Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:36]=[C:35]([NH:37][C@H:38]2[CH2:49][CH2:48][CH2:47][C@:40]3([O:44][C:43](=[O:45])[N:42]([CH3:46])[CH2:41]3)[CH2:39]2)[C:34]([F:50])=[CH:33][N:32]=1.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:31]3[N:36]=[C:35]([NH:37][C@H:38]4[CH2:49][CH2:48][CH2:47][C@:40]5([O:44][C:43](=[O:45])[N:42]([CH3:46])[CH2:41]5)[CH2:39]4)[C:34]([F:50])=[CH:33][N:32]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:21])=[O:22])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Reactant: CN1C[C@@]2(CCC[C@H](Nc3nc(Cl)ncc3F)C2)OC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@]5(C4)CN(C)C(=O)O5)n3)c3cc(Cl)cnc32)cc1
Temperature: 120 °C

Procedure:
To a solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.031 g, 0.0724 mmol) in acetonitrile (0.570 mL) was added (5S,7S)-7-(2-chloro-5-fluoropyrimidin-4-ylamino)-3-methyl-1-oxa-3-azaspiro[4.5]decan-2-one, 63c, (0.019 g, 0.060 mmol) and degassed under N2. Na2CO3 (0.091 ml, of 2 M, 0.1810 mmol) was added followed by Pd(PPh3)4 (0.010 g, 0.009 mmol). The reaction was sealed and heated in a microwave at 120° C. for 30 min. The mixture was then concentrated in vacuo. The material was diluted in CH2Cl2 and silica gel chromatography (Hexanes:EtOAc then 20% MeOH in CH2Cl2) gave product 63d. LCMS+: 585.25 at 4.17 min (10-90% MeOH, 3/5 grad/run, Formic Acid).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:13]2([CH2:18][OH:19])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.FC(F)(F)C1C=CC(C2(C[O:36][S:37]([CH3:40])(=O)=[O:38])CCCC2)=CC=1>>[CH3:40][S:37]([O:19][CH2:18][C:13]1([C:5]2[CH:4]=[C:3]([C:2]([F:20])([F:21])[F:1])[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1)(=[O:38])=[O:36]
Reactant: CS(=O)(=O)OCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Reactant: OCC1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCC1
Product: CS(=O)(=O)OCC1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCC1

Procedure:
(1-(3,5-bis(trifluoromethyl)phenyl)cyclopentyl)methyl methanesulfonate (458) was synthesized from ((1-(3,5-bis(trifluoromethyl)phenyl)cyclopentyl)methanol (457) following the procedure described for methanesulfonic acid 1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl ester (240).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[O:32]1[CH2:37][CH2:36][CH:35](O)[CH2:34][CH2:33]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH:35]2[CH2:36][CH2:37][O:32][CH2:33][CH2:34]2)=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OC1CCOCC1
Reactant: CC(C)(C)Oc1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)Oc1ccc(OC2CCOCC2)cc1
Reaction time: 8 h
Yield: 85.3 %

Procedure:
4-Tert-butoxyphenol (200 mg, 1.203 mmole) and PPh3 (410 mg, 1.564 mmole) were combined in toluene (5 mL). To this was added tetrahydro-2H-pyran-4-ol (0.149 mL, 1.564 mmole). DIAD (0.304 mL, 1.564 mmole) was added dropwise at RT. After stirring overnight the mixture was concentrated. Flash column chromatography (Biotage-SNAP-25 g SiO2, 10% EtOAc/hexanes) gave 4-(4-tert-butoxyphenoxy)tetrahydro-2H-pyran (257 mg, 85%) as a clear oil. 1H NMR (400 MHz, CDCl3): 06.90 (d, J=8.9 Hz, 2 H); 6.83-6.79 (m, 2 H); 4.39 (m, 1 H); 4.03-3.95 (m, 2 H); 3.56 (m, 2 H); 2.04-1.96 (m, 2 H); 1.83-1.72 (m, 2 H); 1.30 (s, 9 H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([O:11][CH2:12][CH2:13][F:14])[N:8]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=3)[C:7]=2[CH:22]=1)#[CH:2].C([N-]C(C)C)(C)C.[Li+].[N:31]1[CH:36]=[CH:35][CH:34]=[N:33][C:32]=1[C:37](=[O:39])[CH3:38]>O1CCCC1>[NH2:21][C:17]1[N:16]=[C:15]([N:8]2[C:7]3[CH:22]=[C:3]([C:1]#[C:2][C:37]([C:32]4[N:33]=[CH:34][CH:35]=[CH:36][N:31]=4)([OH:39])[CH3:38])[CH:4]=[CH:5][C:6]=3[N:10]=[C:9]2[O:11][CH2:12][CH2:13][F:14])[CH:20]=[CH:19][N:18]=1
Reactant: C#Cc1ccc2nc(OCCF)n(-c3ccnc(N)n3)c2c1
Reactant: CC(=O)c1ncccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)(C#Cc1ccc2nc(OCCF)n(-c3ccnc(N)n3)c2c1)c1ncccn1
Yield: 8.8 %

Procedure:
To a solution of 4-[6-ethynyl-2-(2-fluoroethoxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (30 mg, 0.10 mmol) in tetrahydrofuran (0.5 mL) under a nitrogen atmosphere at −78° C. was added a lithium diisopropylamide solution (0.3 mL, 3.00 equiv) dropwise with stirring. The reaction mixture was stirred at −78° C. for 15 min. A solution of 1-(pyrimidin-2-yl)ethan-1-one (48.8 mg, 0.40 mmol) in tetrahydrofuran (0.5 mL) was then added and the mixture was stirred at −78° C. for another 20 min. The resulting solution was then stirred at room temperature for 13 h. The reaction was then quenched by the addition of saturated ammonium chloride solution (1 mL) and the mixture was extracted with 10 mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column (ethyl acetate/petroleum ether, 1:3) to give 3.7 mg (9%) of 4-[1-(2-aminopyrimidin-4-yl)-2-(2-fluoroethoxy)-1H-1,3-benzodiazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol as an off-white solid: 1H NMR (400 MHz, DMSO) delta 8.89 (d, J=4.8 Hz, 2H), 8.40 (d, J=5.6 Hz, 1H), 8.13 (d, J=1.2 Hz, 1H), 7.51-7.44 (m, 2H), 7.25-7.22 (m, 1H), 7.10 (s, 1H), 6.96 (d, J=5.2 Hz, 1H), 6.12 (s, 1H), 4.93-4.88 (m, 2H), 4.80 (s, 2H), 1.88 (s, 3H); LC-MS: m/z=+420 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:40]([Si:42]([C:47]#[CH:48])([CH2:45][CH3:46])[CH2:43][CH3:44])[CH3:41]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:43]([Si:42]([C:40]#[C:41][C:2]1[C:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][N:5]=[CH:4][N:3]=1)([CH2:47][CH3:48])[CH2:45][CH3:46])[CH3:44]
Reactant: CCOC(=O)Cc1cncnc1Cl
Reactant: C#C[Si](CC)(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1cncnc1C#C[Si](CC)(CC)CC
Temperature: 120 °C
Yield: 94 %

Procedure:
To a nitrogen de-gassed solution of ethyl 2-(4-chloropyrimidin-5-yl)acetate (I108) (0.823 g, 4.10 mmol) in dry DMF (15 mL) were added triethylamine (1.715 mL, 12.31 mmol) followed by triphenylphosphine (0.124 g, 0.473 mmol), trans-dichlorobis(triphenyl-phosphine)palladium(II) (0.144 g, 0.205 mmol), Cu(I)I (0.078 g, 0.410 mmol) and finally (triethylsilyl)acetylene (1.470 mL, 8.204 mmol). The reaction mixture was then heated under microwave irradiation at 120° C. for 25 minutes, concentrated in vacuo and purified by silica gel chromatography (Isolera Biotage, 40 g Si cartridge, 0-30% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I109) (1.176 g, 94% yield) as a yellow-orange oil; 1H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), 8.68 (s, 1H), 4.18 (q, J=7.1 Hz, 2H), 3.80 (s, 2H), 1.26 (t, J=7.1 Hz, 3H), 1.10-1.01 (m, 9H), 0.77-0.67 (m, 6H) LCMS Method C: rt 6.64 min; m/z 305.1 [M+H]+.
Reaction SMILES: [I:1]I.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1>C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[I:1][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][C:7]=1[OH:11]
Reactant: COc1cccc(O)c1
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1ccc(I)c(O)c1
Reaction time: 1 h
Yield: 33.8 %

Procedure:
I2 (40.9 g, 161.1 mmol) was dissolved in CHCl3 (850 mL) with stirring over 1 hour. The solution was added slowly into a reaction mixture of 3-methoxyphenol 5-A (20 g, 161.1 mmol) and silver trifluoroacetate in 200 mL CHCl3 over 1.5 hours. The reaction was stirred at room temperature for 16 hours. Solids were removed by filtration. The filtrate was washed with 5% Na2S2O3(500 mL), saturated NaHCO3, brine, dried over MgSO4 and concentrated. The crude mixture was triturated with carbon tetrachloride to give 2-iodo-5-methoxyphenol 5-B (13.6 g) as a white solid. The remaining crude products were purified by silica gel column chromatography eluted with CH2Cl2 to give 28.2 g of compound 5-B.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[C:21]3[C:16](=[C:17]([CH2:23][S:24][CH3:25])[CH:18]=[C:19]([F:22])[CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:10][C:11]#[N:12])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:13]2[C:21]3[C:16](=[C:17]([CH2:23][S:24]([CH3:25])=[O:34])[CH:18]=[C:19]([F:22])[CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:10][C:11]#[N:12])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cc(F)cc2c(C(CCC#N)c3ccc(Cl)cc3)c[nH]c12
Solvent: ClCCl
Product: CS(=O)Cc1cc(F)cc2c(C(CCC#N)c3ccc(Cl)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
64.0 mg (0.17 mmol) of the compound from Example 43 were introduced into 10 ml of dichloromethane at 0° C., 42.3 mg (0.17 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT overnight. It was concentrated, and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 54 mg (79% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([NH:18][NH2:19])=[O:17])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:20][O:21][C:22]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)=[O:23]>O1CCCC1.N1C=CC=CC=1>[CH2:1]([O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]([NH:18][NH:19][C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([C:22]([O:21][CH3:20])=[O:23])=[CH:32][CH:31]=2)=[O:17])=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(CCC(=O)NN)cc1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCOc1ccc(CCC(=O)NNC(=O)c2ccc(C(=O)OC)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a suspension of 3-(4-n-hexyloxyphenyl)propiono-hydrazide (0.92 g) in tetrahydrofuran (25 ml) and pyridine (0.84 ml) was added a solution of 4-methoxycarbonylbenzoyl chloride (0.73 g) in tetrahydrofuran (10 ml) dropwise at 5° C. The reaction mixture was stirred for 1 hour and poured into ice-water. The precipitate was collected by filtration, washed with water and dried under reduced pressure to give 1-[3-(4-n-hexyloxyphenyl)propanoyl]-2-(4-methoxycarbonylbenzoyl)hydrazine (1.43 g).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][O:5][N:4]([CH:8]([CH3:10])[CH3:9])[C:3]1=[O:11].[C:12]([C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[CH:19]=[O:20])([CH3:15])([CH3:14])[CH3:13]>C1C=CC=CC=1.[Zn]>[C:25]([C:22]1[CH:21]=[C:18]([CH:19]([OH:20])[CH:2]2[CH2:7][CH2:6][O:5][N:4]([CH:8]([CH3:10])[CH3:9])[C:3]2=[O:11])[CH:17]=[C:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:23]=1[OH:24])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)N1OCCC(Br)C1=O
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: [Zn]
Solvent: c1ccccc1
Product: CC(C)N1OCCC(C(O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Yield: 63.6 %

Procedure:
A stirred mixture of 1.1 g (5 mmol) dihydro-4-bromo-2-isopropyl-2H-1,2-oxazin-3(4H)-one, 1.2 g (5 mmol) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde and 1 g of zinc dust in 20 ml of benzene were refluxed for 15 hours and concentrated. The concentrate was taken up in methylene chloride and chromatographed on silica gel with 30% ethyl acetate-hexane to yield 1.2 g of dihydro-4-[(3,5-di-tert-butyl-4-hydroxyphenyl)hydroxymethyl]-2-isopropyl-2H-1,2-oxazin-3(4H)-one, mp 150°-153° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[N:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:4](=[O:14])[CH:3]=1.C(N(CC)CC)C.[O:22](S(C(F)(F)F)(=O)=O)[S:23]([C:26]([F:29])([F:28])[F:27])(=O)=[O:24].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[S:23]([O:1][C:2]1[CH:7]=[N:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:4](=[O:14])[CH:3]=1)(=[O:24])=[O:22]
Reactant: O=c1cc(O)cnn1C1CCCCO1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1cc(OS(=O)(=O)C(F)(F)F)cnn1C1CCCCO1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 57.9 %

Procedure:
5-Hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (2.4 g, 13 mmol) dissolved in methylene chloride (75 mL) and cooled to 0° C. Triethylamine (3.5 mL, 25 mmol) and Tf2O (2.3 mL, 14 mmol) were added and the mixture stirred for a further 2.5 h. Saturated NaHCO3 solution was added and the organic phase removed, dried over Na2SO4 and concentrated. Purification by flash column chromatography (silica gel, EtOAc/hexanes) provided the title compound (2.47 g, 60%) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.85 (d, J=2.8 Hz, 1H), 6.86 (d, J=2.7 Hz, 1H), 6.01 (dd, J=10.2, 2.2 Hz, 1H), 4.15-4.12 (m, 1H), 3.75 (dt, J=11.6, 2.5 Hz, 1H), 2.18-2.02 (m, 2H), 1.78-1.66 (m, 3H), 1.62-1.55 (m, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])[CH3:2].C(=O)(O)[O-].[Na+].Cl[CH2:16][C:17]([O:19][CH3:20])=[O:18].C(#N)C>CCOCC>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:6][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: COC(=O)CCl
Reactant: CCc1cccc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Product: CCc1cccc(NCC(=O)OC)c1
Reaction time: 48 h
Yield: 46.3 %

Procedure:
To m-ethylaniline (50 g; 0.413 mol) and sodium bicarbonate (69.33 g; 0.825 mol) was added methyl chloroacetate (39.79 ml; 0.454 mol) and acetonitrile (50 ml). The mixture was allowed to heat to 130° with stirring from 48 hours. The mixture was then taken up in ether. The ether extract was treated with 2N hydrochloric acid, after which the acid layer was extracted with ether. The combined organic extracts were washed with water, brine and then dried (Na2SO4). Filtration and evaporation of the solvent gave the title compound (36.95 g: 46%) as an oil.
Reaction SMILES: [F:1][CH:2]([F:33])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:5]=2[N:4]=1.[Cl:34][CH2:35][S:36](Cl)(=[O:38])=[O:37].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:34][CH2:35][S:36]([NH:26][CH:23]1[CH2:24][CH2:25][N:20]([C:10]2[N:9]=[C:8]([N:7]3[C:6]4[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:5]=4[N:4]=[C:3]3[CH:2]([F:1])[F:33])[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=2)[CH2:21][CH2:22]1)(=[O:38])=[O:37]
Reactant: O=S(=O)(Cl)CCl
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(N)CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(NS(=O)(=O)CCl)CC2)n1
Yield: 56 %

Procedure:
Reaction of 1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinamine (Example 17) with chloromethanesulfonyl chloride and K2CO3 in CH2Cl2 gave chloro-N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}methanesulfonamide in 56% yield: mp (CH2Cl2/MeOH) 230-232° C.; 1H NMR (DMSO-d6) δ7.88 (d, J=8.0 Hz, 1H), 7.87 (br, 1H), 7.69 (t, JHF=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 6.95 (d, J=7.9 Hz, 1H), 4.95 (s, 2H), 4.59-4.49 (m, 2H), 3.98 (s, 3H), 3.81-3.79 (m, 4H), 3.70-3.69 (m, 4H), 3.55 (br, 1H), 3.22-3.12 (m, 2H), 1.96 (br, 2H), 1.46-1.41 (m, 2H); Anal. Calcd. for C22H27ClF2N8O4S: C, 46.1; H, 4.75; N, 19.6. Found: C, 46.4; H, 4.8; N, 19.6%.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([F:24])[CH:17]=[C:18]3[C:23]=2[O:22][CH2:21][CH2:20][CH2:19]3)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[F:24][C:16]1[CH:17]=[C:18]2[C:23](=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:15]=1)[O:22][CH2:21][CH2:20][CH2:19]2
Reactant: Fc1cc2c(c(N3CCN(Cc4ccccc4)CC3)c1)OCCC2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Fc1cc2c(c(N3CCNCC3)c1)OCCC2
Yield: 84.6 %

Procedure:
A mixture of 1-benzyl-4-(6-fluoro-chroman-8-yl)-piperazine (1.64 g, 5 mmol), 10% palladium on carbon (0.4 g) and ammonium formate (0.64 g, 10 mmol) in ethanol (20 ml) was allowed to reflux for 2 hours. The catalyst was filtered off and the solvent removed under vacuum. Chromatography (10-20% methanol-methylene chloride plus ammonium hydroxide) afforded 1.0 g (84%) of product as a yellow oil; MS EI m/e 296 (M+).
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[CH3:40][O:41][C:42]1[CH:50]=[CH:49][C:45]([C:46](Cl)=[O:47])=[CH:44][CH:43]=1>>[CH3:40][O:41][C:42]1[CH:50]=[CH:49][C:45]([C:46]([O:1][CH:2]2[CH2:20][CH:19]3[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]4[C:16]([C:22]([NH:24][S:25]([CH:28]5[CH2:30][CH2:29]5)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]3=[O:21])[CH2:15]4)[CH2:3]2)=[O:47])=[CH:44][CH:43]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Product: COc1ccc(C(=O)OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCCC(NC(=O)OC(C)(C)C)C(=O)N3C2)cc1
Yield: 26.8 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 4-methoxybenzoyl chloride (72 mg, 0.53 mmol). The final trituration (diethyl ether/hexane) and filtration gave 33 mg (27%) of 18-(4-methoxybenzoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 98.0% pure (HPLC), MS m/z 701 (M−H)−, HRMS: calcd. 703.3013 and found 703.3006 (M+H)+, mp 151-153° C.
Reaction SMILES: [CH:1]1([C:6]2[NH:11][C:10](=[O:12])[C:9]([CH:13]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])[CH2:21][CH2:20]3)=O)[CH2:14][CH3:15])=[N:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O>>[CH:1]1([C:6]2[NH:11][C:10](=[O:12])[C:9]3=[C:13]([CH2:14][CH3:15])[N:16]=[C:17]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:26])[CH2:21][CH2:20]4)[N:8]3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(NC(=O)C1CCN(C(=O)OCc2ccccc2)CC1)c1nnc(C2CCCC2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc(C2CCN(C(=O)OCc3ccccc3)CC2)n2nc(C3CCCC3)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 1, 500 mg (1.07 mmol) crude benzyl 4-({[1-(3-cyclopentyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]amino}carbonyl)-1-piperidinecarboxylate, 248 mg (1.7 mmol) phosphoric trichloride are stirred at reflux for 4 hours, proportionate amounts of the solvents are used. The product is purified by chromatography (preparative HPLC).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12](I)=[CH:13][C:8]=2[C:7](=[O:15])[N:6]([CH3:16])[C:5]2[CH:17]=[CH:18][CH:19]=[N:20][C:4]1=2)[CH3:2].[C:21]1([C:27]#[CH:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([C:28]#[C:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:13][C:8]=2[C:7](=[O:15])[N:6]([CH3:16])[C:5]2[CH:17]=[CH:18][CH:19]=[N:20][C:4]1=2)[CH3:2]
Reactant: C#Cc1ccccc1
Reactant: CCN1c2ncc(I)cc2C(=O)N(C)c2cccnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN1c2ncc(C#Cc3ccccc3)cc2C(=O)N(C)c2cccnc21
Temperature: 95 °C
Yield: 53.2 %

Procedure:
A mixture of 5,11-dihydro-11-ethyl-8-iodo-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.20 g, 0.53 mmol), phenylacetylene (0.06 mL, 0.55 mmol), bis(triphenylphosphine)palladium(II) chloride (25 mg, 0.04 mmol), and triethylamine (0.16 mL, 1.14 mmol) in 3 mL of N,N-dimethylformamide was heated at 95° C. under argon for 19 hours. Workup as described in Example 1h and purification by flash chromatography, eluting with ethyl acetate/dichloromethane, afforded 0.1 g of the title compound.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C:7]1=[CH:6][CH2:5][C:4]2=[O:22])[CH3:2].[H][H]>O1CCOCC1.[Ni]>[CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:22])[CH3:2]
Reactant: [H][H]
Reactant: CC[C@]12CCC3=C(CCc4cc(OC)ccc43)C1=CCC2=O
Agent: [Ni]
Solvent: C1COCCO1
Product: CC[C@]12CCC3=C(CCc4cc(OC)ccc43)[C@@H]1CCC2=O
Yield: 59.6 %

Procedure:
Dissolve 13β-ethyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one (2 g) in dioxan (50 cc) containing Raney nickel (ca. 0.5 g) of moderate activity and shake with hydrogen until 160 cc., the amount corresponding to one molecular proportion has been absorbed. Recrystallize the isolated product from methanol to obtain the title product (1.2 g), m.p. 110°-125°; ultraviolet absorption peak at 280 mμ (ε13,200).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][CH:30]([F:41])[O:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[N:36][CH:37]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:34]1[CH:35]=[N:36][CH:37]=[C:32]([O:31][CH:30]([F:41])[F:29])[CH:33]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: OB(O)c1cncc(OC(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cncc(OC(F)F)c3)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 81.6 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (75 mg, 0.17 mmol) were added 48 mg (0.26 mmol) of (5-(difluoromethoxy)pyridin-3-yl)boronic acid, 13 mg (0.02 mmol) of 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex and 170 μl of a 2M aqueous solution of cesium carbonate in dioxane. The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by flash chromatography (0% to 100% hexane/AcOEt, 0-8% AcOEt/MeOH) to give 70 mg (81% yield) of the title compound as a white solid.