Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.CCN(CC)CC>CCOC(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CCOCC2)nc1
Temperature: 25 °C
Yield: 93 %

Procedure:
A mixture of 2-chloro-5-nitropyridine (3.17 g, 20 mmol), morpholine (2.00 g, 23 mmol) and Et3N (2.43 g, 24 mmol) in EtOAc (200 mL) was refluxed for 3 h, then cooled to rt, and washed with water (100 mL×3). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a yellow solid (3.89 g, 93%).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH:7]2[CH2:11][C:10](=[O:12])[CH:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:8]2=[O:22])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>ClCCl>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH:7]2[CH2:11][C:10]([O:12][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[C:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:8]2=[O:22])=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(C2C(=O)CC(Cc3ccc(F)cc3)C2=O)c(C)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(C2=C(OC(=O)C(C)(C)C)CC(Cc3ccc(F)cc3)C2=O)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
To a solution of 4-(4-fluoro-benzyl)-2-(2,4,6-trimethyl-phenyl)-cyclopentane-1,3-dione (30 mg, 0.09 mmol) in dichloromethane (1 ml) and triethylamine (52 μl, 0.37 mmol) is added the pivaloyl chloride (34 μl, 0.37 mmol) at room temperature. The reaction mixture is stirred overnight at room temperature. Silica gel is added to the crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel to give 2,2-dimethyl-propionic acid 4-(4-fluoro-benzyl)-3-oxo-2-(2,4,6-trimethyl-phenyl)-cyclopent-1-enyl ester (31 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)CCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:32]4[S:33][CH:34]=[CH:35][CH:36]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: c1ccc(COc2ccc(Nc3ncnc4ccc(-c5cccs5)cc34)cc2)cc1
Yield: 59.8 %

Procedure:
The (4-benzyloxy-phenyl)-(6-bromoquinazolin-4-yl)-amine (200 mg, 0.49 mmol), 2-(tributylstannyl)thiophene (200 mg, 0.53 mmol) and bis(triphenylphosphine)palladium(II) chloride (catalytic) were dissolved in dioxan (3 ml) and heated at reflux under nitrogen for 4 hr. The cooled reaction mixture was absorbed onto silica and purified by flash column chromatography (silica gel, eluting with an ethyl acetate/iso-hexane gradient). The resulting solid was triturated with iso-hexane/ethyl acetate to give the product (120 mg, 60%) as a pale yellow solid; δH [2H6]-DMSO 9.88 (1H, b, NH), 8.76 (1H, s, 5-H), 8.49 (1H, s, 2-H), 8.12 (1H, d, 7-H), 7.82-7.60 (5 H, m, thiophene-3-H, thiophene-5-H, 8-H, 2′-H, 6′-H), 7.52-7.30 (5H, m, 5×Ph-H), 7.23 (1H, t, thiophene-4H), 7.18 (2H, d, 3′-H, 5′-H), 5.11 (2H, s, CH2); m/z 410 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH3:26][C:27]([NH2:31])([CH3:30])[CH2:28][NH2:29]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:29][CH2:28][C:27]([CH3:30])([NH2:31])[CH3:26])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: CC(C)(N)CN
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(C)(C)N)c2c1

Procedure:
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2-methylpropane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (d, J=7.83 Hz, 1 H), 7.85 (d, J=7.58 Hz, 1 H), 7.70 (s, 1 H), 7.60 (t, J=7.33 Hz, 1 H), 7.48-7.38 (m, 2 H), 7.29-7.27 (m, 1 H), 6.09 (s, 1 H), 5.15 (brs, 2 H), 3.57 (brs, 2 H), 3.26 (s, 2 H), 2.43 (s, 3 H), 1.34-1.20 (m, 6 H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=O)=[CH:7][CH:8]=2)[C:3]([CH:12]=O)=[N:2]1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]>>[NH:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:21]=[C:12]1[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:10]3[NH:21][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[N:14]=3)[CH:5]=2)[NH:1][N:2]=1
Reactant: O=Cc1ccc2[nH]nc(C=O)c2c1
Reactant: Nc1ccccc1N
Product: c1ccc2[nH]c(-c3ccc4[nH]nc(-c5nc6ccccc6[nH]5)c4c3)nc2c1

Procedure:
The title compound was synthesized from 1H-Indazole-3,5-dicarbaldehyde and 1,2-diaminobenzene using the methods described in Example 4 except that an excess of 1,2-diaminobenzene was used. LC/MS m/z 351.2 (MH+), Rt 2.03 minutes.
Reaction SMILES: [CH3:1][NH:2][N+:3]([O-:5])=[O:4].[C:6]1(Cl)[C:7](=[CH:11][C:12](=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[N+:13]([O-:15])=[O:14])[N+:8]([O-:10])=[O:9]>>[CH3:1][N:2]([N+:3]([O-:5])=[O:4])[C:11]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: CN[N+](=O)[O-]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Product: CN(c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-])[N+](=O)[O-]

Procedure:
Methylnitramine decomposes explosively in contact with concentrated sulfuric acid. It is evolved when aniline reacts with tetryl; a diphenylamine derivative is produced simultaneously. Methylnitramine reacts with picryl chloride to form tetryl.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:5]1=[O:22])(=O)C.[CH3:23][N:24]([CH2:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[CH3:25].[OH-].[Na+]>CN(C=O)C.CO>[CH3:25][N:24]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([NH:31]/[C:13](=[C:6]2\[C:5](=[O:22])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[CH:32][CH:33]=1)[CH3:23]
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccc(Cl)cc2)c2ccccc21
Reactant: CN(C)Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccc(Cl)cc2)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(4-chlorophenyl)-methylidene)-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CCO>[F:13][C:12]1[C:6]2[CH2:5][O:4][CH:3]([CH2:2][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[O:8][C:7]=2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=1
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Solvent: CCO
Product: CS(=O)(=O)c1cc(F)c2c(c1)OC(CN1CCCCC1)OC2

Procedure:
Preparation according to Example 34 using 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (7 mg, 0.021 mmol), piperidine (0.5 ml) and EtOH (3 ml). MS m/z (rel. intensity, 70 eV) 329 (M+, 0.6), 99 (8), 98 (bp), 95 (4), 70 (4), 55 (6).
Reaction SMILES: [Br:1]Br.[OH:3][CH2:4][C:5]1[S:21][C:8]2[CH:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][N:11]([CH3:14])[CH2:12][CH2:13][C:7]=2[CH:6]=1.O.O.O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:6]1[C:7]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[S:21][C:5]=1[CH2:4][OH:3]
Reactant: BrBr
Reactant: CN1CCc2cc(CO)sc2C(c2ccccc2)C1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CN1CCc2c(sc(CO)c2Br)C(c2ccccc2)C1

Procedure:
Bromine (0.23 ml) was added dropwise to a stirred solution of 2-hydroxymethyl-6-methyl-8-phenyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine (1.20 g) and sodium acetate trihydrate (1.8 g) in acetic acid (60 ml) at room temperature. After 1 hour the solution was evaporated, the residue dissolved in water (100 ml), basified to pH~11 with 0.880 ammonia solution and extracted with dichloromethane (2×100 ml). The extracts were dried, filtered and evaporated to a brown oil (1.74 g). Chromatography on silica, eluting with 2% methanol in dichloromethane gave a solid (0.80 g) which was recrystallised from toluene (15 ml) to give the title product (m.p. 141°).
Reaction SMILES: [NH2:1][C:2]1([C:26]#[N:27])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])OCC[O:13]2)[CH2:4][CH2:3]1.S(=O)(=O)(O)[OH:29]>O>[NH2:1][C:2]1([C:26]([NH2:27])=[O:29])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:13])[CH2:4][CH2:3]1
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(Cl)cc1C1(CCCCN2CCC(N)(C#N)CC2)OCCO1
Solvent: O
Product: COc1ccc(Cl)cc1C(=O)CCCCN1CCC(N)(C(N)=O)CC1
Temperature: 0 °C

Procedure:
A mixture of 4-amino-1-[5-(5-chloro-2-methoxyphenyl)-5,5-ethylenedioxypentyl]piperidine-4-carbonitrile (5.2 g, 13.1 mmol), prepared as in Example 20, water (1.6 mL) and sulfuric acid (41 mL) was warmed approximately 5 minutes on a steam bath and then cooled to 0° C. and diluted with water (150 mL). The mixture was washed with ethyl acetate (2×), cooled to 0° C. treated with potassium hydroxide, filtered, washed with chloroform and extracted with methylene chloride (4×). The combined extracts were dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate/hexane to give 4-amino-1-[5-(5-chloro-2-methoxyphenyl)-5-oxopentyl]piperidine-4-carboxamide (4.2 g, 11.4 mmol). Free base (135 mg, 0.367 mmol) was recrystallized from a solution of hydrogen chloride in ethanol to give 4-amino-1-[5-(5-chloro-2-methoxyphenyl)-5-oxo-pentyl]piperidine-4-carboxamide hydrochloride (65 mg, 0.16 mmol).
Reaction SMILES: [Cl:1][C:2]([C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([C:14]([Cl:18])=[C:15]([Cl:17])[Cl:16])[CH:13]=1)[CH2:9]Br)=[C:3]([Cl:5])[Cl:4].[N-:19]=[N+:20]=[N-:21].[Na+]>C(O)C>[Cl:1][C:2]([C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([C:14]([Cl:18])=[C:15]([Cl:17])[Cl:16])[CH:13]=1)[CH2:9][N:19]=[N+:20]=[N-:21])=[C:3]([Cl:5])[Cl:4]
Reactant: [N-]=[N+]=[N-]
Reactant: ClC(Cl)=C(Cl)c1cc(CBr)cc(C(Cl)=C(Cl)Cl)c1
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCc1cc(C(Cl)=C(Cl)Cl)cc(C(Cl)=C(Cl)Cl)c1
Yield: 97.6 %

Procedure:
A solution of crude 3,5-di(trichlorovinyl)benzyl bromide (7.9 g) and sodium azide (1.9 g) in 200 ml of ethanol was heated at reflux for 1.5 hours. The reaction mixture was concentrated and the residue partitioned between 100 ml of ether and 100 ml of water. The layers were separated and the aqueous phase further extracted with ether. The ethereal layers were washed with water, dried with MgSO4, and concentrated to give 7.03 g of an oil. This material was chromatographed on silica gel (hexane then 90:10 hexane:CH2Cl2) to give 3.52 g of pure azide.
Reaction SMILES: [F:1][C:2]1([F:20])[C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:10]([O:12]C)=[O:11])=[CH:4][C:3]1=[CH2:19].C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:1][C:2]1([F:20])[C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:10]([OH:12])=[O:11])=[CH:4][C:3]1=[CH2:19]
Reactant: C=C1C=C(Oc2cc(C(=O)OC)ccc2OC)C1(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C=C1C=C(Oc2cc(C(=O)O)ccc2OC)C1(F)F
Temperature: 65 °C

Procedure:
A solution of methyl 3-(4,4-difluoro-3-methylenecyclobut-1-enyloxy)-4-methoxybenzoate (1.39 g) in methanol (22 mL) is treated with a solution of potassium carbonate (0.83 g) in water (8 mL) and the solution is heated at 60-70° C. for 8 hours, cooled and evaporated. The residue is dissolved in water (30 mL), extracted with diethyl ether (50 mL) and acidified to pH 4 by treatment with glacial acetic acid. The precipitated solid is extracted with ethyl acetate (2×75 mL). The combined organic extracts are dried over magnesium sulfate and concentrated, to give 3-(4,4-difluoro-3-methylene-cyclobut-1-enyloxy)-4-methoxybenzoic acid, in the form of a white solid, m.p. 163-165° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Br:5][C:6]1[CH:19]=[CH:18][C:9]([O:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:8]([CH2:20]Cl)[CH:7]=1.O>CN(C=O)C>[N:1]([CH2:20][C:8]1[CH:7]=[C:6]([Br:5])[CH:19]=[CH:18][C:9]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: ClCc1cc(Br)ccc1OCCN1CCCC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCc1cc(Br)ccc1OCCN1CCCC1
Temperature: 35 °C
Reaction time: 16 h

Procedure:
0.33 g (5.00 mmol) of sodium azide were added to a solution of 500 mg (1.57 mmol) of 1-[2-(4-bromo-2-chloromethylphenoxy)ethyl]pyrrolidine in 5 mL of DMF and the mixture was stirred for 16 hours at 35° C. Water was added and the phases were separated. The aqueous phase was exhaustively extracted with DCM, and the combined organic extracts were washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, and evaporated down in vacuo. The crude product was used in the next reaction step without any further purification. Yield: 0.42 g (82% of theoretical); C13H17BrN4O (M=325.204); HPLC-MS: 5.62 minutes (method A).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[CH:21]2)(=[O:14])=[O:13].[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28].CCN(C(C)C)C(C)C>>[N:24]1[C:25]2[C:20](=[CH:19][CH:18]=[CH:17][C:16]=2[NH:15][S:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:7][C:2]=2[NH:1][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])(=[O:13])=[O:14])[CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)C(=O)Cl
Reactant: Nc1cc(C(F)(F)F)ccc1S(=O)(=O)Nc1cccc2cccnc12
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)Nc1cc(C(F)(F)F)ccc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 41.6 %

Procedure:
In a similar fashion using route 15 general procedure 30, 2-amino-N-(quinolin-8-yl)-4-trifluoromethyl-benzenesulfonamide (Example Compound 35) (40 mg, 0.11 mmol), isobutyryl chloride (11 μl, 0.11 mmol) and DIPEA (47 μl, 0.27 mmol) gave the title compound (20 mg, 43%) after purification by column chromatography with DCM/n-hexane (4:1) as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12>CN(C)C=O.C(OCC)C>[Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[N:4]1[C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]2[C:10]1=[O:15]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1ccc(I)cc1Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1c1ccc(I)cc1Cl

Procedure:
2-Chloro-4-iodoaniline (12.65 g) and phthalic anhydride (7.4 g) are dissolved in 30 mL of dimethylformamide. The solution is heated to reflux for 16 hours. The reaction mixture is diluted with diethyl ether and washed with brine to yield a precipitate which is filtered off and washed with water and diethyl ether to yield N-(2-chloro-4-iodophenyl)phthalimide as a white solid.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:4]=2[CH2:3]1.[C:18]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)(Cl)Cl>[C:18]([N:23]1[CH2:28][CH2:27][N:26]([CH:2]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[S:6][C:5]3[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:4]=3[CH2:3]2)[CH2:25][CH2:24]1)([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Cc1ccc2c(c1)CC(Cl)c1ccccc1S2
Reactant: CCOC(=O)N1CCNCC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCN(C2Cc3cc(C)ccc3Sc3ccccc32)CC1

Procedure:
19.7 g of 10-chloro-10,11-dihydro-2-methyl-dibenzo-[b,f]thiepine dissolved in 100 ml of chloroform are heated under reflux for 24 hours together with 36.5 g of 1-carbethoxy-piperazine. Then the mixture is concentrated under reduced pressure and the residue crystallised from acetone/hexane. There is obtained 1-carbethoxy-4-(10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-piperazine of melting point 96°-98° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11]([C:13]2[C:21]3[CH:20]=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH:22]([CH3:24])[CH3:23])[CH:14]=2)=[O:12])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH3:10].[CH3:25][C:26]1[N:30]([CH2:31][C:32](O)=[O:33])[N:29]=[C:28]([C:35]([F:38])([F:37])[F:36])[CH:27]=1>>[CH2:9]([O:8][C:7]1[C:2]([NH:1][C:32](=[O:33])[CH2:31][N:30]2[C:26]([CH3:25])=[CH:27][C:28]([C:35]([F:38])([F:37])[F:36])=[N:29]2)=[CH:3][C:4]([C:11]([C:13]2[C:21]3[CH:20]=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH:22]([CH3:23])[CH3:24])[CH:14]=2)=[O:12])=[CH:5][N:6]=1)[CH3:10]
Reactant: CCOc1ncc(C(=O)c2cn(C(C)C)c3ncncc23)cc1N
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Product: CCOc1ncc(C(=O)c2cn(C(C)C)c3ncncc23)cc1NC(=O)Cn1nc(C(F)(F)F)cc1C

Procedure:
The title compound was prepared according to the method described for Example 1 using (5-Amino-6-ethoxy-pyridin-3-yl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (Preparation 242) and (5-Methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid to afford the title compound as off white solid in 50% yield, 40 mg.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:10][C:11]1[CH:12]=[C:13]([CH:28]=[CH:29][C:30]=1[CH3:31])[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1>C1COCC1>[CH3:10][C:11]1[CH:12]=[C:13]([CH:28]=[CH:29][C:30]=1[CH3:31])[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]3=[N:27][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:23]3[CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(Oc2ccc(-c3cccnc3N)cc2)cc1C
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)cc1C
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 99 mg) in THF (dry) (10 mL) was added 2-chloroethanesulfonyl chloride (0.156 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-(4-(3,4-dimethylphenoxy)phenyl)pyridin-2-amine (144 mg) in THF (dry) (10 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen overnight. The mixture was quenched with water at 0° C. and extracted with EtOAc/THF. Silica-gel was added to the organic phase and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) to give the title compound (119.7 mg). A part of product was recrystallized from MeCN/IPE.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](C)[CH:10]=2)[NH:5][C:4](=O)[N:3]=1.F[C:15](F)(F)C1C=C(C=CC=1)N>C(O)C>[CH3:15][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][N:3]=[C:2]2[Cl:1]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc2[nH]c(=O)nc(Cl)c2c1
Solvent: CCO
Product: Cc1cccc2c(Cl)ncnc12

Procedure:
0.45 g of 4-chloro 6-methyl quinazolone and 0.405 g, of m-trifluoromethylaniline in 20 ml ethanol were refluxed 1 hour. Treatment with aqueous Na2CO3 and extraction with CH2Cl2 gave 0.2 g of P15 as a white solid, mp-215° C., as the free base. NMR CDCl3 δ 8.78 (1H,S), 8.06 (2H,m), 7.86(1H,d,J=7.6 Hz), 7.65 (2H,m), 7.54(1H,t,J=8.0 Hz), 7.42 (1H,m), 2.58 (3H,S).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:9][C:10]([NH:13][C:14]2[CH:15]=[C:16]([NH2:29])[C:17]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)=[CH:18][C:19]=2[O:20][CH3:21])=[N:11][CH:12]=1.CCN(C(C)C)C(C)C.[Cl-]>C(Cl)Cl>[Cl:6][C:7]1[C:8]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]3)=[C:16]([NH:29][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1
Reactant: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reactant: C=CC(=O)Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3cnn4ccccc34)n2)c(OC)cc1N1CCN(C)CC1
Reaction time: 0.25 h
Yield: 73 %

Procedure:
A solution of acryloyl chloride (0.092 mL, 1.14 mmol) in CH2Cl2 (1 mL) was added dropwise to a mixture of N′-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine (Intermediate 63, 480 mg, 1.03 mmol) and DIPEA (0.214 mL, 1.24 mmol) in CH2Cl2 (18 mL) at r.t. After 0.25 h, additional acrolyl chloride (15 mg in 0.15 mL CH2Cl2) was added. The mixture was stirred for 0.5 h and then washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 2.5% 7N methanolic ammonia in CH2Cl2 gave the title compound (390 mg, 73%) as a yellow solid, after trituration with CH3OH; 1H NMR: 2.27 (3H, s), 2.53-2.61 (4H, m), 2.84-2.97 (4H, m), 3.77 (3H, s), 5.70 (1H, d), 6.17 (1H, d), 6.61 (1H, dd), 6.89 (1H, s), 7.11 (1H, t), 7.3-7.42 (1H, m), 8.10 (1H, s), 8.26-8.47 (2H, m), 8.70 (1H, s), 8.83 (1H, d), 8.96 (1H, s), 9.02 (1H, s); m/z: ES+ MH+ 519.
Reaction SMILES: [Br:1][CH:2](Br)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)C.[S:12]([O-:15])([O-:14])=[O:13].[Na+:16].[Na+]>O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:12]([O-:15])(=[O:14])=[O:13].[Na+:16]
Reactant: CCCCCC(Br)Br
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])CCCCCCBr
Temperature: 25 °C

Procedure:
To a stirred mixture of dibromohexane (81.0 g), ethanol (120 ml) and water (50 ml) is added dropwise an aqueous solution (50 ml) of sodium sulfite (12.5 g) under reflux over 2 hours. After additional refluxing for 2 hours, the reaction mixture is allowed to cool and unreacted dibromohexane is removed and then the resulting solution is concentrated under reduced pressure. 95% Ethanol (200 ml) is added and the mixture is allowed to cool at room temperature overnight and precipitated crystals are collected by filtration to give the title compound as colorless prisms. The filtrate is concentrated and is allowed to cool overnight and precipitated crystals are collected by filtration to give additional title compound.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.Br[CH:16]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C1COCC1>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([C:22]1[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=1)[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)[CH3:21]
Reactant: CCOC(=O)C(Br)c1ccc(C)cc1
Reactant: Oc1ccccc1-n1cccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Oc1ccccc1-n1cccc1)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
Sodium hydride (90 mg, 3.9 mmol) was added to a solution of 1-(2-hydroxyphenyl)pyrrole (0.41 g, 2.5 mmol) in anhydrous THF (5 mL) at RT. The reaction mixture was stirred for 1 h at RT, and then a solution of ethyl α-bromo-p-tolylacetate (1.0 g, 3.9 mmol) in anhydrous THF (5 mL) was added dropwise. After 12 h at RT, the solvent was removed in vacuo, and the residue was taken up in dichloromethane. The organic layers were washed with brine, dried, and evaporated. The residue was purified by chromatography (toluene) to give 0.46 g of the title compound as a colorless oil; IR (neat): 1734 cm−1; 1H NMR(CDCl3) d 1.16 (t, 3 H, J=7.0 Hz), 2.33 (s, 3 H), 4.13 (q, 2 H, J=7.0 Hz), 5.48 (s, 1H), 6.31 (m, 2 H), 6.95-7.40 (m, 10 H).