Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[S:11])=[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:4]=1.[NH3:18]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH2:18])=[S:11])=[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:4]=1
Reactant: COc1ccc(N=C=S)c(N2CCOCC2)c1
Reactant: N
Solvent: CCO
Product: COc1ccc(NC(N)=S)c(N2CCOCC2)c1

Procedure:
Reaction of 4-methoxy-2-morpholinophenyl isothiocyanate (4.1 g) with a saturated solution of ammonia in ethanol (30 ml) for 24 hours at room temperature gave 1-(4-methoxy-2-morpholinophenyl)thiourea (m.p. 175° C.).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]([C:7]1[N:27]=[CH:26][C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8]=1[CH2:28][O:29][CH3:30])=[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:15]=[CH:14][CH:13]=3)=[O:6])[CH3:3].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:3][CH:2]([O:4][C:5]([C:7]1[N:27]=[CH:26][C:10]2[N:11]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:12]3[C:17]([C:9]=2[C:8]=1[CH2:28][O:29][CH3:30])=[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:15]=[CH:14][CH:13]=3)=[O:6])[CH3:1]
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3cccc(OCc4ccccc4)c3c12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCc1c(C(=O)OC(C)C)ncc2c1c1c(OCc3ccccc3)cccc1n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.2 %

Procedure:
404.5 mg of 5-benzyloxy-4-methoxymethyl-9H-pyrido[3,4-b]indole-3-carboxylic acid-(1-methylethyl)-ester (1 mmol) is dissolved in 15 ml of dimethylformamide and mixed with 188 mg (1.1 mmol) of benzyl bromide and 358 mg of cesium carbonate. It is stirred for 48 hours at room temperature, the reaction mixture s worked up as described in Example 26, and after chromatography, 194 mg of 5-benzyloxy-4-methoxymethyl-9-benzyl-9H-pyrido[3,4-b]indole-3-carboxylic acid-(1-methylethyl)-ester is obtained.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][CH:20]=[N:19][C:18]=3[C:22]([F:25])([F:24])[F:23])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[Li]CCCC.C(Br)(Br)(Br)[Br:32]>C1COCC1>[Br:32][C:20]1[S:21][C:17]([C:13]2[N:8]3[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]3=[N:15][C:14]=2[CH3:16])=[C:18]([C:22]([F:23])([F:24])[F:25])[N:19]=1
Reactant: CCC(CC)c1cc(C)nn2c(-c3scnc3C(F)(F)F)c(C)nc12
Reactant: BrC(Br)(Br)Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(Br)nc3C(F)(F)F)c(C)nc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
To a solution of 8-(1-ethyl-propyl)-2,6-dimethyl-3-(4-trifluoromethyl-thiazol-5-yl)-imidazo[1,2-b]pyridazine (915 mg, 2.48 mmol) in 40 mL of THF under N2 atmosphere al −78° C., BuLi (1.86 mL 1.6 M in hexane, 2.98 mmol) is slowly added. The mixture is stirred at −78° C. for 30 minutes. Then, a solution of CBr4 (989 mg, 2.98 mmol) in 3 mL of THF is added, and the mixture is stirred at −78° C. for 45 minutes. The reaction is quenched by addition of NH4Cl saturated solution (50 mL), extracted with Et2O (2×50 mL), dried over MgSO4, and concentrated in vacuo. Crude product is purified by flash chromatography on silica gel (eluent CH2Cl2) to obtain 685 mg of the title compound (Yield: 62%). 1H NMR (CDCl3): δ0.86 (t, J=7.5 Hz, 6H), 1.82 (m, 4H), 2.45 (s, 3H), 2.51 (s, 3H), 3.27 (m, 1H), 6.74 (s, 1H). ESIMS: m/z 447, 449 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:4]2[C@@H:5]([NH:27]C(=O)OC(C)(C)C)[CH2:6][CH2:7][CH2:8][C@@H:9]([CH3:26])[C:10](=[O:25])[NH:11][C:12]3[C:17]([C:18]=1[N:19]=2)=[CH:16][CH:15]=[C:14]([NH:20][C:21]([O:23][CH3:24])=[O:22])[CH:13]=3.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:27][C@@H:5]1[C:4]2=[N:19][C:18](=[C:2]([Cl:1])[N:3]2[CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:41])([CH3:42])[CH3:40])[C:17]2[C:12](=[CH:13][C:14]([NH:20][C:21](=[O:22])[O:23][CH3:24])=[CH:15][CH:16]=2)[NH:11][C:10](=[O:25])[C@H:9]([CH3:26])[CH2:8][CH2:7][CH2:6]1
Reactant: COC(=O)Nc1ccc2c(c1)NC(=O)[C@H](C)CCC[C@H](NC(=O)OC(C)(C)C)c1nc-2c(Cl)n1COCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)Nc1ccc2c(c1)NC(=O)[C@H](C)CCC[C@H](N)c1nc-2c(Cl)n1COCC[Si](C)(C)C
Reaction time: 1 h

Procedure:
135I (0.476 g, 0.765 mmol) was treated with TFA (2.95 mL, 38.2 mmol) in DCM (15 mL). After 1 hour, the reaction mixture was concentrated to dryness. The residue was dissolved in EtOAc and washed with 1.5M potassium phosphate. The organic layer was washed further with brine, dried over sodium sulfate, filtered, and concentrated. This material was carried forward as is. MS (ESI) m/z: 522.3 (M+H)+.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[CH3:5][C:6]([CH3:11])([CH3:10])[C:7](Cl)=[O:8]>N1C=CC=CC=1>[CH3:5][C:6]([CH3:11])([CH3:10])[C:7]([O:4][CH2:1][CH:2]=[CH2:3])=[O:8]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C=CCO
Solvent: c1ccncc1
Product: C=CCOC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 432.5 %

Procedure:
A stirred solution of 11.6 grams (0.20 mole) of 2-propen-1ol in 100 ml of pyridine was heated to reflux. To this was added dropwise 24.1 grams (0.02 mole) of trimethylacetyl chloride. The exothermic reaction caused the reaction mixture temperature to become excessive. The heat source was removed, and the reaction mixture was cooled in an ice bath. The addition of the acid chloride was continued to completion. Upon completion of addition, the reaction mixture was warmed to reflux where it stirred for one hour. After this time the reaction mixture was cooled to ambient temperature where it stood for 60 hours. The reaction mixture was shaken with 700 ml of water, and the organic layer was separated. The aqueous layer was washed with two 15o ml portions of diethyl ether. The washes and the organic layer were combined and washed with two 75 ml portions of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. Low boiling volatile materials were removed from the oil by distillation under reduced pressure (b.p. 87°-100° C./21 mm), yielding 12.3 grams of 2-propenyl trimethylacetate as a residue. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:39][CH2:40][N:41]1[CH:45]=[CH:44][CH:43]=[CH:42]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:39][CH2:40][N:41]4[CH:45]=[CH:44][CH:43]=[CH:42]4)=[CH:27][CH:28]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: BrCCn1cccc1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCn3cccc3)cc2)c2ccccc21
Temperature: 80 °C
Yield: 86.4 %

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (0.11 g, 0.25 mmol) was dissolved in DMF at room temperature and K2CO3 (0.207 g, 1.5 mmol) was added. 1-(2-Bromo-ethyl)-1H-pyrrole (0.088 g, 0.5 mmol) was added and the reaction was allowed to heat to 80° C. overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (70% EtOAc/30% Hexane) to afford the product (0.114 g, 85%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]1[C:14]([S:20][CH3:21])=[N:15][CH:16]=[CH:17][C:18]=1[CH3:19])=[O:11].[SH:22][C:23]1[O:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[O:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[S:22][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]1[C:14]([S:20][CH3:21])=[N:15][CH:16]=[CH:17][C:18]=1[CH3:19])=[O:11]
Reactant: CSc1nccc(C)c1NC(=O)CCCCCCCCBr
Reactant: Sc1nc2ccccc2o1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nccc(C)c1NC(=O)CCCCCCCCSc1nc2ccccc2o1
Temperature: 80 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
Triethylamine (302 mg, 2.99 mmol) was added to a chloroform (4 ml) solution of this aminopyridine (307 mg, 1.99 mmol), and a chloroform (4 ml) solution of 9-bromononanyl chloride (2.99 mmol) was then slowly added thereto dropwise while being cooled with ice. The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 125 g, eluent-hexane:ethyl acetate=3:1→2:1) to obtain 261 mg (yield 35%) of 9-bromo-N-(4-methyl-2-methylthio-3-pyridyl)nonanamide as a colorless powdery crystal (melting point: 77 to 78° C.). To a DMF (5 ml) solution of this amide (114 mg, 0.31 mmol) and 2-mercaptobenzoxazole (46 mg, 0.31 mmol) were added 18-crown-6 (8 mg, 0.03 mmol) and potassium carbonate (51 mg, 0.37 mmol), and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through preparative thin-layer chromatography (eluent—chloroform:methanol=20:1) to obtain 89 mg (yield 66%) of the desired compound as a colorless powdery crystal.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][CH3:24])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[CH:28]=[C:29]([NH:33][NH2:34])[CH:30]=[CH:31][CH:32]=1>>[F:26][C:27]1[CH:28]=[C:29]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([S:20]([NH:23][CH3:24])(=[O:22])=[O:21])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:34]2)[CH:30]=[CH:31][CH:32]=1
Reactant: NNc1cccc(F)c1
Reactant: CNS(=O)(=O)c1ccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)cc1
Product: CNS(=O)(=O)c1ccc(-n2ccc(=O)c(-c3ccnn3-c3cccc(F)c3)n2)cc1

Procedure:
The product was obtained starting from 4-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N-methyl-benzenesulfonamide (A-30) and 3-fluoro-phenylhydrazine according to the method described for example 91. MS: M=426.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][CH2:18][C:19]([OH:21])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:34]([NH:37][CH2:38][CH2:39][CH3:40])[CH2:35][CH3:36]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][CH2:18][C:19]([N:37]([CH2:38][CH2:39][CH3:40])[CH2:34][CH2:35][CH3:36])=[O:21])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CCCNCCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)CCn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-propanoic acid (5.0 g, 0.0166 mole), 1,1'-carbonyldiimidazole (3.21 g, 0.0198 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 1 hour with nitrogen bubbling through it. The reaction mixture was then heated at reflux for 1 hour under nitrogen during which a solution formed. A solution of dipropylamine (5.04 g, 0.050 mole) in tetrahydrofuran (7 ml) was added and the reaction mixture was heated at 50° C. overnight under nitrogen. The reaction mixture was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate (100 ml of each). The two layer mixture was filtered to remove an insoluble solid and the layers were separated. The aqueous layer was re-extracted once with ethyl acetate and the combined organic layers were washed once with a 5% potassium hydroxide solution (100 ml), dried over sodium sulfate, filtered, and evaporated to a residue weighing 8.9 g. The residue was dissolved in hot isopropyl alcohol, filtered, cooled to room temperature, and water was added. Solid formed which was collected by filtration to give 4.84 g (76%) of a white solid, after drying under vacuum overnight, mp 104°-105.5° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([NH2:12])[C:6]=2[CH:5]=[C:4]([CH3:13])[N:3]=1.[F:14][C:15]([F:27])([F:26])[C:16]1[CH:25]=[CH:24][C:19]([CH2:20][N:21]=[C:22]=[O:23])=[CH:18][CH:17]=1>>[CH3:1][C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:22]([NH:21][CH2:20][C:19]3[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:27])[F:26])=[CH:25][CH:24]=3)=[O:23])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:13])[N:3]=1
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Reactant: Cc1cc2c(N)cccc2c(C)n1
Product: Cc1cc2c(NC(=O)NCc3ccc(C(F)(F)F)cc3)cccc2c(C)n1

Procedure:
Prepared from 1,3-dimethylisoquinolin-5-amine (Description 83) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 374 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][N:19]3[C:23]4=[N:24][CH:25]=[C:26]([C:28](O)=[O:29])[CH:27]=[C:22]4[N:21]=[CH:20]3)[CH:15]=[CH:14][C:12]=2[N:13]=1.CN.F[P-](F)(F)(F)(F)F.[N:40]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:44]2C=CC=CC=2N=N1>C1COCC1>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][N:19]3[C:23]4=[N:24][CH:25]=[C:26]([C:28]([NH:40][CH3:44])=[O:29])[CH:27]=[C:22]4[N:21]=[CH:20]3)[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)c1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CNC(=O)c1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 36.1 %

Procedure:
To a stirred mixture of 3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (70 mg, 0.165 mmol) from Example 81 and TEA (67 mg, 0.660 mmol) in anhydrous THF (2.5 mL) at rt was added methylamine (2 M solution in THF, 413 μL, 0.825 mmol) followed by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (109 mg, 0.248 mmol). The mixture was stirred at rt for 4.5 h. The mixture was purified by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford 3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-N-methyl-3H-imidazo[4,5-b]pyridine-6-carboxamide (26 mg, 36%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.86 (d, J=1.88 Hz, 1H), 8.69 (s, 1H), 8.59 (d, J=4.52 Hz, 1H), 8.49 (d, J=1.88 Hz, 1H), 7.97 (d, J=7.54 Hz, 1H), 7.67 (d, J=1.13 Hz, 1H), 7.19-7.32 (m, 2H), 5.51 (s, 2H), 4.73 (br. s., 1H), 3.51 (m, 1H), 3.30 (m, 1H), 2.82 (d, J=4.33 Hz, 3H), 2.02 (m, 1H), 1.88 (m, 1H), 1.55-1.65 (m 2H), 1.10-1.30 (m, 4H). LCMS (ESI) m/z 437 (M+H)+.
Reaction SMILES: Cl.[CH2:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH2:5][CH2:4][NH:3]1.CCN(C(C)C)C(C)C.Br[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(#N)C>[CH2:31]([N:3]1[CH2:4][CH2:5][C:6]2[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH2:2]1)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCCc1ccccc1
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CNCC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)Cn1c2c(c3ccccc31)CN(CCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
Step a): To a stirred solution of Intermediate 1 (50 mg, 0.17 mmol) and DIEA (73 μl, 0.42 mmol) in acetonitrile (1 ml) is added (2-bromo-ethyl)-benzene (26 μl, 0.19 mmol). The reaction mixture is stirred at rt overnight. The solvent is removed under reduced pressure and the crude product is purified by silica gel column chromatography (hexane/EtOAc 3:1, 1% NEt3), affording pure ethyl (2-phenethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-acetate (37 mg) in 60% yield: tR (LC-2) 1.69 min; ESI-MS (pos. ion): m/z 363.26 [M+H]+ (calcd 362.46 for C23H26N2O2).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:20]2[CH:21]=[C:22]([C:26](=[O:28])[CH3:27])[CH:23]=[CH:24][CH:25]=2)[N:3]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C(O)CCC>[N:29]1([C:2]2[CH:7]=[C:6]([NH:8][C:9]3[CH:10]=[CH:11][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=3)[N:5]=[C:4]([C:20]3[CH:21]=[C:22]([C:26](=[O:28])[CH3:27])[CH:23]=[CH:24][CH:25]=3)[N:3]=2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: C1COCCN1
Reactant: CC(=O)c1cccc(-c2nc(Cl)cc(Nc3ccc(OC(F)(F)F)cc3)n2)c1
Solvent: CCCCO
Product: CC(=O)c1cccc(-c2nc(Nc3ccc(OC(F)(F)F)cc3)cc(N3CCOCC3)n2)c1
Temperature: 30 °C
Yield: 75 %

Procedure:
A mixture of compound 1-{3-[4-chloro-6-(4-trifluoromethoxy-phenylamino)-pyrimidin-2-yl]-phenyl}-ethanone (0.13 g, 0.32 mmol) and morpholine (0.22 g, 2.55 mmol) in n-butanol (10 mL) was refluxed for 24 hours under nitrogen atmosphere. The mixture was cooled to temperature in the range of 20-40° C. and concentrated under vacuum. The crude compound was purified by column chromatography using 18-20% ethylacetate in petroleum ether to afford the desired compound (0.11 g, 75%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[OH:26][CH2:27][CH:28]([NH:30][S:31]([C:34]1[CH:35]=[N:36][CH:37]=[C:38](Br)[CH:39]=1)(=[O:33])=[O:32])[CH3:29]>>[OH:26][CH2:27][CH:28]([NH:30][S:31]([C:34]1[CH:35]=[N:36][CH:37]=[C:38]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:39]=1)(=[O:33])=[O:32])[CH3:29]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(CO)NS(=O)(=O)c1cncc(Br)c1
Product: CC(CO)NS(=O)(=O)c1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (300 mg, 1.0 mmol) and 5-Bromo-pyridine-3-sulfonic acid (2-hydroxy-1-methyl-ethyl)-amide (example B.16) (265 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (390 mg, 65%). MS (ISP) 570.2 [(M+H)+]; mp 225-226° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[CH3:18])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:14][C:5]2[C:4]3[CH:3]=[C:2]([N:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)[CH:11]=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:12]=1)=[O:16]
Reactant: CN1CCNCC1
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(Br)ccc1OC2)c1ccc(F)cc1F
Product: CN1CCN(c2ccc3c(c2)-c2sc(C(=O)N(C)c4ccc(F)cc4F)cc2CO3)CC1

Procedure:
Following Example 70 and General Procedure D, 8-bromo-N-(2,4-difluorophenyl)-N-methyl-4H-thieno[3,2-c]chromene-2-carboxamide 160bp and N-methylpiperazine were reacted to give 128bp. 1H NMR (400 MHz, CDCl3) δ 7.30 (m, 1 H), 6.94-7.00 (m, 2 H), 6.85 (m, 1 H), 6.75-6.82 (m, 2 H), 6.68 (s, 1 H), 5.03 (s, 2 H), 3.69 (m, 2 H), 3.46 (m, 2 H), 3.39 (s, 3 H), 3.30 (m, 2 H), 3.07 (m, 2 H), 2.90 (s, 3 H). LCMS (ESI) m/z: 456.2.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[CH3:10][C:11]1([CH3:35])[CH2:20][CH2:19][C:18]2[N:17]=[CH:16][N:15]=[C:14]([N:21]3[CH2:27][C:26]4[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:25]=4[O:24][CH2:23][CH2:22]3)[C:13]=2[CH2:12]1>>[CH3:10][C:11]1([CH3:35])[CH2:20][CH2:19][C:18]2[N:17]=[CH:16][N:15]=[C:14]([N:21]3[CH2:27][C:26]4[CH:28]=[C:29]([C:2]5[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=5)[CH:30]=[CH:31][C:25]=4[O:24][CH2:23][CH2:22]3)[C:13]=2[CH2:12]1
Reactant: COc1cncc(Br)c1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Product: COc1cncc(-c2ccc3c(c2)CN(c2ncnc4c2CC(C)(C)CC4)CCO3)c1

Procedure:
Prepared according to the method of example 5 by using 3-bromo-5-methoxypyridine and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, DMSO-d6): 8.49 (s, 1H), 8.40 (s, 1H), 8.26 (s, 1H), 7.75 (s, 1H), 7.59 (m, 2H), 7.07 (d, 1H), 4.65 (s, 2H), 4.35 (m, 2H), 3.90 (s, 3H), 3.84 (m, 2H), 2.67 (t, 2H), 2.44 (s, 2H), 1.57 (t, 2H), 0.82 (s, 6H); MS (EI) for C25H28N4O2: 417 (MH+).
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH:9]1[CH:14]=[C:13]([CH:15]=O)[C:12]([CH:17]=O)=[CH:11][CH:10]=1.[OH-].[Na+]>C(O)C>[CH:11]1[C:12]2[C:13](=[CH:15][C:6]3[C:1](=[O:8])[C:2]4[C:3]([C:4](=[O:7])[C:5]=3[CH:17]=2)=[CH:15][C:13]2[C:12](=[CH:11][CH:10]=[CH:9][CH:14]=2)[CH:17]=4)[CH:14]=[CH:9][CH:10]=1
Reactant: O=Cc1ccccc1C=O
Reactant: O=C1CCC(=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1c2cc3ccccc3cc2C(=O)c2cc3ccccc3cc21
Temperature: 47 °C

Procedure:
A solution of 62.7 grams (0.559 mmoles, 1.0 equivalents) of cyclohexan-1,4-dione and 150 grams of o-phthalaldehyde (1.12 mmoles, 2.0 equivalents) in 2000 mL of ethanol was heat to 28° C. To this solution was added 220 mL of a 1M aqueous solution of sodium hydroxide. The reaction temperature increased to 47° C. during the addition. The mixture was then heated at 40° C. for 4 hours. The mixture was cooled and a yellow solid precipitate was collected. The solid was stirred in 2000 mL of N,N-dimethylformamide and heated to 50° C. for 2 hours. The mixture was cooled to room temperature (i.e., 20° C. to 25° C.) and the yellow solid was collected and washed with N,N-dimethylformamide, then with acetone and dried to give 108.3 grams (62 mole percent yield) of a bright yellow solid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]#[N:8].CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:16]=[CH:17][C:18]([Cl:26])=[C:19]([N:21]([CH3:25])[C:22](=[O:24])[CH3:23])[CH:20]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[Cl:26][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[N:6]3[N:5]=[CH:4][C:3]([C:7]#[N:8])=[C:2]3[N:1]=[CH:11][CH:12]=2)=[CH:20][C:19]=1[N:21]([CH3:25])[C:22](=[O:24])[CH3:23]
Reactant: N#Cc1cn[nH]c1N
Reactant: CC(=O)N(C)c1cc(C(=O)C=CN(C)C)ccc1Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N(C)c1cc(-c2ccnc3c(C#N)cnn23)ccc1Cl
Yield: 77.1 %

Procedure:
A mixture of 0.046 g (0.43 mmol) of 5-amino-1H-pyrazole-4-carbonitrile and 0.120 g (0.43 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-chloro-phenyl]-N-methyl-acetamide in 10 mL of glacial acetic acid was refluxed for 2.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 108 mg of N-{2-chloro-5-[3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide as a solid (yield 77%).