Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:8]([CH3:10])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.B(OC)(OC)[O:17]C.OO>O1CCCC1.CCCCCC.O>[OH:17][CH2:1][C:2]1[C:3]([N:8]([CH3:10])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1N(C)C
Reactant: COB(OC)OC
Agent: OO
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)c1ncccc1CO
Temperature: 0 °C
Reaction time: 4 h
Yield: 18.8 %

Procedure:
To a cold (ca. -78° C.) solution of 2.9 g (21 mMol) of 3-methyl-2-(N,N-dimethylamino)pyridine in 35 ml of tetrahydrofuran was added dropwise 15 ml (23 mMol) of 1.55 M butyllithium in hexane. The mixture was stirred at 0° C. for four hours and then recooled to ca. -78° C. Trimethyl borate (2.65 ml, ca. 23 mMol) was added dropwise and the mixture was stirred at 0° C. After one hour 2.9 ml of 30% hydrogen peroxide was added and the mixture was stirred at 25° C. After another hour, the reaction mixture was poured into water and extracted with several portions of diethyl ether. The combined ether extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to an oil. Chromatography on silica gel (using ethanol-toluene as eluent) yielded 600 mg of 3-hydroxymethyl-2-(N,N-dimethylamino)pyridine, as confirmed by the nmr and infrared spectra. Using the method of Example 79 with 3-hydroxymethyl-2-(N,N-dimethylamino) pyridinamine instead of 3-hydroxymethyl-2-pyridinamine yielded the title compound, which was used in subsequent reactions without further purification. Structure assignment was supported by the nmr and infrared spectra.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[I:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>S(=O)(=O)(O)O.O>[C:11]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[I:10])(=[O:13])[CH3:12]
Reactant: N#Cc1ccc(N)c(I)c1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Nc1ccc(C#N)cc1I
Yield: 94.7 %

Procedure:
A mixture of 8.54 g (0.035 mole) of 4-amino-3-iodobenzonitrile (31), 16 mL (16.32 g, 0.16 mole) of acetic anhydride and five drops of concentrated sulfuric acid was heated at 70° under reflux for 10 minutes (the mixture became thick when the temperature reached 40° and some manual stirring was required). The reaction mixture was poured over 400 mL of cold water and stirred for 5 minutes to give a white solid which was filtered and dried, yielding 9.48 g (95%) of 32 as white powder, mp 176-181°. Infrared (IR) and NMR analysis gave the following results:
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH3:7])[CH3:6].[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[NH:22][CH:23]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[C:28]([Cl:33])[CH:27]=3)[N:25]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[OH-].[K+]>CS(C)=O.C(Cl)Cl>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[N:22]([CH2:3][CH2:4][N:5]([CH3:7])[CH3:6])[CH:23]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[C:28]([Cl:33])[CH:27]=3)[N:25]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CN(C)CCCl
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(Cl)c3)c[nH]2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN(C)CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
Add (2-chloro-ethyl)-dimethyl-amine hydrochloride (1.10 equiv; 579 μmol; 83 mg) in one portion to a mixture of 4-[4-(3-chloro-4-fluoro-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1 equiv; 526 μmol; 200 mg) and powdered KOH (2.5 equiv; 1.316 mmol; 73.8 mg) in DMSO (3 mL). Warm to 50° C. and stir for 2 h. Dilute with DCM, wash with water, brine, dry over MgSO4, filter, evaporate and purify on 40 g silica gel with 10% methanol/ACN to provide the title compound (194 mg; 0.43 mmol; 82%). MS (ES+): m/z=451 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][CH2:18][C:19]#[N:20]>C(#N)C>[OH:8][CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][N:1]([CH2:16][CH2:17][CH2:18][C:19]#[N:20])[CH2:2]1
Reactant: N#CCCCBr
Reactant: OCC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCCCN1CCCC(CO)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In an oven-dried 25 mL flask was placed piperidine-3-yl-methanol (1.12 g, 10 mmol) in acetonitrile (10 mL), followed by addition of potassium carbonate (1.38 g, 10 mmol) and 4-bromobutyronitrile (0.90 mL, 9 mmol). The reaction mixture was stirred at rt. for 12 h. The mixture was filtered and evaporated to dryness. Addition of H2O (20 mL) was followed by extraction with ethyl acetate (3×20 mL) and the combined organic phases were dried (MgSO4) and evaporated to dryness to produce 1.50 g of crude 6 which was used without further purification in the synthesis of compound 7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[N:31]1([CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:35]=[CH:34][N:33]=[CH:32]1>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:41]4[CH2:42][CH2:43][N:38]([CH2:37][CH2:36][N:31]5[CH:35]=[CH:34][N:33]=[CH:32]5)[CH2:39][CH2:40]4)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: c1cn(CCN2CCNCC2)cn1
Reactant: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Solvent: CN1CCCC1=O
Product: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1N1CCN(CCn2ccnc2)CC1
Temperature: 105 °C
Yield: 70 %

Procedure:
Following the procedure of Example 11, a mixture of 220 mg (0.5 mmol) of 4-[3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)-phenylamino]-7-fluoro-6-methoxyquinoline-3-carbonitrile and 290 mg (1.6 mmol) of 1-(2-imidazole-1-yl-ethyl)piperazine in 1.2 mL of 1-methyl 2-pyrrolidinone is heated at 105° C. for 20 hours to yield the crude product. Purification by silica gel chromatography (gradient 95:5methylene chloride/methanol to 85:15 methylene chloride/methanol) gives 210 mg of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-7-{4-[2-(1H-imidazole-1-yl)ethyl]piperazin-1-yl}-6-methoxyquinoline-3-carbonitrile as a beige solid, mp 251-253° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-])=O)[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:12][C:4]1[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: CC(=O)c1cc(Br)cc([N+](=O)[O-])c1O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(=O)c1cc(Br)cc(N)c1O

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-3-nitrophenyl)ethanone (25 g, 96 mmol), iron (27 g, 481 mmol), and NH4Cl (5.1 g, 96 mmol) in EtOH/H2O (5:1,300 ml) was heated at reflux in 2 h, the mixture was cooled filtered the solid, the filtrate was concentrated, taken up in H2O, extracted with DCM (3×), dried over MgSO4, concentrated and purified by ISCO (10% EtOAc/Hexanes) to give the title compound as a yellow solid. MS (m+2): 232.1.
Reaction SMILES: [CH3:1][N:2]([CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][N:4]=1>CO.[Pd]>[CH3:1][N:2]([CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1
Reactant: CN(c1ccc([N+](=O)[O-])cn1)C1CCOCC1
Agent: [Pd]
Solvent: CO
Product: CN(c1ccc(N)cn1)C1CCOCC1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a solution of N-methyl-5-nitro-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine (217 mg, 0.92 mmol) in MeOH (30 mL) was added Pd/C (0.5 g). The mixture was stirred for 3 hours at 20° C. under 1 atm. H2. The reaction was filtered and concentrated to give dark red oil. MS (m/z): 208 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].[C:18]1([CH3:33])[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:19]=1>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:26]2[CH:25]=[C:24]([C:21]3[CH:20]=[CH:19][C:18]([CH3:33])=[CH:23][CH:22]=3)[CH:29]=[CH:28][CH:27]=2)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: Cc1ccc(-c2cccc(B(O)O)c2)cc1
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Product: Cc1ccc(-c2cccc(-c3cnc(N)c(C(=O)Nc4ccncc4)c3)c2)cc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with [3-(p-tolyl)phenyl]-boronic acid gives the compound “A23”;
Reaction SMILES: CSC.[Cl-].[Al+3].[Cl-].[Cl-].C[O:9][C:10]([CH2:12][CH:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]([C:24](=[O:42])[C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:41])[CH2:33][O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:27][CH:26]=2)[CH2:16][CH2:15][CH2:14]1)=[O:11].Cl>ClCCl>[C:10]([CH2:12][CH:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]([C:24](=[O:42])[C:25]2[CH:26]=[CH:27][C:28]([NH:31][C:32](=[O:41])[CH2:33][O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:29][CH:30]=2)[CH2:16][CH2:15][CH2:14]1)([OH:11])=[O:9]
Reactant: COC(=O)CC1CCCN(C(=O)c2ccc(NC(=O)COc3ccccc3)cc2)c2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CSC
Solvent: ClCCl
Product: O=C(O)CC1CCCN(C(=O)c2ccc(NC(=O)COc3ccccc3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To dimethylsulfide (170 ml) is added dropwise with stirring aluminum chloride (23.6 g) under ice-cooling, and further thereto is added dropwise a solution of 5-methoxycarbonylmethyl-1-[4-(2-phenoxyacetylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (16.76 g) in dichloromethane (150 ml), and the mixture is stirred at room temperature for two hours. The reaction mixture is poured into a mixture of conc. hydrochloric acid and crashed ice, and the mixture is extracted with dichloromethane. The organic layer is washed with water, dried over magnesium sulfate, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=30:1) to give 5-carboxymethyl-1-[4-(2-phenoxyacetylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (13.67 g) as white powder.
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22](SC)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[N:16]1)(=O)C1C=CC=CC=1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][C:33]=1[O:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=1)[NH2:30].Cl.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[Cl:26][C:27]1[CH:28]=[C:29]([NH:30][C:22]2[C:23]3[N:15]([CH2:14][CH2:13][O:12][CH2:11][CH2:10][OH:9])[N:16]=[CH:17][C:18]=3[N:19]=[CH:20][N:21]=2)[CH:31]=[CH:32][C:33]=1[O:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:43])([F:44])[F:42])[CH:36]=1
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1
Reactant: CSc1ncnc2cnn(CCOCCOC(=O)c3ccccc3)c12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Product: OCCOCCn1ncc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 140 °C
Reaction time: 33.5 h
Yield: 11.1 %

Procedure:
A mixture of 2-{2-[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethoxy}ethyl benzoate (328 mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (264 mg), pyridine hydrochloride (159 mg) and 1-methyl-2-pyrrolidone (7.5 mL) was stirred at 140° C. for 33.5 hrs. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate (15 mL), and extracted with ethyl acetate (35 mL×2). The organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→0:100). The object fraction was concentrated under reduced pressure and the residue was dissolved in methanol (5 mL). 1N Aqueous sodium hydroxide solution (1 mL) was added and the mixture was stirred at room temperature for 2 hrs. After concentration of the reaction mixture under reduced pressure, water (30 mL) was added, and the mixture was extracted with ethyl acetate (40 mL×2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→0:100) and recrystallized from ethyl acetate-hexane to give the title compound (50 mg).
Reaction SMILES: [Na].[F:2][C:3]([F:9])([CH:6]([F:8])[F:7])[CH2:4][OH:5].[NH2:10][C:11]1[N+:16]([O-:17])=[C:15]([NH2:18])[CH:14]=[C:13](Cl)[N:12]=1>>[NH2:10][C:11]1[N+:16]([O-:17])=[C:15]([NH2:18])[CH:14]=[C:13]([O:5][CH2:4][C:3]([F:9])([F:2])[CH:6]([F:8])[F:7])[N:12]=1
Reactant: Nc1cc(Cl)nc(N)[n+]1[O-]
Reactant: OCC(F)(F)C(F)F
Agent: [Na]
Product: Nc1cc(OCC(F)(F)C(F)F)nc(N)[n+]1[O-]
Temperature: 90 °C

Procedure:
2 g of sodium are introduced into 100 g of 2,2,3,3-tetrafluoropropanol at 40° C. After the addition of 10 g of 2,4-diamino-6-chloropyrimidine 3-oxide, the reaction mixture is maintained for 32 hours at 90° C.
Reaction SMILES: C1(=O)CCCC(=O)C1.C1(NN)C=CC=CC=1.C1[C:29]2[NH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2C(=O)CC1>>[NH:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:29]1
Reactant: O=C1CCCc2[nH]c3ccccc3c21
Agent: O=C1CCCC(=O)C1
Solvent: NNc1ccccc1
Product: c1ccc2[nH]ccc2c1

Procedure:
A 0.25 mol/L 1,3-cyclohexanedione/50% sulfuric acid solution was sent as a first fluid from the center at a ratio of supply pressure/back pressure of 0.07 MPa/0.02 MPa, a rotation speed of 500 rpm, and a sending temperature of 25° C., and a 0.25 mol/L phenylhydrazine/50% sulfuric acid solution was introduced as a second fluid into a space between the processing surfaces at 18 mL/min. The first fluid and the second fluid were mixed in a thin film fluid, and then a solution obtained after processing was discharged from the space between the processing surfaces at 29 mL/min. As a result of HPLC analysis, the production rate of 1,2,3,4-tetrahydrocarbazol-4-one was 80% or higher.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:33]([O:34][CH3:35])=[CH:32][C:6]2[CH2:7][C:8](=O)[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:30])[CH:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[CH:22]=4)[CH2:17]3)[CH:10]=[CH:11][C:5]=2[CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:35][O:34][C:33]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:30])[CH:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[CH:22]=4)[CH2:17]3)[CH:8]=[CH:7][C:6]=2[CH:32]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C1CCc3cc(OC)c(OC)cc3C1)C=C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1cc2c(cc1OC)CCN(CCCN(C)C1CCc3cc(OC)c(OC)cc3C1)C=C2

Procedure:
The title compound is prepared from 1-[7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-N-(6,7-dimethoxy-1,2,3,4-tetrahydronaphth-2-yl)-amino]-propane and lithium aluminum hydride analogously to Example 13. Mp: 115°-116° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:8]=[C:9]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)[NH2:10])[N:3]=1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([C:37]2[CH:42]=[CH:41][C:40]([CH2:43][C:44](O)=[O:45])=[C:39]([F:47])[CH:38]=2)[CH:24]=[N:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[CH3:19].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.O>N1C=CC=CC=1>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([C:37]2[CH:42]=[CH:41][C:40]([CH2:43][C:44]([NH:10][C:9]3[CH:11]=[C:12]([C:14]([F:15])([F:17])[F:16])[CH:13]=[C:7]([N:4]4[CH:5]=[CH:6][C:2]([CH3:1])=[N:3]4)[CH:8]=3)=[O:45])=[C:39]([F:47])[CH:38]=2)[CH:24]=[N:25][C:26]=1[O:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[CH3:19]
Reactant: Cc1ccn(-c2cc(N)cc(C(F)(F)F)c2)n1
Reactant: CCOc1cc(-c2ccc(CC(=O)O)c(F)c2)cnc1OCc1ccc(OC)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: c1ccncc1
Solvent: O
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(-n4ccc(C)n4)cc(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Temperature: 16 °C
Reaction time: 1 h
Yield: 34.5 %

Procedure:
To a solution of 3-(3-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)aniline (250 mg, 1.036 mmol) and 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (429 mg, 1.036 mmol) in pyridine (5 mL) was added T3P® (3298 mg, 5.18 mmol) in portions. The mixture was stirred at 16° C. for 1 h. LCMS analysis showed the starting material disappeared. 10 mL of water was added dropwise into the reaction solution and then the mixture was filtered. The filter cake was washed with water (20 mL) and dried in vacuo to afford pure product 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridine-3-yl)-2-fluorophenyl)-N-(3-(3-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide (280 mg, 0.357 mmol, 34.5% yield). 1H NMR (400 MHz, CD3OD): δ 8.25 (s, 1H), 8.15 (d, J=2.6 Hz, 1H), 7.96 (d, J=2.0 Hz, 1H), 7.85 (s, 1H), 7.75 (s, 1H), 7.50-7.43 (m, 3H), 7.41 (d, J=9.0 Hz, 3H), 6.92 (d, J=8.8 Hz, 2H), 6.36 (d, J=2.4 Hz, 1H), 5.37 (s, 2H), 4.18-4.13 (m, 2H), 3.86 (s, 2H), 3.79 (s, 3H), 2.34 (s, 3H), 1.43 (t, J=7.0 Hz, 3H). ES-LCMS: m/z 635.1 (M+H).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][OH:7])[CH2:2][CH3:3].CC(C)([O-])C.[K+].F[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[N:16]=1>C1COCC1.[Cl-].[Na+].O>[F:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:7][CH2:6][CH2:5][O:4][CH2:1][CH2:2][CH3:3])[N:16]=1
Reactant: CCCOCCO
Reactant: Fc1cccc(F)n1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCOCCOc1cccc(F)n1
Yield: 93 %

Procedure:
2-Propoxyethanol (1.89 g, 18.1 mmol) was dissolved in 50 mL THF, treated with potassium tert-butoxide (3.05 g, 27.2 mmol), stirred to uniform solution, placed in an addition funnel, and added dropwise to a solution of 2,6-difluoropyridine in 50 mL THF. After stirring overnight at room temperature, the solution was diluted with brine and extracted with ether. The ether extracts were combined and dried over Na2SO4, then concentrated in vacuo to yield 2-fluoro-6-(2-propoxyethoxy)-pyridine (3.33 g, 93%) as a yellow oil.
Reaction SMILES: [CH:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][S:6](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C(C)=CC=CC=1C.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:27].C([O-])(O)=O.[Na+]>C(#N)C.O>[CH:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]([OH:27])[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=S1Cc2ccccc2-c2ccccc21
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: Cc1cccc(C)n1
Product: OC1Sc2ccccc2-c2ccccc21
Temperature: 25 °C
Yield: 60 %

Procedure:
To a stirred solution of 6H-dibenzo[b,d]thiopyran-5-oxide (2 g; 0.0093 mol), 2,6-lutidine (4 ml; 0.034 mol) and acetonitrile (40 ml) was added a solution of trifluoro acetic anhydride (3.2 ml; 0.022 mol) in acetonitrile (10 ml) at 0° C. After 2 hours a solution of NaHCO3 (1 g) in water (25 ml) was quickly added at 0° C. and then the mixture was allowed to warm to room temperature. After 2 hours the mixture was poured into water (200 ml) and extracted with diethyl ether. The extracts were dried, concentrated and separated on silica gel chromatography column (ethyl acetate:cyclohexane 1:4 as eluant) to give 6H-dibenzo[b,d]thiopyran-6-ol; (1.2 g; yield 60%); m.p. 83°-86° C. By proceeding analogously the following compounds were obtained:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:5][CH2:4][CH2:3][CH2:2][O:13][C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCOc1ccc(Cl)cc1
Yield: 90 %

Procedure:
A mixture of 157 g of 3-bromo-1-chloropropane, 129 g of p-chlorophenol and 165 g of potassium carbonate in 1 liter of acetone is refluxed for 3 days. The mixture is cooled, filtered and the filtrate concentrated under reduced pressure. The residue is distilled to give 184 g of product as an oil, bp 107°-116° C. at 0.5mm.
Reaction SMILES: C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.[CH3:19][O:20][C:21]1[N:26]=[C:25]([CH2:27][CH2:28]O)[CH:24]=[CH:23][CH:22]=1.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.C(P(CCCC)CCCC)CCC>C(OCC)(=O)C.C1COCC1>[CH3:19][O:20][C:21]1[N:26]=[C:25]([CH2:27][CH2:28][N:34]2[C:30](=[O:40])[C:31]3[C:32](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:33]2=[O:35])[CH:24]=[CH:23][CH:22]=1
Reactant: COc1cccc(CCO)n1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(CCN2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
ADDP (49.0 g, 194.09 mmol) was added to a mixture of 2-(6-methoxypyridin-2-yl)ethanol (22.87 g, 149.30 mmol), phthalimide (24.16 g, 164.23 mmol), tributylphosphine (48.5 mL, 194.09 mmol) and THF (340 mL) at 0° C. under argon atmosphere to give a solution. The solution was stirred at room temperature for 16 hr, to the reaction mixture was added ethyl acetate (about 500 mL), and the mixture was stirred at 0° C. for 20 min. The insoluble substance was removed by filtration with ethyl acetate, and washed with ethyl acetate. The filtrate was poured into water (1000 mL), and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5→20% ethyl acetate/hexane), and the precipitate was collected by filtration with hexane to give 2-(2-(6-methoxypyridin-2-yl)ethyl)isoindoline-1,3-dione (29.03 g, 103 mmol, 69%) as an off-white powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1I)[C:5]([O:7][CH3:8])=[O:6].Cl.[CH3:14][N:15](C=O)C>[C-]#N.[C-]#N.[Zn+2].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:14]([C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[OH:1])#[N:15]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(I)c(O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [C-]#N
Product: COC(=O)c1ccc(C#N)c(O)c1
Temperature: 80 °C

Procedure:
A solution of methyl 3-hydroxy-4-iodobenzoate (2.38 g, 7.0 mmol) (as described in Step B) and Zn(CN)2 (0.575 g, 4.9 mmol) in DMF was degassed with argon for 25 minutes. Pd(Ph3P)4 (0.404 g, 0.35 mmol) was added and the mixture heated to 80° C. for 16 hr. The mixture was poured into 1N HCl and extracted with EtOAc (2×), washed with water then brine, dried (MgSO4) and the solvent removed. Chromatography of the residue (silica gel; hexane:EtOAc 9:1) afforded the title compound as a white solid.