Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[N:12][O:13][CH3:14])[C:10]#[N:11].[Cl:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>CN(C)C=O>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[O:22][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[N:12][O:13][CH3:14])[C:10]#[N:11]
Reactant: CON=C(C#N)c1ccccc1CBr
Reactant: Oc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CON=C(C#N)c1ccccc1COc1cccc(Cl)c1
Yield: 61.5 %

Procedure:
2-Bromomethyl-α-methoxyiminophenylacetonitrile (5.0 g, 20 mmol) and 3-chlorophenol (3.0 g, 23 mmol) were dissolved in N,N-dimethylformamide (25 ml), and the mixture was stirred at room temperature for 2 hours in the presence of potassium carbonate (3.3 g, 24 mmol). After completion of the reaction, diethyl ether (ca. 100 ml) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) and crystallized from diethyl ether/n-hexane to give 2-(3-chlorophenoxymethyl)-α-methoxyiminophenylacetonitrile (3.7 g, 62%) as colorless crystals.
Reaction SMILES: Cl.[CH2:2]([S:4][C:5]1[CH:6]=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)[CH3:3].[O:12]=[C:13](Cl)OC(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH2:2]([S:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]=[C:13]=[O:12])[CH:6]=1)[CH3:3]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCSc1cccc(N)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: CCSc1cccc(N=C=O)c1

Procedure:
To a slurry of the above 3-ethylsulfanylphenylamine hydrochloride (31.6 mmol, 6 g) in toluene (100 mL) was added diphosgene (trichloromethyl chloroformate, 158 mmol, 31.3 g) and the mixture was refluxed for 2 hours affording a clear solution. The solvent was removed in vacuo and the residue was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][OH:14].[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][N:20]=1)=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:21][N:20]=1)=[O:18]
Reactant: COC(=O)c1ccc(O)cn1
Reactant: Cc1onc(-c2ccccn2)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.2 %

Procedure:
To a solution of (5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-methanol (100 mg, 0.53 mmol) in THF (5 mL) was added 5-hydroxy-pyridine-2-carboxylic acid methyl ester (89 mg, 0.58 mmol) and triphenylphosphine (207 mg, 0.79 mmol) at ambient temperature under an argon atmosphere. Then diethyl azodicarboxylate (362 μL, 40% solution in toluene, 0.79 mmol) was added and the reaction mixture was stirred for 3 h at room temperature. The reaction mixture was evaporated and then purified by chromatography (silica, heptane:ethyl acetate=100:0 to 2:3) to afford the title compound (78 mg, 44%) as a white solid. MS: m/e=326.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:13]1[CH2:18][C:17](=[O:19])[C:16]([C:20](=[O:23])[CH2:21][CH3:22])=[C:15]([OH:24])[CH2:14]1.[Cl-].[Cl-].[Cl-].[Al+3].[C:29](Cl)(=[O:31])[CH3:30].Cl>ClCCCl>[C:29]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:13]2[CH2:18][C:17](=[O:19])[C:16]([C:20](=[O:23])[CH2:21][CH3:22])=[C:15]([OH:24])[CH2:14]2)=[C:2]([CH3:1])[C:11]=1[CH3:12])(=[O:31])[CH3:30]
Reactant: CCC(=O)C1=C(O)CC(c2c(C)c(C)cc3ccccc23)CC1=O
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCC(=O)C1=C(O)CC(c2c(C)c(C)c(C(C)=O)c3ccccc23)CC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-(2,3-dimethylnaphth-1-yl)-3-hydroxy-2-propionylcyclohex-2-en-1-one (1.7 g; 5.3 mmol) in 1,2-dichloroethane (5 ml) was added to a suspension of aluminium trichloride (2.2 g; 16.75 mmol) in 1,2-dichloroethane (10 ml) at 0° C. The mixture was stirred at 0° C. for 30 min and a solution of acetyl chloride (0.5 g; 6.36 mmol) in 1,2-dichloroethane (5 ml) was added. After stirring at 0° C. for 30 min and at room temperature for 2 hr, the mixture was poured into a cold aqueous 50% hydrochloric acid solution which was then stirred vigorously for 1 hr. The solution was extracted with dichloromethane and the organic phase was washed with water. The dried (MgSO4) organic fraction was evaporated and the residue was purified by preparative thin-layer chromatography with dichloromethane/ethyl acetate (2:1 v/v) elution to give 5-[4-acetyl-2,3-dimethylnaphth- 1-yl]-3-hydroxy-2-propionylcyclohex-2-en-1-one as a yellow oil.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([OH:7])[CH:4]=[C:3]([CH:8]([OH:11])[CH2:9][NH2:10])[CH:2]=1.Cl.CO[C:15]([C:17]1[N:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=N>O1CCCC1.C(OCC)(=O)C.O.C(#N)C>[OH:7][C:5]1[CH:4]=[C:3]([CH:8]2[O:11][C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:22]=3)=[N:10][CH2:9]2)[CH:2]=[CH:1][CH:6]=1
Reactant: COC(=N)c1ccccn1
Reactant: NCC(O)c1cccc(O)c1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: Oc1cccc(C2CN=C(c3ccccn3)O2)c1

Procedure:
A mixture of (±) norphenylephrine hydrochloride (10 g, 0.05 mol) and methyl iminopicolinate (8 g, 0.059 mol) in tetrahydrofuran (300 ml) is heated to reflux for 16 hours. The mixture is dissolved in ethyl acetate and water. The aqueous layer is extracted twice with ethyl acetate. The combined ethyl acetate solutions are washed twice with dilute aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to dryness to obtain a partially crystalline material. This material is triturated with ether to obtain crystals. These crystals are dissolved in hot acetonitrile and the hot solution is filtered and allowed to cool. The crystals (4 g) are filtered off, washed with acetonitrile and dried in vacuo, m.p. 139°-141° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=O)=[N:4][CH:3]=1.N1C=CC=CC=1.[OH:15][NH2:16].Cl>CCO.C(Cl)Cl>[CH3:1][C:2]1[S:6][C:5]([CH:7]=[N:16][OH:15])=[N:4][CH:3]=1
Reactant: NO
Reactant: Cc1cnc(C=O)s1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: ClCCl
Product: Cc1cnc(C=NO)s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5-methylthiazole-2-carbaldehyde (6.1 g, 48 mmol) in EtOH (30 mL), was added pyridine (4 mL, 49 mmol) and HONH2.HCl (3.3 g, 47 mmol). The mixture was stirred at ambient temperature for 12 hours. The reaction mixture was diluted with DCM and extracted with water. The organic solution was dried, filtered and concentrated to give the crude oxime. Yield: 6 g LCMS: (ES+) m/z=143.8 (M+H)+
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1(/[C:7](/[N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:6]\[C:5]2[CH:13]=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccccc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Product: C(=C(\c1ccccc1)n1c2ccccc2c2ccccc21)\c1ccccc1

Procedure:
N-Phenylbenzaldimine (1.35 g, 0.0075 mol) and 9-benzylcarbazole (1.29 g, 0.0077 mol) were heated at 75° C. for 30 min in dimethylformamide (dry), 50 mL, and potassium tert-butoxide (0.10 g, 0.00089 mol). Based on reversed-phase HPLC results, the reaction was complete after 3 min. Aqueous work-up as above and recrystallization of the precipitate frommethanol gave needles mp 160°-2° C. (81%). 1H NMR (200 MHz, CDCl3) δ (assignment): 6.85-7.09 (m, 2H, aromatic). MS [m/e (70 eV, % of base peak)] C26H19N 345 (M+.,100), 267 (M+. -PhH, 25.8), 178 PhCCPh+., 47.5), 167 (carbazole+., 63.6). HRMS (m/z) for C26H19N (M+.) calcd. 345.1517 found 345.1513. FTIR (CDCl3): 3083, 3064, 3027, 1624, 1598, 1493, 1479, 1450, 1384, 1335, 1314, 1232 cm-1. Analysis: calcd. for C26H19N: C 90.40, H 5.54, N 4.05%; found: C 90.25, H 5.66, N 4.20%.
Reaction SMILES: [OH:1][CH2:2][C:3]1([NH:6][CH:7]=[C:8]([C:14](=[O:25])[C:15]2[CH:20]=[C:19](F)[C:18]([F:22])=[C:17]([F:23])[C:16]=2F)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C(OC(=O)C)C>[F:23][C:17]1[CH:16]=[C:15]2[C:20]3=[C:19]([O:1][CH2:2][C:3]4([CH2:5][CH2:4]4)[N:6]3[CH:7]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:14]2=[O:25])[C:18]=1[F:22]
Reactant: CCOC(=O)C(=CNC1(CO)CC1)C(=O)c1cc(F)c(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)OCC21CC1
Temperature: 200 °C

Procedure:
A mixture of ethyl 3-(1-(hydroxymethyl)cyclopropylamino)-2-(2,3,4,5-tetrafluoro-benzoyl)acrylate (300 mg, 0.83 mmol), K2CO3 powder (344 mg, 2.49 mmol), and 3 ml of anhydrous DMF were heated in a CEM Discover microwave for 10 min at 200° C. After that the sample was rapidly cooled to room temperature yielding a dark brown liquid. The DMF was removed by evaporation to give a dark solid. The solid was dissolved in 50 ml of ethylacetate and washed two times with 10 ml of water. The organic layer was dried over Na2SO4 to afford a light yellow solid as the title compound which was used without further purification in the next step (133 mg, 0.415 mmol). MS (EP) m/z: 322 (M++1). (Calcd. for C16H13F2NO4, 321.28)
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH:7]([CH2:9][OH:10])[O:8][C:4]=2[C:3]=1[Cl:13].[H-].[Na+].[CH2:16](Br)[CH3:17]>CN(C=O)C>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH:7]([CH2:9][O:10][CH2:16][CH3:17])[O:8][C:4]=2[C:3]=1[Cl:13]
Reactant: OCC1Cc2ccc(Cl)c(Cl)c2O1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCC1Cc2ccc(Cl)c(Cl)c2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
To a solution of 2.88 g of 6,7-dichloro-2-hydroxymethyl-2,3-dihydrobenzofuran dissolved in 22 ml of DMF is added 790 mg of sodium hydride (50% suspension) and stirred at room temperature for 30 minutes. After addition of 1.73 g of ethyl bromide, the reaction mixture is stirred at room temperature for 17 hours and extracted with water and ether. The ether layer is washed with water, dried over magensium sulfate, and evaporated under reduced pressure to give a residue, which is chromatographed on silica gel with dichloromethane as an eluent to give 2.0 g of oily 6,7-dichloro-2-ethoxymethyl-2,3-dihydrobenzofuran. To a solution of 2.0 g of the 6,7-dichloro-2-ethoxymethyl-2,3-dihydrobenzofuran dissolved in 5 ml of thionyl chloride is dropwise added 3 g of chlorosulfonic acid under ice-cooling. The reaction mixture is stirred at room temperature for 2 hours, then poured into iced water, and extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried and evaporated under reduced pressure to give an oil, which is then dissolved in 30 ml of dichloromethane. After introduction of 30 ml of ammonia at -30° to -20° C., the mixture is allowed to stand at room temperature for a night and evaporated under reduced pressure to give an oily residue, which is then dissolved in ethyl acetate and washed with water. The ethyl acetate layer is dried and evaporated to dryness to give 2.7 g of an oily product, which is chromatographed on silica gel with dichloromethane (1000 ml) and successively dichloromethane/acetone (20/1) as eluents to give 900 mg of the objective 6,7-dichloro-2-ethoxymethyl-5-sulfamoyl-2,3-dihydrobenzofuran (I j-84) as crystals, yield 24%, m.p. 148°-149° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10](=O)[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][CH:7]=1.Cl.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][NH2:28]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[Cl:20])[N:28]=[C:10]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C=Cc1cccc(Br)c1)C(F)(F)C(F)(F)F
Reactant: NNc1ccccc1Cl
Agent: Cl
Solvent: CC(=O)O
Product: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2cccc(Br)c2)C1
Temperature: 100 °C
Reaction time: 12 h
Yield: 56.4 %

Procedure:
1-(3-Bromo-phenyl)-4,4,5,5,5-pentafluoro-pent-1-en-3-one (1.4 g, 4.3 mmol) prepared in Step 1 of Preparation 5 and 2-chlorophenylhydrazine hydrochloride (0.8 g, 4.3 mmol) were added to acetic acid (30.0 mL). The reaction mixture was stirred at 100° C. for 12 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: diethyl ether/n-hexane=1/9) to give 1.1 g of the titled compound as a brown liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:4]([CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH:20]([CH3:24])[CH:19]2[CH3:25])[CH:3]=1.C(=O)(O)[O-].[Na+].[C:31]1([CH2:37][C:38](Cl)=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl.O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:4]([CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:38](=[O:39])[CH2:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:20]([CH3:24])[C@@H:19]2[CH3:25])[CH:3]=1
Reactant: CC1NCCN(Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)C1C
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1[C@H](C)N(Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)CCN1C(=O)Cc1ccccc1
Reaction time: 2 h

Procedure:
To a vigorously stirred solution/suspension of the product from example 71 part a) (0.189 g) and solid sodium bicarbonate (0.215 g) in DCM (2 ml) and water (2 ml) was added phenylacetyl chloride (0.14 ml) dropwise. The mixture was stirred for 2 h. The organic layer and 1 further DCM extract were combined, dried (Na2SO4) and purified by passage through SCX resin eluting with MeCN, MeOH followed by 7M NH3 in MeOH. The basic fractions were concentrated in vacuo to give the sub-titled product as a white foam (0.205 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[N:27]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[N:27]=2)[CH:8]=1)=[O:6]
Reactant: COc1cccc(CBr)n1
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(Cn2cc(C(=O)c3ccc(C)c(C)c3)c(=O)c3ccccc32)n1

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 50 mg (0.18 mmol) of 3-(3,4-dimethyl-benzoyl)-1H-quinolin-4-one, 9 mg (0.21 mmol) of 60% sodium hydride, 44 mg (0.22 mmol) 2-bromomethyl-6-methoxy-pyridine and 0.8 mL of N,N-dimethylformamide. Yield: 45 mg of a white solid: LC-MSD, m/z for C25H22N2O3 [M+H]+=399.3; HPLC retention time: 2.8 min.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:21]=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=3)=[C:15]([CH3:27])[CH:14]=1)=[N:5][CH:6]=[N:7]2.[NH2:28][CH2:29][C@H:30]([OH:32])[CH3:31]>>[NH2:28][CH2:29][C@@H:30]([CH3:31])[O:32][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:21]=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=3)=[C:15]([CH3:27])[CH:14]=1)=[N:5][CH:6]=[N:7]2
Reactant: C[C@@H](O)CN
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(F)c34)cc2C)cn1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(O[C@H](C)CN)c34)cc2C)cn1
Yield: 77 %

Procedure:
The procedure described in Example 103 (preparation of starting materials) was repeated using 5-fluoro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (obtained as described in Example 103, preparation of starting materials) and (2R)-1-aminopropan-2-ol to give 5-[(1R)-2-amino-1-methylethoxy]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine in 77% yield; Mass spectrum: MH+ 416
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18]C(=O)C(F)(F)F)=[CH:14][C:13]=2[F:25])[N:4](COCC[Si](C)(C)C)[CH:3]=1.FC(F)(F)C(O)=O.O.[OH-].[Li+]>ClCCl>[Cl:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=2[F:25])[NH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(Cl)c2c(Cc3ccc(NC(=O)C(F)(F)F)cc3F)ccnc21
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1ccc(Cc2ccnc3[nH]cc(Cl)c23)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
567 mg (1.13 mmol) of N-{4-[(3-chloro 1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)methyl]-3-fluorophenyl}-2,2,2-trifluoroacetamide are dissolved in 5 ml of dichloromethane. 5 ml (65 mmol) of trifluoroacetic acid are added, and the mixture is stirred at RT for 3 h. The mixture is then concentrated, EA is added and the mixture is washed with sat. sodium carbonate solution. The organic phase is dried over sodium sulfate and concentrated. The residue is taken up in 35 ml of THF, and 15 ml of water and 542 mg (22.7 mmol) of lithium hydroxide are added. The mixture is stirred at RT for 20 h. The mixture is then concentrated under reduced pressure, and the residue is diluted with water. The mixture is extracted with ethyl acetate and the extract is dried over sodium sulfate and concentrated. The residue is purified by chromatography on silica gel (mobile phase dichloromethane:methanol 25:1). This gives crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:9][CH:10]=[C:11]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=3)[C:4]=12)#[CH:2].[F:20][C:21]([F:31])([F:30])[C:22]1[N:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][CH:23]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>O.C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:9][CH:10]=[C:11]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([NH:19][CH2:28][C:25]4[CH:26]=[N:27][C:22]([C:21]([F:31])([F:20])[F:30])=[CH:23][CH:24]=4)=[N:17][CH:18]=3)[C:4]=12)#[CH:2]
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Reactant: C#Cc1ccnc2[nH]cc(Cc3ccc(N)nc3)c12
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C#Cc1ccnc2[nH]cc(Cc3ccc(NCc4ccc(C(F)(F)F)nc4)nc3)c12
Yield: 10.4 %

Procedure:
In a round bottom flask, 5-(4-ethynyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (164, 0.055 g, 0.22 mmol) was combined with 6-trifluoromethyl-pyridine-3-carbaldehyde (160, 50.4 mg, 0.288 mmol), 0.682 mL of acetonitrile, trifluoroacetic acid (0.0853 mL, 1.11 mmol), and triethylsilane (0.212 mL, 1.33 mmol) and the reaction heated to reflux for 3 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, then dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with methanol and dichloromethane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (P-1717, 9.3 mg). MS (ESI) [M+H+]+=408.5.
Reaction SMILES: OCCCN1C=C(C2C=CC(N[C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=C3C=2CN(C)C3=O)C=N1.[NH2:50][C:51]1[C:52]([C:67]([NH:69][CH3:70])=[O:68])=[N:53][C:54]([C:57]2[CH:58]=[N:59][N:60]([CH2:62][CH2:63][CH2:64][CH2:65][OH:66])[CH:61]=2)=[CH:55][CH:56]=1>>[OH:66][CH2:65][CH2:64][CH2:63][CH2:62][N:60]1[CH:61]=[C:57]([C:54]2[N:53]=[C:52]([C:67](=[O:68])[NH:69][CH3:70])[C:51]([NH:50][C:26]3[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:25]=3)=[CH:56][CH:55]=2)[CH:58]=[N:59]1
Reactant: CNC(=O)c1nc(-c2cnn(CCCCO)c2)ccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCCO)c4)nc3C(=O)NC)n2)c(OC)c1)OCC
Yield: 40 %

Procedure:
Prepared analogously to Compound 1B using 3-amino-6-[1-(4-hydroxybutyl)-1H-pyrazol-4-yl]-N-methylpyridine-2-carboxamide (Compound 15C, 95 mg, 333 μmol) to afford 95 mg of the title compound (40%). 1H NMR (400 MHz, CD3OD) δ 8.98 (d, J=8.3 Hz, 1H), 8.42 (s, 1H), 8.28 (s, 1H), 8.20 (s, 1H), 7.76 (d, J=6.1 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.01 (d, J=1.8 Hz, 1H), 6.90 (td, J=2.2, 8.1 Hz, 1H), 4.22 (t, J=7.1 Hz, 2H), 4.01-4.11 (m, 4H), 3.87 (s, 3H), 3.59 (t, J=6.4 Hz, 2H), 3.28-3.29 (m, 1H), 3.24 (s, 1H), 2.96 (s, 3H), 1.92-2.04 (m, 2H), 1.51-1.60 (m, 2H), 1.25 (t, J=7.1 Hz, 6H). MS (ESI): m/z 707.71 [M+H]+. UPLC: tR=1.25 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[N:13]([CH2:14][CH2:15][CH3:16])[CH:12]=[N:11][CH:10]=2)=[N:5][C:4]([N+:17]([O-])=O)=[N:3]1.[Cl-].[Ca+2].[Cl-]>C(O)C>[CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[N:13]([CH2:14][CH2:15][CH3:16])[CH:12]=[N:11][CH:10]=2)=[N:5][C:4]([NH2:17])=[N:3]1
Reactant: CCCn1cncc1CSc1nc([N+](=O)[O-])nn1C
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: CCCn1cncc1CSc1nc(N)nn1C
Temperature: 25 °C
Yield: 34.4 %

Procedure:
To 1-methyl-3-nitro-5-[[(1-propylimidazol-5-yl)methyl]thio]-1,2,4-triazole (2.8 g) was added 85% ethanol solution (84 ml), calcium chloride (0.57 g) and reduced iron (2.9 g) were added to the mixture, and the mixture was heated to reflux for 3 hours. After cooling to room temperature, the mixture was filtered with Celite, and washed with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 1-methyl-5-[[(1-propylimidazol-5-yl)methyl]thio]-1,2,4-triazole-3-amine (0.86 g).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])=[CH:3][CH:2]=1.C1C2NC3C(=CC=CC=3)C=2C(OC(C)(C)C(O)=O)=CC=1.Cl[CH2:43][C:44]1[CH:62]=[CH:61][C:47]([O:48][CH2:49][C:50]2[N:51]=[C:52]([C:56]3[S:57][CH:58]=[CH:59][CH:60]=3)[O:53][C:54]=2[CH3:55])=[C:46]([O:63][CH3:64])[CH:45]=1.ClCC1C=CC(OCC2N=C(C3C=CC=CC=3)OC=2C)=C(OC)C=1>>[CH3:64][O:63][C:46]1[CH:45]=[C:44]([CH:62]=[CH:61][C:47]=1[O:48][CH2:49][C:50]1[N:51]=[C:52]([C:56]2[S:57][CH:58]=[CH:59][CH:60]=2)[O:53][C:54]=1[CH3:55])[CH2:43][N:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[C:4]([O:14][CH2:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])[C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CC(C)(COc1cccc2[nH]c3ccccc3c12)C(=O)O
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2cccs2)oc1C
Agent: CC(C)(Oc1cccc2[nH]c3ccccc3c12)C(=O)O
Agent: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Product: COc1cc(Cn2c3ccccc3c3c(OCC(C)(C)C(=O)O)cccc32)ccc1OCc1nc(-c2cccs2)oc1C

Procedure:
The subject compound was prepared by performing the same operation as that of the example 3 by using 3-(9H-carbazole-4-yloxy)-2,2-dimethylpropionic acid prepared by the reference 30 instead of 2-(9H-carbazole-4-yloxy)-2-methylpropionic acid used in the example 3, and using 4-((4-(chloromethyl)-2-methoxyphenoxy)methyl)-2-(thiophene-2-yl)-5-methyloxazole prepared by the reference 3 instead of 4-((4-(chloromethyl)-2-methoxyphenoxy)methyl)-5-methyl-2-phenyloxazole.