Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:13]=2[F:22])[N:3]=1.[CH3:23]CN(C(C)C)C(C)C.CN(C=O)C.C(Cl)(=O)C(Cl)=O>ClCCl.CO>[CH3:23][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Si:18]([CH3:19])([CH3:21])[CH3:20])=[CH:14][C:13]=1[F:22]
Reactant: CCN(C(C)C)C(C)C
Reactant: C[Si](C)(C)c1ccc(Nc2nc(Cl)ccc2C(=O)O)c(F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)nc1Nc1ccc([Si](C)(C)C)cc1F
Reaction time: 0.17 h

Procedure:
To a suspension of 6-chloro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-nicotinic acid (33.7 g, 99.5 mmol) in dichloromethane (500 mL) at 0° C. was added DIPEA (17.1 mL, 99.5 mmol). The reaction mixture was stirred for 10 minutes, then DMF (2 mL) and oxalyl chloride (8.7 mL, 99.5 mmol) were added dropwise (CAUTION: EFFERVESCENCE). The reaction mixture was stirred at room temperature for 2 hours and then added dropwise to a solution of DIPEA (17.1 mL, 99.5 mmol) in MeOH (500 mL) at 0° C. over a 45 minutes period. The reaction mixture was stirred at room temperature for 18 hours before being concentrated in vacuo. The resultant residue was dissolved in ethyl acetate and washed with a saturated aqueous solution of sodium hydrogen carbonate, followed by water, then brine, dried (Na2SO4), filtered and evaporated in vacuo to afford the title compound as a brown foam which was used without purification into the next step (36.4 g). LCMS (method B) RT=5.35 min, M+H+=353.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][N:14]([CH3:21])[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:18]2[CH2:19][CH2:20][CH:15]([N:14]([CH3:21])[CH3:13])[CH2:16][CH2:17]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CN(C)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(N2CCC(N(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
A 100 ml flask was charged with 4-fluoro-2-methoxy-1-nitrobenzene (5.13 g, 30 mmol), N,N-dimethylpiperidin-4-amine (4.23 g, 33.0 mmol) and N,N-dimethylformamide (60 ml). To the mixture was added N-ethyl-N-isopropylpropan-2-amine (10.45 ml, 60.0 mmol) and the mixture was heated at 70° C. overnight under nitrogen. The reaction mixture was concentrated under high vacuum and the residue was partitioned between brine (100 ml) and methylene chloride (100 ml) and the pH adjusted to ca. 12-14 with sodium hydroxide. The layers were separated and the aqueous layer was extracted with methylene chloride (3×100 ml). The combined organics were dried over sodium sulfate, filtered and adsorbed directly on to silica gel (ca. 25 g). This was split in two portions each of which was purified on a silica gel cartridge (150 g) eluted with a 2.5, 4.5, 6% 7N methanolic ammonia in methylene chloride step gradient. The combined product fractions were concentrated to provide the title compound. MS (DCI(+)) m/e 280.2 (M+H)+.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][C:12]([CH3:15])([O-:14])[CH3:13].[K+]>C1COCC1>[C:12]([O:14][C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])([CH3:15])([CH3:13])[CH3:11]
Reactant: CC(C)(C)[O-]
Reactant: N#Cc1ccc(Br)cc1F
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)Oc1cc(Br)ccc1C#N
Reaction time: 0.67 h
Yield: 98.4 %

Procedure:
To a solution of 2-fluoro-4-bromobenzonitrile (2.0 g, 10 mmol) in 10 mL of THF, cooled to −15° C., was added a solution of potassium t-butoxide (10 mL, 10 mmol) over 7 min. The cooling bath was removed, and the reaction stirred for another 40 min. The reaction was poured into ether/10% HCl, and the ether layer was separated. The ether layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated to give 2.5 g of 2-t-butoxy-4-bromobenzonitrile.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:30])[NH:4][CH:5]=[C:6]([C:8]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:18]=[CH:17]3)([OH:13])[C:9]([F:12])([F:11])[F:10])[CH:7]=1.[H-].[Na+].I[CH3:34]>CN(C=O)C.O>[CH3:34][N:4]1[CH:5]=[C:6]([C:8]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[N:18]=[CH:17]3)([OH:13])[C:9]([F:10])([F:11])[F:12])[CH:7]=[C:2]([CH3:1])[C:3]1=[O:30]
Reactant: CI
Reactant: Cc1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cn(C)c1=O
Reaction time: 1 h
Yield: 27.7 %

Procedure:
To a solution of 3-methyl-5-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-hydroxyethyl}-1H-pyridin-2-one (0.184 mmol) in 1 mL DMF was added NaH (0.221 mmol; 60% suspension in oil) in several portions. After 1 hour, iodomethane (0.20 mmol) was added. After 1 hour, the mixture was diluted with water and the solid was collected by filtration, washed with water and dried. The residue was purified with flash silica gel chromatography using 25% hexanes in ethyl acetate. The product-rich fractions were concentrated in vacuo to provide the title compound (0.051 mmol), m.p.>200° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[N:13][C:14]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)=[N:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH3:29][C:30]([CH3:32])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH:30]([N:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[N:13][C:14]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)=[N:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1)([CH3:32])[CH3:29]
Reactant: CC(C)=O
Reactant: FC(F)(F)c1cccc(Nc2ncc3ccc(OC4CCNCC4)cc3n2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N1CCC(Oc2ccc3cnc(Nc4cccc(C(F)(F)F)c4)nc3c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 7-(piperidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)quinazolin-2-amine in DCM was added acetone (10 eq), a few drops of acetic acid and sodium triacetoxy borohydride (4 eq). The reaction mixture was stirred for 16 h at ambient temperature. The reductive amination went to completion to give 7-(1-isopropylpiperidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)quinazolin-2-amine. The mixture was then purified on prep HPLC to give 7-(1-isopropylpiperidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)quinazolin-2-amine. ES/MS m/z 431 (MH+).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][S:8]([CH3:11])(=[O:10])=[O:9].[NH2:12][C:13]([CH3:30])([CH3:29])[CH2:14][CH2:15][N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25](OC)=[O:26])=[CH:22][CH:23]=2)[CH:18]=[CH:17]1.C(O)(C(F)(F)F)=O>CS(C)=O>[NH2:12][C:13]([CH3:30])([CH3:29])[CH2:14][CH2:15][N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25](=[O:26])[CH2:7][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:22][CH:23]=2)[CH:18]=[CH:17]1
Reactant: CS(C)(=O)=O
Reactant: COC(=O)c1ccc2c(ccn2CCC(C)(C)N)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)CCn1ccc2cc(C(=O)CS(C)(=O)=O)ccc21
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Potassium tert. butoxide (741 mg, 6.62 mmol) is added in two batches to a solution of dimethylsulphone (661 mg, 7.03 mmol) in 5 ml DMSO. After 10 minutes stirring at RT a solution of methyl 1-(3-amino-3-methyl-butyl)-indole-5-carboxylate (Component IV) (520 mg, 2.00 mmol) in 2 ml DMSO is added dropwise over 10 minutes. The reaction mixture is stirred for 16 hours at 70° C., acidified with TFA while cooling with ice and chromatographed on Microsorb C18-reverse-phase [acetonitrile (0.1% TFA)/water (0.13% TFA)=10:90→100:0]. Then the residue is chromatographed again on silica gel (DCM/methanol/ammonia=90:9:1).
Reaction SMILES: [C:1]1([C@H](O)C)C=CC=CC=1.[CH3:10][O:11][CH2:12][O:13][C@H:14]1[CH2:18][CH2:17][N:16]([C@@H:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)CO)[CH2:15]1.[CH3:28][NH:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=1>>[CH3:10][O:11][CH2:12][O:13][C@H:14]1[CH2:18][CH2:17][N:16]([CH2:19][C@H:22]([N:29]([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)[CH3:28])[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:1]=2)[CH2:15]1
Reactant: COCO[C@H]1CCN([C@H](CO)c2ccccc2)C1
Reactant: C[C@@H](O)c1ccccc1
Reactant: CNc1ccc(C(=O)OC)cc1
Product: COCO[C@H]1CCN(C[C@@H](c2ccccc2)N(C)c2ccc(C(=O)OC)cc2)C1
Yield: 49 %

Procedure:
This was prepared from 2-(3S)-methoxymethoxypyrrolidin-1-yl)-1-(R)-phenylethanol and 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(S)-phenylethanol and methyl 4-methylaminobenzoate in 49% yield according to a procedure similar to that described in Example 1 (i).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:41]=[CH:40][C:9]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])=[CH:14][CH:13]=2)=[O:11])=[CH:8][CH:7]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:41]=[CH:40][C:9]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:14][CH:13]=2)=[O:11])=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCNc1ccc(C(=O)c2ccc(OCCCN)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCOc1ccc(C(=O)c2ccc(NCCOCCOCCOCCOCCC(=O)O)cc2)cc1
Reaction time: 1 h
Yield: 109.6 %

Procedure:
tert-butyl 1-((4-(4-(3-aminopropoxy)benzoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oate (3.24 g, 5.63 mmol) was dissolved in a solution of DCM:TFA (2:1, 20 ml) and stirred ca. 1 h. Upon completion, reaction was then concentrated under reduced pressure, co-evaporated with toluene, and dried on oil pump for 5 hs to yield 3.20 g of crude 1-((4-(4-(3-aminopropoxy)benzoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oic acid as yellow oil. The crude product was used without any further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH3:11])[CH3:2].[N+:12]([O-])([OH:14])=[O:13]>C(OC(=O)C)(=O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:12]([O-:14])=[O:13])=[CH:6][C:5]=1[CH2:10][CH3:11])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOc1ccccc1CC
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOc1ccc([N+](=O)[O-])cc1CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-ethoxy-2-ethyl benzene (3.5 g, Reference Example 51) in acetic anhydride (30 mL) was chilled in an ice-water bath. A solution of nitric acid (1.4 mL of 90%-30% excess) in acetic acid (25 mL) was added dropwise and the mixture was stirred overnight at ambient temperature. The reaction mixture was poured into ice water (300 mL) and the aqueous mixture was extracted with ethyl acetate (2×200 mL). The combined extracts were evaporated and the residue was chromatographed on silica gel (heptane with gradient of 5 to 10% ethyl acetate) to give 1-ethoxy-2-ethyl-4-nitrobenzene (1.4 g) as a clear liquid. LC-MS (Method E) RT=3.75 minutes, 196 (M+H)+. (i) N-(5-Chloro-4-methoxy-2-nitrophenyl)acetamide
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([CH:22]=[N:23]OCC)[CH:20]=4)[NH:15][N:14]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[NH2:27][NH:28][C:29](=O)[CH2:30][N:31]([CH3:33])[CH3:32].C[O-].[Na+]>CO>[CH3:32][N:31]([CH2:30][C:29]1[N:23]=[C:22]([C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[C:9]2[CH:8]=[C:7]([C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)=[O:6])[CH:12]=[CH:11][CH:10]=2)[NH:27][N:28]=1)[CH3:33]
Reactant: CCON=Cc1ccc2[nH]nc(-c3cccc(C(=O)NC4CC4)c3)c2c1
Reactant: CN(C)CC(=O)NN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1n[nH]c(-c2ccc3[nH]nc(-c4cccc(C(=O)NC5CC5)c4)c3c2)n1

Procedure:
The title compound was prepared according to the procedure of Example 367 C using N-cyclopropyl(3-[5-(ethoxyiminomethyl)(1H-indazol-3-yl)]phenyl)carboxamide.2HCl (377 mg, 0.89 mmol), N-amino-2-(dimethylamino) acetamide (315 mg, 2.69 mmol) and sodium methoxide (515 μL of a 25% w/w in methanol) in anhydrous methanol (5.0 mL) with a reaction time of 24 h. Purification of the residue by flash chromatography on silica gel with 50% methanol in ethyl acetate gave the desired product as a light orange solid. Further purification by preparatory TLC using 50% methanol in ethyl acetate afforded the title compound (145 mg, 40% yield) as an off-white powder. 1H NMR (DMSO-d6) δ 8.8 (br d, 1H), 8.7 (s, 1H), 8.4 (s, 1H), 8.14-8.05 (m, 2H), 7.84 (d, 1H), 7.7-7.6 (m, 2H), 3.55 (s, 2H), 2.92-2.85 (m, 1H), 2.2 (s, 6H); ES-MS (m/z) 402 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)=[O:19])=[CH:15][CH:14]=[C:13]([OH:28])[CH:12]=2)=[O:10])=[N:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>CN(C=O)C.CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([CH:14]=[CH:15][C:16]=2[NH:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)=[O:19])[O:28][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:10])=[N:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: N#Cc1ccc(C(=O)Nc2ccc(O)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(NC(=O)c2ccc(C#N)cc2)c(C(=O)Nc2ccc(Cl)cn2)c1
Reaction time: 1 h
Yield: 112.4 %

Procedure:
To a mixture of compound N-(5-chloro(2-pyridyl)){6-[(4-cyanophenyl)-carbonylamino]-3-hydroxyphenyl}carboxamide (50 mg, 0.13 mmol) and Cs2CO3 (83 mg, 0.25 mmol) in DMF (1 mL) at room temperature was added ethyl bromoacetate (15 μL, 0.13 mmol). The mixture was stirred for 1 hour before diluted with EtOAc (20 mL) and water (10 mL). The organic layer was washed with brine dried and evaporated to give 70 mg of the crude compound, which was used without farther purification. MS found for C24H19ClN4O5 (M+H)+: 479.0.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[S:25]1[CH:29]=[CH:28][C:27]2[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:26]1=2.O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[S:25]1[CH:29]=[CH:28][C:27]2[CH:30]=[C:31]([C:2]3[N:7]4[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]4[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]4[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=4)[CH:3]=3)[CH:32]=[CH:33][C:26]1=2
Reactant: OB(O)c1ccc2sccc2c1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3ccc4sccc4c3)n2n1
Temperature: 110 °C
Yield: 36.4 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 60 mg, 0.174 mmol), benzo[b]thiophen-5-ylboronic acid (40 mg, 0.226 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 13.6 mmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.58 mL of 1,4-dioxane and 0.29 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (65-65% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (28 mg, 36%). 1HNMR (DMSO-d6) δ: 11.21 (s, 1H), 8.62 (d, J=1.3 Hz, 1H), 8.26 (d, J=8.6 Hz, 1H), 8.05 (s, 1H), 7.99-8.04 (m, 3H), 7.93 (d, J=5.3 Hz, 1H), 7.67 (d, J=5.6 Hz, 1H), 7.61 (d, J=8.6 Hz, 2H), 6.41 (s, 1H), 5.20 (s, 1H), 2.41 (s, 3H), 1.46 (s, 6H); ESI-MS: m/z 443.2 (M+H)+.
Reaction SMILES: C[CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]3[C:22]([N:23]=[C:24]4[CH2:30][CH2:29]CC[CH2:26][C:25]=24)=[CH:21][CH:20]=[N:19]3)=[CH:13][CH:12]=1.ClCCC[O:35]C1C=CC(C2N3C(=CC=N3)N=C3C=2CCC3)=CC=1.O[C@H]1CCNC1>>[N:19]1[N:18]2[C:22]([N:23]=[C:24]3[C:25](=[C:17]2[C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:3]4[CH2:4][CH2:5][C@H:6]([OH:35])[CH2:2]4)=[CH:12][CH:13]=2)[CH2:26][CH2:29][CH2:30]3)=[CH:21][CH:20]=1
Reactant: CC1CCCN1CCCOc1ccc(-c2c3c(nc4ccnn24)CCCCC3)cc1
Reactant: ClCCCOc1ccc(-c2c3c(nc4ccnn24)CCC3)cc1
Agent: O[C@H]1CCNC1
Product: O[C@H]1CCN(CCCOc2ccc(-c3c4c(nc5ccnn35)CCC4)cc2)C1

Procedure:
Using the method described for the preparation of 10-{4-[3-(2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]indene, the reaction of 8-[4-(3-chloro-propoxy)-phenyl]-6,7-dihydro-5H-1,4,8a-triaza-s-indacene and 3-(S)-hydroxy-pyrrolidine provided the title compound.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].O.C([C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26])=O>O1CCCC1>[OH:3][N:2]=[C:12]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[C:14]([CH2:15][N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])[CH2:13]1
Reactant: NO
Reactant: COc1ccc(CN2C(=O)c3ccccc3C2=O)cc1C=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC1=CC=C(CN2C(=O)c3ccccc3C2=O)CC1=NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
5.2 g of hydroxylamine hydrochloride, 12.2 g of sodium acetate, and 50 ml water were added to a mixture of 20 g N-(3-formyl-4-methoxybenzyl)phthalimide and 200 ml tetrahydrofuran, and stirred at room temperature for 1 hr. It was stirred at 60° C. for 1 hr, and then evaporated. Water was added to the resulting residue, and the insoluble matters were collected by filtration. These were washed with diethyl ether to give 20 g of N-(3-hydroxyimino-4-methoxybenzyl)phthalimide.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][SH:4].[H-].[Na+].CS(O[CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)(=O)=O>CN(C=O)C.O>[F:1][C:2]([F:6])([F:5])[CH2:3][S:4][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: FC(F)(F)CS
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CSCC(F)(F)F)CC1
Reaction time: 0.25 h

Procedure:
2,2,2-Trifluoroethane-1-thiol (471 μL, 3.41 mmol) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 0.065 g, 1.636 mmol) in dry DMF (10 mL) at 0 C and the mixture was stirred for 15 min. A solution of tert-butyl 4-[(methanesulfonyloxy)methyl]piperidine-1-carboxylate (prepared in an analogous manner to Intermediate 181, 1 g, 3.41 mmol) in DMF (5 mL) was added dropwise and the mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with saturated aq. sodium bicarbonate (25 mL) then brine (25 mL), dried over magnesium sulfate and concentrated under reduced pressure to provide the title compound as a light yellow oil (1.13 g, quant.). Method B HPLC-MS: MH+ requires m/z=314 Found: m/z=258 (MH+-tBu), Rt=2.39 min (98%).
Reaction SMILES: FC(F)(F)C(O[Si](C)(C)C)=O.[NH2:12][C:13]1[N:14]=[CH:15][C:16]2[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH2:19][C:17]=2[N:18]=1.[CH:25](OCC)(OCC)OCC.[N:35]([Si](C)(C)C)=[N+:36]=[N-:37]>C(OCC)(=O)C>[N:12]1([C:13]2[N:14]=[CH:15][C:16]3[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH2:19][C:17]=3[N:18]=2)[CH:25]=[N:35][N:36]=[N:37]1
Reactant: Nc1ncc2c(n1)CCC2C(=O)O
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCOC(OCC)OCC
Agent: C[Si](C)(C)OC(=O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C(O)C1CCc2nc(-n3cnnn3)ncc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Trimethylsilyl trifluoroacetate (1.5 mL, 8.7 mmol) was added to a suspension of 2-amino-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxylic acid (845 mg, 4.72 mmol) in ethyl acetate (10 mL). A solution was obtained but a precipitate formed within 5 minutes. The reaction mixture was stirred at RT for 5 minutes and triethyl orthoformate (1.4 mL, 8.4 mmol) was added. The mixture was stirred at RT for 5 minutes and azidotrimethylsilane (1.1 mL, 8.4 mmol) was added. The resulting suspension was stirred at RT overnight. The solvent was evaporated. The residue was purified by chromatography on silica gel (80 g cartridge) using CH2Cl2 (A) and CH2Cl2:MeOH:AcOH 90:10:1 (B) with gradient elution (100% A to 100% B over 16 column volumes) to afford crude product which was further purified by preparative HPLC to afford the title compound: NMR 500 MHz (CD3OD) 10.00 (s, 1H); 8.88 (s, 1H); 4.32 (t, 1H); 3.11-3.15 (m, 2H); 2.47-2.63 (m, 2H); LC/MS (M+Na)+ at 255, (M+1)+ at 233, (M+1-N2)+ at 205.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH3:21][O:22][C:23]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][NH:29][CH2:28]2)=[O:24].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:21][O:22][C:23]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][N:29]([C:11]1[CH:12]=[C:13]3[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=1[F:15])[CH2:28]2)=[O:24]
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: COC(=O)c1ccc2c(c1)CNC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ccc2c(c1)CN(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2
Yield: 34.9 %

Procedure:
133 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, 109 mg of 5-methoxycarbonylisoindoline hydrochloride, 228 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 74 mg of the target compound.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH:16]=O)=[CH:15][C:10]=3[N:9]=[C:8]2[NH:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][C:33]=4[O:34][CH3:35])[CH:26]=3)[N:21]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH2:16][N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[CH:15][C:10]=3[N:9]=[C:8]2[NH:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][C:33]=4[O:34][CH3:35])[CH:26]=3)[N:21]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:42])([CH3:41])[CH3:43])[N:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: COc1ccncc1-c1ccc2c(c1)c(Nc1nc3cc(C=O)ccc3n1C1CCCCC1)nn2COCC[Si](C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccncc1-c1ccc2c(c1)c(Nc1nc3cc(CN4CCOCC4)ccc3n1C1CCCCC1)nn2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.8 %

Procedure:
In a 20 mL vial was added 1-cyclohexyl-2-(5-(4-methoxypyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-ylamino)-1H-benzo[d]imidazole-5-carbaldehyde (28 mg, 0.047 mmol.), morpholine (10 mg, 0.11 mmol) and methylene chloride (2 mL). A catalytic amount of acetic acid was added and the reaction mixture stirred at room temperature for 10 min. Sodium triacetoxyborohydride (30 mg, 0.14 mmol) was then added and the reaction mixture stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride and washed with water, saturated sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and concentrated to give the title compound (15 mg) which was used directly in the next step.