Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1.CCN(C(C)C)C(C)C.Cl.Cl.[N:37]1([CH:42]2[CH2:46][CH2:45][NH:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:44]4[CH2:45][CH2:46][CH:42]([N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[CH2:43]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1
Reactant: C1CCN(C2CCNC2)C1
Reactant: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(N3CCC(N4CCCC4)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-1-hydroxycyclohexylmethyl)-amide, DIPEA and 3-pyrrolidin-yl-pyrrolidine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (1H), 7.48 (2H), 6.69 (1H), 4.59 (s, 1H), 3.89 (m, 1H), 3.70 (m, 1H), 3.45 (m, 1H), 3.26 (m, 2H), 2.85 (m, 1H), 2.54 (m, 4H), 2.15 (m, 1H), 2.06 (m, 2H), 1.85 (m, 3H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 494 [M+H]
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:11]([N:16]=1)=[N:12][CH:13]=[CH:14][CH:15]=2.[OH:17]O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:11]([N:16]=1)=[N+:12]([O-:17])[CH:13]=[CH:14][CH:15]=2
Reactant: Fc1ccccc1-c1nc2ncccc2o1
Reactant: OO
Solvent: CC(=O)O
Product: [O-][n+]1cccc2oc(-c3ccccc3F)nc21
Temperature: 0 °C

Procedure:
A solution of 1 g. of 2-(2-fluorophenyl)oxazolo[4,5-b]pyridine (from Example 6) in 10 ml. of acetic acid was treated with 2 ml. of 30% hydrogen peroxide and heated on the steam bath for 16 hours. After cooling the mixture was diluted with ice-water. The precipitate was collected and recrystallized from dioxane-ether to give 2-(2-fluorophenyl)oxazolo [4,5-b]pyridine-4-oxide, m.p. 214°-216° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][CH2:17][C:18]2=[O:21])=[CH:13][CH:12]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][CH2:17][C:18]3=[O:21])=[CH:13][CH:12]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Nc1ccc2c(c1)C(=O)CCC2
Reactant: Fc1cnc(Cl)nc1Cl
Product: O=C1CCCc2ccc(Nc3nc(Cl)ncc3F)cc21

Procedure:
In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 7-amino-1-tetralone were reacted to provide 2-chloro-5-fluoro-N4-(1,2,3,4-tetrahydro-1-oxonaphthalen-7-yl)-4-pyrimidineamine. 1H NMR (DMSO-d6): δ 10.08 (s, 1H), 8.31 (d, 1H, J=3.3 Hz), 8.15 (d, 1H, J=2.4 Hz), 7.82 (dd, 1H, J=2.4 and 8.1 Hz), 7.36 (d, 1H, J=8.1 Hz), 2.91 (t, 2H, J=6.0 Hz), 2.59 (t, 2H, J=6.0 Hz), 2.07-1.98 (m, 2H); LCMS: purity: 93%; MS (m/e): 294 (MH+).
Reaction SMILES: C1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9](CCCCCCCBr)[C:8]2=[O:32])C=CC=CC=1.[P:33]([O:40][CH2:41][CH3:42])([O:37]CC)[O:34][CH2:35][CH3:36]>C1(C)C(C)=CC=CC=1>[C:12]1([N:9]2[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:7]=[C:8]2[O:32][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:10][CH2:11][P:33]([O:34][CH2:35][CH3:36])(=[O:37])[O:40][CH2:41][CH3:42])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=c1n(CCCCCCCBr)c(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Reactant: CCOP(OCC)OCC
Solvent: Cc1ccccc1C
Product: CCOP(=O)(CCCCCCCOc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1)OCC

Procedure:
A mixture of 1,4,5-triphenyl-3-(7-bromoheptyl)-imidazol-2-one (1.0 g) and triethyl phosphite (1.66 g) was heated at reflux temperature in xylene (5 ml) for 40 hours. The solution was evaporated to an oil and re-evaporated from ethanol. The oil was partitioned between ether and water, the ether solution was separated, dried over magnesium sulphate and evaporated to an oil which was chromato-graphed on silica gel (ethyl acetate) to give diethyl 7-(1,4,5-triphenylimidazol-2-yl-oxy)heptanephosphonate as an oil which solidified on standing to a white solid (0.83 g; 75%), m.p. 76°-7° C. Found: C, 70.49; H, 7.40; N, 4.94%; C32H39N2O4P; Requires: C, 70.31; H, 7.19; N, 5.12%.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[CH:14][N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]=3[C:4]=2[CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1B(O)O>>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[CH:14][N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]=3[C:4]=2[CH:3]=1
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(Br)cc3c21
Product: COc1ccc(-c2ccc3nc(N)c4ncn(CC(C)C)c4c3c2)c(OC)c1

Procedure:
8-Bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and 2,4-dimethoxybenzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. Purification by chromatography on silica gel (7% methanol in CH2Cl2) afforded 8-(2,4-dimethoxyphenyl)-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 223-227° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C1C=CC2N(O)N=[N:18]C=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.N.CO>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: On1nnc2ccccc21
Reactant: Nc1cc(Cl)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: NC(=O)c1ccc(Cl)cc1N
Temperature: 25 °C
Reaction time: 96 h
Yield: 66.1 %

Procedure:
To solution of 2-amino-4-chlorobenzoic acid (4.4 g, 25.8 mmol) in degassed DMF (75 mL) were added successively HOBt (4.19 g, 31 mmol), DIEA (5.4 mL, 31 mmol), EDCI (5.37 g, 28 mmol), and 2N NH3/MeOH (18 mL, 36 mmol), and the solution was stirred at rt for 4 d. The mixture was concentrated under reduced pressure and the residue was partitioned between H2O (200 mL) and DCM (200 mL). The separated aqueous phase was extracted with DCM (2×200 mL) and the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 10-50% EtOAc/hexanes to afford 2-amino-4-chlorobenzamide as a solid (2.91 g, 66%). 1H NMR (300 MHz, DMSO-d6) δ 6.50 (dd, J=8.48, 2.26 Hz, 1H), 6.75 (d, J=2.26 Hz, 1H), 6.84 (br s, 2H), 7.18 (br s, 1H), 7.48-7.63 (m, 1H), 7.80 (br s, 1H).
Reaction SMILES: C(Cl)Cl.[C:4]([NH:8][S:9]([C:12]1[S:16][C:15](B(O)O)=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH3:7])([CH3:6])[CH3:5].Br[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:32]=[C:31]([CH:33]3[CH2:35][CH2:34]3)[NH:30][N:29]=2)[C:24]([Br:36])=[CH:23][N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:36][C:24]1[C:25]([NH:27][C:28]2[CH:32]=[C:31]([CH:33]3[CH2:35][CH2:34]3)[NH:30][N:29]=2)=[N:26][C:21]([C:15]2[S:16][C:12]([S:9]([NH:8][C:4]([CH3:7])([CH3:6])[CH3:5])(=[O:11])=[O:10])=[CH:13][CH:14]=2)=[N:22][CH:23]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)s1
Reactant: Brc1ncc(Br)c(Nc2cc(C3CC3)[nH]n2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2ncc(Br)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Temperature: 90 °C
Yield: 57.4 %

Procedure:
The mixture of Pd(dppf)Cl2.CH2Cl2 (457 mg, 0.56 mmol, 0.1 eq), 5-(N-tert-butylsulfamoyl)thiophen-2-ylboronic acid (2.95 g, 11.2 mmol, 2.0 eq), 2,5-dibromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (2 g, 5.6 mmol, 1.0 eq) and saturate Na2CO3 (5 mL) in dioxane (30 mL) was heated to 90° C. for 1 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, and extracted with THF. The combined layers were evaporated and residue purified by silica gel chromatography (EtOAc/Petroleum ether from 10:1 to 2:1) to afford compound 5-(5-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)-N-tert-butylthiophene-2-sulfonamide (1.6 g, 59%). LC-MS (m/z)=497 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:25])[NH:10]2)=[O:4].CO>O1CCCC1>[Br:1][CH2:2][C@@H:3]([C:5]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:25])[NH:10]2)[OH:4]
Reactant: COc1ccc(COc2ccc(C(=O)CBr)c3ccc(=O)[nH]c23)cc1
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(COc2ccc([C@@H](O)CBr)c3ccc(=O)[nH]c23)cc1
Temperature: -20 °C
Reaction time: 0.67 h
Yield: 42.5 %

Procedure:
Under an argon flow, 5-(2-bromoacetyl)-8-[(4-methoxyphenyl)methoxy]-1,2-dihydroquinolin-2-one (7.15 g, 17.8 mmol) was suspended in dehydrated tetrahydrofuran (40 mL), the CBS catalyst (493 mg) was added thereto, and the reaction mixture was stirred at −20° C. for 40 minutes. After adding dropwise a 1.0 M solution of borane-tetrahydrofuran complex in tetrahydrofuran (21.4 mL) at the same temperature, the mixture was warmed gradually to 0° C. After adding methanol (20 mL) dropwise, insoluble matter was filtered off and washed with tetrahydrofuran. The filtrate and the washing were mixed and concentrated under reduced pressure. To the residue was added purified water (100 mL) and the mixture was stirred at room temperature overnight. The precipitate was collected by filtration and washed with purified water. The precipitate was further suspension-washed with ethyl acetate (200 mL), collected by filtration, and dried under reduced pressure to obtain 5-[(1R)-2-bromo-1-hydroxyethyl]-8-[(4-methoxyphenyl)methoxy]-1,2-dihydroquinolin-2-one (3.06 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])(O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(S(F)(F)[F:28])CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:28])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2F)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(2-Fluoro-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.69 mmol) in DCM (20 mL) was cooled to −78° C. Diethylaminosulphur trifluoride (2 mmol) was added and the mixture stirred for 0.5 hour and allowed to warm to room temperature. The mixture was diluted with DCM and washed with water then dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum to give the title compound as a brown oil which was used without further purification. LCMS m/z 298.3 [M+H]+. R.T.=4.97 min (Analytical Method 4).
Reaction SMILES: [CH2:1]([C:3]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH3:24])[CH:18]=1)([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:8]=2[CH:7]=1)[CH2:4][CH3:5])[CH3:2].Br[CH2:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([C:3]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[C:19]([CH3:24])[CH:18]=1)([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:8]=2[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1cc2cc(OC)ccc2s1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(OC)ccc2s1
Yield: 91.6 %

Procedure:
4-[1-Ethyl-1-(5-methoxy-benzo[b]thiophen-2-yl)-propyl]-2-methyl-phenol (7.80 g, 22.9 mmol), 1-bromopinacolone (8.20 g, 45.8 mmol), and K2CO3 (6.32 g, 45.8 mmol) in acetone (100 mL) are reacted analogous to Example 1D to provide the title compound (9.20 g, 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15].[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][CH:11]1[C:10](=[O:15])[CH:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:14][CH2:13][CH2:12]1
Reactant: BrBr
Reactant: O=C1CCCCC1c1cc(F)ccc1F
Solvent: ClC(Cl)Cl
Product: O=C1C(Br)CCCC1c1cc(F)ccc1F
Temperature: 25 °C
Yield: 105.2 %

Procedure:
2-(2,5-Difluoro-phenyl)-cyclohexanone (51 mg, 0.24 mmol) was dissolved in chloroform (1 mL). To this solution bromine (40.7 mg, 0.26 mmol) in chloroform (0.5 mL) was added drop wise at room temperature. The reaction was stirred for 1½ hours at room temperature. The solvent was removed under reduced pressure to yield the cude title compound (73 mg) which was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Cl)=[CH:4][CH:3]=1.[CH3:10][N:11]([CH3:24])[C:12]1(C#N)[CH2:21][CH2:20][C:15]2([O:19][CH2:18][CH2:17][O:16]2)[CH2:14][CH2:13]1.[Cl-].[NH4+]>C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:18]2[CH2:17][O:16][C:15]3([CH2:20][CH2:21][CH:12]([N:11]([CH3:24])[CH3:10])[CH2:13][CH2:14]3)[O:19]2)=[CH:4][CH:3]=1
Reactant: Cl[Mg]c1ccc(Cl)cc1
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)C1CCC2(CC1)OCC(c1ccc(Cl)cc1)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Starting with 38 ml 1.0 molar 4-chlorophenyl magnesium chloride solution in diethylether, 4.00 g 8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile, dissolved in 60 ml diethylether, were added dropwise and stirred overnight at ambient temperature. To work up the mixture, 30 ml ammonium chloride solution (20% by weight) were added with ice cooling, the phases were separated, the ethereal phase was washed in succession with 30 ml water and saturated sodium chloride solution, dried over sodium sulfate, filtered, concentrated and substantially freed of solvent residues under vacuum. The crude [-(4-chlorophenyl)-1,4-dioxaspiro[4.5]dec-8-yl]dimethylamine (4.18 g) obtained was initially stirred for 24 hours with a mixture of 10 ml concentrated hydrochloric acid (32% by weight) and 6.0 ml water at ambient temperature without further purification and then heated for 3 hours to reflux. Subsequently, the reaction mixture was first washed three times with 50 ml diethylether in each case, then made basic by addition of concentrated ammonia solution (25% by weight) with ice cooling, extracted three times with 100 ml diethylether in each case, the combined diethylether extracts were dried over sodium sulfate, filtered, concentrated and substantially freed of solvent residues under vacuum. 3.84 g 4-(4-chlorophenyl)-4-dimethylaminocyclohexanone were obtained as a brown oil.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:54]=[CH:53][C:8]([C:9]([O:24][CH2:25][C@H:26]2[O:30][C@@H:29]([N:31]3[CH:39]=[C:37]([CH3:38])[C:35](=[O:36])[NH:34][C:32]3=[O:33])[CH2:28][C@:27]2([CH2:41]OS(C2C=CC(C)=CC=2)(=O)=O)[OH:40])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][C:13](OC)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1.C1C[O:58][CH2:57]C1>>[CH3:57][O:58][C:13]1[CH:12]=[CH:11][C:10]([C:9]([O:24][CH2:25][C@H:26]2[O:30][C@@H:29]([N:31]3[CH:39]=[C:37]([CH3:38])[C:35](=[O:36])[NH:34][C:32]3=[O:33])[CH2:28][C@:27]32[CH2:41][O:40]3)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]2[CH:53]=[CH:54][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: C1CCOC1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@]2(O)COS(=O)(=O)c2ccc(C)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@]23CO3)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a suspension of NaH (60% in mineral oil, 0.18 g; 7.5 mmol) in anhydrous THF (18 ml) at 0° C. under argon was added dropwise a solution of 5'-O-(4,4'-dimethoxytrityl)-3'-p-toluensulfonyloxymethylthymidine (1.5 g; 2.06 mmol) in THF (10 ml). The resulting reaction mixture was stirred at room temperature for 2 h, cooled to 0° C., and quenched by addition of water. The mixture was diluted with EtOAc (250 ml), washed with water (2×200 ml), then with 10% NaHCO3 (2×200 ml), dried over Na2SO4, and concentrated. The residue was purified by chromatography on silica (5% CH3OH in CH2Cl2) to yield 0.97 g (85%) of 5'-O-(4,4'-dimethoxytrityl)-3'-C,O-methylene thymidine as a foam.
Reaction SMILES: F[C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([CH3:18])[C:5]([C:16]#[N:17])=[C:6]2[C:10]=1[O:9][C:8]([C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)=[N:7]2.C(N(CC)CC)C.[CH3:32][N:33]([CH3:39])[C@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1.C(OCC)(=O)C>CS(C)=O.[Cl-].[Na+].O>[CH3:32][N:33]([CH3:39])[C@H:34]1[CH2:38][CH2:37][N:36]([C:2]2[C:3]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:4]([CH3:18])[C:5]([C:16]#[N:17])=[C:6]3[C:10]=2[O:9][C:8]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[N:7]3)[CH2:35]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(-c3ccco3)nc2c1C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(-c3ccco3)nc2c1C#N
Temperature: 90 °C
Reaction time: 11 h

Procedure:
7-Fluoro-2-(2-furyl)-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-105) (40 mg, 0.13 mmol) was dissolved in anhydrous dimethyl sulfoxide (2 ml), and at room temperature, triethylamine (26 μl, 0.19 mmol) and (3S)-3-(dimethylamino)pyrrolidine (21 μl, 0.16 mmol) were added. This mixture liquid was stirred at 90° C. for 11 hours, then cooled to room temperature. This was fractionated with ethyl acetate and saturated brine. The aqueous layer was separated, and this was extracted twice with ethyl acetate.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[I:12][C:13]1[CH:14]=[N:15][NH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[I:12][C:13]1[CH:14]=[N:15][N:16]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=2)[CH:17]=1
Reactant: Ic1cn[nH]c1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(-n2cc(I)cn2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 93.2 %

Procedure:
A mixture of 5-fluoro-2-nitrotoluene (2.33 g), 4-iodo-1H-pyrazole (2.91 g) and potassium carbonate (2.49 g) was heated and stirred in DMF (30 ml) at 140° C. for 4 hours. After cooling to room temperature, the reaction mixture was poured into ice water to separate out crystals. The obtained crystals were filtered, washed with water and dried, and 4-iodo-1-(3-methyl-4-nitrophenyl)-1H-pyrazole (4.60 g) was obtained.
Reaction SMILES: CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1.[OH:59][CH2:60]/[C:61](/[CH3:90])=[CH:62]/[CH2:63][CH2:64][C@H:65]([C@@H:67]1[C@:83]2([CH3:84])[C@:70]([CH3:89])([C:71]3[C:80](=[CH:81][CH2:82]2)[C@:79]2([CH3:85])[CH:74]([C:75]([CH3:88])([CH3:87])[C:76](=[O:86])[CH2:77][CH2:78]2)[CH2:73][CH:72]=3)[CH2:69][CH2:68]1)[CH3:66].CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1>>[OH:59][CH2:60]/[C:61](/[CH3:90])=[CH:62]\[CH2:63][CH2:64][C@H:65]([C@@H:67]1[C@:83]2([CH3:84])[C@:70]([CH3:89])([C:71]3[C:80](=[CH:81][CH2:82]2)[C@:79]2([CH3:85])[CH:74]([C:75]([CH3:88])([CH3:87])[C:76](=[O:86])[CH2:77][CH2:78]2)[CH2:73][CH:72]=3)[CH2:69][CH2:68]1)[CH3:66]
Reactant: C/C(=C\CC[C@@H](C)[C@H]1CC[C@@]2(C)C3=CCC4C(C)(C)C(=O)CC[C@]4(C)C3=CC[C@]12C)CO
Agent: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Product: C/C(=C/CC[C@@H](C)[C@H]1CC[C@@]2(C)C3=CCC4C(C)(C)C(=O)CC[C@]4(C)C3=CC[C@]12C)CO
Yield: 64 %

Procedure:
AD-mix. Alcohol 12Z (0.0138 g, 0.0325 mmol, 1.0 equiv) was dissolved in t-BuOH (0.33 mL) and water (0.33 mL). To this solution AD-mix-α (0.091 g, 2.8 g/mmol) was added followed by methanesulfonamide (0.0062 g, 0.065 mmol, 2.0 equiv). This solution was allowed to stir for 6 h at 25° C. Upon completion, an aqueous solution of sodium sulfite (5 mL) was added, and the quenched reaction mixture was allowed to stir for 1 h. The mixture was then diluted with ethyl acetate (5 mL), the phases separated, and the aqueous layer was then washed with ethyl acetate (4×5 mL). The combined organic layers were then washed with a saturated brine solution (20 mL), dried over MgSO4, vacuum filtered through a pad of Celite, and the resulting filtrate was evaporated to dryness using a rotary evaporator. The solid was then purified using silica gel chromatography (pre-absorbed on silica gel, step gradient of 3:1 hexane/EtOAc followed by 100% MeOH) to afford 1 as a pure white crystalline solid (0.0114 g, 76% yield). The other isomeric triols were made by an analogous procedure to afford 13 (0.0100 g, 56% yield from 12Z with AD-mix-β), 14 (0.0137 g, 64% yield 12Z with AD-mix-α), 15 (0.0169 g, 76% yield from 12E with AD-mix-β).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=2[N:12]2[CH:20]=[N:21][C:22]([C:23]([OH:25])=O)=[C:11]2[CH2:10][N:9]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:32]([NH2:34])[CH3:33].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=2[N:12]2[CH:20]=[N:21][C:22]([C:23]([NH:34][CH2:32][CH3:33])=[O:25])=[C:11]2[CH2:10][N:9]=1
Reactant: O=C(O)c1ncn2c1CN=C(c1ccccc1Br)c1cc(F)ccc1-2
Reactant: CCN
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCNC(=O)c1ncn2c1CN=C(c1ccccc1Br)c1cc(F)ccc1-2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 0.4 g (1 mmol) of 6-(2-bromophenyl)-8-fluoro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid, 50 mL of methylene chloride and 0.3 g (1.44 mmol) of phosphorus pentachloride was stirred at room temperature for 2.5 hours. Ethylamine was introduced until the reaction mixture was basic. It was layered with 10% aqueous sodium carbonate solution and the two phases were stirred for 15 minutes The organic layer was separated, dried and evaporated. The residue was crystallized from ethyl acetate/hexane to yield 0.37 g of product having the above formula. For analysis it was recrystallized from ethanol to leave colorless crystals with m.p. 218°-220° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH3:31].CCN(C(C)C)C(C)C.[Cl:41][CH2:42][C:43](Cl)=[O:44]>ClCCl.CO>[Cl:41][CH2:42][C:43]([N:18]1[CH2:19][CH2:20][CH:15]([CH2:14][O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([O:21][C:22]4[CH:23]=[C:24]5[C:28](=[CH:29][CH:30]=4)[NH:27][CH:26]=[C:25]5[CH3:31])=[N:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2][CH3:1])[CH2:16][CH2:17]1)=[O:44]
Reactant: O=C(Cl)CCl
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCC1CCN(C(=O)CCl)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-methoxy-4-[(3-methyl-1H-indol-5-yl)oxy]-7-[(piperidin-4-yl)methoxy]quinazoline (0.4 g), prepared as described for the starting material in Example 1, was dissolved in dichloromethane (15 ml). PS-DIEA resin (0.6 g; 4 mmol/g) was added followed by chloroacetyl chloride (0.091 ml). The reaction mixture was stirred at ambient temperature for 3 hours then diluted with methanol and the resin removed by filtration. The solvent was evaporated under vacuum and the residue was purified by column chromatography on silica using increasingly polar solvent mixtures, starting with dichloromethane and ending with dichloromethane/methanol (92/8). Removal of the solvents by evaporation gave 7-{[1-(chloroacetyl)piperidin-4-yl]methoxy}-6-methoxy-4-[(3-methyl-1H-indol-5-yl)oxy]quinazoline (0.237 g) as a solid foam.