Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].[Br:13][C:14]1[S:15][C:16]([CH2:20]OS(C)(=O)=O)=[C:17]([CH3:19])[N:18]=1.O>CN(C)C=O.C(OCC)(=O)C>[Br:13][C:14]1[S:15][C:16]([CH2:20][O:10][C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[C:17]([CH3:19])[N:18]=1
Reactant: Cc1nc(Br)sc1COS(C)(=O)=O
Reactant: N#Cc1ccc(O)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(Br)sc1COc1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.4 %

Procedure:
To a solution of 2-Chloro-4-hydroxy-benzonitrile (1.6 g, 10.1 mmol) in dry dimethylformamide (30 mL) is carefully added sodium hydride (486 mg, 12.1 mmol). The resulting mixture is stirred for 20 minutes at room temperature. A solution of Methanesulfonic acid 2-bromo-4-methyl-thiazol-5-ylmethyl ester (3.0 g, 10.1 mmol) in dry dimethylformamide (5 mL) is added and the reaction mixture is stirred at room temperature. The reaction mixture is diluted with 100 mL of ethyl acetate after 5 h and water (20 mL) is carefully added (Caution: development of H2). The phases are separated and the organic phase is dried over MgSO4. The solvent is removed under reduced pressure and the crude product is purified by reversed phase HPLC to yield 2.2 g of 4-(2-Bromo-4-methyl-thiazol-5-ylmethoxy)-2-chloro-benzonitrile. C12H8BrClN2OS (343.63), MS (ESI): 343.0 (M+H+).
Reaction SMILES: C(OC([NH:11][CH:12]1[CH:17]([NH:18][C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])[CH2:16][CH2:15][CH:14]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:13]1)=O)C1C=CC=CC=1.[H][H]>[Pd].C(O)(C)C>[NH2:11][CH:12]1[CH:17]([NH:18][C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:25])[CH3:26])=[O:20])[CH2:16][CH2:15][CH:14]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:13]1
Reactant: [H][H]
Reactant: CCOC(=O)C1CCC(NC(=O)OCC[Si](C)(C)C)C(NC(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CC(C)O
Product: CCOC(=O)C1CCC(NC(=O)OCC[Si](C)(C)C)C(N)C1
Yield: 81.8 %

Procedure:
A mixture of Racemate-ethyl 3-(benzyloxycarbonylamino)-4-((2-(trimethylsilyl)ethoxy)carbonylamino)cyclohexanecarboxylate (1.7 g, 3.7 mmol) and 5% palladium on carbon (50% wet, 300 mg) in isopropanol (35 mL) was stirred under 1 atm hydrogen atmosphere at room temperature for 18 hours. The mixture was filtered through a pad of celite. The filtrate was concentrated and purified by silica gel chromatography (methanol/dichloromethane=1/30 to 1/10) to afford the title compound (1.0 g, 89%) as a yellow oil. MS (ES+) C15H30H2O4Si requires: 330, found: 331 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH:9]([CH3:16])[CH2:8][N:7]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[C:6]=2[CH:25]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=2)O1.C(=O)([O-])[O-].[K+].[K+].O1CCCC1>C(OCC)(=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.O>[NH2:40][C:37]1[N:38]=[CH:39][C:34]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]4[C:12]([CH3:15])=[N:13][N:14]=[C:10]4[CH:9]([CH3:16])[CH2:8][N:7]([C:17]4[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=4)[C:6]=3[CH:25]=2)=[CH:35][CH:36]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(C#N)cc1)CC2C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nnc2n1-c1ccc(-c3ccc(N)nc3)cc1N(c1ccc(C#N)cc1)CC2C
Temperature: 100 °C
Yield: 59.4 %

Procedure:
A mixture of 4-(8-bromo-1,4-dimethyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-6(5H)-yl)benzonitrile (244 mg, 0.62 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (274 mg, 1.24 mmol), tetrakis(triphenylphosphine)palladium(0) (50 mg) and potassium carbonate (350 mg, 2.53 mmol) in a mixed solution of tetrahydrofuran (10 mL) and water (1 mL) was heated at 100° C. for 30 minutes under microwave (pressure: 17.2 bar, equipment power: 150 W). The reaction mixture was diluted with ethyl acetate (20 mL) and washed with brine (10 mL*3). The organic phase was separated, dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated to give a crude product, which was purified by column chromatography (silica gel, dichloromethane/methanol=12:1) to afford 4-(8-(6-aminopyridin-3-yl)-1,4-dimethyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-6(5H)-yl)benzonitrile as a light yellow solid (150 mg, 59.4%). LRMS (M+H)+: calcd 407.19. found 407.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:29][CH2:28][CH2:27][C@@:15]3([C:19](=[O:20])[N:18]([CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:17][CH2:16]3)[CH2:14]2)=[N:11][CH:12]=1.C(N(CC)C(C)C)(C)C.C(Cl)Cl>>[CH3:5][O:4][C:2](=[O:3])[NH:6][C:7]1[CH:12]=[N:11][C:10]([N:13]2[CH2:29][CH2:28][CH2:27][C@@:15]3([C:19](=[O:20])[N:18]([CH:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[CH2:17][CH2:16]3)[CH2:14]2)=[CH:9][CH:8]=1
Reactant: COC(=O)Cl
Reactant: Nc1ccc(N2CCC[C@]3(CCN(C4CCOCC4)C3=O)C2)nc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Nc1ccc(N2CCC[C@]3(CCN(C4CCOCC4)C3=O)C2)nc1
Reaction time: 1 h

Procedure:
Methyl chloroformate (4.4 μL, 0.000057 mol) was added to a solution of (5S)-7-(5-aminopyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one (15.8 mg, 0.0000478 mol), N,N-diisopropylethylamine (27 μL, 0.00016 mol) and methylene chloride (1.0 mL, 0.016 mol); and the mixture was stirred for 1 h. The volatiles were removed in-vacuo and the crude product was purified by prep-HPLC. LC-MS: 389.2 (M+H)+.
Reaction SMILES: [CH:1]([C@H:4]1[NH:9][CH2:8][CH2:7][N:6]2[C:10]3[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[CH:13][C:11]=3[N:12]=[C:5]12)([CH3:3])[CH3:2].Cl[C:26]1[N:31]=[C:30]([CH:32]2[CH2:34][CH2:33]2)[C:29]([C:35]([O:37][CH3:38])=[O:36])=[CH:28][N:27]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CC(O)C>[CH:32]1([C:30]2[C:29]([C:35]([O:37][CH3:38])=[O:36])=[CH:28][N:27]=[C:26]([N:9]3[CH2:8][CH2:7][N:6]4[C:10]5[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[CH:13][C:11]=5[N:12]=[C:5]4[C@H:4]3[CH:1]([CH3:3])[CH3:2])[N:31]=2)[CH2:33][CH2:34]1
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN[C@@H]3C(C)C
Reactant: COC(=O)c1cnc(Cl)nc1C1CC1
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(=O)OC)c(C2CC2)n1)[C@@H]3C(C)C
Temperature: 120 °C
Reaction time: 16 h
Yield: 43.1 %

Procedure:
The mixture of (R)-methyl 1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (77 mg, 0.22 mmol), methyl 2-chloro-4-cyclopropylpyrimidine-5-carboxylate (57 mg, 0.26 mmol, 1.2 eq.) and DIEA (172 mg, 1.3 mmol, 6 eq.) in CH2Cl2/i-PrOH (1 mL/1 mL) was stirred at 120° C. for 16 h. TLC showed (R)-methyl 1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate was consumed completely (PE:EtOAc=1:1). Water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford (R)-methyl 2-(4-cyclopropyl-5-(methoxycarbonyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (50 mg, 43% yield) as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH:5]([NH:13][C:14]([C:16]1[N:17]=[C:18]([Br:21])[S:19][CH:20]=1)=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].[OH-].[Na+].O.Cl>CO>[Br:21][C:18]1[S:19][CH:20]=[C:16]([C:14]([NH:13][CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:12])[CH2:4][C:3]([OH:22])=[O:2])=[O:15])[N:17]=1
Reactant: COC(=O)CC(NC(=O)c1csc(Br)n1)c1ccccc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccccc1C(CC(=O)O)NC(=O)c1csc(Br)n1
Reaction time: 1 h

Procedure:
100 mg (0.26 mmol) 3-[(2-bromo-thiazole-4-carbonyl)-amino]-3-o-tolyl-propionic acid methyl ester are dissolved in 10 ml MeOH, 0.55 ml of 1N NaOH solution (2.1 Eq NaOH) are added and the resulting mixture is stirred for 1 h. 10 ml of water are added and the pH of the resulting mixture is adjusted to 5.5 by addition of 10% HCl and the MeOH removed in vacuo. The remaining aqueous phase is extracted three times with 10 ml of CH2Cl2, the organic layer is collected, dried over Na2SO4 and the solvent removed in vacuo to deliver 3-[(2-Bromo-thiazole-4-carbonyl)-amino]-3-o-tolyl-propionic acid in yields below 90%
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[C:9]1([S:15]([NH2:18])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:18][S:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])[CH:2]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=Cc1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=S(=O)(N=Cc1cccnc1)c1ccccc1
Temperature: 40 °C

Procedure:
A stirred mixture consisting of 4.00 g (37 mmol) of 3-pyridinecarboxaldehyde, 5.88 g (37 mmol) of benzenesulfonamide and 20 mg of p-toluenesulfonic acid monohydrate in 120 mL of toluene was heated to reflux under a blanket of nitrogen. The reaction vessel was equipped with a Soxhlet extractor containing 4A molecular sieves. After heating 18 hours, the mixture was allowed to cool to approximately 40° C. and was filtered to remove colored impurities. Addition of hexane to the filtrate led to precipitation of a white solid. Filtration provided 9.10 g (73%) of sulfonimine: mp 123° C.; IR (Nujol) 1640, 1605, 1585, 1560, 1300, 1280, 1220, 860 cm-1 ; 1H NMR (CDCl3, TMS, 60 MHz) δ9.15 (s, 1), 8.9-8.7 (m, 2), 8.4-7.4 (m, 7).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:29][C:30]1[CH:35]=[CH:34][C:33](B2OC3C=CC=CC=3O2)=[CH:32][CH:31]=1>>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:12]2[N:13]([CH:18]([CH3:19])[CH3:20])[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)=[CH:32][CH:31]=1
Reactant: Clc1ccc(B2Oc3ccccc3O2)cc1
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CC(C)n1nc2c(c1-c1ccc(Cl)cc1)CCNCC2
Yield: 59 %

Procedure:
The title compound (82 mg) was prepared as in Example 177, Steps C and D, using 205 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 332 mg of 2-(4-chloro-phenyl)-benzo[1,3,2]dioxaborole. MS (ESI): exact mass calculated for C16H20ClN3, 289.13; found, m/z 290.4 [M+H]+, 292.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.57 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 4.36 (m, 1H), 3.44-3.40 (m, 2H), 3.20-3.18 (m, 2H), 2.81-2.76 (m, 2H), 1.40 (d, J=6.6 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.[H-].[Na+].[F:12][C:13]([F:22])([F:21])[CH2:14][CH2:15][CH:16]([C:19]#[N:20])[C:17]#[N:18]>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][C:16]([CH2:15][CH2:14][C:13]([F:12])([F:21])[F:22])([C:17]#[N:18])[C:19]#[N:20]
Reactant: Cc1cccc(CCl)c1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(CC(C#N)(C#N)CCC(F)(F)F)c1
Yield: 64.1 %

Procedure:
Using 0.14 g of 3-metylbenzyl chloride, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.17 g of 2-(3-methylbenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (37)).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16](=O)[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[C:19](O[K])(C)(C)C>C1COCC1>[C:2]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:16]=1[CH3:17])[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]2([CH3:15])[CH3:14])([CH3:1])=[CH2:19]
Reactant: CC(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reactant: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: C=C(C)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a nitrogen-filled glove box, to 250 ml round bottomed flask fitted with a magnetic stirring bar containing 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene-2-yl)ethanone (0.5 g, 2.05 mmol) and 50 ml of dry THF was added [+PPh3MeI−] (1.24 g, 3.07 mmol), followed by tBuOK (343 g, 3.06 mmol). The mixture was stirred at room temperature. After 24 h, in situ GC/MS analysis showed complete conversion of the carbonyl compound to the alkene product. The mixture was filtered to remove the salt. The solvent was removed in vacuo and the resulting solid was redissolved in hexane and then cooled in the refrigerator for 24 h to crystallise the PPh3O. The mixture was filtered and cooled again to remove additional PPh3O. This step has to be repeated at least 4 times to remove all of the PPh3O. Finally, the solvent was removed in vacuo to obtain the pure alkene. Alternatively, a faster method of purification, after removal of the salt by filtration, involves concentration in vacuo and then Kugelrohr distillation (100-140° C., 3×10−4 torr), which gave an analytically pure sample of 4a (396 mg, 80%); m.p. 39-40° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:13])=[CH:4][CH:3]=1.I[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH3:21].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[CH3:21])[C:9]2=[O:13])=[CH:4][CH:3]=1
Reactant: Cc1ccncc1I
Reactant: O=C1NCCc2ccc(Cl)c(F)c21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2ccc(Cl)c(F)c2C1=O
Yield: 28.3 %

Procedure:
Using analogous reaction conditions as described in Example 1, 7-chloro-8-fluoro-3,4-dihydro-2H-isoquinolin-1-one (I-33d: 150 mg, 0.753 mmol) was reacted with 3-iodo-4-methyl-pyridine (165 mg, 0.73 mmol), 1,4-dioxane (10 mL), copper iodide (143 mg, 0.075 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (32 mg, 0.225 mmol) and potassium phosphate (399 mg, 1.88 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in CHCl3) afforded 60 mg of the product (27.6% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:47])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[C:20]3[CH2:21][N:22]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:23](=[O:24])[C:19]=3[C:18]([O:33]C(C3C=CC=CC=3)C3C=CC=CC=3)=[C:17]3[C:12]=2[CH:13]=[CH:14][CH:15]=[N:16]3)[CH:6]=1)[CH3:2].[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].C([SiH](CC)CC)C>ClCCl>[CH2:1]([O:3][C:4](=[O:47])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[C:20]3[CH2:21][N:22]([CH2:25][C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=4)[C:23](=[O:24])[C:19]=3[C:18]([OH:33])=[C:17]3[C:12]=2[CH:13]=[CH:14][CH:15]=[N:16]3)[CH:6]=1)[CH3:2].[C:50]([OH:52])([C:49]([F:54])([F:53])[F:48])=[O:51]
Reactant: CCOC(=O)c1cccc(-c2c3c(c(OC(c4ccccc4)c4ccccc4)c4ncccc24)C(=O)N(Cc2ccc(F)cc2)C3)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cccc(-c2c3c(c(O)c4ncccc24)C(=O)N(Cc2ccc(F)cc2)C3)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 277 dissolved in dichloromethane (2 mL) was added trifluoroacetic acid (200 μl) and triethylsilane (400 μl). The reaction mixture was stirred at room temperature for ½ hours under an inert atmosphere then concentrated in vacuo. The residue was redissolved in DMSO (1 mL) and purified by prep-HPLC to afford 3-[7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl]-benzoic acid ethyl ester 278, TFA salt, (25 mg, 0.003 mmol, 44% in two steps) as a yellow solid: 1H NMR (CDCl3) δ 9.0 (d, 1H), 8.2 (d, 1H), 8.0 (s, 1H), 7.7 (m, 1H), 7.6 (dd, 1H), 7.5 (dd, 2H), 7.0 (m, 2H), 7.1 (t, 2H), 4.7 (dd, 2H), 4.4(q, 2H), 4.3 (dd, 2H), 1.4 (t, 3H); MS: 457 (M+1). HPLC conditions: mobile phase A was 0.1% TFA in water, mobile phase b was 0.1% TFA in CH3CN; gradient from 5% to 60% B in 20 min; flow rate was 20 mL/min; column was Phenomenex, luna 5μ, C18 (2), 150 mm×21.1 mm.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]2[C:13]([CH3:18])=[C:14]([CH2:16][OH:17])[S:15][C:3]=12.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>Cl>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:8]([C:7]2[C:2]([OH:1])=[C:3]3[S:15][C:14]([CH2:16][OH:17])=[C:13]([CH3:18])[C:4]3=[N:5][CH:6]=2)=[O:10])=[CH:22][CH:21]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2c(C)c(CO)sc2c1O
Agent: Cl
Product: Cc1c(CO)sc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Temperature: 80 °C
Yield: 92.4 %

Procedure:
Ethyl 7-hydroxy-2-(hydroxymethyl)-3-methylthieno[3,2-b]pyridine-6-carboxylate (1.27 g, 4.77 mmol) was dissolved in 4-chlorobenzylamine (11.6 mL, 95.4 mmol) and heated to 80° C. for 18 hours. After cooling to room temperature, the mixture was treated with 1 N HCl (100 mL). After chilling in the refrigerator for 2 hrs, the resulting thick precipitate was collected and washed with copious amounts of 1 N HCl until all unreacted 4-chlorobenzylamine had been washed away. The resulting off-white solid was dried in vacuo to give the title compound (1.60 g). 1H NMR (DMSO-d6) δ 2.27 (3 H), 4.53 (2 H), 4.72 (2 H), 5.06 (1 H), 7.38 (4 H), 8.52 (1 H), 10.49 (1 H), 12.95 (1 H). HPLC retention time: 2.73 minutes; MS (ESI−) for C17H15ClN2O3S m/z 361, 363.
Reaction SMILES: CO[C:3](=[O:25])[CH:4]=[CH:5][C:6]1[C:14]2[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[N:11][C:10]=2[CH:9]=[C:8]([C:21]([F:24])([F:23])[F:22])[CH:7]=1.C[N:27]1[CH2:32][CH2:31]N(C(=O)C=CC2N(C3C=CC=CC=3)C3C=CC(C(F)(F)F)=CC=3N=2)[CH2:29][CH2:28]1>>[CH2:28]([N:27]([CH2:32][CH3:31])[C:3](=[O:25])[CH:4]=[CH:5][C:6]1[C:14]2[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[N:11][C:10]=2[CH:9]=[C:8]([C:21]([F:24])([F:23])[F:22])[CH:7]=1)[CH3:29]
Reactant: COC(=O)C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Reactant: CN1CCN(C(=O)C=Cc2nc3cc(C(F)(F)F)ccc3n2-c2ccccc2)CC1
Product: CCN(CC)C(=O)C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Yield: 53 %

Procedure:
This was prepared from 3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid methyl ester in a similar manner to 1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzoimidazol-yl)prop-2-en-1-one. The oily residue was purified by flash chromatography over silica gel (eluted with dichloromethane/methanol 0.5-2.5% gradient) to afford the title compound as a white solid (300 mg, 53%), m/z 388.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([CH2:9][CH2:10][OH:11])=[C:4]([CH3:12])[N:3]=1.[CH3:13][O-].[Na+].IC>C(O)C>[NH2:1][C:2]1[N:7]([CH3:13])[C:6](=[O:8])[C:5]([CH2:9][CH2:10][OH:11])=[C:4]([CH3:12])[N:3]=1
Reactant: Cc1nc(N)[nH]c(=O)c1CCO
Reactant: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: Cc1nc(N)n(C)c(=O)c1CCO
Reaction time: 4 h
Yield: 79.6 %

Procedure:
To a stirred mixture of 67.7 parts of 2-amino-5-(2-hydroxyethyl)-6-methyl-4(3H)-pyrimidinone and 800 parts of ethanol were added 80 parts of a sodium methoxide solution 30%. The reaction mixture was heated to reflux temperature and 62.5 parts of iodomethane were added dropwise. Upon complete addition, stirring was continued for 4 hours at reflux temperature. The reaction mixture was evaporated and the residue was suspended in 400 parts of water. The precipitated product was filtered off, washed with 40 parts of ethanol and dried, yielding 58.3 parts (79.6%) of 2-amino-5-(2-hydroxy-ethyl)-3,6-dimethyl-4(3H)-pyrimidinone (interm. 12).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](Br)[N:15]=2)[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]1[C:35]2[C:30](=[CH:31][C:32]([C:36]#[N:37])=[CH:33][CH:34]=2)[C:29]([Sn](CCCC)(CCCC)CCCC)=[N:28]1.O.C(OCC)C>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>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:29]3[C:30]4[C:35](=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=4)[N:27]([CH3:26])[N:28]=3)[N:15]=2)[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(C#N)cc12
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
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
Solvent: CCOCC
Solvent: O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(C#N)ccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
In a 50 ml round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (300 mg, 0.70 mmol) and 1-methyl-3-tributylstannyl-1H-indazole-5-carbonitrile (crude from Step 3, 847 mg, 1.14 mmol) were dissolved in DMF (6.6 ml). The reaction mixture was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium (0) (41 mg, 0.036 mmol) and copper (I) iodide (27 mg, 0.14 mmol) were added. The reaction mixture was stirred at 80° C. overnight then cooled to room temperature and water and diethyl ether were added. The resulting brown precipitate was collected via filtration washing with water and diethyl ether. The brown powder was absorbed on silica gel and chromatographed with MeOH/CH2Cl2/0.5% NH4OH (gradient: 0-2% MeOH) to afford 254 mg (72%) of 2-(5-cyano-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a light yellow solid.
Reaction SMILES: Cl[C:2]1[C:15]2[CH:14]=[C:13]3[C:8]([CH:9]=[CH:10][CH:11]=[N:12]3)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.N.[CH3:17][N:18](C)C(=O)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].[Zn].[C-]#N.[C-]#N.[Zn+2]>[C:17]([C:2]1[C:15]2[CH:14]=[C:13]3[C:8]([CH:9]=[CH:10][CH:11]=[N:12]3)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:18]
Reactant: Clc1cccc2cc3cccnc3cc12
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: N
Product: N#Cc1cccc2cc3cccnc3cc12
Yield: 91 %

Procedure:
A N,N-dimethylacetamide (110 mL) solution of the 9-chlorobenzo[g]quinoline (10.8 g, 55.27 mmol) from Step 2, Pd2(dba)3 (1.02 g, 0.02 eq), dppf (1.25 g, 0.04 eq), Zn powder (0.457 g, 0.13 eq) and Zn(CN)2 (3.97 g, 0.61 eq) was heated at 150° C. for 8 h in a sealed tube. The mixture was then poured into aqueous ammonia (2 N, 500 mL). The resulting yellow precipitate was collected by filtration and redissolved in CH2Cl2. The filtrate was extracted once with ethyl acetate. The organic phase was combined, dried over MgSO4, filtered and concentrated to ˜10% of original solvent volume. Pure 9-cyanobenzo[g]quinoline (10.3g, 91%) was obtained by filtration. MS Found: (M+H)+=205.