), 8.10 (1H, s), 870 (1H, s), 8.84 (1H, s), 9.80 (1H, s) MS (ES+) m/e 386 [MH+].
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:5]2[S:10][CH:9]=[C:8]([CH:11]=[CH2:12])[C:6]=2[N:7]=1.[O:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][NH2:30])[CH2:24][CH2:23]1>>[O:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][NH:30][C:2]2[N:3]=[C:4]([NH:13][C@@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:5]3[S:10][CH:9]=[C:8]([CH:11]=[CH2:12])[C:6]=3[N:7]=2)[CH2:24][CH2:23]1
Reactant: C=Cc1csc2c(N[C@H](C)c3ccccc3)nc(Cl)nc12
Reactant: NCCN1CCOCC1
Product: C=Cc1csc2c(N[C@H](C)c3ccccc3)nc(NCCN3CCOCC3)nc12
Yield: 65.4 %

Procedure:
The target compound of Example 47 (34 mg, 65% yield) was prepared in the same manner as Step 3 of Example 44 using (R)-2-chloro-N-(1-phenylethyl)-7-vinylthieno[3,2-d]pyrimidin-4-amine (40 mg, 0.127 mmol) and 2-morpholinoethanamine (82 mg, 0.63 mmol).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11](=[O:20])[CH:10]2[CH2:21][CH2:22][CH:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[OH:24])=[CH:5][CH:4]=1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[CH2:39]([C:43]1([CH2:77][CH3:78])[CH2:49][S:48](=[O:51])(=[O:50])[C:47]2[CH:52]=[CH:53][C:54]([N:56]([CH3:58])[CH3:57])=[CH:55][C:46]=2[CH:45]([C:59]2[CH:60]=[C:61]([NH:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][C:73](O)=[O:74])[CH:62]=[CH:63][CH:64]=2)[CH:44]1[OH:76])[CH2:40][CH2:41][CH3:42].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(N(CC)CC)C>[F:32][C:33]([F:38])([F:37])[C:34]([O-:36])=[O:35].[CH2:39]([C:43]1([CH2:77][CH3:78])[CH2:49][S:48](=[O:51])(=[O:50])[C:47]2[CH:52]=[CH:53][C:54]([NH+:56]([CH3:58])[CH3:57])=[CH:55][C:46]=2[CH:45]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([NH:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][C:73](=[O:74])[NH:1][CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH:9]4[CH:10]([CH2:21][CH2:22][CH:23]([C:25]5[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=5)[OH:24])[C:11](=[O:20])[N:12]4[C:13]4[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=4)=[CH:5][CH:4]=3)[CH:60]=2)[CH:44]1[OH:76])[CH2:40][CH2:41][CH3:42]
Reactant: O=C(O)C(F)(F)F
Reactant: NCc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Reactant: CCCCC1(CC)CS(=O)(=O)c2ccc(N(C)C)cc2C(c2cccc(NCCOCCOCC(=O)O)c2)C1O
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCC1(CC)CS(=O)(=O)c2ccc([NH+](C)C)cc2C(c2cccc(NCCOCCOCC(=O)NCc3ccc(C4C(CCC(O)c5ccc(F)cc5)C(=O)N4c4ccc(F)cc4)cc3)c2)C1O
Product: O=C([O-])C(F)(F)F
Reaction time: 12 h

Procedure:
55 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one are added to a solution of 40 mg of (2-{2-[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenylamino]ethoxy}ethoxy)acetic acid compound with trifluoroacetic acid, 37 μl of diisopropylcarbodiimide, 26 mg of hydroxybenzotriazole and 40 μl of triethylamine in 2 ml of dimethylformamide, and the mixture is stirred for 12 h. The reaction solution is concentrated and separated by HPLC (Merck-Hibar-Lichrospher 100-RP-18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90).
Reaction SMILES: [Br:1][C:2]1[C:15](=[O:16])[N:14]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.[NH2:22][CH2:23][C:24]([CH3:27])([OH:26])[CH3:25].C(N(CC)CC)C>O1CCOCC1.[Cl-].[Na+].O>[Br:1][C:2]1[C:15](=[O:16])[N:14]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:5]2[N:6]=[C:7]([NH:22][CH2:23][C:24]([OH:26])([CH3:27])[CH3:25])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1
Reactant: CC(C)(O)CN
Reactant: Cc1nc(S(C)=O)nc2c1cc(Br)c(=O)n2C1CCCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1nc(NCC(C)(C)O)nc2c1cc(Br)c(=O)n2C1CCCC1
Temperature: 110 °C
Yield: 88.2 %

Procedure:
To a solution of 6-bromo-8-cyclopentyl-4-methyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one (600 mg, 1.62 mmol) and 1-amino-2-methylpropan-2-ol (294 mg, 2.34 mmol) in dioxane (6 mL) was added triethylamine (1.2 mL, 8.6 mmol). The mixture was then heated at 110° C. in a sealed tube for 1 h. The solution was poured into brine and extracted with ethyl acetate. The organic was dried (anhydrous sodium sulfate), filtered and concentrated to dryness. The crude product was purified by silica gel flash chromatography to give the title compound as a solid (565 mg, 88%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:32]2([CH3:33])[C:9](=[CH:10][CH:11](Br)[C@@H:12]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:34])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:27])[CH2:18][CH2:19][C:20]([F:26])([F:25])[C:21]([OH:24])([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:36][C:37](=[O:39])[CH3:38])[CH2:6]1)(=[O:3])[CH3:2].CC1C=C(C)N=C(C)C=1.C1(C)C(C)=CC=CC=1>C1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@@:32]2([CH3:33])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:34])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:27])[CH2:18][CH2:19][C:20]([F:26])([F:25])[C:21]([OH:24])([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:36][C:37](=[O:39])[CH3:38])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=CC(Br)[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(F)(F)C(C)(C)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Solvent: Cc1ccccc1C
Solvent: Cc1cc(C)nc(C)c1
Solvent: c1ccccc1
Product: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H]([C@H](C)CCC(F)(F)C(C)(C)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Temperature: 140 °C

Procedure:
A mixture of 1.33 g (0.0019 mol) of [1α,3β,7ξ]-7-bromo-24,24-difluorocholest-5-en-1,3,25-triol 1,3-diacetate, 0.8 mL of s-collidine and 10 mL of xylene was heated at reflux (140° C.) for 0.5 hr and cooled. The mixture was diluted with 30 mL of benzene. This solution was washed with 10% aqueous sulfuric acid, and saturated aqueous sodium bicarbonate solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography on 0.06-0.20 mm silica gel to yield [1α,3β]-24,24-difluorocholesta-5,7-dien-1,3,25-triol 1,3-diacetate, [α]D25 -31° (c 0.4, CHCl3), mp 130°-132°. UV max (C2H5OH) 261 (ε 7750), 270 (ε 11,200), 281 (ε 12,100) and 293 (ε 7100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1I)[CH:14]=[CH:13][O:12]2.F[C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][N:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].O.[NH2:35][NH2:36]>O1CCOCC1.C(O)CC.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:22]1[CH:23]=[CH:24][C:19]([NH:35][NH2:36])=[N:20][CH:21]=1)[CH:14]=[CH:13][O:12]2
Reactant: NN
Reactant: OB(O)c1ccc(F)nc1
Reactant: Fc1ccc(-c2nc3occn3c2I)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCCO
Product: NNc1ccc(-c2c(-c3ccc(F)cc3F)nc3occn23)cn1
Temperature: 80 °C
Yield: 62.8 %

Procedure:
A mixture of 6-(2,4-difluorophenyl)-5-iodo-imidazo[2,1-b]oxazole (5 g, 14.5 mmol), 2-fluoropyridine-5-boronic acid (3.1 g, 22 mmol; Asymchem), Cs2CO3 (12 g, 36 mmol), and trans-dichloro[bis(triphenylphosphine)]palladium (II) (1.1 g, 1.5 mmol) was dissolved in 1,4-dioxane (100 mL) and water (10 mL) at ambient temperature. The reaction was vacuum purged with N2 three times followed by heating to about 80° C. for about 2 h. The reaction was allowed to cool to ambient temperature upon which time it was concentrated under reduced pressure. The resulting oil was dissolved in DCM, filtered through a pad of silica gel and the silica gel was washed DCM (3×10 mL). The filtrate was concentrated under reduced pressure to provide a yellow solid. This solid was dissolved in n-PrOH (50 mL) followed by the addition of hydrazine hydrate (5.0 mL, 160 mmol) and the reaction was heated at about 100° C. for about 16 h. After this time the reaction was concentrated, and the resulting solid was triturated with Et2O and filtered. The filter cake was washed with water and dried in a vacuum oven for about 16 h to provide the title compound (2.98 g, 63% for 2 steps) as an off-white solid: LC/MS (Table 1, Method a) Rt=1.62 min; MS m/z: 342.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:14])[CH:11]([CH3:13])[CH3:12])=[CH:6][CH:5]=1.[Cl:15][C:16]([Cl:20])([Cl:19])[C:17]#[N:18].CC(C)=O.CCOC(C)=O>CCOCC.CCOC(C)=O>[Cl:15][C:16]([Cl:20])([Cl:19])[C:17](=[NH:18])[O:14][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([Br:3])=[CH:9][CH:8]=1)[CH:11]([CH3:12])[CH3:13]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(C)C(O)c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)C(OC(=N)C(Cl)(Cl)Cl)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium Hydride (60%, 0.87 mmol) was suspended in Et2O (9 mL) and a solution of 1-(4-bromophenyl)-2-methylpropan-1-ol of step 1 (8.7 mmol, 2.0 g) in Et2O (6 mL) was added. The mixture was stirred at r.t. for 0.25 h. The mixture was cooled to 0° C. Trichloroacetonitrile (11 mmol) was added. The mixture was allowed to warmed to r.t. over 1 h. The mixture was diluted with EtOAc and washed with NaHCO3. The organic extract was dried (anhyd. MgSO4) and concentrated under reduced pressure to give an oil. Chromatography (10% Acetone/EtOAc) gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([NH2:25])[C:19]=3[CH:18]=[N:17]2)([CH2:14][CH3:15])[CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.CN1CCOCC1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([NH:25][S:34]([CH3:33])(=[O:36])=[O:35])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[N:17]2)([CH2:14][CH3:15])[CH2:9][C:10]([F:13])([F:11])[F:12])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCC(CC(F)(F)F)(c1ccc(Cl)cc1)n1ncc2c(N)cccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(CC(F)(F)F)(c1ccc(Cl)cc1)n1ncc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of the product of Step F (50 mg, 0.13 mmol) and NMM (31 mg, 0.3 mmol) in DCM (3 mL) was added methanesulfonyl chloride (20 mg, 0.21 mmol). The mixture was stirred at room temperature for 3 h, then quenched with saturated ammonium chloride solution (10 mL), and extracted with ethyl acetate. The organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by Pre-HPLC (Mobile phase: acetonitrile/water (0.03% TFA)) to afford the title compound. LC/MS m/z=446.1[M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19]C)[N:3]=1.B(Br)(Br)Br.C(N(CC)CC)C.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>C(Cl)Cl>[CH3:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[N:3][C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])=[N:5]2)=[CH:10][CH:9]=1
Reactant: COc1ccccc1-c1nc(Cl)c2ccc(C)cc2n1
Reactant: C1CNCCN1
Agent: BrB(Br)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CCNCC3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
A stirring solution of 4-chloro-2-(2-methoxyphenyl)-7-methylquinazoline (91 g, 320 mmol) and CH2Cl2 (2.0 L) under an N2 atmosphere was cooled to −30° C. Boron tribromide (957 mL, 957 mmol, 1.0 M in CH2Cl2) was added dropwise over a period of 30 minutes at −30 to −40° C. The cooling bath was removed, and the mixture was allowed to warm to 25° C. The mixture was carefully poured into a stirring solution of saturated aqueous NaHCO3 (4.0 L). The organic portion was separated, dried over MgSO4, and evaporated to dryness. The resulting solid was suspended in CH2Cl2 (400 mL) under an N2 atmosphere, followed by the addition of triethylamine (64.8 g, 640 mmol). The solution was cooled to −10° C. A solution of piperazine (55.0 g, 640 mmol) in CH2Cl2 (400 mL) was added in a single portion, and the solution was stirred at ambient temperature for 1 hour. The solution temperature rose to 23° C. upon addition of the piperazine. The solution was partitioned between CH2Cl2 and H2O. The organic portion was dried over MgSO4 and evaporated to dryness. The residue was purified via silica gel chromatography using 5% MeOH in CH2Cl2 to obtain a tan solid. The resulting solid was triturated with 1:1 Et2O/hexanes to obtain a yellow solid which was vacuum dried to give 2-(7-methyl-4-piperazin-1-yl-quinazolin-2-yl)-phenol as a light yellow solid (93.0 g, 290 mmol, 91%). LC/MS: m/z 321.1 (M+H)+ at 2.34 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).