Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([CH2:12][NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH:9]=[CH:8][C:7]=1[Cl:22])=[O:4].[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>C1COCC1>[Cl:22][C:7]1[CH:8]=[CH:9][C:10]([CH2:12][NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C[C@@H](NCc1ccc(Cl)c(NC(=O)CCl)c1)c1ccccc1
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: C[C@@H](NCc1ccc(Cl)c(NC(=O)CN2CCCC2)c1)c1ccccc1
Temperature: 50 °C
Yield: 65.4 %

Procedure:
To a solution of (R)-2-chloro-N-(2-chloro-5-((1-phenylethylamino)methyl)phenyl)acetamide 46 (0.397 g, 1.2 mmol) in THF (6 mL) was added pyrrolidine (3.0 mL, 36 mmol). The reaction mixture was heated to 50° C. for 30 min, cooled to room temperature, partially concentrated under reduced pressure, quenched with saturated NaHCO3, and diluted with EtOAc. The aqueous phase was extracted with EtOAc (3×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 1% to 10% MeOH in DCM) gave (R)—N-(2-chloro-5-((1-phenylethylamino)methyl)phenyl)-2-(pyrrolidin-1-yl)acetamide 47 (0.292 g, 67% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.36 (d, J=6.5 Hz, 3H), 1.83-1.91 (m, 4H), 2.68-2.79 (m, 4H), 3.33 (s, 2H), 3.58 (d, J=13.5 Hz, 1H), 3.64 (d, J=13.3 Hz, 1H), 3.81 (q, J=6.7 Hz, 1H), 6.98 (d, J=8.2 Hz, 1H), 7.23-7.37 (m, 7H), 8.38 (s, 1H), 9.93 (s, 1H). Mass spectrum: calculated for C21H26ClN3O 371.2. found 372.2 (M++1).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=3[Se:10][C:6]=2[N:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[O:17][C:18]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][C:20]=1[C:21]#[N:22].[OH-].[Na+]>CN(C=O)C>[C:23]([C:18]1[O:17][C:16]([NH:15][C:2]2[C:7]3[C:8]4[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=4[Se:10][C:6]=3[N:5]=[CH:4][N:3]=2)=[C:20]([C:21]#[N:22])[CH:19]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: Clc1ncnc2[se]c3c(c12)CCCC3
Reactant: CC(C)(C)c1cc(C#N)c(N)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C#N)c(Nc2ncnc3[se]c4c(c23)CCCC4)o1
Yield: 54.7 %

Procedure:
To a solution of 4-chloro-5,6,7,8-tetrahydrobenzo[1,2-b]pyrimidino[5,4-d]selenophene (500 mg, 1.83 mmol, from step b of example 1) in DMF (15 mL) was added sequentially 2-amino-5-tert-butylfuran-3-carbonitrile (300 mg, 1.83 mmol) and powdered NaOH (210 mg, 5.49 mmol) at rt. Work-up as described in example 2, gave the product as a yellow color solid (400 mg, 55%), mp 230-232° C. 1H NMR (400 MHz, CDCl3): δ 9.78 (1H, s, H-2), 6.94 (1H, br s, exchangeable with D2O, —NH), 6.35 (1H, s, H-4′), 3.30-3.31 (2H, m, H-8), 2.95 (2H, br s, H-5), 1.90-1.92 (4H, m, H-6,7), 1.38 (9H, s, tert-butyl); 13C NMR (100 MHz, CDCl3): δ 163.2, 161.7, 158.0, 154.0, 144.7, 142.9, 137.1, 133.8, 125.9, 101.4, 97.8, 33.0, 29.0, 28.8, 28.4, 23.1, 22.5; LC-MS (positive ion mode): m/z 399, 401 (M+H)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:28][OH:29])[CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2.Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>CN(C=O)C>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2)[CH2:28][O:29][CH2:31][C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)CBr
Reactant: OCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reaction time: 0.25 h

Procedure:
Sodium hydride (0.015 mL, 0.35 mmol) was added to a light yellow solution of (3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)methanol (0.110 g, 0.29 mmol) in DMF (3.00 mL); the color changed to dark brown. The reaction mixture was treated with methyl 2-bromoacetate (0.032 mL, 0.35 mmol), and the color changed to green, then yellow, and then became cloudy. After 15 min, additional methyl 2-bromoacetate (0.032 mL, 0.35 mmol) was added, and after 15 min, the reaction mixture was quenched with NH4Cl, extracted with EtOAc, and the organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with 15-20% EtOAc/hexanes to give methyl 2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyloxy)acetate. MS (ESI) m/z: calculated: 448.1; Observed: 449.0 (M++1).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.CCCCCC.C([Li])CCC.[F:18][C:19]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:20]=1[CH:21]=[O:22].[Cl-].[NH4+]>O1CCCC1>[F:18][C:19]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:20]=1[CH:21]([OH:22])[C:2]1[S:3][CH:4]=[CH:5][N:6]=1
Reactant: O=Cc1cc(F)ccc1F
Reactant: Brc1nccs1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1nccs1)c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
To a tetrahydrofuran (10 ml) solution of 2-bromothiazole (180 μg, 2 mmol) was added dropwise a hexane solution (1.57M, 1.40 ml, 2.2 mmol) of n-butyl lithium at −78° C., followed by stirring for 10 minutes. Then, 2,5-difluorobenzaldehyde (238 μl, 2.2 mmol) was added and the temperature of the resulting mixture was raised gradually to 0° C. under stirring. An aqueous solution of ammonium chloride was added to terminate the reaction and ether was added to the reaction mixture. The ether layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. After filtration, the solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (358 mg, 79%) as an oil.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[O:26]1[CH2:31][CH2:30][CH2:29][O:28][CH:27]1[CH2:32][CH2:33][N:34]1[C:42]2[C:37](=[CH:38][C:39]([O:43][CH:44]([F:46])[F:45])=[CH:40][CH:41]=2)[C:36]([Sn](CCCC)(CCCC)CCCC)=[N:35]1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[O:28]1[CH2:29][CH2:30][CH2:31][O:26][CH:27]1[CH2:32][CH2:33][N:34]1[C:42]2[C:37](=[CH:38][C:39]([O:43][CH:44]([F:46])[F:45])=[CH:40][CH:41]=2)[C:36]([C:2]2[N:3]=[C:4]3[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]3=[N:6][CH:7]=2)=[N:35]1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(CCC2OCCCO2)c2ccc(OC(F)F)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCC4OCCCO4)c4ccc(OC(F)F)cc34)nc12
Temperature: 90 °C
Reaction time: 4 h
Yield: 62.5 %

Procedure:
2-Bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (244 mg, 571 μmol) and 1-(2-(1,3-dioxan-2-yl)ethyl)-5-(difluoromethoxy)-3-(tributylstannyl)-1H-indazole (335 mg, 571 μmol) were dissolved in DMF (3.00 mL) under argon, tetrakis(triphenylphosphine)palladium (0) (33.0 mg, 28.6 μmol) and CuI (21.7 mg, 114 mmol, Eq: 0.20) were added and the mixture sonicated for 5 min with bubbling argon. The reaction mixture was stirred at 90° C. (oil bath temperature) for 4 h. The reaction mixture was concentrated under high vacuum and the residue (dark solid) was purified by chromatography (80 g column, 50 μm from Analogix, 0-50% EtOAc in hexanes over 30 min) to give 2-(1-(2-(1,3-dioxan-2-yl)ethyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (230 mg, 357 μmol, 62.5%) as an off-white solid. MS (M+Na)+=667.1; 1H NMR (CDCl3) δ: 9.25 (s, 1H), 8.37 (s, 1H), 8.32 (d, J=2.0 Hz, 1H), 8.06 (s, 1H), 7.56 (dd, J=9.1, 0.5 Hz, 1H), 7.35 (dd, J=9.1, 2.3 Hz, 1H), 6.55 (t, J=74.3 Hz, 1H), 5.75 (s, 2H), 4.65 (t, J=6.9 Hz, 2H), 4.55 (t, J=4.9 Hz, 1H), 4.12-4.21 (m, 2H), 3.74 (td, J=12.3, 2.5 Hz, 2H), 3.56-3.65 (m, 2H), 2.34 (td, J=6.8, 5.3 Hz, 2H), 2.05-2.23 (m, 1H), 1.65 (s, 9H), 1.39 (dt, J=13.4, 1.3 Hz, 1H), 0.94-1.04 (m, 2H), −0.06-0.05 (m, 9H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[O:20][C@H:19]3[CH2:21][C@H:22]([N:24]4[C:28]5[N:29]=[CH:30][N:31]=[C:32]([CH3:33])[C:27]=5[C:26]([C:34]#[C:35][Si](C)(C)C)=[CH:25]4)[CH2:23][C@H:18]3[CH2:17][O:16]2)=[CH:11][CH:10]=1>CO.CCOC(C)=O>[C:34]([C:26]1[C:27]2[C:32]([CH3:33])=[N:31][CH:30]=[N:29][C:28]=2[N:24]([C@H:22]2[CH2:21][C@@H:19]3[O:20][CH:15]([C:12]4[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:14][CH:13]=4)[O:16][CH2:17][C@@H:18]3[CH2:23]2)[CH:25]=1)#[CH:35]
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](n4cc(C#C[Si](C)(C)C)c5c(C)ncnc54)C[C@@H]3O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1cn([C@@H]2C[C@H]3COC(c4ccc(OC)cc4)O[C@H]3C2)c2ncnc(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
Potassium carbonate (191 mg, 1.38 mmol) was added to a solution of 7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-6-yl]-4-methyl-5-[(trimethylsilyl)ethynyl]-7H-pyrrolo[2,3-d]pyrimidine (314 mg, 0.680 mmol) in MeOH (10.0 mL), and the mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc, washed with saturated aqueous sodium bicarbonate solution, dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound as an oil (215 mg, 81%). LC/MS: Rt=1.94 min, ES+ 390 (AA standard).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH3:25])=[O:5])C.[N:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=1)=[C:27]=[O:28]>>[CH3:25][O:24][C:10]1[C:9]2[N:8]=[CH:7][C:6]3[C:4](=[O:5])[N:26]([C:29]4[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=4)[C:27](=[O:28])[N:16]([CH:17]4[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]4)[C:15]=3[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCC(C)CC1
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(C)c3)c(=O)n(C3CCC(C)CC3)c12
Yield: 108.4 %

Procedure:
7-Methoxy-1-(4-methyl-cyclohexyl)-3-m-tolyl-1H-pyrimido[5,4-c]quinoline-2,4-dione (135 mg) was prepared from 8-methoxy-4-(4-methyl-cyclohexylamino)-quinoline-3-carboxylic acid ethyl ester (0.29 mmol) and 1-isocyanato-3-methyl-benzene (0.44 mmol) following general procedure C. LCMS: m/z 430 [M+1]+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([NH:15][C:16]([C:18]3[NH:19][C:20]4[C:25]([CH:26]=3)=[C:24]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH:23]=[CH:22][CH:21]=4)=[O:17])[CH2:11][CH2:10]2)[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.Cl.[F:33]C1CCCNC1.CCN(C(C)C)C(C)C.[I-].C(C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#N>C(#N)CC.CCOC(C)=O>[F:33][CH:5]1[CH2:4][CH2:3][CH2:2][N:1]([CH2:7][CH2:8][N:9]2[CH2:10][CH2:11][CH:12]([NH:15][C:16]([C:18]3[NH:19][C:20]4[C:25]([CH:26]=3)=[C:24]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH:23]=[CH:22][CH:21]=4)=[O:17])[CH2:13][CH2:14]2)[CH2:6]1
Reactant: FC1CCCNC1
Reactant: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CC=CCC4)CC3)cc12
Agent: Cl
Agent: N#CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Solvent: CCOC(C)=O
Product: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCC(F)C4)CC3)cc12
Temperature: 90 °C

Procedure:
To a suspension of 190 (see example 150) (100 mg, 0.28 mmol), 3-fluoropiperidine hydrochloride (43 mg, 0.208 mmol) and DIEA (0.189 ml, 1.12 mmol) in 0.5 ml of propionitrile is added cyanomethyl-triphenyl phosphonium iodide (81 mg, 0.336 mmol). The mixture is heated at 90° C. for 14 hours. The resulting solution is then diluted with EtOAc (20 ml) and washed twice with saturated sodium bicarbonate, dried over sodium sulfate and evaporated. The crude product is further purified by preparative HPLC.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]([S:13][CH3:14])[C:9]([F:12])([F:11])[F:10])(=O)=O.[F:15][C:16]([F:26])([F:25])[CH2:17][CH2:18][S:19]([CH2:22][C:23]#[N:24])(=[O:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:12][C:9]([F:10])([F:11])[CH:8]([S:13][CH3:14])[CH2:7][CH2:6][CH:22]([S:19]([CH2:18][CH2:17][C:16]([F:26])([F:15])[F:25])(=[O:21])=[O:20])[C:23]#[N:24]
Reactant: N#CCS(=O)(=O)CCC(F)(F)F
Reactant: CSC(CCOS(C)(=O)=O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CSC(CCC(C#N)S(=O)(=O)CCC(F)(F)F)C(F)(F)F
Temperature: 60 °C
Reaction time: 48 h
Yield: 34.6 %

Procedure:
To a solution of 1.0 g of 4,4,4-trifluoro-3-methylthio-butyl methanesulfonate and 0.8 g of (3,3,3-trifluoropropylsulfonyl)acetonitrile in 30 ml of dimethyl sulfoxide was added 0.5 g of potassium carbonate at room temperature, heated to 60° C. and then stirred at the same temperature for 2 days. The reaction mixture was allowed to stand to cool to nearly room temperature. To the reaction mixture was added 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 0.49 g of 6,6,6-trifluoro-5-methylthio-2-(3,3,3-trifluoropropylsulfonyl)hexanenitrile (hereinafter referred to as the present compound (30)).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:8])[C:4]([C:16]([F:19])([F:18])[F:17])=[N:3]1.C([N-]C(C)C)(C)C.[Li+].[CH:28]([CH:30]=[CH2:31])=[O:29].[NH4+].[Cl-]>C1COCC1>[OH:29][CH:28]([CH:30]=[CH2:31])[CH:10]([NH:9][C:7]([C:5]1[C:4]([C:16]([F:18])([F:17])[F:19])=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:8])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CNC(=O)c1cn(C)nc1C(F)(F)F
Reactant: C=CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC(O)C(NC(=O)c1cn(C)nc1C(F)(F)F)C(=O)OCC
Temperature: -50 °C
Reaction time: 1.5 h

Procedure:
At −50° C., 3.45 g (12.4 mmol) of ethyl [(1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)amino]acetate dissolved in THF were added dropwise to 18.5 ml (37.0 mmol) of a 2M solution of lithium diisopropylamide in THF/heptanelethylbenzene. After 1.5 h of stirring at −50° C., the mixture was cooled to −78° C. and 0.83 g (14.8 mmol) of acrolein dissolved in THF were added dropwise. After 2 h of stirring at −78° C., the mixture was hydrolyzed with sat. NH4Cl solution and warmed to RT. After separation of the phases, the organic phase was dried and the solvent was removed. The residue was purified chromatographically (SiO2, cyclohexane/ethyl acetate). This gave 1.65 g (40% of theory) of the title compound as a colorless solid (about 1:1 diastereomer mixture) which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:13]=[N:12][C:5]2[NH:6][CH2:7][C:8](=[O:11])[NH:9][CH2:10][C:4]=2[CH:3]=1.[C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[CH:15]=[CH2:16].C(N(C(C)C)CC)(C)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:19]([O:18][C:14](=[O:17])[CH:15]=[CH:16][C:2]1[CH:13]=[N:12][C:5]2[NH:6][CH2:7][C:8](=[O:11])[NH:9][CH2:10][C:4]=2[CH:3]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=C1CNc2ncc(Br)cc2CN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C=Cc1cnc2c(c1)CNC(=O)CN2
Temperature: 90 °C
Yield: 55.3 %

Procedure:
7-Bromo-1,2,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-3-one (145 mg, 0.6 mmol) and tert-butyl acrylate (307 mg, 2.4 mmol) were dissolved in DMF (3 mL) and the reaction vessel was purged with argon for 5 min. Tri-σ-tolylphosphine (37 mg, 0.12 mmol) and palladium acetate (14 mg, 0.06 mmol) were added and the solution was degassed with argon. Diisopropylethylamine (0.23 mL, 1.32 mmol) was added and the solution was degassed with argon, sealed and heated to 90° C. for 16 h. The reaction was cooled to room temperature and filtered through a bed of celite. The filter cake was washed with ethyl acetate (50 mL) and the filtrate was washed with H2O (5 mL) and brine (5 mL), dried over MgSO4 and concentrated to a brown oil. The oil was subjected to silica gel chromatography (5% MeOH/CH2Cl2 to 10% MeOH/CH2Cl2) to yield the title compound as a yellow solid (96 mg, 52%). 1H NMR (300 MHz, DMSO-d6) 8.18 (t, J=5.7 Hz, 1H), 8.07 (d, J=2.1 Hz, 1H), 7.37 (d, J=15.8 Hz, 1H), 7.35 (t, J=5.3 Hz, 1H), 6.24 (d, J=15.8 Hz, 1H), 4.28 (d, J=5.7 Hz, 2H), 3.98 (d, J=5.1 Hz, 2H), 1.45 (s, 9H); ESI MS m/z 290 [C15H19N3O3+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=O)[CH:2]([CH3:4])[CH3:3].Cl.[CH2:20]([S:22]([C:25]1[CH:26]=[CH:27][C:28]2[O:32][C:31]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[N:30][C:29]=2[CH:39]=1)(=[O:24])=[O:23])[CH3:21]>>[CH2:20]([S:22]([C:25]1[CH:26]=[CH:27][C:28]2[O:32][C:31]([N:33]3[CH2:34][CH2:35][N:36]([C:8]([C:7]4[CH:11]=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:13]=[CH:14][C:6]=4[O:5][CH2:1][CH:2]([CH3:3])[CH3:4])=[O:10])[CH2:37][CH2:38]3)=[N:30][C:29]=2[CH:39]=1)(=[O:23])=[O:24])[CH3:21]
Reactant: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: CCS(=O)(=O)c1ccc2oc(N3CCNCC3)nc2c1
Agent: Cl
Product: CCS(=O)(=O)c1ccc2oc(N3CCN(C(=O)c4cc(S(C)(=O)=O)ccc4OCC(C)C)CC3)nc2c1

Procedure:
Prepared in analogy to example 1.1 b) from 2-isobutoxy-5-methanesulfonyl-benzoic acid (Example 2.4) and 5-ethanesulfonyl-2-piperazin-1-yl-benzoxazole hydrochloride. The crude material was purified by chromatography (SiO2, ethyl acetate) to yield the title compound as a colorless solid.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][C:8]2[N:13]=[C:12]([NH:14][C:15]([NH:17][C:18]3[N:19]=[C:20]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)[S:21][CH:22]=3)=[O:16])[CH:11]=[CH:10][CH:9]=2)C(=O)C2=CC=CC=C12.CCO.O.NN>C(Cl)(Cl)Cl>[NH2:5][CH2:6][CH2:7][C:8]1[N:13]=[C:12]([NH:14][C:15]([NH:17][C:18]2[N:19]=[C:20]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[S:21][CH:22]=2)=[O:16])[CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Nc1cccc(CCN2C(=O)c3ccccc3C2=O)n1)Nc1csc(-c2ccncc2)n1
Agent: NN
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: NCCc1cccc(NC(=O)Nc2csc(-c3ccncc3)n2)n1
Temperature: 25 °C

Procedure:
To a mixture of 1-{6-[2-(phthalimidyl)ethyl]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)urea (75 mg, 0.16 mmol, Example 88) and EtOH (10 mL) was added hydrazine hydrate (0.1 mL, 0.18 mmol). The mixture was heated at reflux for 2 h then cooled to RT. The residue was dissolved in 3:1 CHCl3/IpOH, washed with saturated NaHCO3, dried (MgSO4) and concentrated in vacuo to afford the title compound as a yellow solid. MS m/z: 341.0 (M+H). Calc'd for C16H16N6OS: 340.11.
Reaction SMILES: [Li][CH2:2]CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:15]=[C:16]([C:20]2[O:24][N:23]=[C:22]([CH:25]([N:27]([CH3:40])[C:28]3[N:32]([CH3:33])[C:31]([C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)=[N:30][N:29]=3)[CH3:26])[N:21]=2)[CH:17]=[CH:18][CH:19]=1.CI>O>[Cl:13][C:14]1[CH:15]=[C:16]([C:20]2[O:24][N:23]=[C:22]([C:25]([N:27]([CH3:40])[C:28]3[N:32]([CH3:33])[C:31]([C:34]4[CH:35]=[CH:36][N:37]=[CH:38][CH:39]=4)=[N:30][N:29]=3)([CH3:2])[CH3:26])[N:21]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: CC(c1noc(-c2cccc(Cl)c2)n1)N(C)c1nnc(-c2ccncc2)n1C
Reactant: [Li]CCCC
Solvent: O
Solvent: CI
Solvent: CC(C)NC(C)C
Product: CN(c1nnc(-c2ccncc2)n1C)C(C)(C)c1noc(-c2cccc(Cl)c2)n1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
n-BuLi (132 ml 2.5 M in hex., 0.33 mmol) was added to diisopropyl amine (55 ml, 0.39 mmol). After stirring for 20 minutes at 0° C. the mixture was cooled to −78° C. and N-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-N,4-dimethyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine (110 mg, 0.28 mmol) was added. After 15 min. methyl iodide (20 μl, 0.33 mmol) was added and the temperature was raised to r.t. After stirring for 2 h five drops of water were added. After solvent removal in vacuo, the crude was taken up in DCM, washed with water and brine, dried and concentrated. The desired product was obtained by prep. HPLC in 20 mg yield. 1H NMR: 1.7 (s, 6 H) 2.8 (s, 3 H) 3.8 (s, 3 H) 7.5 (t, 1 H) 7.6 (d, 1 H) 7.7 (s, 2 H) 8.0 (d, 1 H) 8.1 (s, 1 H) 8.8 (s, 2 H)
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:29])[N:4]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12]N3C(CC4C=CC(C#N)=CC=4)=CN=C3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][N:7]=1.C1C(=O)N([Br:37])C(=O)C1.S(C)C.O>C(Cl)Cl.CCOC(C)=O>[Br:37][CH2:12][C:11]1[CH:27]=[CH:28][C:8]([N:4]2[CH:5]=[CH:6][N:7]=[C:2]([CH3:1])[C:3]2=[O:29])=[CH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nccn(-c2ccc(Cn3cncc3Cc3ccc(C#N)cc3)cc2)c1=O
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nccn(-c2ccc(CBr)cc2)c1=O
Reaction time: 8 h

Procedure:
The pyrazinone intermediate from Step 3 (430 mg, 1.99 mmol) was dissolved in CH2Cl2 and added to a yellow suspension of NBS (531 mg, 2.98 mmol) and Me2S (0.248 mL, 3.38 mmol) at -20°. The sulfoxium salt was formed at 0° then cooled to -20° before the addition of alcohol. After addition of the alcohol, the reaction mixture was stirred at 0° for several hours and then the cooling bath was allowed to expire overnight. The light brown solution was poured into H2O and extracted with CHCl3 (3×). The organic layers were combined, dried (MgSO4), filtered and concentrated to yield a dark brown oil. Dissolved in EtOAc and filtered off resulting brown solid. The filtrate solidified to give the title compound as a yellow solid which will be used in the next step without further purification.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[O:10][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)=[CH:8][CH:7]=1.[H-].[Na+].[C:22]([C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br)#[N:23].O>CN(C=O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:22]([C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([C:9]2[O:10][C:6]([CH:2]3[O:1][CH2:5][CH2:4][O:3]3)=[CH:7][CH:8]=2)=[N:12]1)#[N:23]
Reactant: c1ccc2c(-c3ccc(C4OCCO4)o3)n[nH]c2c1
Reactant: N#Cc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: N#Cc1ccccc1Cn1nc(-c2ccc(C3OCCO3)o2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2 g (7.41 mmol) of 3-(5-(1,3-dioxolan-2-yl)-furan-2-yl)indazole in 10 ml of DMF is added to a suspension of 355 mg of NaH (60 per cent in paraffin) in 10 ml of DMF under argon and the mixture is stirred at room temperature for 1 hour. 1.5 g of 2-cyanobenzyl bromide are then added. The mixture is stirred at 100° C. for 30 minutes, introduced into water and extracted with ethyl acetate, the organic phase is dried with sodium sulphate and evaporated in vacuo and the residue is chromatographed over silica gel using toluene/ethyl acetate mixtures as the eluent. 2.1 g (73.5% of theory) of an oil are obtained. Rf(SiO2, toluene/ethyl acetate 1:1): 0.63