Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[CH:8][C:9]1[CH:13]([CH:14]([CH3:16])[CH3:15])[CH2:12][CH2:11][C:10]=1[CH3:17])[C:3](OCC)=[O:4].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>CCOCC>[CH3:1][C:2](=[CH:8][C:9]1[CH:13]([CH:14]([CH3:15])[CH3:16])[CH2:12][CH2:11][C:10]=1[CH3:17])[CH2:3][OH:4]
Reactant: CCOC(=O)C(C)=CC1=C(C)CCC1C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(=CC1=C(C)CCC1C(C)C)CO
Yield: 95.5 %

Procedure:
40 g of ethyl 2-methyl-3-(2-methyl-5-isopropyl-cyclopent-1-en-1-yl)-prop-2-enoate in 100 ml cooled ether were added under stirring to a suspension of 4 g of LiAlH4 in 50 ml ether. After addition of water to the thus obtained suspension, the separated organic phase was dried and evaporated to dryness. There was thus obtained 31.4 g (yield 95%) of the desired alcohol; bp. 75°-80°/0.01 Torr.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([Li])[C:4]2[C:12]([CH:13]=1)=[CH:11][C:10]1[CH2:9][CH2:8][CH2:7][C:6]=1[CH:5]=2.[CH3:15][SiH:16]([N:18](Cl)[C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:17]>C1COCC1>[CH3:20][C:19]([NH:18][Si:16]([CH3:17])([CH3:15])[CH:3]1[C:4]2[C:12](=[CH:11][C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[CH:5]=2)[CH:13]=[C:2]1[CH3:1])([CH3:22])[CH3:21]
Reactant: [Li]C1C(C)=Cc2cc3c(cc21)CCC3
Reactant: C[SiH](C)N(Cl)C(C)(C)C
Solvent: C1CCOC1
Product: CC1=Cc2cc3c(cc2C1[Si](C)(C)NC(C)(C)C)CCC3
Reaction time: 20 h
Yield: 88.3 %

Procedure:
(1,5,6,7-tetrahydro-2-methyl-s-indacen-1-yl) lithium (25.0 g, 0.1419 moles) in THF (200 mL) was added dropwise to a solution of dimethylsilyl(t-butylamino)chloride (23.518 g, 0.1419 moles) in THF (250 mL) over a 1 hour period of time. This mixture was then allowed to stir for 20 hours. After the reaction period the volatiles were removed and the residue extracted and filtered using hexane. Removal of the hexane resulted in the isolation of the desired product as a red-yellow oil (37.55 g, 88.0 percent).
Reaction SMILES: [N+](=[CH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH2:5])=[N-].[OH:12][C@H:13]1[CH2:33][C@@:32]2([CH3:34])[C@@H:24]([CH2:25][C@@H:26]([OH:36])[C@:27]2([OH:35])[C:28](=[O:31])[CH2:29][OH:30])[C@H:23]2[C@H:14]1[C@:15]1([CH3:38])[C:20]([CH2:21][CH2:22]2)=[CH:19][C:18](=[O:37])[CH:17]=[CH:16]1>>[OH:12][C@H:13]1[CH2:33][C@@:32]2([CH3:34])[C@@H:24]([CH2:25][C@@H:26]([O:36][CH2:5][C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH2:3])[C@:27]2([OH:35])[C:28](=[O:31])[CH2:29][OH:30])[C@H:23]2[C@H:14]1[C@:15]1([CH3:38])[C:20]([CH2:21][CH2:22]2)=[CH:19][C:18](=[O:37])[CH:17]=[CH:16]1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](O)[C@]2(O)C(=O)CO
Reactant: C=C(C=[N+]=[N-])c1ccccc1
Product: C=C(CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO)c1ccccc1

Procedure:
A solution of 1-diazo-2-phenyl-2-propene (prepared from 0.3 mole of N-nitrosourethane precursor) in methanolether at 0° is treated with 11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate (84 mmoles) until nitrogen evolution ceases. Solvent removal gives the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[CH:5]=[C:6]([CH2:8][CH3:9])[CH:7]=1>C(O)(=O)C.C(O)C.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH2:8][CH3:9])[CH:7]=1)[NH2:10]
Reactant: CCc1cc(Br)cc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1cc(N)cc(Br)c1

Procedure:
Dissolve 3-bromo-5-ethylnitrobenzene (6.21g, 27mmol) in acetic acid (40mL) and ethanol (30mL) and treat with iron powder (2.7g). Reflux for 3 hours, filter through Celite and evaporate the solvent in vacuo. Purify by silica gel chromatography to give 3-bromo-5-ethylaniline.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([C:13](O)=[O:14])[CH2:10][CH2:9][C:8]=2[CH:16]=1)([O-:3])=[O:2].CO>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([CH2:13][OH:14])[CH2:10][CH2:9][C:8]=2[CH:16]=1)([O-:3])=[O:2]
Reactant: O=C(O)C1CCc2cc([N+](=O)[O-])ccc2O1
Solvent: C1CCOC1
Solvent: CO
Product: O=[N+]([O-])c1ccc2c(c1)CCC(CO)O2
Reaction time: 2 h
Yield: 70 %

Procedure:
To a stirred mixture of 11.1 parts of 3,4-dihydro-6-nitro-2H-1-benzopyran-2-carboxylic acid and 63 parts of tetrahydrofuran were added dropwise, during a 30 minutes-period, 23.6 parts of a borane dimethyl sulfide complex solution 2M in tetrahydrofuran (slightly exothermic reaction: temp. rose to 27° C.). Upon completion, the whole was heated to reflux and stirring was continued for 2 hours at reflux temperature. The reaction mixture was decomposed by the dropwise addition of 8 parts of methanol at reflux temperature. After stirring and refluxing for 10 minutes, the solvents were distilled off and the residue was taken up in water. The solution was treated with concentrate hydrochloric acid and extracted with 1,1'-oxybisethane. The extract was washed with water, dried, filtered and evaporated. The solid residue was suspended in warm 2,2'-oxybispropane. The product was filtered off and dried, yielding 7.0 parts (70%) of 3,4-dihydro-6-nitro-2H-1-benzopyran-2-methanol; mp. 96.5° C. (intermediate 8).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10](=O)[C@@H:9]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1C(=O)N(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: C[C@H]1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 97.9 %

Procedure:
To a stirred solution of (S)-1-tert-butoxycarbonyl-2-methyl-3-oxo-4-benzylpiperazine (1.0 g) in tetrahydrofuran (15 ml) was added borane-dimethylsulfide complex (0.49 ml) at 0° C. under nitrogen atmosphere. After stirring at 45° C. for 1.5 hours, borane-dimethylsulfide complex (0.46 ml) was added and the reaction mixture was stirred at 45° C. for another 2 hours. After cooled to 0° C., the reaction mixture was quenched with methanol. After evaporation of the solvent, the residue was purified by flash column chromatography eluting with a mixture of ethyl acetate and n-hexane (1:8) to give (S)-1-tert-butoxycarbonyl-2-methyl-4-benzylpiperazine (934 mg).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([N+:13]([O-:15])=[O:14])[C:7]=1C(=O)C)(=[O:5])=[O:4].Cl[Si](C)(C)C.C([OH:26])C>S(=O)(=O)(O)O>[CH3:1][NH:2][S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([N+:13]([O-:15])=[O:14])[C:7]=1[OH:26])(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1C(C)=O
Reactant: CCO
Agent: C[Si](C)(C)Cl
Agent: O=S(=O)(O)O
Product: CNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Yield: 100 %

Procedure:
A solution of N-methyl-2-acetyl-6-chloro-3-nitrobenzenesulfonamide (170 mg, 0.55 mmol), 0.5 mL of chlorotrimethylsilane and 3 drops of fuming sulfuric acid in ethanol was heated to reflux for 20 hours. The solvent was evaporated. The residue was diluted with ethyl acetate and washed with water. The organic layer was then dried (Na2SO4) and concentrated to give the desired product (160 mg, >100%). EI-MS (m/z) 265.2, 267.2 (M−).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[N:14])[CH:8]=1)=[O:5].[C:19]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([NH:1][C:2]2[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[N:14])[CH:8]=2)=[O:5])=[O:28])=[CH:30][CH:31]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: N#Cc1cccc(NC(=O)c2ccccc2N)c1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2cccc(C#N)c2)cc1

Procedure:
Using a procedure similar to Example 1B except starting with 2-amino-N-(3-cyanophenyl)benzamide and 4-t-butylbenzoyl chloride, the title compound was obtained as a white solid (92%); MP: 194-6° C.; IR(KBr): 757, 1584, 1647, 2969, 3256 cm−1; NMR(300 MHz, CDCl3): 1.40 (s, 9H); 6.90 (t, 1H, J=7.2 Hz); 7.31 (m, 1H); 7.49-7.55 (m, 3H); 7.60 (d, 2H, J=7.5 Hz); 7.95 (d, 3H, J=8.4 Hz); 8.36 (s, 1H); 8.46 (d, 1H, J=8.4 Hz); 9.19 (s, 1H); 11.42 (s, 1H); MS(FD): 397.1.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:2]1.F[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:3]1[CH:4]=[CH:5][N:1]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[CH:2]=1
Reactant: c1ccc(-c2cc[nH]c2)nc1
Reactant: N#Cc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(-n2ccc(-c3ccccn3)c2)c1
Temperature: 25 °C

Procedure:
2-(1H-Pyrrol-3-yl)pyridine (0.144 g, 11.0 mmol), 3-fluorobenzonitrile (1.21 g, 10 mmol), and potassium carbonate (0.0.276 g, 2 mmol) were heated at 145° C. in DMF (0.5 mL) for 14 h. After this time, the reaction mixture was cooled to rt and quenched with H2O (30 mL). The mixture was extracted with EtOAc (3×25 mL) and the combined organic extracts washed with brine. The organic phase was dried over Na2SO4, concentrated in vacuo and the residue was chromatographed on silica gel eluting with EtOAc:hexane (2:3) to afford a white solid which was recrystallized from dichloromethane-hexane to give 3-(3-pyridin-2-yl-1H-pyrrol-1-yl)benzonitrile as white crystals. 1H NMR (CD3Cl, 300 MHz) δ 8.59 (ddd, 1H), 7.78˜7.71 (m, 3H), 7.68 (dd, 1H), 7.62˜7.53 (m, 3H), 7.17˜7.11 (m, 2H), 6.89 (dd, 1H). MS (ES) 246.1 (M++H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:18]([F:19])=[C:17]2[C:9]([C:10]3[CH:11]=[CH:12][C:13](B(O)O)=[C:14]([F:20])[C:15]=3[CH2:16]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[OH:24]O>COC(C)(C)C>[CH2:1]([O:5][C:6]1[C:18]([F:19])=[C:17]2[C:9]([C:10]3[CH:11]=[CH:12][C:13]([OH:24])=[C:14]([F:20])[C:15]=3[CH2:16]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OO
Reactant: CCCCOc1ccc2c(c1F)Cc1c-2ccc(B(O)O)c1F
Solvent: COC(C)(C)C
Product: CCCCOc1ccc2c(c1F)Cc1c-2ccc(O)c1F

Procedure:
The oxidation of 24 mmol of 7-butoxy-1,8-difluorofluorene-2-boronic acid with 22 ml of hydrogen peroxide (35 percent) in 60 ml of tert-butyl methyl ether is effected in a similar manner to the procedure described in Example 1. 7-Butoxy-1,8-difluorofluoren-2-ol is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15]O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:50].[Cl-].[NH4+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15][Br:50])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(=O)OCc1ccc(Cl)cc1N([C@H](C)CCCO)S(=O)(=O)c1ccc(Cl)cc1
Reactant: BrC(Br)(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(=O)OCc1ccc(Cl)cc1N([C@H](C)CCCBr)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
To a solution of 4-chloro-N-[5-chloro-2-(acetoxymethyl)phenyl]-N-[(R)-1-methyl-4-hydroxybutyl]benzenesulfonamide (500 mg, 1.09 mmol) in acetonitrile (2 mL) was added triphenylphosphine (571 mg, 2.18 mmol) and carbon tetrabromide (720 mg, 2.18 mmol) at 0° C. The resulting mixture was allowed to stir at 22° C. for 12 h followed by the addition of 25 mL of sat. ammonium chloride. The product was extracted with ether (2×25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:4 ethyl acetate:hexanes) of the concentrate afforded 479 mg of 4-chloro-N-[5-chloro-2-(acetoxymethyl)phenyl]-N-[(R)-1-methyl-4-bromobutyl]benzenesulfonamide as a colorless oil in 84% yield.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.[F:15][C:16]([F:37])([F:36])[CH2:17][N:18]1[C:23](=[O:24])[C:22](Cl)=[C:21]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)[CH:20]=[N:19]1.N>C1COCC1>[F:37][C:16]([F:15])([F:36])[CH2:17][N:18]1[C:23](=[O:24])[C:22]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:21]([C:26]2[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=2)[CH:20]=[N:19]1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(CC(F)(F)F)c(=O)c2Cl)cc1
Agent: N
Solvent: C1CCOC1
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(-c2cnn(CC(F)(F)F)c(=O)c2Cc2ccccc2)cc1
Temperature: 25 °C

Procedure:
The title compound was prepared by adding 1.0 M benzylmagnesium chloride in ether (0.53 mL, 0.53 mmol) to a THF (20 mL) solution of 2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (150 mg, 0.41 mmol), prepared according to the method of Example 193E, at 0° C., then allowing the mixture to warm to room temperature over 2 hours. After an aqueous work-up, the crude material was purified by column chromatography (silica gel, 65:35 hexanes/ethyl acetate) and crystallized from ethyl acetate/hexanes to provide white, crystalline product (yield: 74 mg, 43%). mp 112-114° C. 1H NMR (300 MHz, CDCl3) δ 3.12 (s, 3H), 3.94 (s, 2H), 4.85 (q, J=12 Hz, 2H), 6.99 (dd, J=7.5 Hz, 3 Hz, 2H), 7.2 (m, 3H), 7.48 (d, J=9 Hz, 2H), 7.72 (s, 1H), 8.06 (d, J=9 Hz, 2H).: MS (DCI/NH3) m/z 423 (M+H)+. Anal. calc. for C20H17F3N2O3S: C, 56.86; H, 4.05; N, 6.63. Found: C, 56.60; H, 4.13; N, 6.57.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)#[CH:2].C([Li])CCC.CC(C)([O-])C.[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>O.C(OCC)C.O1CCCC1.CCCCCC>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])#[CH:2]
Reactant: CCCCCCCCCCBr
Reactant: C#Cc1cccc2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: C#Cc1c(CCCCCCCCCC)ccc2ccccc12
Temperature: -80 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
To 25 mL of a tetrahydrofuran solution of 3.05 g of ethynylnaphthalene was added 27.5 mL of a 1.6 mol/L hexane solution of n-butyl lithium at −50° C. under a nitrogen atmosphere, and the mixture was cooled to −80° C., and then 15 mL of a tetrahydrofuran solution of 2.25 g of potassium tert-butoxide was added thereto. After stirring at −80° C. for 1 hour, the temperature was raised up to 5° C. At −70° C., 4.42 g of bromodecane was dropped to the resulting solution, and stirred at 20° C. for 2 hours. After addition of 150 mL of diethyl ether at 0° C., 50 mL of water was dropped to the resulting solution to extract the generated compound. The diethyl ether layer was washed with 50 mL of distilled water for 3 times, dried over anhydrous magnesium sulfate for 1 hour, followed by filtration, and the solvent was removed by evaporation. The resulting product was purified on a column using hexane as a developing solvent, thereby 2.1 g of 1-ethynyl-2-n-decylnaphthalene was obtained. The obtained 1-ethynyl-2-n-decylnaphthalene was analyzed by 1H-NMR (270 MHz, CDCl3), and the NMR spectra showed peak at δ 8.3 (1H), 7.8 (2H), 7.5 (3H), 3.6 (1H), 3.0 (2H) 1.7 (2H), 1.3 (16H), 0.9 (3H).
Reaction SMILES: [F:1][CH:2]([F:37])[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][N:23]([S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>O1CCOCC1>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)(=[O:28])=[O:27])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: C=CS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Reactant: C1CCNC1
Solvent: C1COCCO1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCN3CCCC3)CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.5 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (Example 3) (150 mg, 0.280 mmol) and pyrrolidine (0.23 mL, 2.80 mmol) in 1,4-dioxane (20 mL) was stirred at room temperature for 16 hrs and then refluxed for 3 hrs. The solvent was removed under vacuum, the residue was diluted with water and the resulting precipitate was dissolved in CH2Cl2. The organic layer was separated and dried (Na2SO4), and solvent was removed under vacuum. Chromatography on silica eluting with CH2Cl2/MeOH (98:2), followed by recrystallization from CH2Cl2/hexanes gave 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(1-pyrrolidinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (137 mg, 81%): mp 186-188° C.; 1H NMR (CDCl3) δ7.86 (dd, J=8.4, 0.6 Hz, 1H), 7.44 (t, JHF=53.5 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.6 Hz, 1H), 4.05 (s, 3H), 3.99 (br s, 4H), 3.88 (br s, 4H), 3.79 (m, 4H), 3.39 (t, J=5.0 Hz, 4H), 3.16 (m, 2H), 2.93 (m, 2H), 2.53 (m, 4H), 1.76 (m, 4H); Anal. Calcd. for C26H35F2N9O4S: C, 51.4; H, 5.8; N, 20.7. Found: C, 51.3; H, 5.9; N, 20.5%.
Reaction SMILES: [CH:1]1([N:4](CC2C=CC(OC)=CC=2)[C:5]2[C:10]3=[N:11][CH:12]=[C:13]([C:14]#[N:15])[N:9]3[N:8]=[C:7](S(C)(=O)=O)[N:6]=2)[CH2:3][CH2:2]1.[NH2:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([N:39]2[CH2:44][CH2:43][O:42][CH:41]([C:45]([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)=[O:46])[CH2:40]2)[C:37]=1[Cl:38])[C:33]#[N:34].C([O-])([O-])=O.[Cs+].[Cs+].C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Cl:38][C:37]1[C:36]([N:39]2[CH2:44][CH2:43][O:42][CH:41]([C:45]([N:47]3[CH2:48][CH2:49][O:50][CH2:51][CH2:52]3)=[O:46])[CH2:40]2)=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=1[NH:29][C:7]1[N:6]=[C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)[C:10]2=[N:11][CH:12]=[C:13]([C:14]#[N:15])[N:9]2[N:8]=1
Reactant: N#Cc1cc(N)c(Cl)c(N2CCOC(C(=O)N3CCOCC3)C2)c1
Reactant: COc1ccc(CN(c2nc(S(C)(=O)=O)nn3c(C#N)cnc23)C2CC2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2CCOC(C(=O)N3CCOCC3)C2)c1
Temperature: 50 °C

Procedure:
A mixture of 4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (38.6 mg, 0.097 mmol), 3-amino-4-chloro-5-(2-(morpholine-4-carbonyl)morpholino)benzonitrile (34 mg, 0.097 mmol) and Cs2CO3 (63.2 mg, 0.194 mmol) in DMF (692 μl) up was heated at 50° C. for 4 h. After cooling to rt ON, the reaction mixture was transferred to a separatory funnel containing ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (3×). The combined organics were washed with 10% lithium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Material carried forward as is.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].NC1C=CC2CCCC=2C=1C(OC)=O.N1C=CC=CC=1.Cl[C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37].Cl>C(Cl)Cl>[CH:39]([O:38][C:36]([NH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12])=[O:37])([CH3:41])[CH3:40]
Reactant: COC(=O)c1cc2c(cc1N)CCC2
Reactant: CC(C)OC(=O)Cl
Agent: COC(=O)c1c(N)ccc2c1CCC2
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc2c(cc1NC(=O)OC(C)C)CCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of a mixture of methyl 6-aminoindane-5-carboxylate and methyl 5-aminoindane-4-carboxylate (760 mg, 3.98 mmol), and pyridine (805 uL, 9.95 mmol) in CH2Cl2 (8 mL) at 0° C. under N2 was added isopropyl chloroformate (1 M in toluene) (3.98 mL, 3.98 mmol). The resulting mixture was stirred at room temperature for 16 h. 1M HCl was added to the reaction mixture and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si, hexanes/EtOAc) to afford methyl 6-[(isopropoxycarbonyl)amino]indane-5-carboxylate. LCMS calc.=300.1; found=299.9 (M+Na)+. 1H NMR (500 MHz, CDCl3) δ 10.43 (s, 1H); 8.34 (s, 1H); 7.86 (s, 1H); 5.06-5.00 (m, 1H); 3.92 (s, 3H); 2.96 (t, J=7.5 Hz, 2H); 2.88 (t, J=7.4 Hz, 2H); 2.13-2.07 (m, 2H); 1.33 (d, J=6.2 Hz, 6H). Methyl 5-[(isopropoxycarbonyl)amino]indane-4-carboxylate was isolated as a by-product. LCMS calc.=300.1; found=299.9 (M+Na)+. 1H NMR (500 MHz, CDCl3) a 10.07 (s, 1H); 8.21 (d, J=8.4 Hz, 1H); 7.36 (d, J=8.4 Hz, 1H); 5.06-5.00 (m, 1H); 3.93 (s, 3H); 3.19 (t, J=7.5 Hz, 2H); 2.89 (t, J=7.5 Hz, 2H); 2.08-2.02 (m, 2H); 1.32 (d, J=6.2 Hz, 6H).
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.[H-].[Na+].[Cl:11][C:12]1[CH:13]=[C:14]([CH2:19][C:20]#[N:21])[CH:15]=[CH:16][C:17]=1[Cl:18].Cl>C1(C)C=CC=CC=1.O>[C:20]([CH:19]([C:14]1[CH:15]=[CH:16][C:17]([Cl:18])=[C:12]([Cl:11])[CH:13]=1)[C:1]([O:5][CH2:6][CH3:7])=[O:8])#[N:21]
Reactant: CCOC(=O)OCC
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(C#N)c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
To a solution of diethyl carbonate (4.1 mL, 33.88 mmol) in toluene (150 mL) at r.t, sodium hydride (1.43 g, 60% in mineral oil, 35.75 mmol) and 3,4-dichlorophenyl acetonitrile (6.34 g, 34.09 mmol) were added. The content was stirred at 80° C. overnight. After cooling to r.t, HCl was added (1 N in H2O, 100 mL). The content was extracted with ethyl acetate (3×). The combined organic layer was washed with water, dried (Na2SO4), filtered and concentrated. The residue was purified by flash column chromatography with hexane/ethyl acetate (6/1) to give 7.42 g product (85% yield) as brown oil. 1H NMR (400 MHz, CDCl3) δ[ppm]: 7.60 (1H, broad s), 7.54 (1H, d, J=8.3 Hz), 7.35 (1H, broad d, J=8.3 Hz), 4.72 (1H, s), 4.29 (2H, q, J=14.2 Hz, 7.0 Hz), 1.28 (3H, t, J=6.7 Hz). LRMS calculated for C11H9Cl2NO2 M+ 257. found 257.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]#[C:12][CH2:13][NH:14][C:15](=[O:22])[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.[NH4+].[Cl-]>[Fe]>[NH2:27][C:25]1[CH:24]=[CH:23][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[C:11]#[C:12][CH2:13][NH:14][C:15](=[O:22])[CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:2]([F:1])[CH:26]=1
Reactant: O=C(CN1CCCC1)NCC#Cc1cnccc1Oc1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: Nc1ccc(Oc2ccncc2C#CCNC(=O)CN2CCCC2)c(F)c1

Procedure:
The title compound was prepared by the reduction of N-(3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-ynyl)-2-(pyrrolidin-1-yl)acetamide (35 mg, 0.088 mmol) in the manner similar to that of Step E of Example 35 using Fe powder (67 mg, 1.21 mmol) and NH4Cl (128 mg, 2.42 mmol). The product was used in subsequent reactions without any purification. Yellow oil (30 mg, 93%). MS(ESI+): m/z 319.24 (M+H)+.