Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:6][CH:5]([OH:7])[CH2:4]1)[CH3:2].F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1>>[CH2:1]([N:3]1[CH2:6][CH:5]([O:7][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:4]1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCN1CC(O)C1
Product: CCN1CC(Oc2ccc([N+](=O)[O-])cc2)C1

Procedure:
The title compound is prepared from 1-ethyl-3-azetidinol and 1-fluoro-4-nitrobenzene according to the procedures of Example 5.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C@H:11]2[CH2:14][C@H:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4([CH3:27])OCC[O:23]4)=[CH:18][N:17]=3)[CH2:12]2)[C:3]1=[O:28].Cl>O1CCOCC1>[C:22]([C:19]1[CH:20]=[CH:21][C:16]([NH:15][C@H:13]2[CH2:12][C@H:11]([N:4]3[C:5]4=[N:6][CH:7]=[CH:8][CH:9]=[C:10]4[C:2]([CH3:29])([CH3:1])[C:3]3=[O:28])[CH2:14]2)=[N:17][CH:18]=1)(=[O:23])[CH3:27]
Reactant: CC1(c2ccc(N[C@H]3C[C@H](N4C(=O)C(C)(C)c5cccnc54)C3)nc2)OCCO1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)c1ccc(N[C@H]2C[C@H](N3C(=O)C(C)(C)c4cccnc43)C2)nc1
Temperature: 80 °C

Procedure:
3,3-Dimethyl-1-(trans-3-((5-(2-methyl-1,3-dioxolan-2-yl)pyridin-2-yl)amino)cyclobutyl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (68 mg, 0.172 mmol) was dissolved in dioxane (345 μl). Aqueous hydrochloric acid (2 M, 862 μl, 1.724 mmol) was added and the reaction mixture heated at 80° C. for 3 h. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The aqueous layer was back extracted with ethyl acetate and the combined organic layer was dried with sodium sulfate and concentrated. The crude product was purified silica chromatography eluting with a gradient of ethyl acetate in hexane (0-70%) to give 1-(trans-3-((5-acetylpyridin-2-yl)amino)cyclobutyl)-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (30 mg, 0.086 mmol, 49.7% yield) as white solid. M+1: 351.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12](=[O:14])[CH3:13])=[N:7]2.[F:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:17]=1[C:31]1[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=1>>[C:12]([C:6]1[N:7]=[C:8]2[C:3]([C:2]([C:19]3[CH:20]=[CH:21][C:16]([F:15])=[C:17]([C:31]4[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:18]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1)(=[O:14])[CH3:13]
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Reactant: CC(=O)c1ccc2c(Cl)ccnc2n1
Product: CC(=O)c1ccc2c(-c3ccc(F)c(-c4ccccc4C#N)c3)ccnc2n1
Yield: 83 %

Procedure:
This was prepared in 83% yield from 1-(5-chloro-[1,8]naphthyridin-2-yl)ethanone (from step a) and 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (from Example 2, step e) using a similar procedure to that described in Example 55, step a. δH (400 MHz, CDCl3) 2.97 (3H, s), 7.45 (1H, t, J 9.0), 7.55 (1H, td, J 7.4, 1.2), 7.58-7.62 (4H, m), 7.71 (1H, td, J 7.4, 1.2), 7.84 (1H, dd, J 7.8, 0.8), 8.26 (1H, d, J 8.6), 8.59 (1H, d, J 8.6), 9.26 (1H, d, J 4.3). m/z (ES+) 368 [MH]+.
Reaction SMILES: Br[C:2]1[C:3]([F:27])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]4[NH:22][N:21]=[C:20]([CH:23]5[CH2:25][CH2:24]5)[N:19]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1.[CH3:28][O:29][CH2:30][C:31]([CH3:35])([OH:34])[C:32]#[CH:33].C(NC(C)C)(C)C>CN(C=O)C>[CH:23]1([C:20]2[N:19]=[C:18]([C:12]3[N:8]4[CH2:9][CH2:10][O:11][C:5]5[CH:4]=[C:3]([F:27])[C:2]([C:33]#[C:32][C:31]([OH:34])([CH3:35])[CH2:30][O:29][CH3:28])=[CH:26][C:6]=5[C:7]4=[N:14][C:13]=3[C:15]([NH2:17])=[O:16])[NH:22][N:21]=2)[CH2:25][CH2:24]1
Reactant: NC(=O)c1nc2n(c1-c1nc(C3CC3)n[nH]1)CCOc1cc(F)c(Br)cc1-2
Reactant: C#CC(C)(O)COC
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: COCC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1-c1nc(C2CC2)n[nH]1
Yield: 26.3 %

Procedure:
3-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)-9-fluoro-10-(3-hydroxy-4-methoxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was prepared similarly according to General Procedure E with slight modification. 10-bromo-3-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was reacted with 1-methoxy-2-methyl-but-3-yn-2-ol in a solution of DMF (1.3 mL/mmol) and diisopropylamine (2.6 mL/mmol) to afford 17 mg of the titled compound (26.3% yield). M+1=467.2. 1H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J=8.3 Hz, 1H), 8.38 (br s, 1H), 7.79 (br s, 1H), 7.05 (d, J=10.4 Hz, 1H), 5.66 (s, 1H), 5.00-4.81 (m, 2H), 4.65-4.52 (m, 2H), 3.47-3.34 (m, 2H), 3.37 (s, 3H), 2.13-2.04 (m, 1H), 1.45 (s, 3H), 1.03-0.95 (m, 2H), 0.93-0.87 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH2:9]([O:11][C:12]([C:14](=[CH:35][CH:36]=[CH:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH3:45])=[CH:40][CH:39]=1)[N:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13])[CH3:10]>C(#N)C>[CH2:44]([C:41]1[CH:40]=[CH:39][C:38]([C:37]2[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[N:15][C:14]([C:12]([O:11][CH2:9][CH3:10])=[O:13])=[CH:35][CH:36]=2)=[CH:43][CH:42]=1)[CH3:45]
Reactant: CCOC(=O)C(=CC=Cc1ccc(CC)cc1)N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccncc1
Solvent: CC#N
Product: CCOC(=O)c1ccc(-c2ccc(CC)cc2)c(-c2ccncc2)n1

Procedure:
Following General Procedure K, 4-pyridinecarboxaldehyde (92 mg, 0.86 mmol) and 3-ethoxycarbonyl-1,1,1-triphenyl-6-(4-ethylphenyl)-2-aza-1λ5-phosphahexa-1,3,5-triene (Compound 46, 434 mg, 0.86 mmol) in dry acetonitrile (10 ml) were reacted to produce the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28](I)[CH:27]=1>CO.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>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[C:30]([C:3]2[C:4]([OH:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:31]=1
Reactant: Fc1ccc(Br)cc1I
Reactant: OB(O)c1c(O)cccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Oc1cccc(F)c1-c1cc(Br)ccc1F
Temperature: 105 °C
Yield: 88.5 %

Procedure:
(2-Fluoro-6-hydroxyphenyl)boronic acid (50 mg, 0.321 mmol, 1.0 equiv), Pd(PPh3)4 (37.1 mg, 0.032 mmol, 0.1 equiv) and aqueous Na2CO3 (2 M, 401 μl, 0.802 mmol, 2.5 equiv) were mixed with toluene (2 mL) in a sealed microwave tube. 4-Bromo-1-fluoro-2-iodobenzene (96 mg, 0.321 mmol, 1.0 equiv) in MeOH (1.00 mL) was added to the above mixture. The resulted mixture was heated at 105° C. overnight. TLC showed the starting material disappeared and a new spot was produced. The reaction was allowed to cool to ambient temperature and then loaded on 12 g ISCO column and purified by 30% EtOAc/hexane to afford 5′-bromo-2′,6-difluoro-[1,1′-biphenyl]-2-ol (81 mg, 89%). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.54 (dd, J=6.3, 2.5 Hz, 1H), 7.48 (ddd, J=8.7, 4.5, 2.6 Hz, 1H), 7.21 (td, J=8.2, 6.7 Hz, 1H), 7.07 (t, J=8.9 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 6.71 (t, J=8.8 Hz, 1H). LCMS (M+1)=286.1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH2:12])=[O:11])#[CH:2].Cl[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][N:32]3[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:27][CH:26]=2)[N:15]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[Cu]I>[NH2:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:18]1[C:19]([C:20]([F:21])([F:22])[F:23])=[CH:14][N:15]=[C:16]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][N:32]3[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:29][CH:30]=2)[N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Reactant: C#Cc1ccccc1CC(N)=O
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCCC1c1ccc(Nc2ncc(C(F)(F)F)c(C#Cc3ccccc3CC(N)=O)n2)cc1
Temperature: 120 °C
Yield: 74 %

Procedure:
To a nitrogen de-gassed solution of 2-(2-ethynylphenyl)acetamide (I39) (0.054 g, 0.788 mmol) and tert-butyl 2-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I37) in dry DMF (4 mL) were added triethylamine (0.159 mL, 1.138 mmol), triphenylphosphine (0.011 g, 0.043 mmol), trans-dichlorobis(triphenylphosphine) palladium(II) (0.020 g, 0.028 mmol) and CuI (0.008 g, 0.04 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes. The reaction was concentrated to dryness in vacuo and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-5% methanol in EtOAc) to give the title compound (I40) (0.122 g, 74% yield) as a yellow glassy solid; 1H NMR (400 MHz, d6-DMSO) δ 10.48 (s, 1H), 8.82 (s, 1H), 7.73 (d, J=8.7 Hz, 2H), 7.65-7.55 (m, 1H), 7.55-7.47 (m, 1H), 7.47-7.33 (m, 3H), 7.16 (d, J=8.5 Hz, 2H), 7.01 (s, 1H), 5.29-5.22 (m, 1H), 3.92 (d, J=13.1 Hz, 1H), 3.70 (s, 2H), 2.71 (t, J=13.3 Hz, 1H), 2.34-2.24 (m, 1H), 1.82-1.68 (m, 1H), 1.54 (d, J=11.3 Hz, 2H), 1.45-1.22 (m, 11H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:33]([F:36])([F:35])[F:34])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:22](=[O:32])[CH2:23][NH:24]C(=O)OC(C)(C)C)[CH:17]=[CH:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:24][CH2:23][C:22]([N:18]1[C:19]2[C:15](=[CH:14][C:13](/[CH:12]=[CH:11]/[CH:10]([C:4]3[CH:3]=[C:2]([Cl:1])[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=3)[C:33]([F:35])([F:36])[F:34])=[CH:21][CH:20]=2)[CH:16]=[CH:17]1)=[O:32]
Reactant: CC(C)(C)OC(=O)NCC(=O)n1ccc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)n1ccc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (E)-tert-butyl 2-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indol-1-yl)-2-oxoethylcarbamate (0.05 g, 0.09 mmol) in DCM (5.0 mL) was added TFA (0.01 mL) and the reaction was stirred at RT for 16 h. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water and brine solution. The separated DCM layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude title compound which was used in the next step without further purification (50 mg).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH3:5])[CH3:3].[N:6]1([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:10]=[N:9][CH:8]=[N:7]1.C(#N)C>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:3])[CH:4]([CH3:5])[O:13][C:12]1([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1
Reactant: O=C(Cn1cncn1)c1ccccc1
Reactant: CC=C(C)C
Solvent: c1ccccc1
Solvent: CC#N
Product: CC1OC(Cn2cncn2)(c2ccccc2)C1(C)C
Yield: 27.1 %

Procedure:
4.0 ml (37.64 mmole) of 2-methyl-2-butene were added to a solution of 1.1 g (5.88 mmole) of 2-(1H-1,2,4-triazol-1-yl)acetophenone in 15 ml of a 2:1 by volume mixture of acetonitrile and benzene. The mixture was then irradiated with a 450 watt medium pressure mercury-arc lamp (Hannovea Co., Inc.) for 15 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was subjected to column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to afford 409.7 mg (yield 27%) of the title compound, melting at 102° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1.[CH3:16][NH:17][C@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19]>CS(C)=O.CC(=O)OCC>[CH3:11][C:8]1[N:6]2[N:7]=[C:2]([N:17]([CH3:16])[C@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2=[N:10][N:9]=1
Reactant: COC(=O)c1cc(Cl)nn2c(C)nnc12
Reactant: CN[C@@H](C)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1cc(N(C)[C@@H](C)c2ccccc2)nn2c(C)nnc12
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 13.9 %

Procedure:
A mixture of compound methyl 6-chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate (2.0 g, 8.85 mmol) and (S)-N-methyl-1-phenylethanamine (2.39 g, 17.7 mmol) in anhydrous DMSO (20 mL) was stirred for 30 min at 130° C. under microwave condition. After cooled to room temperature, the mixture was diluted with EA (100 mL) and washed with H2O (100 mL*3). The organic layer was dried over Na2SO4, concentrated in vacuum and purified by flash column chromatography (silica-gel, DCM: MeOH=10:1) to give product (S)-methyl 3-methyl-6-(methyl (1-phenylethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate as a yellow oil (400 mg, 14.5%). LRMS (M+H+) m/z: calcd 326; found 326.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.Cl.[CH3:12][O:13][NH2:14].C(N(CC)CC)C>C1COCC1.O.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:14][O:13][CH3:12])=[S:10])=[CH:4][CH:3]=1
Reactant: CON
Reactant: Fc1ccc(N=C=S)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CONC(=S)Nc1ccc(F)cc1
Yield: 59.9 %

Procedure:
4-Fluorophenyl isothiocyanate (306 mg, 2.0 mmol), O-methyl hydroxylamine hydrochloride (835 mg, 10.0 mmol), and triethylamine (1.5 mL, 11.0 mmol) are stirred in THF-water (6 mL) for 2 h. The reaction mixture is diluted with ether, washed with water, dried (MgSO4), and concentrated yielding 240 mg of pale yellow crystals.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15](=O)[C@@H:16]([NH:20][C:21](=O)OC(C)(C)C)[CH:17]([CH3:19])[CH3:18])[CH2:11][CH2:10]1.O.[OH-].[Na+]>C1COCC1>[CH3:7][O:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@@H:16]([NH:20][CH3:21])[CH:17]([CH3:19])[CH3:18])[CH2:11][CH2:10]1
Reactant: COC1CCN(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN[C@H](CN1CCC(OC)CC1)C(C)C
Temperature: 70 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
To a 1M solution of LAH in THF (22.26 mL, 22.26 mmol) was (S)-tert-butyl 1-(4-methoxypiperidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (Compound I1) (1.75 g, 5.57 mmol) dropwise added (over approximately 60 min) as a solution in THF (20 mL) under a nitrogen atmosphere. The resultant mixture was stirred at rt for 30 min and heated at 70° C. over night. The reaction was cooled to 0° C. Water (1 mL) was slowly added, followed by 15% aq. NaOH (1 mL), THF (20 mL) and additional water (2 mL). The reaction mixture was warmed to rt and stirred for 1 h. The mixture was filtered and the solid was washed with THF. The filtrate was dried (Na2SO4) and concentrated under reduced pressure to give the title compound (0.95 g, 80%). The obtained crude product was used without further purification. 1H NMR (400 MHz, CH3OD) δ 0.90, 1.44-1.69, 1.74-1.98, 1.98-2.12, 2.32, 2.53-2.71, 2.71-2.93, 3.15-3.29, 3.30. LCMS (M+H)+: 215.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[C:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)=[O:15].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:9]=[C:8]2[C:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)=[O:15]
Reactant: COc1ccc2[nH]cc(C(=O)c3cccc4ccccc34)c2c1
Reactant: CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCn1cc(C(=O)c2cccc3ccccc23)c2cc(OC)ccc21
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (1.54 g, 45.7 mmol, 60% in mineral oil) in DMF (100 ml) under nitrogen was added dropwise a solution of 5-methoxy-3-(1-naphthoyl)-1H-indole 4 (9.83 g, 32.6 mmol) in DMF (50 ml) and the mixture was stirred at 40° C. for 1 h. The solution was then cooled to room temperature and to this mixture was added a solution of 1-bromopentane (8.2 g, 54.3 mmol) in DMF (25 ml). The mixture was stirred at 60° C. for 1 h. The solvent was removed under high vacuum and the crude product was suspended in water (200 ml) and extracted by ethyl acetate (2×200 ml). The combined ethyl acetate phases were washed by water (1×100 ml), brine (1×100 ml), dried over sodium sulphate, filtered and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane/ethyl acetate (7/3) to give the title compound 5 as an oil which solidified upon cooling (7.1 g, 59%).
Reaction SMILES: [O:1]=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[CH2:13]1COCC1.C[Mg]Br.C1COCC1.O>CCOC(C)=O>[OH:1][C:2]1([CH3:13])[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(O)CN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h

Procedure:
tert-Butyl 3-oxoazetidine-1-carboxylate (1 g) and THF (20 ml), which had been cooled to 0° C., were mixed, and a 1.12M methylmagnesium bromide/THF solution (10 ml) was added thereto, followed by stirring at the same temperature for 1 hour. Water and EtOAc were added to the reaction mixture, the organic layer was dried over Na2SO4, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl 3-hydroxy-3-methylazetidine-1-carboxylate (1.0 g).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[C:28]([CH3:29])=[CH:27][S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[N:19]=1>>[N:21]1[CH:22]=[CH:23][N:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:15]2[C:28]([CH3:29])=[CH:27][S:26][C:16]=2[N:17]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: Cc1csc2nc(-c3cnccn3)nc(Cl)c12
Product: Cc1csc2nc(-c3cnccn3)nc(NCCc3ccc4c(c3)OCO4)c12

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyrazin-2-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-methylenedioxyphenethylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[C:26]3[C:27]4[C:19]([CH2:20][CH2:21][C:22]=4[CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1)=O.[CH3:28][C:29]([CH3:32])([O-])[CH3:30].[K+].CO.O>CN(C)C=O>[CH3:28][C:29]1[CH:32]=[CH:4][C:3]([CH:8]=[CH:1][C:3]2[CH:8]=[CH:7][C:6]([N:9]([C:16]3[C:26]4[C:27]5[C:19]([CH2:20][CH2:21][C:22]=5[CH:23]=[CH:24][CH:25]=4)=[CH:18][CH:17]=3)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:5][CH:4]=2)=[CH:1][CH:30]=1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccc3c4c(cccc24)CC3)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(C=Cc2ccc(N(c3ccccc3)c3ccc4c5c(cccc35)CC4)cc2)cc1
Reaction time: 0.33 h
Yield: 85 %

Procedure:
20.96 g (0.06 mol) of 5-[N-(4-formylphenyl)-N-phenylamino]acenaphthene prepared in Preparation Example 1 and 17.44 g (0.072 mol) of diethyl 4-methylbenzyl phosphonate were dissolved in 300 ml of N,N-dimethylformamide, and 10.1 g (0.09 mol) of potassium-tert-butoxide was added thereto at room temperature for 20 minutes. After the addition, the resultant mixture was further stirred for 2 hours. The reaction was determined to be finished when disappearance of the formyl compound was identified. The reaction product was poured into 1500 ml of methanol at a temperature of 5° C. or lower, and 150 ml of water was further dropwise added thereto to precipitate a crystal, which was then filtrated, washed with methanol and dried to obtain 22.18 g (yield: 84.5%) of a crude crystal. 21.0 g of the crude crystal thus obtained was purified by column chromatography (carrier: silica gel, eluent: toluene/hexane=1/4) to obtain 17.85 g of (purification yield: 85.0%, melting point: 148.0°-149.0° C.) of 5-{N-[4-(4-methylstyryl)phenyl]-N-phenylamino}acenaphthene (Compound No. 4).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].P(Br)(Br)[Br:20]>>[Br:20][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCCCO
Reactant: BrP(Br)Br
Product: CCCCCCCCCCCCCCCCCBr
Temperature: 60 °C
Reaction time: 48 h
Yield: 57.7 %

Procedure:
1-Heptadecanol (10 g, 39.1 mmol) was placed in a dry 25 ml round bottom flask attached to a reflux condenser and heated to 60° C. under a nitrogen atmosphere. Phosphorous tribromide (10 g, 39.1 mmol) was added dropwise and the resulting solution was stirred for 48 h. The reaction mixture was then cooled in an ice bath and quenched with a saturated solution of NaHCO3 (10 ml). The aqueous layer was extracted with ether (4×10 ml). The combined organic layers were dried over MgSO4, filtered and concentrated. The crude residue was flash chromatographed (hexanes) to afford 7.2 g (57%) of 1-bromoheptadecane as a colorless oil.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]#[N:13])[CH2:3][CH2:2]1.[C:14](OC(=O)C)(=[O:16])[CH3:15].C([O-])(=O)C.[Na+]>[Ni]>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[CH2:3][CH2:2]1
Reactant: N#CCC1CCOc2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: [Ni]
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)NCCC1CCOc2ccccc21
Temperature: 50 °C

Procedure:
The saturated cyano compound obtained in Step B is solubilized in the reactor of a Parr apparatus with acetic anhydride. Sodium acetate (1.5 eq.) and also Raney nickel (6 mg per 50 mg of product) are then introduced into the reaction medium. The whole is heated at 50° C. under hydrogen pressure of 40 psi for 12 hours. Once the solvent has been removed after returning to normal temperature and pressure conditions, extraction is carried out with ethyl acetate. Purification of the concentrated organic phase by flash chromatography (CHCl3/AcOEt 7/3) results in the desired amide. Colourless gum.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:28]>>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[NH:28])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Fc1cccc(F)c1COc1cccnc1NC(=S)Nc1ccc(Cl)cc1
Reactant: N
Product: N=C(Nc1ccc(Cl)cc1)Nc1ncccc1OCc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of yellow mercuric oxide (0.75 g, 0.0035 mol), N-[3-(2,6-difluorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea (1.18 g, 0.003 mol) and methanolic ammonia solution (40 ml) was stirred for 2 days at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent and recrystallisation from acetonitrile gave the desired product. Yield 0.5 g (44%), m.p. 146°-148 ° C.