Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[N:3]=1.[CH3:13][C:14]1(C)[C:18](C)(C)OB(C(C)=C)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(N(C)C)=O>C(OCC)(=O)C.[Cl-].[Na+].O.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.O>[CH3:9][O:8][C:7]1[C:2]([C:14]([CH3:18])=[CH2:13])=[N:3][C:4]([N+:10]([O-:12])=[O:11])=[CH:5][CH:6]=1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc([N+](=O)[O-])nc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(C)c1nc([N+](=O)[O-])ccc1OC
Temperature: 150 °C
Yield: 65.8 %

Procedure:
In a microwave vial was added a mixture of 2-bromo-3-methoxy-6-nitropyridine (1.5 g, 6.44 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.41 g, 8.37 mmol), tetrakis(triphenylphosphine)palladium (0) (744 mg, 644 μmol), potassium phosphate tribasic (2.73 g, 12.9 mmol), DMA (16.1 mL) and water (5.36 mL). The vial was sealed and heated in the microwave for 20 min at 150° C., then cooled and diluted with ethyl acetate and brine. The organic phase was separated and washed with brine (3×), then concentrated in vacuo and purified by chromatography (silica, 5 to 35% ethyl acetate in hexanes) to give 3-methoxy-6-nitro-2-(prop-1-en-2-yl)pyridine (824 mg, 4.24 mmol, 66%) as a brown solid. MS (EI/CI) m/z: 194.8 [M+H].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]=[CH:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[CH:11][CH:12]=1)[CH3:2].[Bi](Cl)(Cl)Cl.[BH4-].[Na+].Cl>C(O)C.ClCCl>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(-c2ccccc2F)nc1
Agent: Cl
Agent: Cl[Bi](Cl)Cl
Agent: [BH4-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCc1ccc(-c2ccccc2F)nc1
Temperature: 7.5 °C
Reaction time: 1 h

Procedure:
Under nitrogen, 16.26 g (0.06 mol) of 3-[6-(2-fluoro-phenyl) -pyridin-3-yl]-acrylic acid ethyl ester were dissolved in 500 ml of 95% ethanol and cooled to 5 to 10° C. After addition of 9.42 g (0.03 mol) of bismuth trichloride, a total of 9.12 g (0.24 mol) of sodium borohydride was added in portions over 45 min. The resulting mixture was stirred at 15 to 20° C. for 1 h, then cooled to 10° C. and poured onto ice/water. The pH was adjusted to 7 with 2 N hydrochloric acid, dichloromethane was added, and the precipitated salts were separated by filtration. The organic phase of the mother liquor was separated, and the aqueous phase extracted once with dichloromethane. The combined organic phases were washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness. The remaining solid was purified by chromatography (silica gel, n-heptane/ethyl acetate 3:1). Yield: 11.5 g.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1>C(OCC)C>[Br:1][CH2:11][C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=1)=[O:12]
Reactant: CC(=O)c1cccc(Cl)c1
Reactant: BrBr
Solvent: CCOCC
Product: O=C(CBr)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Bromine (5.17 g, 32.3 mmol) was slowly added dropwise to a solution of 1-(3-chlorophenyl)ethanone (5.00 g, 32.3 mmol) in diethyl ether (100 ml), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was distilled off under reduced pressure, and the desired product was obtained quantitatively as an oil.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]2=[O:16])[CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:17][C:18]1[CH:19]=[C:20]([N:25]=[C:26]=[O:27])[CH:21]=[CH:22][C:23]=1[Cl:24]>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:25][C:26]([N:13]2[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][N:3]3[CH2:7][CH2:6][CH2:5][CH2:4]3)[C:11](=[O:16])[CH2:12]2)=[O:27])[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: O=C1CNCCN1CCN1CCCC1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: O=C1CN(C(=O)Nc2ccc(Cl)c(Cl)c2)CCN1CCN1CCCC1
Yield: 72 %

Procedure:
In analogy to the procedure described in Example 1, 1-(2-pyrrolidin-1-yl-ethyl)-piperazin-2-one-dihydrochloride (intermediate 12) and 3,4-dichlorophenyl isocyanate gave the title compound in 72% yield as an off-white powder. MS: 385.5 (MH+, 2Cl).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([C:9](=[O:20])[CH2:10][C:11]2[NH:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[N:12]=2)[CH:6]=[CH:7][CH:8]=1.C[O-].[Na+].[C:24](OC)(=[O:27])[C:25]#[CH:26]>>[CH3:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:9]([C:10]1[CH:26]=[CH:25][C:24](=[O:27])[N:15]2[C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[NH:12][C:11]=12)=[O:20]
Reactant: Cc1cccc(C(=O)Cc2nc3c([nH]2)CCCC3)c1
Reactant: C#CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1cccc(C(=O)c2ccc(=O)n3c4c([nH]c23)CCCC4)c1

Procedure:
The compound is prepared as described in example 25 with 200 mg (0.63 mmol) of 1-(3-Methylphenyl)-2(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone hydrochloride (example XXXXVIII, 68.4 mg (1.27 mmol) of sodium methylate and 53.2 mg (0.63 mmol) methyl propiolate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].[C:30](Cl)(=[O:34])[CH:31]([CH3:33])[CH3:32]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN2CCOC2=O)c1
Reactant: CC(C)C(=O)Cl
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)C(C)C)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 100, Step 1, using the following starting materials: {3-[4-amino-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and isobutyryl chloride.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[K+].[CH:16]([N:19]1[C:23]([C:24]2[S:25][C:26]3[CH2:27][CH2:28][O:29][C:30]4[CH:37]=[C:36](B5OC(C)(C)C(C)(C)O5)[CH:35]=[CH:34][C:31]=4[C:32]=3[N:33]=2)=[N:22][C:21]([CH3:47])=[N:20]1)([CH3:18])[CH3:17].[NH4+].[Cl-]>C(#N)C.O.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.C(Cl)Cl>[CH:16]([N:19]1[C:23]([C:24]2[S:25][C:26]3[CH2:27][CH2:28][O:29][C:30]4[CH:37]=[C:36]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=5[S:7]([NH2:10])(=[O:9])=[O:8])[CH:35]=[CH:34][C:31]=4[C:32]=3[N:33]=2)=[N:22][C:21]([CH3:47])=[N:20]1)([CH3:18])[CH3:17]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(B4OC(C)(C)C(C)(C)O4)ccc2-3)n(C(C)C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(-c4ccccc4S(N)(=O)=O)ccc2-3)n(C(C)C)n1
Temperature: 140 °C

Procedure:
To a microwave vial was added benzenesulfonamide (0.0992 g, 0.420 mmol) and potassium acetate (0.124 g, 0.00126 mol) in acetonitrile (2.0 mL) and water (2.0 mL). The mixture was thoroughly purged with N2. 2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.200 g, 0.442 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.0485 g, 0.0420 mmol) were added and the vial was sealed immediately. The reaction was heated to 140° C. for 20 minutes in the microwave. Methylene chloride and saturated NH4Cl were added and the mixture was extracted 3 times with methylene chloride. The organic layers were combined, dried with MgSO4 and concentrated. The crude was purified by reverse-phase HPLC to give 545 as a white solid. MS(ESI+) 482.1. 1H NMR (400 MHz, DMSO) δ 8.35 (d, J=8.2 Hz, 1H), 8.05 (dd, J=7.7, 1.3 Hz, 1H), 7.67-7.55 (m, 2H), 7.37 (dd, J=7.4, 1.4 Hz, 1H), 7.23 (m, 3H), 7.10 (d, J=1.7 Hz, 1H), 5.79 (hept, J=6.6 Hz, 1H), 4.41 (t, J=4.9 Hz, 2H), 3.46 (t, J=4.9 Hz, 2H), 2.33 (s, 3H), 1.54 (d, J=6.6 Hz, 6H)
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][N:16]=[C:15]([Cl:24])[N:14]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[Li+].[OH-].Cl>C1COCC1>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13]3[C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=[C:15]([Cl:24])[N:14]=3)=[CH:10][CH:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CCOC(=O)c1cnc(Cl)nc1Nc1ccc(-n2cncn2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Cl)nc1Nc1ccc(-n2cncn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Ethyl 4-(4-(1H-1,2,4-triazol-1-yl)phenylamino)-2-chloropyrimidine-5-carboxylate (ii) (870 mg, 2.523 mmol), in THF (12 mL), was added 1M LiOH (3.30 mL, 3.30 mmol, 1.30 equiv), and the mixture was stirred at room temperature for 3 h. Then THF was rotavopped off, and the aqueous mixture was acidified with 2N HCl to pH 2. The precipitated solid product was collected by filtration, rinsed with water, and air dried; yield 712 mg (89%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Cl:10][C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15](Cl)[CH:14]=[C:13]([CH3:21])[N:12]=1.[NH4+].[Cl-]>C1COCC1>[Cl:10][C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:14]=[C:13]([CH3:21])[N:12]=1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: Nc1ccccn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2ccccn2)c([N+](=O)[O-])c(Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.2 %

Procedure:
To a solution of 2-aminopyridine (361 mg, 3.72 mmol) in THF (30 mL) was added 60% sodium hydride (164 mg, 4.09 mmol). After stirring for 2 h at rt, 2,4-dichloro-6-methyl-3-nitropyridine (864 mg, 4.09 mmol) was added. After stirring 3.5 h additional at rt, sat. NH4Cl solution (30 mL) was added. The organic layer was separated and the water layer was extracted with CH2Cl2 two times. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated. Chromatography on silica gel (0-30% ethyl acetatehexanes) provided the desired product (366 mg, 37%). MS (ESI) mass calcd. C11H9ClN4O2, 264.04. m/z found, 265.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.51 (br s, 1H), 8.39 (ddd, J=5.0, 1.9, 0.7, 1H), 8.32 (s, 1H), 7.71 (ddd, J=8.2, 7.4, 1.9, 1H), 7.07 (ddd, J=7.4, 5.0, 0.9, 1H), 6.93 (dt, J=8.2, 0.8, 1H), 2.53 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(F)c(Cl)c1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(F)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
2,3-dichloro-4-fluorobenzoic acid (I32) (5.76 g, 27.6 mmol) was suspended in dichloromethane (DCM) (150 mL) at 0° C. and treated with oxalyl chloride (2.89 mL, 33.1 mmol). The mixture was stirred at 0° C. for 10 minutes before 5 drops of DMF were added. The mixture was stirred to room temperature over 4 h. Solvents were removed in vacuo and the residue was azeotroped with toluene (3×100 mL). The residue was used directly in subsequent steps without further purification, assuming 100% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].N1CC[CH2:23][CH2:22]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:19][CH2:23][CH2:22][CH2:20]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: C1CCNC1
Reactant: COc1cc(N2CCC(N(C)C)CC2)ccc1[N+](=O)[O-]
Product: COc1cc(N2CCC(N3CCCC3)CC2)ccc1[N+](=O)[O-]

Procedure:
1-(3-Methoxy-4-nitro-phenyl)-4-pyrrolidin-1-yl-piperidine was prepared in an analogous fashion to [1-(3-Methoxy-4-nitro-phenyl)-piperidine-4-yl]dimethyl-amine of Example 475a replacing Dimethylamine with Pyrrolidine. The crude material was used after workup without further manipulation (350 mg, 96%).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([OH:16])[C:9]([C:13]([OH:15])=[O:14])=[CH:10]2)=[CH:5][CH:4]=1)=O.C(O)(=O)C.[CH3:21][CH:22]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)[CH3:23].C([BH3-])#N.[Na+].Cl>CO>[OH:16][C:8]1[C:9]([C:13]([OH:15])=[O:14])=[CH:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[C:3]([CH2:1][NH:28][C:27]1[CH:29]=[CH:30][C:24]([CH:22]([CH3:23])[CH3:21])=[CH:25][CH:26]=1)[CH:12]=2
Reactant: O=Cc1ccc2cc(O)c(C(=O)O)cc2c1
Reactant: CC(C)c1ccc(N)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)c1ccc(NCc2ccc3cc(O)c(C(=O)O)cc3c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
7-Formyl-3-hydroxynaphthalene-2-carboxylic acid (40 mg, 0.19 mmol) (example 342) was suspended in methanol (300 μL). Acetic acid (16 μL, 17 mg, 0.28 mmol) and 4-(2-propyl)aniline (40 μL, 40 mg, 0.30 mmol) were added consecutively, and the resulting mixture was stirred vigorously at room temperature for 2 hours. Sodium cyanoborohydride (1.0 M in tetrahydrofuran, 300 μL, 0.3 mmol) was added, and the stirring was continued for another 17 hours. The reaction mixture was poured into 6 N hydrochloric acid (aq.) (6 mL), and the precipitate was filtered off and rinsed with water (3×2 mL) to yield the title compound (40 mg) as its hydrochloride salt. No further purification was necessary.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([C@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:35])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([CH3:34])[CH:28]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:36](I)[CH:37]=[CH2:38].[NH4+].[Cl-]>C1COCC1>[CH2:11]([C@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:35])[C@H:25]([O:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([CH3:34])[CH:28]=1)[CH2:38][CH:37]=[CH2:36])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc(OCC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)ccc1F
Reactant: C=CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@H](Oc1ccc(F)c(C)c1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
To the solution of lithium bis(trimethylsilyl)amide (5.2 mL, 5.2 mmol, 1M in THF) in anhydrous 30 mL THF at −70° C. was slowly added over 15 minutes (S)-4-Benzyl-3-(2-(4-fluoro-3-methylphenoxy)acetyl)oxazolidin-2-one (1.5 g, 4.3 mmol) as a solution in 8.0 mL THF. The reaction mixture was stirred for 30 min at −70° C. and then was slowly added a pre-cooled solution of allyl iodide (2.2 g, 13 mmol) in 8 mL of THF. The resulting mixture was stirred at −70° C. for 1 h and the temperature was slowly raised over a period of 2 h. The mixture was poured into 60 mL saturated NH4Cl and extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine (2×30 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the product isolated by Flash column chromatography eluting with 0% to 50% ethyl acetate/hexane to give 521 mg of the title compound as a light yellow oil.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH:14]=[C:13]([C:27]([F:30])([F:29])[F:28])[N:12]=2)[CH:10]=1)CCC.[C:39]([NH:43][S:44]([C:47]1[S:48][C:49](Br)=[CH:50][CH:51]=1)(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40].CCCCCCC>C1(C)C=CC=CC=1.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>[C:39]([NH:43][S:44]([C:47]1[S:48][C:49]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=4)[CH:14]=[C:13]([C:27]([F:28])([F:29])[F:30])[N:12]=3)[CH:10]=2)=[CH:50][CH:51]=1)(=[O:45])=[O:46])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(-c3ccc(C(F)(F)F)cc3)cc(C(F)(F)F)n2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Yield: 57.4 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridine (Example G.12) (0.570 g, 0.88 mmol), commercially available 5-bromo-thiophene-2-sulfonic acid tert-butylamide (0.295 g, 0.99 mmol), tetrakis(triphenylphosphine)palladium (0.061 g, 0.046 mmol) in toluene (6 mL) was heated under reflux conditions for 16 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (290 mg, 57%). MS (ISP) 575.2 [(M+H)+]; mp>250° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10](=[O:13])CBr)[C:4]=2[O:3][CH2:2]1.ClC1C=C(Cl)C=CC=1C=O>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]=[O:13])[C:4]=2[O:3][CH2:2]1
Reactant: O=C(CBr)c1cccc2c1OCO2
Agent: O=Cc1ccc(Cl)cc1Cl
Product: O=Cc1cccc2c1OCO2

Procedure:
This compound was prepared using 1-Benzo[1,3]dioxol-4-yl-2-bromo-ethanone prepared in method I-7 (0.15 g, 10.62 mmol), in the manner described for 3-amino-5,6,7,8-tetrahydro-naphtho[2,3-b]furan-2-yl)(2,4-dichloro-phenyl)-methanone (Method III-1):, affording 0.36 g (21%) of 3-Amino-5,6,7,8-tetrahydro-naphtho-[2,3-b]furan-2-yl)benzo[1,3]dioxol-4-yl-methanone as a yellow solid. 1H-NMR (MeOH-d4) δ 7.40 (s, 1H), 7.31 (dd, J=8 Hz, 1 Hz), 6.97 (dd, J=7 Hz, 1 Hz, 1H), 6.82 (s, 1H), 6.19 (s, 2H), 2.68–2.60 (m, 4H), 1.68–1.62 (m, 4H); MS LC-MS (MH+=336.2), RT=3.86 min.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH:4]=O.[Cl:7][C:8]1[CH:49]=[CH:48][C:11]([CH2:12][NH:13][CH2:14][C:15]([C@:17]23[CH2:43][C:42](=[O:44])[C:41]([CH:45]([CH3:47])[CH3:46])=[C:18]2[C@@H:19]2[C@@:32]([CH3:35])([CH2:33][CH2:34]3)[C@@:31]3([CH3:36])[C@@H:22]([C@:23]4([CH3:40])[C@@H:28]([CH2:29][CH2:30]3)[C:27]([CH3:38])([CH3:37])[C@@H:26]([OH:39])[CH2:25][CH2:24]4)[CH2:21][CH2:20]2)=[O:16])=[CH:10][CH:9]=1.CCN(CC)CC.C([BH3-])#N.[Na+]>CO.ClCCCl.O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][N:13]([CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[CH2:14][C:15]([C@:17]23[CH2:43][C:42](=[O:44])[C:41]([CH:45]([CH3:46])[CH3:47])=[C:18]2[C@@H:19]2[C@@:32]([CH3:35])([CH2:33][CH2:34]3)[C@@:31]3([CH3:36])[C@@H:22]([C@:23]4([CH3:40])[C@@H:28]([CH2:29][CH2:30]3)[C:27]([CH3:37])([CH3:38])[C@@H:26]([OH:39])[CH2:25][CH2:24]4)[CH2:21][CH2:20]2)=[O:16])=[CH:48][CH:49]=1
Reactant: CN(C)CC=O
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(C(=O)CNCc2ccc(Cl)cc2)CC1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(C(=O)CN(CCN(C)C)Cc2ccc(Cl)cc2)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 2-(dimethylamino)acetaldehyde (4.79 g, 38.8 mmol) in methanol (50 ml) and 1,2-dichloroethane (DCE) (25 ml) was added (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-(4-chlorobenzylamino)acetyl)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3a,4,5,5a,6,7,7a,8,9,10,11,11a,11b,12,13,13a-hexadecahydro-3H-cyclopenta[a]chrysen-2(5bH)-one (15) (5 g, 7.75 mmol) at 000° C. The pH was adjusted to 7 with Et3N. The reaction mixture was stirred at rt for 1 h. Sodium cyanoborohydride (0.487 g, 7.75 mmol) was added and the mixture was stirred overnight. The reaction was diluted with water (40 ml), and extracted with DCM (60 ml×3). The combined organic layer was washed with brine (20 ml), dried over sodium sulfate and filtered to afford crude product (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-chlorobenzyl)(2-(dimethylamino)ethyl)amino)acetyl)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3a,4,5,5a,6,7,7a,8,9,10,11,11a,11b,12,13,13a-hexadecahydro-3H-cyclopenta[a]chrysen-2(5bH)-one (52) (5 g, 5.89 mmol, 76% yield) as a light yellow solid, which was used in the next step. LC/MS: m/z calculated 678.5. found 679.3 (M+1)+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.C(N(CC)CC)C.Cl[CH2:33][CH2:34][S:35](Cl)(=[O:37])=[O:36]>C1COCC1.C(OCC)(=O)C>[Cl:17][C:12]1[CH:11]=[C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][C@H:3]2[CH2:2][NH:1][S:35]([CH:34]=[CH2:33])(=[O:37])=[O:36])[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN)C1
Reactant: O=S(=O)(Cl)CCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (633 mg) in THF (10 mL) were added triethylamine (0.705 mL) and 2-chloroethanesulfonyl chloride (0.213 mL) at 0° C., and the mixture was gradually warmed from 0° C. to room temperature, and stirred overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (0.965 g).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][N:29]([C:32](=[O:35])[CH2:33]Cl)[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][N:29]([C:32](=[O:35])[CH2:33][N:40]5[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]5)[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: Nc1ncnn2c(C3CCN(C(=O)CCl)C3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Product: CN1CCN(CC(=O)N2CCC(c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)C2)CC1
Yield: 45.9 %

Procedure:
5-(2-benzyl-2H-indazol-6-yl)-7-[1-(chloroacetyl)pyrrolidin-3-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.206 mmol) was reacted with 4-methylpiperazine (46 uL, 0.412 mmol) using the procedure of Example 132 to yield 52 mg (46%) of title compound. 1H NMR (300 MHz, methanol-d4) δ 8.04 (s, 1 H), 7.92 (s, 1 H), 7.78 (m, 3 H), 7.41 (m, 4 H), 7.22 (d, 1 H), 6.63 (d, 1 H), 5.46 (s, 2 H), 4.15-3.95 (m, 2 H), 3.90-3.40 (m, 4 H), 3.12 (m, 2 H), 2.60-2.10 (d, 13 H); ES-MS m/z 550.2 [M+H]+, HPLC RT (min) 2.10.