Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([C:5]1[CH:6]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:8]=[C:9]([F:11])[CH:10]=1)([F:4])[CH3:3].[Cl:21][C:22]1[CH:23]=[C:24]([CH2:28][N:29]2[CH:33]=[CH:32][N:31]=[C:30]2[CH3:34])[N:25]=[N:26][CH:27]=1>>[ClH:21].[F:4][C:2]([C:5]1[CH:6]=[C:7]([C:22]2[CH:23]=[C:24]([CH2:28][N:29]3[CH:33]=[CH:32][N:31]=[C:30]3[CH3:34])[N:25]=[N:26][CH:27]=2)[CH:8]=[C:9]([F:11])[CH:10]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1cc(F)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: Cc1nccn1Cc1cc(-c2cc(F)cc(C(C)(F)F)c2)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=333.3 (M+H+), was prepared from 2-[3-(1,1-difluoro-ethyl)-5-fluoro-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7](=O)[C:8]3[C:13]([C:2]=12)=[CH:12][CH:11]=[CH:10][CH:9]=3.O.NN>C(O)COCCO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[C:13]([C:2]=12)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: O=C1c2ccccc2-c2ncccc21
Agent: NN
Solvent: OCCOCCO
Solvent: O
Product: c1ccc2c(c1)Cc1cccnc1-2
Temperature: 170 °C
Yield: 80.7 %

Procedure:
A mixture of 18.1 g (100 mmol) of 5H-indeno[1,2-b]pyridin-5-one, 27 ml (400 mmol) of hydrazine monohydrate, and 500 ml diethylene glycol was degassed and placed under nitrogen, and then heated at 170° C. for 12 h. After the reaction finish, the mixture was allowed to cool to room temperature. The organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed to give product 13.5 g (81%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=O)=[C:4]([N:11]([CH3:20])[C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]=1[CH3:21].BrC1SC(C(OC)=O)=C(NC)C=1C.CCN(C(C)C)C(C)C.ClC(=O)CC(OCC)=O>CN(C)C1C=CN=CC=1.CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[S:6][C:5]2[C:7]([OH:9])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12](=[O:19])[N:11]([CH3:20])[C:4]=2[C:3]=1[CH3:21]
Reactant: CCOC(=O)CC(=O)N(C)c1c(C(=O)OC)sc(Br)c1C
Agent: CCOC(=O)CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: CNc1c(C(=O)OC)sc(Br)c1C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(O)c2sc(Br)c(C)c2n(C)c1=O
Reaction time: 18 h

Procedure:
Methyl 5-bromo-3-(3-ethoxy-N-methyl-3-oxopropanamido)-4-methylthiophene-2-carboxylate. A solution of methyl 5-bromo-4-methyl-3-(methylamino)thiophene-2-carboxylate (0.28 g, 1.1 mmol), DIEA (0.22 mL, 1.3 mmol), N,N-dimethylpyridin-4-amine (0.020 g, 0.16 mmol) in DMF (4 mL) was treated at room temperature with ethyl 3-chloro-3-oxopropanoate (0.16 mL, 1.3 mmol) and stirred for 18 hours. The mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, and evaporated. The residue was purified by flash chromatography using EtOAc/hexanes to give the title compound. MS (ESI) m/z: Calculated 378.2; Observed; 379.0. 1H NMR (300 MHz, CDCl3) δ ppm 4.12-4.11 (2H, m), 3.86 (3H, s), 3.16 (3H, s), 3.12 (2H, s), 2.10 (3H, s), 1.23 (3H, t, J=7.1 Hz).
Reaction SMILES: N([CH2:8][CH2:9][OH:10])(CCO)CCO.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16](N)[CH:15]=1)([O-])=O>O>[NH2:11][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:17](=[O:20])[C:16]1[C:9](=[CH:8][CH:19]=[CH:14][CH:15]=1)[OH:10]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: OCCN(CCO)CCO
Solvent: O
Product: Nc1ccccc1
Product: O=Cc1ccccc1O

Procedure:
The 1:1-chrome complex containing 43.4 parts of the dye formed from diazotised 4-nitro-2-aminophenol-6-sulfonic acid and 1-(4'-methylphenyl)-3-methyl-5-pyrazolone as well as 5.2 parts of chromium is introduced into 250 parts of water and 250 parts of triethanolamine, and 15.4 parts of 4-nitro-2-aminophenol and 22.6 parts of the monoazo dye formed from diazotised aniline and salicylaldehyde are added. The reaction mixture is held, with stirring, at pH 7.5-8 and at 80° C. until the formation of the 1:2-complex dye is complete. The reaction mixture is then neutralised with hydrochloric acid; it is subsequently filtered, and the dye is rinsed with 750 parts of 25% sodium chloride solution and dried. It dyes wool, polyamide and leather in an orange shade having good fastness properties.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2N=N[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:11][C:10]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:5][CH:4]=1)[CH3:2].[CH:26](N1CCCC1)=[CH:27][CH3:28]>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:26]=[C:27]([CH3:28])[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:11][C:10]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)c1nnc(-c2ccc(CC)cc2)c(-c2ccccc2)n1
Reactant: CC=CN1CCCC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1nc(-c2ccccc2)c(-c2ccc(CC)cc2)cc1C

Procedure:
Following General Procedure D, ethyl 6-(4-ethylphenyl)-5-phenyl-1,2,4-triazine-3-carboxylate (Compound 13, 200 mg, 0.60 mmol) and crude 1-propenyl-pyrrolidine (Compound 39, 2 g) in CHCl3 (10 ml) were reacted to produce the title compound as a yellow oil.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[S:13])=[C:10]([CH3:17])[C:9]=1[O:18][CH3:19]>ClCCl>[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([Cl:4])=[S:13])=[C:10]([CH3:17])[C:9]=1[O:18][CH3:19]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1c(F)ccc(C(O)=S)c1C
Solvent: ClCCl
Product: COc1c(F)ccc(C(=S)Cl)c1C
Yield: 103.5 %

Procedure:
2,4-Difluoro-3-methoxybenzoic acid (38.2 g) was added to a stirred solution of methyl mercaptan (9.7 g) in dry tetrahydroftran under an inert atmosphere. A solution of n-butyl lithium (162 ml of a 2.5M solution in hexane) was added dropwise at −78° C. After 1 hour the mixture was allowed to warm to 20° C. overnight and evaporated. Hydrochloric acid (2M) and ether were added and the organic phase washed (water), dried mil (magnesium sulphate) and evaporated. The residue was triturated with hexane to give 4-fluoro-3-methoxy-2-methylthiobenzoic acid (29.2 g), NMR 2.6 (s, 3H), 4.0 (s, 3H), 7.1 (m, 1H), 7.9 (m, 1H). oxalyl chloride (51.5 g) was added to a stirred solution of 4-fluoro-3-methoxy-2-methylthiobenzoic acid (29.2 g) in dichloromethane. After 3.5 hours the mixture was evaporated to give the title compound (33.0 g), used directly in the above reactions.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:16][C@@H:17]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:18](Cl)=[O:19]>>[CH3:16][C@@H:17]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:18]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:19]
Reactant: COc1ccc(-c2cccc(O)c2)cc1
Reactant: CCCCCC[C@H](C)C(=O)Cl
Product: CCCCCC[C@H](C)C(=O)Oc1cccc(-c2ccc(OC)cc2)c1

Procedure:
Using 3'-hydroxy-4-methoxy-1,1'-biphenyl (4.2 g, 20.4 mmol) obtained in Example 1, (3) and (S)-2-methyloctanoylchloride (4.1 g, 21.5 mmol), the reaction was carried out in the same manner as described in Example 1, (5), to give the title compound as a pale yellow oil; yield: 5.4 g.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([Cl:6])=[O:5].[CH3:13][N:14]([CH3:29])[CH:15]1[CH2:20][CH2:19][C:18]([C:21]2[CH:22]=[C:23]([NH2:28])[CH:24]=[C:25]([F:27])[CH:26]=2)=[CH:17][CH2:16]1>>[ClH:6].[CH3:13][N:14]([CH3:29])[CH:15]1[CH2:20][CH2:19][C:18]([C:21]2[CH:22]=[C:23]([NH:28][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:10][C:9]([F:11])=[CH:8][C:7]=3[F:12])[CH:24]=[C:25]([F:27])[CH:26]=2)=[CH:17][CH2:16]1
Reactant: CN(C)C1CC=C(c2cc(N)cc(F)c2)CC1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Product: CN(C)C1CC=C(c2cc(F)cc(NC(=O)c3c(F)cc(F)cc3F)c2)CC1
Product: Cl

Procedure:
Using a method similar to example 10, using 2,4,6-trifluoro-benzoyl chloride and 3-(4-dimethylamino-cyclohex-1-enyl)-5-fluoro-phenylamine (isomer 5A, preparation 5) provides the title compound: Free base MS (ES) m/z=393 (M+H)+; 1H NMR of free base (CDCl3): δ 7.68 (s, 1H), 7.42 (d, 1H, J=10 Hz), 7.28 (s, 1H), 6.91 (dd, 1H, J=10 Hz, J=2 Hz), 6.77 (dd, 2H, J=10 Hz, J=10 Hz), 6.11 (bs, 1H), 2.43 (m, 4H), 2.35 (s, 6H), 2.16 (m, 2H), 1.58 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[CH:32]#[C:33][CH2:34][CH2:35][CH2:36][CH3:37]>CN(C=O)C.C(N(CC)CC)C.CCOCC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([C:32]#[C:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: C#CCCCC
Reactant: COC(=O)c1cc(Br)cc(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCC#Cc1cc(C)c(N(Cc2ccccc2)S(=O)(=O)c2ccc(OC)cc2)c(C(=O)OC)c1
Yield: 60.9 %

Procedure:
To a solution of 0.324 g (0.643 mmol) of the product of Example 11 in 2.0 mL of DMF and 2.0 mL of triethylamine was added 0.088 mL (0.771 mmol) of 1-hexyne, 9 mg (0.013 mmol) of bis(triphenylphosphine)palladium(II)dichloride and 1.2 mg of copper(I)iodide. The reaction mixture was then heated to 65 degrees for 5 h and an additional 0.22 mL of 1-hexyne was added to the reaction. The motion was then heated to zeflux for 6 h and then cooled to room tempemaure and diluted with ether. The organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica eluting with EtOAc-Hex (1:10) to provide 0.198 g (61%) of the desired product as a yellow oil. Electrospray Mass Spec: 506.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.FC1C=C([N+]([O-])=O)C=CC=1OC1C2SC(C(NCCN3CCOCC3)=O)=CC=2N=CN=1.FC1C=C([N+]([O-])=O)C=CC=1O.[Cl:53][C:54]1[CH:55]=[C:56]([OH:63])[CH:57]=[CH:58][C:59]=1[N+:60]([O-:62])=[O:61]>>[Cl:53][C:54]1[CH:55]=[C:56]([CH:57]=[CH:58][C:59]=1[N+:60]([O-:62])=[O:61])[O:63][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1Cl
Reactant: Clc1ncnc2ccsc12
Agent: O=C(NCCN1CCOCC1)c1cc2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: O=[N+]([O-])c1ccc(O)c(F)c1
Product: O=[N+]([O-])c1ccc(Oc2ncnc3ccsc23)cc1Cl
Yield: 72 %

Procedure:
Starting from the chloride 20 (scheme 4) and following the procedure described above for the synthesis of compound 24 (scheme 4, example 22) remplacing 2-fluoro-4-nitrophenol with 3-chloro-4-nitrophenol, title compound 171 was obtained in 72% yield. LRMS (M+1) 307.7 (100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH2:9].[Li]CCCC.[CH:15](=[O:20])[CH2:16][CH2:17][CH:18]=[CH2:19].Cl[Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24]>C1COCC1.C1C=CC=CC=1>[CH:23]([Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[O:20][CH:15]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH2:9])[CH2:16][CH2:17][CH:18]=[CH2:19])([CH3:25])[CH3:24]
Reactant: C=Cc1ccccc1Br
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: C=CCCC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: C=CCCC(O[Si](C(C)C)(C(C)C)C(C)C)c1ccccc1C=C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 74 %

Procedure:
1-Bromo-2-vinylbenzene (2.8146 g, 15.38 mmol) was azeotropped by dry benzene twice before taken up in THF (50 ml). The solution was cooled to −78° C. BuLi (6.77 ml, 16.91 mmol) was added to the reaction mixture at −78° C. and stirred for 20 min at this temperature. pent-4-enal (1.670 ml, 16.91 mmol) was added to the reaction mixture and stirred for 4 hours while the bath temperature gradually warmed up. Chlorotriisopropylsilane (3.58 ml, 16.91 mmol) was added to the reaction mixture and the reaction was stirred overnight while the reaction was warmed up to room temperature. The solvent was mostly removed via vacuum and the crude was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, dried (Na2SO4), filtered and concentrated. The product was obtained by flash column eluted with ether in hexane from 0 to 30% (3.9 g, 74% yield). MS(ESI)[M+H+]=346.46.
Reaction SMILES: [C:1]1(O)[C:5](=[O:6])[C:3](=O)[C:2]=1[OH:7].[CH3:9][N:10]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21](=[O:24])[CH:22]=[CH2:23])[CH:15]=1)[CH2:11][CH2:12][OH:13].[CH3:25][CH2:26][CH2:27][CH2:28][OH:29]>C1(C)C=CC=CC=1>[C:21]([O:20][C:16]1[CH:15]=[C:14]([N:10]([CH2:11][CH2:12][OH:13])[CH3:9])[CH:19]=[CH:18][C:17]=1[C:3]1[C:2]([OH:7])=[C:1]([C:27]2[CH:26]=[CH:25][C:14]([N:10]([CH2:11][CH2:12][OH:13])[CH3:9])=[CH:15][C:28]=2[O:29][C:16](=[O:20])[CH:17]=[CH2:18])[C:5]=1[OH:6])(=[O:24])[CH:22]=[CH2:23]
Reactant: O=c1c(O)c(O)c1=O
Reactant: CCCCO
Reactant: C=CC(=O)Oc1cccc(N(C)CCO)c1
Solvent: Cc1ccccc1
Product: C=CC(=O)Oc1cc(N(C)CCO)ccc1C1=C(O)C(c2ccc(N(C)CCO)cc2OC(=O)C=C)=C1O
Temperature: 120 °C

Procedure:
342 mg of squaric acid and 2.12 g of 2-(methyl(3-acryloxyphenyl)amino)ethan-1-ol were put in a 100 mL 3-necked round bottom flask, and 40 mL of n-BuOH and 20 mL of toluene were added thereto. The mixture was heated and refluxed at 120° C. for 7 hours. Next, a Dean-Stark trap set was used to remove water generated during the reaction and kept being reacted. When the reaction was complete, the reactant was cooled down, producing crystals. The crystals were filtered, several times cleaned with hexane, and once more recrystallized, obtaining a desired compound.
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH:12][C:13]2[N:14]([CH3:19])[N:15]=[C:16]([CH3:18])[CH:17]=2)=[CH:10][CH:9]=[C:8]([CH3:20])[N:7]=1)=[O:5])C.[NH2:21][C:22]1[N:23]=[C:24]([CH3:27])[S:25][CH:26]=1>>[CH3:27][C:24]1[S:25][CH:26]=[C:22]([NH:21][C:4]([C:6]2[C:11]([NH:12][C:13]3[N:14]([CH3:19])[N:15]=[C:16]([CH3:18])[CH:17]=3)=[CH:10][CH:9]=[C:8]([CH3:20])[N:7]=2)=[O:5])[N:23]=1
Reactant: Cc1nc(N)cs1
Reactant: CCOC(=O)c1nc(C)ccc1Nc1cc(C)nn1C
Product: Cc1ccc(Nc2cc(C)nn2C)c(C(=O)Nc2csc(C)n2)n1

Procedure:
The title compound, was prepared from 3-(2,5-Dimethyl-2H-pyrazol-3-ylamino)-6-methyl-pyridine-2-carboxylic acid ethyl ester and 4-Amino-2-methylthiazole in accordance with the general method of Example 78, step 2 to yield the final compound as a light-yellow solid, MS (ISP): m/e=343.0 (M+H+).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:14]N1C(=O)C2=CC=CC=C2C1=O.O=O>C(O)(=O)C>[C:1]1(=[O:14])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=O
Solvent: CC(=O)O
Product: O=C1C=CC=C2C1=Cc1ccccc12
Yield: 48 %

Procedure:
A mixture of 10 millimoles of fluorene, 1 millimole of N-hydroxyphthalimide, 0.05 millimole of acetylacetonatovanadium V(AA)3 and 25 milliliters of acetic acid was stirred, in an oxygen atmosphere, at a temperature of 90° C. for 6 hours. In analyzing a product in the reaction mixture by gas chromatography, fluorene was transformed into fluorenone (yield 48%) with a transformation rate of 54 percent.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=[O:26])[CH2:21][CH2:20]2)=[C:7]2[CH:15]=[N:14][N:13]([CH2:16][CH3:17])[C:8]2=[N:9][C:10]=1[CH2:11][CH3:12])=[N+:2]=[N-:3].Cl.C([N:36](CC)C(C)C)(C)C.C[Si](N=C=O)(C)C>O1CCOCC1.ClCCl.O>[N:1]([CH2:4][C:5]1[C:6]([NH:18][CH:19]2[CH2:20][CH2:21][N:22]([C:25]([NH2:36])=[O:26])[CH2:23][CH2:24]2)=[C:7]2[CH:15]=[N:14][N:13]([CH2:16][CH3:17])[C:8]2=[N:9][C:10]=1[CH2:11][CH3:12])=[N+:2]=[N-:3]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCN(C(=O)OC(C)(C)C)CC2)c1CN=[N+]=[N-]
Reactant: CCN(C(C)C)C(C)C
Agent: C[Si](C)(C)N=C=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCN(C(N)=O)CC2)c1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
A solution of 1,1-dimethylethyl 4-{[5-(azidomethyl)-1,6-diethyl-1H-pyrazolo[3,4-b]pyridin-4-yl]amino}-1-piperidinecarboxylate (8.9 g, 20.8 mmol, e.g. which can be as prepared in Intermediate 15) in 1,4-dioxane (50 ml) was treated with 4M HCl in 1,4-dioxane (125 ml). After 2 hours the solvent was evaporated and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic phase was collected and washed with saturated aqueous sodium bicarbonate solution. The combined aqueous phases were back-extracted with dichloromethane. The combined organic phases were dried (Na2SO4) and the solvent was evaporated to give an oil (LCMS showed MH+=329; TRET=1.75 min). The oil was dissolved in dichloromethane (100 ml), and the solution was treated with N,N-diisopropylethylamine (6.1 ml, 35.0 mmol) followed by trimethylsilyl isocyanate (3.6 ml, 26.6 mmol, commercially available e.g. trimethylsilyl isocyanate 85% from Aldrich). The reaction mixture was stirred at room temperature overnight. Additional N,N-diisopropylethylamine (6.1 ml, 35.0 mmol) and trimethylsilyl isocyanate (3.6 ml, 26.6 mmol) was added. After stirring for a further 7 hours, additional trimethylsilyl isocyanate (3.6 ml) was added and stirring was continued over the weekend (e.g. this can be about 62 hours). Water (100 ml) was added and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration, washed with water followed by diethyl ether, and then dried to give the title compound (2.21 g). LCMS m/z 372 [MH+]; TRET=2.08 min.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[C:8]1([C:14]([CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)O)=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N:24]1C=CC=CC=1>>[C:8]1([C:14]2[N:24]=[C:1]([CH2:2][CH2:3][C:4]([OH:6])=[O:5])[O:7][C:16]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1ccncc1
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: O=C1CCC(=O)O1
Product: O=C(O)CCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Yield: 67 %

Procedure:
A 5 liter flask was set up and equipped with stirrer, thermometer, reflux condenser and nitrogen inlet. Succinic anhydride (373 grams), benzoin (531 grams) and pyridine (300 milliliters; 296 grams) were introduced. The flask was purged with nitrogen and the reaction mixture heated to 90°-95° C. The mixture was stirred for one and a half hours at this temperature. Glacial acetic acid (1300 milliliters) and ammonium acetate (385 grams) were added to the reaction mixture and the mixture reheated to 90°-95° C. Stirring was continued and this temperature was maintained for a further 2 hours. The mixture was filtered, rinsing through with glacial acetic acid (150 milliliters). Distilled water (750 milliliters) was added and the mixture reheated to 90°-95° C. before gradual cooling with stirring to 15° C. over 1 hour. After filtering and washing with a mixture of acetic acid and distilled water in a ratio of 2:1 (600 milliliters), the product was slurried with distilled water (1000 milliliters). After filtering and washing with distilled water (2×400 milliliters), the product was dried at 90°-100° C. under vacuum. 702 Grams (67% yield) of β-(4,5-diphenyloxazol-2-yl)propionic acid were obtained as a white crystalline powder, m.p. 163°-165° C. The material was investigated for quality by TLC. The product had high purity and merely showed a number of very faint trace impurities.
Reaction SMILES: Cl.[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([C:29]5[O:30][C:31]([CH:34]6OCC[O:35]6)=[CH:32][CH:33]=5)=[CH:26][CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>C1COCC1>[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([C:29]5[O:30][C:31]([CH:34]=[O:35])=[CH:32][CH:33]=5)=[CH:26][CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(Cn2ncc3cc(Nc4ncnc5cc(-c6ccc(C7OCCO7)o6)ccc45)ccc32)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccc3c(Nc4ccc5c(cnn5Cc5ccccc5)c4)ncnc3c2)o1

Procedure:
Prepared according to Procedure C from (1-benzyl-1H-indazol-5-yl)-[7-(5-(1,3-dioxolan-2-yl)furan-2-yl)quinazolin-4-yl]-amine hydrochloride (0.27 g) stirred in THF:2N HCl (2:1, 15 ml) at 20° C. for 1 hour. Filtration gave 5-[4-(1-benzyl-1H-indazol-5-ylamino)-quinazolin-7-yl]-furan-2-carbaldehyde, which was not further characterised.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:27]=[CH:26][C:7]([NH:8][CH:9]=[C:10]([C:24]#[N:25])[C:11]([NH:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([Cl:22])=[CH:16][C:15]=2[Cl:23])=O)=[CH:6][C:5]=1[F:28])[CH3:2].P(Cl)(Cl)(Cl)=O>C(#N)C.CO>[Cl:23][C:15]1[CH:16]=[C:17]([Cl:22])[C:18]([O:20][CH3:21])=[CH:19][C:14]=1[NH:13][C:11]1[C:26]2[C:7](=[CH:6][C:5]([F:28])=[C:4]([O:3][CH2:1][CH3:2])[CH:27]=2)[N:8]=[CH:9][C:10]=1[C:24]#[N:25]
Reactant: CCOc1ccc(NC=C(C#N)C(=O)Nc2cc(OC)c(Cl)cc2Cl)cc1F
Solvent: CC#N
Solvent: CO
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
A suspension of 4-ethoxy-3-fluoroanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide (6.28 9, 14.8 mmol) in 54 mL of acetonitrile and 2.0 mL of methanol was heated to reflux and phosphorous oxychloride (8.3 mL, 88.8 mmol) was added dropwise. The mixture was heated at reflux for 17 hours. The resultant solution was concentrated in vacuo and acetonitrile was added to the residue. The solid was collected by filtration, washed with acetonitrile. The solid was suspended in tetrahydrofuran and neutralized with concentrated ammonium hydroxide. After stirring for 30 minutes, water was added and the mixture was stirred for 1 hour. The solid was collected by filtration, washed with water, followed by 1:1 diethyl ether and hexane. The light yellow solid was dried in vacuo to provide 2.2 g (37%) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-fluoro-3-quinolinecarbonitrile, mp 185-187° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.95 (t, J=7 Hz, 3H), 3.87 (s, 3H), 4.29 (q, J=7 Hz, 2H), 7.39 (s, 1H), 7.66-7.81 (m, 2H), 8.09 (d, J=9 Hz, 1H), 8.49 (s, 1H), 9.80 (s, 1H); MS (ES) m/z 406.1, 408.2 (M+H)+
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([OH:11])=O)[CH:2]=[CH2:3].[CH2:12]([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])[CH3:13].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C.S([O-])(O)(=O)=O.[K+]>ClCCl>[CH2:1]([N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[C:14]([CH2:12][CH3:13])[CH:15]=1)=[O:11])[CH:2]=[CH2:3]
Reactant: CCc1cccc(N)c1
Reactant: C=CCn1cccc1C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCn1cccc1C(=O)Nc1cccc(CC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
A mixture of 1-allyl-1H-pyrrole-2-caboxylic acid (270 mg, 1.79 mmol), m-ethylaniline (0.43 g, 2.48 mmol), BOP-Cl (500 mg, 1.96 mmol) and triethylamine (210 mg, 2.08 mmol) in dichloromethane (3 ml) was stirred for 2 hours at room temperature. To the reaction mixture was added an aqueous 5% potassium hydrogensulfate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water, an aqueous saturated sodium hydrogencarbonate solution and an aqueous saturated sodium chloride solution, and dried over magnesium sulfate. The solvent was removed and the residue was purified with silica gel chromatography (hexane:ethyl acetate=5:1→3:1) to give the subject compound (229 mg, 50%).