Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[Cl:19][C:20]1[C:21]([NH:30][C:31]2[C:36]([Cl:37])=[CH:35][N:34]=[C:33](Cl)[N:32]=2)=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([NH:25][CH3:26])=[O:24]>>[Cl:19][C:20]1[C:21]([NH:30][C:31]2[C:36]([Cl:37])=[CH:35][N:34]=[C:33]([NH:1][C:2]3[CH:18]=[CH:17][C:5]4[CH2:6][CH2:7][N:8]([CH2:11][C:12](=[O:13])[N:14]([CH3:15])[CH3:16])[CH2:9][CH2:10][C:4]=4[CH:3]=3)[N:32]=2)=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([NH:25][CH3:26])=[O:24]
Reactant: CN(C)C(=O)CN1CCc2ccc(N)cc2CC1
Reactant: CNC(=O)c1cccc(Cl)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(Cl)c1Nc1nc(Nc2ccc3c(c2)CCN(CC(=O)N(C)C)CC3)ncc1Cl

Procedure:
3-Chloro-2-[5-chloro-2-(3-dimethylcarbamoylmethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide was prepared from 2-(7-amino-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide and 3-chloro-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide in an analogous manner to Example 308c. Product isolated as a yellow foam (26 mg, 12%). LCMS (m/e) 542 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.09 (s, 1H), 7.86 (s, 1H), 7.60 (d, 1H, J=8.0 Hz), 7.47 (d, 1H, J=7.7 Hz), 7.34-7.26 (m, 1H), 7.12 (s, 1H), 7.05-6.99 (m, 1H), 6.91-6.83 (m, 2H), 6.06-5.97 (m, 1H), 3.29 (s, 2H), 3.14 (s, 3H), 2.99 (s, 3H), 2.90-2.84 (m, 2H), 2.77 (d, 3H, J=4.9 Hz), 2.77-2.71 (m, 2H), 2.70-2.62 (m, 4H).
Reaction SMILES: [K+].[Br-].N1C2C=CC=CC=2C=C[CH:5]=N1.FC(F)(F)COC(C1N=C[N:23]2[C:29]3[CH:30]=[CH:31][C:32]([Br:34])=[CH:33][C:28]=3[C:27]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3F)=[N:26]CC=12)=O.CCO[C:47]([CH3:49])=[O:48]>>[Br:34][C:32]1[CH:31]=[CH:30][C:29]2[NH:23][C:47](=[O:48])[CH:49]([CH3:5])[N:26]=[C:27]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:28]=2[CH:33]=1
Reactant: O=C(OCC(F)(F)F)c1ncn2c1CN=C(c1ccccc1F)c1cc(Br)ccc1-2
Reactant: C1=Cc2ccccc2NN=C1
Reactant: CCOC(C)=O
Agent: [Br-]
Agent: [K+]
Product: CC1N=C(c2ccccc2)c2cc(Br)ccc2NC1=O

Procedure:
To a stirred solution of 110 (66.5 g, 265 mmol) in glacial acetic acid (400 mL), sulfuric acid (80 mL) was added to the solution. Bromine (28 mL, 530 mmol) dissolved in acetic acid (150 mL) was added dropwise into the mixture. The reaction mixture was allowed to stir until NMR spectroscopy indicated that all of the starting material 110 had been consumed. The solution was concentrated under reduced pressure and then neutralized by addition of 1N NaOH solution and then extracted with EtOAc. The crude product 111 was purified by recrystallization from CH2Cl2 to afford 5 (70.4 g, 81%). mp 210-212° C.; IR (KBr, cm−1) 2931, 1692, 1603, 1563, 1475, 1445, 1375, 1259, 1235, 1130, 1090; 1H NMR (CDCl3) δ 9.36 (s, 1 H), 7.63 (dd, J=2.22, 8.58 Hz, 1 H), 7.54-7.39 (m, 6 H), 7.12 (d, J=8.61 1 H), 3.76 (q, J=6.3 Hz, 1 H), 1.76 (d, J=6.45 Hz, 3 H). MS (EI) m/e (relative intensity) 330 (M++1, 21), 329 (M+, 50), 328 (22), 327 (48), 289 (44), 288 (46), 287 (100), 286 (49), 285 (60), 205 (25), 77 (49); [α]26D=313.1 (c 0.34, EtOAc).
Reaction SMILES: C1C2NC3C(=CC=CC=3)C=2C=CC=1.N[C@H](C(O)=O)CS.[OH:21][CH2:22][C:23]([C@H:25]([C@@H:27]([C@@H:29]([CH2:31][OH:32])[OH:30])[OH:28])[OH:26])=[O:24]>>[O:21]=[CH:22][C@@H:23]([C@H:25]([C@@H:27]([C@@H:29]([CH2:31][OH:32])[OH:30])[OH:28])[OH:26])[OH:24]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: N[C@@H](CS)C(=O)O
Agent: c1ccc2c(c1)[nH]c1ccccc12
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
A mixture of 0.2 ml of a 1 M aqueous D-glucose solution, 0.2 ml of a 0.05 M aqueous MgSO4.7H2O solution, 0.2 ml of a 0.5 M aqueous phosphate buffer solution (pH=7.2) and a given amount of aqueous glucose isomerase extract is diluted with water to make 2 ml. The resulting mixture is maintained at a temperature of 70° C. for 60 minutes to effect the glucose isomerization which is terminated by the addition of 2 ml of 0.5 M perchloric acid. The amount of fructose produced is determined by cystein carbazole method. The value obtained by dividing the amount of fructose produced by the amount of aqueous glucose isomerase extract is the activity, the unit of which is expressed by the abbreviation "U".
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22]([NH:24][CH2:25][C:26]([CH3:33])([CH3:32])[C:27]([O:29]CC)=[O:28])=[O:23])[N:4]=1)#[N:2].O.CCOC(C)=O.Cl>CO.[OH-].[Na+]>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22]([NH:24][CH2:25][C:26]([CH3:33])([CH3:32])[C:27]([OH:29])=[O:28])=[O:23])[N:4]=1)#[N:2]
Reactant: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3cccc(F)c3)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3cccc(F)c3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Ethyl 3-(1-cyano-7-(3-fluorophenoxy)-4-hydroxyisoquinoline-3-carboxamido)-2,2-dimethylpropanoate (22 mg, 0.05 mmol) was dissolved in MeOH (4 mL) and 2 N NaOH (4 mL). After stirring for 5 hours at room temperature, H2O (15 mL) and EtOAc (15 mL) were added. To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-30% MeOH/CH2Cl2) to give the title compound in 15 mg. MS: (−) m/z 421.91 (M−1).
Reaction SMILES: [Mg].[CH:2]1([C:5]([CH2:7][CH2:8][CH2:9][CH3:10])=[O:6])[CH2:4][CH2:3]1.[CH2:11](Br)[C:12]#[CH:13].[Cl-].[NH4+]>CCOCC>[CH:2]1([C:5]([OH:6])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:13][C:12]#[CH:11])[CH2:4][CH2:3]1
Reactant: CCCCC(=O)C1CC1
Reactant: C#CCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: C#CCC(O)(CCCC)C1CC1

Procedure:
To a stirred, refluxing suspension of amalgam prepared from 6.2 g of magnesium and 50 mg of mercuric chloride suspended in 60 ml of ether is added a solution of a mixture of 30.4 g of n-butyl cyclopropyl ketone (Example 8) and 29.8 g of propargyl bromide in 65 ml of ether during 60 minutes. After reaction at reflux temperature for an additional 30 minutes, the mixture is cooled to 0° and treated with 35 ml of saturated ammonium chloride. The mixture is diluted with ether and filtered through Celite. The filtrate is washed with brine, dried over potassium carbonate, and concentrated. The residue is distilled to provide a liquid, b.p. 93°-94° C. (12 mm), pmr spectrums (CDCl3): δ0.43 (cyclopropyl hydrogens), 2.07 (triplet, HC≡C), and 2.44 (doublet, C≡CCH2).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][S:11][C:5]=2[N:4]=[C:3]1[CH2:12][CH3:13].[C:14]12([CH2:24][C:25](Cl)=[O:26])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2>>[C:14]12([CH2:24][C:25]([NH:1][N:2]3[C:7](=[O:8])[C:6]4[CH:9]=[CH:10][S:11][C:5]=4[N:4]=[C:3]3[CH2:12][CH3:13])=[O:26])[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2
Reactant: CCc1nc2sccc2c(=O)n1N
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: CCc1nc2sccc2c(=O)n1NC(=O)CC12CC3CC(CC(C3)C1)C2

Procedure:
3-Amino-2-ethylthieno[2,3-d]pyrimidin-4(3H)-one and 1-adamantaneacetyl chloride were reacted as described in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.20 (t, J=7.3 Hz, 3H), 1.59-1.74 (m, 12H), 1.93-1.98 (m, 3H), 2.08-2.18 (m, 2H), 2.56-2.80 (m, 2H), 7.39 (d, J=6.0 Hz, 1H), 7.59 (d, J=6.0 Hz, 1H), 10.83 (s, 1H) ppm; MS (DCI/NH3) m/z 372 (M+H)+; Elemental Analysis: Calculated for C20H25N3O2S: C, 63.74; H, 6.85; N, 11.15. Found: C, 63.77; H, 6.89; N, 11.13.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:14])[CH:3]=1.[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[K+].[Br-]>C(O)(=O)C>[CH:26]1([CH2:27][CH:28]([C:3]2[C:4](=[O:14])[O:5][C:6]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:7][C:2]=2[OH:1])[S:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:24][CH2:25]1
Reactant: SCc1ccccc1
Reactant: O=c1cc(O)cc(-c2ccccc2)o1
Reactant: C1CCNCC1
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=c1oc(-c2ccccc2)cc(O)c1C(CC1CC1)SCc1ccccc1

Procedure:
The title compound was prepared by Method C using 4-hydroxy-6-phenyl-2H -pyran-2-one (1.5 g, 7.98 mmol), 2-cyclopropylmethylcarboxaldehyde (0.67 g, 7.98 mmol), benzylmercaptan (1.98 g, 15.96 mmol), piperidine, (0.5 mL), acetic acid (0.5 mL). m.p. 59-61° C.; 1H NMR (400 MHz, DMSO-d6) δ-0.97 (m, 2 H), 0.28 (m, 2 H), 0.58 (m, 1 H), 1.61 (m, 1 H), 2.01 (m, 1 H), 3.72 (ABXq, 2 H), 4.22 (q, 1H), 6.67 (s, 1H), 7.18 (t, 1H), 7.25 (d, 2H), 7.31 (t, 2H), 7.53 (m, 3H), 7.75 (m, 2H); IR (KBr) 3061, 2919, 2631, 1649, 1564, 1404, 1267, 766, 691 cm-1 ; MS (CI) m/e 255 ((M-SBzl), 19), 201 (5), 147 (2); Analysis calc'd for C23H2203S1: C, 72.99; H, 5.86; found: C, 72.31; H, 6.08.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[CH3:14][O:15][C:16](=[O:41])[C@@H:17]([O:19][C:20]1[CH:21]=[C:22]([CH:38]=[CH:39][CH:40]=1)[CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([C:33](O)=[O:34])=[CH:30][CH:31]=2)[C:26]([CH3:36])=[C:25]1[CH3:37])[CH3:18]>>[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH:13][C:33]([C:29]2[CH:28]=[C:27]3[C:32](=[CH:31][CH:30]=2)[N:24]([CH2:23][C:22]2[CH:21]=[C:20]([CH:40]=[CH:39][CH:38]=2)[O:19][C@@H:17]([CH3:18])[C:16]([O:15][CH3:14])=[O:41])[C:25]([CH3:37])=[C:26]3[CH3:36])=[O:34])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: COC(=O)[C@H](C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: Cl
Product: COC(=O)[C@H](C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (S)-1-(3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4]([O:6][CH3:7])=[O:5].CCN(C(C)C)C(C)C.[N+:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35])([O-:27])=[O:26]>C(Cl)Cl>[C:12]([O:11][C:9]([NH:8][C@@H:3]([CH2:2][NH:1][S:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[N+:25]([O-:27])=[O:26])(=[O:35])=[O:36])[C:4]([O:6][CH3:7])=[O:5])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(=O)[C@H](CN)NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
To a mixture of methyl 3-amino-2(S)-(tert-butoxycarbonylamino)propanoate ii (1.6 g, 7.3 mmol.) in DCM (50 mL) was added DIPEA (1.64 mL, 9.4 mmol.) and 2-nitrobenzene sulfonyl chloride (1.62 g, 7.3 mmol.). The mixture was stirred at rt for 2 h. It was then concentrated, dissolved in ethyl acetate, which was then washed with sat. sodium bicarbonate, brine and dried over magnesium sulfate. It was then filtered, concentrated to yield 2.9 g (98%) of methyl 2(S)-(tert-butoxycarbonylamino)-3-(2-nitrophenylsulfonamido)propanoate iii as a yellow foam. 1H NMR (CD3OD, 300 MHz) δ 1.41 (s, 9H), 3.36-3.51 (m, 2H), 3.71 (s, 3H), 4.22 (m, 1H), 7.80-7.90 (m, 3H), 8.07-8.10 (m, 1H).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[N:23]=[CH:24][N:25]5[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=45)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[N:23]=[CH:24][N:25]5[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=45)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: Cc1ccc2c(-c3cnc4c(n3)c(C(=O)N[C@H](C)C(=O)N3CC(C#N)C3)cn4COCC[Si](C)(C)C)ncn2c1
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)N[C@H](C)C(=O)N5CC(C#N)C5)c4n3)ncn2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
In a round-bottomed flask, 2-(6-methyl-imidazo[1,5-a]pyridin-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (92 mg, 0.165 mmol) was dissolved in dichloromethane (0.8 ml) and trifluoroacetic acid (0.5 ml, 6.6 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (0.8 ml) and ethylenediamine (0.67 ml, 9.9 mmol) was added. The reaction was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 48 mg (65%) of 2-(6-methyl-imidazo[1,5-a]pyridin-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a yellow powder. MS: (M+H)+=429; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.40 (br. s, 1H), 9.11 (s, 1H), 8.39-8.61 (m, 3H), 8.34 (d, J=7.2 Hz, 1H), 8.28 (s, 1H), 6.79-7.05 (m, 1H), 4.41-4.86 (m, 3H), 4.15-4.33 (m, 1H), 3.99-4.15 (m, 1H), 3.71-3.94 (m, 1H), 2.26 (s, 3H), 1.40 (d, J=4.9 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[F:12].[CH:13]1(B(O)O)[CH2:15][CH2:14]1>>[CH:13]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[F:12])[CH2:15][CH2:14]1
Reactant: COC(=O)c1ccc(Br)c(F)c1
Reactant: OB(O)C1CC1
Product: COC(=O)c1ccc(C2CC2)c(F)c1

Procedure:
The title compound was prepared from methyl 4-bromo-3-fluorobenzoate and cyclopropylboronic acid according to the procedure for the preparation of EXAMPLE 152, part A. 1H NMR (400 MHz, CDCl3): δ 0.77-0.81 (2H, m), 1.04-1.09 (2H, m), 2.12-2.16 (1H, m), 3.89 (3H, s), 6.88-6.92 (1H, m), 7.63-7.66 (1H, m), 7.69-7.72 (1H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([O:19][CH3:18])[CH:21]=2)[CH:5]=[N:6][CH:7]=1
Reactant: Nc1cncc(Br)c1
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cccc(C(=O)Nc2cncc(Br)c2)c1
Yield: 115.4 %

Procedure:
5-Bromopyridin-3-amine (1.5 g, 8.67 mmol) was dissolved in dichloromethane (40 ml). Diisopropylethylamine (1.81 ml, 10.39 mmol) first and then a solution of 3-methoxybenzoyl chloride (1.18 ml, 8.66 mmol) in dichloromethane (25 ml) were added. After 1 h at room temperature the reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulphate, filtered and evaporated under reduced pressure to give 3.07 g (89% yield) of the title compound. Purity 77%.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[F:22][C:23]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=1[CH2:25]Br>>[F:22][C:23]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=1[CH2:25][N:8]1[C:9]([C:10](=[O:19])[C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]1=[O:20]
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: Fc1ccc(F)c(CBr)c1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(F)ccc2F)c1
Yield: 48.5 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 2,5-difluorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (200 mg, yield: 48.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14]OS(C)(=O)=O)=[CH:10][C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:8]2)=[CH:4][CH:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14][N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)=[CH:10][C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:8]2)=[CH:29][CH:30]=1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3ccc(Cl)cc3)n2)cc1F
Reactant: CN1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(Cc3ccc(Cl)cc3)n2)cc1F
Yield: 39.5 %

Procedure:
Following the procedure of Example 1(10), 2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as pale brown prisms (yield: 39.5%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:16]=[C:15]3[NH:40][C:41](=[O:58])[C:42]2[CH:47]=[CH:46][C:45]([N:48]([CH2:50][CH2:51][N:52]([CH3:54])[CH3:53])[CH3:49])=[CH:44][C:43]=2[N+:55]([O-])=O)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C1CCCCC=1>[Pd].O1CCOCC1>[NH2:55][C:43]1[CH:44]=[C:45]([N:48]([CH2:50][CH2:51][N:52]([CH3:54])[CH3:53])[CH3:49])[CH:46]=[CH:47][C:42]=1[C:41]([NH:40][C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([S:9]([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=3)(=[O:11])=[O:10])[CH:13]=2)[N:17]([C:21]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:16]=1)=[O:58]
Reactant: CN(C)CCN(C)c1ccc(C(=O)Nc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(S(=O)(=O)c4cc(F)cc(F)c4)cc23)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: C1COCCO1
Product: CN(C)CCN(C)c1ccc(C(=O)Nc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(S(=O)(=O)c4cc(F)cc(F)c4)cc23)c(N)c1
Temperature: 85 °C
Reaction time: 5 h
Yield: 94.4 %

Procedure:
A mixture of N-[5-(3,5-difluoro-benzenesulfonyl)-1-trityl-1H-indazol-3-yl]-4-[(2-dimethylamino-ethyl)-methyl-amino]-2-nitro-benzamide (1.0 g, 1.25 mmol), cyclohexene (2 mL), 1,4-dioxane (50 mL) and 10% Pd/C (0.1 g) was stirred at 85° C. for 5 hours. More cyclohexene (3 mL) and 10% Pd/C (0.2 g) were then added and the mixture stirred at 90° C. for additional 6 hours. The reaction mixture was then cooled to room temperature and filtered over celite washing thoroughly with ethanol. The filtrate was evaporated to dryness affording the title compound as a pale brown solid (910 mg, 94% yield).
Reaction SMILES: CCN(C(C)C)C(C)C.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:19]([OH:21])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:44][CH2:45][C:46]([N:48]1[CH2:53][CH2:52][N:51]([C:54](=[O:65])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=2[C:61]([F:64])([F:63])[F:62])[CH2:50][CH2:49]1)=[O:47]>CN(C=O)C.O>[O:47]=[C:46]([N:48]1[CH2:49][CH2:50][N:51]([C:54](=[O:65])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=2[C:61]([F:64])([F:63])[F:62])[CH2:52][CH2:53]1)[CH2:45][NH:44][C:19]([C:11]1[NH:10][C:18]2[C:13]([CH:12]=1)=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:21]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 66 %

Procedure:
DIPEA (193 mg, 0.25 mL, 1.11 mmol) was added to a stirred solution of 1H-Indole-2-carboxylic acid (60 mg, 0.37 mmol) in DMF (2 mL). HOBT (60 mg, 0.44 mmol) and EDCI (85 mg, 0.44 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (157 mg, 0.44 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 112 mg (65.88% yield) of 1H-indole-2-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 94.15%. 1H NMR (DMSO-d6): δ 11.6 (s, 1H), 8.6 (s, 1H), 7.9-7.4 (m, 6H), 7.2 (m, 2H), 7.1-7.0 (m, 1H), 4.3-4.1 (m, 2H), 3.8-3.4 (m, 6H), 3.2-3.0 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][CH2:19][NH2:20])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.F[C:24](F)(F)C(O)=O>C(O)C>[CH2:1]([N:8]1[CH:24]=[C:13]2[CH:14]=[CH:15][CH2:16][C:17]3[NH:20][CH2:19][CH2:18][N:11]([C:12]=32)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCN1CCN(Cc2ccccc2)c2ccccc21
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Solvent: CCO
Product: C1=CC2=CN(Cc3ccccc3)CCN3CCNC(=C23)C1
Temperature: 25 °C
Yield: 39.4 %

Procedure:
A solution of 1.089 g (4.07 mmol) of 2-(4-benzyl-3,4-dihydro-2H-quinoxalin-1-yl)ethylamine and 20 ml ethanol was treated with 122 mg (4.07 mmol) of formaldehyde and 511 mg (4.48 mmol) of trifluoroacetic acid and stirred over night at room temperature. The solvent was evaporated and dichloromethane was added to the crude mixture. The organic phase was washed with 1 molar sodium hydroxide solution. The organic phase was dried and purified by column chromatography on silica (eluent: starting with dichloromethane and then up to 100% methanol) to yield 448 mg of the title compound.
Reaction SMILES: Cl[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[C:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:23])[CH3:22].C(N)(=O)C1C=CC=NC=1>>[C:21]([N:24]1[CH2:29][CH2:28][N:27]([C:2]2[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=3)=[O:7])=[CH:4][N:3]=2)[CH2:26][CH2:25]1)(=[O:23])[CH3:22]
Reactant: O=C(Nc1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Cl)nc1
Reactant: CC(=O)N1CCNCC1
Agent: NC(=O)c1cccnc1
Product: CC(=O)N1CCN(c2ccc(C(=O)Nc3ccc(Cl)c([N+](=O)[O-])c3)cn2)CC1

Procedure:
6-chloro-N-(4-chloro-3-nitrophenyl)nicotinamide (1.6 mmol) was used in general procedure 3 with 1-acetylpiperazine (4.8 mmol to give 6-(4-acetylpiperazin-1-yl)-N-(4-chloro-3-nitrophenyl))-nicotinamide. MS (Q1) 404.4 (M)+