Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]([NH:5][C@H:6]1[C@@H:16]2[N:10]([C:11]3[CH:24]=[C:23]([NH:25]CC4C=CC=CC=4)[CH:22]=[CH:21][C:12]=3[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=32)[CH2:9][CH2:8][CH2:7]1)=[O:4].Cl.O1CCOCC1>C(O)C.[Pd]>[NH2:25][C:23]1[CH:22]=[CH:21][C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[C@@H:16]3[C@H:6]([NH:5][C:3](=[O:4])[C:2]([F:33])([F:34])[F:1])[CH2:7][CH2:8][CH2:9][N:10]3[C:11]=2[CH:24]=1
Reactant: O=C(N[C@@H]1CCCN2c3cc(NCc4ccccc4)ccc3Oc3ccccc3[C@H]12)C(F)(F)F
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Nc1ccc2c(c1)N1CCC[C@@H](NC(=O)C(F)(F)F)[C@H]1c1ccccc1O2
Reaction time: 6 h
Yield: 3.8 %

Procedure:
To a solution of trans-2,2,2-trifluoro-N-[2,3,4,14b-tetrahydro-7-[(phenylmethyl)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl]acetamide (944 mg, 2.0 mmol) in ethanol (16 mL) were added Pd/C 10% (111 mg) and a solution of 4M HCl in dioxane (778 μl, 3.11 mmol). The resulting reaction mixture was hydrogenated at 3 bar for 6 h. The reaction mixture was quenched with sat. NaHCO3 (aq) and diluted with ethanol. After filtration through dicalite and thorough washing with ethyl acetate, the volatiles were removed in vacuo. A part of the crude product was purified with HPLC to afford the title compound (29 mg, 53%). Data (m/z)=378 (M+H)+.
Reaction SMILES: [S-2].[Na+].[Na+].[CH3:4][C:5]1[C:12]([C:13]#[N:14])=[C:11]([S:15]C#N)[CH:10]=[CH:9][C:6]=1[C:7]#[N:8]>O.CO>[CH3:4][C:5]1[C:12]([C:13]#[N:14])=[C:11]([SH:15])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: Cc1c(C#N)ccc(SC#N)c1C#N
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CO
Product: Cc1c(C#N)ccc(S)c1C#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
At 25-35° C., a solution of 110.5 g (0.85 mol) of 60 percent pure sodium sulfide in 425 ml of water was added dropwise to a solution of 170 g (0.85 mol) of 2-methyl-4-thiocyanoisophthalonitrile in 850 ml of methanol, and the mixture was stirred at room temperature for 3 hours. The mixture was then admixed with 1000 ml of water and extracted with methyl tert-butyl ether. The aqueous phase was acidified to pH 1 using HCl, and the thiophenol was extracted with methylene chloride. The extract was washed three times with water, and the organic phase was then separated off, dried over sodium sulfate and concentrated. Yield: 150 g (99%).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:15]2[C:10]3=[C:11]([C:16]4[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=4[N:9]3[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=3)[CH:12]=[CH:13][CH:14]=2.Cl[C:27]1[CH:40]=[CH:39][C:38]2[N:37]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([CH3:48])([CH3:47])[C:29]=2[CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCOCC1>[CH3:1][C:2]1([CH3:25])[C:3]2[CH:4]=[C:5]([C:27]3[CH:28]=[CH:29][C:38]4[N:37]5[C:41]6[CH:42]=[CH:43][CH:44]=[CH:45][C:46]=6[C:30]([CH3:48])([CH3:47])[C:31]6[C:36]5=[C:35]([CH:34]=[CH:33][CH:32]=6)[C:39]=4[CH:40]=3)[CH:6]=[CH:7][C:8]=2[N:9]([C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]2[C:15]1=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: CC1(C)c2ccccc2-n2c3ccc(B(O)O)cc3c3cccc1c32
Reactant: CC1(C)c2ccccc2N(c2ccccc2)c2ccc(Cl)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CC1(C)c2ccccc2N(c2ccccc2)c2ccc(-c3ccc4c(c3)c3cccc5c3n4-c3ccccc3C5(C)C)cc21

Procedure:
36 g (110 mmol) of 8,8-dimethyl-8H-indolo[3,2,1-de]acridine-3-boronic acid, 35.2 g (110 mmol) of 2-chloro-9,9-dimethyl-10-phenyl-9,10-dihydroacridine and 9.7 g (92 mmol) of sodium carbonate are suspended in 350 ml of toluene, 350 ml of dioxane and 500 ml of water. 913 mg (3.0 mmol) of tri-o-tolylphosphine and 112 mg (0.5 mmol) of palladium(II) acetate are added to this suspension, and the reaction mixture is heated under reflux for 16 h. After cooling, the organic phase is separated off, filtered through silica gel, washed three times with 200 ml of water and subsequently evaporated to dryness. The residue is recrystallised from toluene and from CH2Cl2/isopropanol and finally sublimed in a high vacuum.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:20].O1CCOCC1>CO>[ClH:20].[ClH:20].[CH3:17][C:16]([CH3:19])([CH3:18])[CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)CCN1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)CCN1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A solution of 4-(3,3-dimethyl-butyl)-piperazine-1-carboxylic acid tert-butyl ester from Example E4.1 (9.1 g, 31.8 mmol) in methanol (100 ml) was treated with 4N HCl/dioxan (100 ml) and the mixture was stirred at room temperature for 30 min then concentrated in vacuo. The residue was triturated with diethyl ether and the resulting solid recrystallised from methanol/diethyl ether to yield 1-(3,3-dimethyl-butyl)-piperazine dihydrochloride (7.4 g, 90%).
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:12]([C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)#[N:13].[Br-].[Li+].C(N(C(C)C)CC)(C)C>O1CCCC1.O>[C:12]([C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]1[CH:26]=[CH:25][C:22]([CH2:23][CH:3]([C:2](=[O:1])[CH2:9][CH2:10][CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:21][CH:20]=1)#[N:13]
Reactant: N#Cc1ccsc1-c1ccc(CBr)cc1
Reactant: CCCC(=O)CC(=O)OCC
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(=O)C(Cc1ccc(-c2sccc2C#N)cc1)C(=O)OCC
Temperature: 25 °C
Yield: 99.5 %

Procedure:
11 g of ethyl 3-oxohexanoate are dissolved in 150 ml of tetrahydrofuran. 12.9 g of 4-(3-cyano-2-thienyl)benzyl bromide and 6.1 g of lithium bromide are added and the mixture is stirred at room temperature. 24.2 ml of diisopropylethylamine are then added dropwise. After the addition is complete, the reaction mixture is brought to reflux for 24 hours. After evaporation under vacuum, the residue obtained is taken up with water and then extracted with chloroform. The organic phase is dried and then evaporated under vacuum. The excess ethyl 3-oxohexanoate is removed using a vane pump. 16.4 g of ethyl 2-[4-(3-cyano-2-thienyl)benzyl]-3-oxohexanoate are thereby obtained in the form of a pale yellow oil, which is used without further purification for the next step.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([CH:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([O:22]C)=[O:21].O.[OH-].[Li+].C(Cl)Cl.C(Cl)Cl.CO>CO.C1COCC1.O>[CH3:1][C@@H:2]1[CH2:7][N:6]([CH:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([OH:22])=[O:21]
Reactant: COC(=O)CN1CCN(C2CCCCc3ccccc32)C[C@H]1C
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: C[C@@H]1CN(C2CCCCc3ccccc32)CCN1CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
To methyl 2-((R)-2-methyl-4-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)piperazin-1-yl)acetate (420 mg, 1.327 mμmol) in 14 mL of MeOH/THF/H2O (3:3:1) was added lithium hydroxide monohydrate (195 mg, 4.645 mmol). After stirring at rt for 3 h when HPLC-MS showed complete conversion, the solvent was evaporated to dryness under high vacuum. The residue was redissolved in water and the solution was adjusted to PH=4 with 2 N HCl, extracted with DCM, dried over Na2SO4, filtered and evaporated to dryness. Column chromatography (SiO2, DCM to DCM/MeOH=100:10 to 100:20 to 100:30) gave 2-((R)-2-methyl-4-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)piperazin-1-yl)acetic acid (360 mg, 89.7% yield) as a white solid. MS (ESI, pos. ion) m/z: 303.2 (M+1).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.Cl[CH2:6][C:7]1[CH:41]=[CH:40][C:10]([C:11]([NH:13][C:14]2[C:15]3[CH:28]=[C:27]([C:29]([NH:31][N:32]([CH3:39])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])[S:26][C:16]=3[N:17](C(OC(C)(C)C)=O)[N:18]=2)=[O:12])=[CH:9][CH:8]=1.ClCC1C=CC(C(NC2C3C=C(C(NN(C4C=CC(Cl)=CC=4)C)=O)SC=3N(C(OC(C)(C)C)=O)N=2)=O)=CC=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][C:14]3[C:15]4[CH:28]=[C:27]([C:29]([NH:31][N:32]([CH3:39])[C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)=[O:30])[S:26][C:16]=4[NH:17][N:18]=3)=[O:12])=[CH:40][CH:41]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccccc1
Reactant: C1CNC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccc(Cl)cc1
Agent: [I-]
Solvent: CN(C)C=O
Product: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CN4CCC4)cc3)n[nH]c2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
27 mg (74 μmol) of tetrabutylammonium iodide and then 75 μL (1.11 mmol) of azetidine are added to a solution of 200 mg (0.37 mmol) of an approximately 70:30 mixture of tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-methyl-N′-phenylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate and tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-(4-chlorophenyl)-N′-methylhydrazinocarbonyl)-thieno[2,3-c]pyrazole-1-carboxylate in 6 mL of dimethylformamide under argon. The reaction mixture is stirred at a temperature in the region of 25° C. for 16 hours, and then poured onto ice. It is then extracted twice with a 50/50 mixture of ethyl acetate and heptane. The organic extracts are combined, dried over magnesium sulfate and then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is dissolved in 4 mL of methanol and the solution is introduced into a microwave oven tube. The tube is stoppered and the reaction mixture is irradiated at a temperature in the region of 100° C. for 30 minutes. The reaction mixture is then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is purified by preparative LC/MS (conditions B). 3 mg of 4-azetidin-1-ylmethyl-N-[5-(N′-methyl-N′-phenylhydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]benzamide are thus obtained in the form of a yellow powder melting from 155 to 160° C. LC-MS-DAD-ELSD: 461(+)=(M+H)(+).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=O)[C:5]1=[O:29])[CH:2]=[CH2:3].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][NH2:40])=[CH:35][CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][NH:40][CH2:39][C:36]2[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Reactant: COc1ccc(CN)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: C=CC[C@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNCc2ccc(OC)cc2)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal (300 mg, 0.675 mmol; Example 91, Step C) and (4-methoxyphenyl)methanamine (131 μL, 1.01 mmol) in DCE (4.5 mL) was added sodium triacetoxyborohydride (429 mg, 2.03 mmol) at 0° C. in several portions. After being stirred at 25° C. for 18 h, the reaction was quenched by adding ice-cold saturated aqueous NaHCO3 and extracted (2×DCM). The combined organic layers were washed (1×sat. aq. NaCl solution) and concentrated under reduced pressure to provide the title compound as a yellow film. The product was used in the next step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:21][N:22]([CH2:24][CH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=O)[O:26]1)[CH3:23].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1>C(COC)OC.C1COCC1>[CH3:23][N:22]([CH2:24][CH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])[O:26]1)[CH3:21]
Reactant: O=C1Cc2ccccc2N1
Reactant: CN(C)CC1OC(=O)c2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: CN(C)CC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24.4 %

Procedure:
To a solution of oxindole (205 mg, 1.54 mmol) in dimethoxyethane (4.0 ml) at room temperature was added 1.0M LiHMDS in THF (1.54 ml). After stirring for 10 minutes at room temperature, 3-dimethylaminomethyl-3H-isobenzofuran-1-one (235 mg, 1.23 mmol) in dimethoxyethane (0.5 ml) was added and the mixture was stirred rapidly for 1 hour. Additional 1.0M LiHMDS/THF (1.54 ml) was added. After 2 hours the reaction was quenched into 10% HCl (50 ml) and 25 ml water added. The aqueous layer was washed with EtOAc and then basified with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with EtOAc. The EtOAc layer was washed with brine, dried over anhydrous Na2SO4, and rotary evaporated to provide a yellow solid. The yellow solid was chromatographed silica gel column (CHCl3 to 2.5% MeOH/CHCl3 gradient) and then recrystallized from MeOH to give 3-(3-dimethylaminomethy-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one as yellow needles (92 mg, 24%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].Cl[C:21]1[N:26]=[CH:25][C:24]([C:27]23[CH2:33][N:30]([CH2:31][CH2:32]2)[CH2:29][CH2:28]3)=[CH:23][CH:22]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:21]2[N:26]=[CH:25][C:24]([C:27]34[CH2:33][N:30]([CH2:29][CH2:28]3)[CH2:31][CH2:32]4)=[CH:23][CH:22]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc(C23CCN(CC2)C3)cn1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCN(c3ccc(C45CCN(CC4)C5)cn3)CC2)cc1
Temperature: 100 °C
Yield: 39.6 %

Procedure:
0.055 g (0.32 mmol) of 1-benzylpiperazine is introduced into a 50 ml round-bottomed flask under argon comprising 0.036 g (0.37 mmol) of sodium tert-butoxide in solution in 5 ml of toluene through which argon has been bubbled beforehand. 0.06 g (0.29 mmol) of 4-(6-chloropyridin-3-yl)-1-azabicyclo[2.2.1]heptane obtained in stage 5.1 of Example 5, 0.003 g (0.01 mmol) of palladium(II) acetate and 0.011 g (0.03 mmol) of 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl are then successively added under an argon atmosphere. The mixture is heated at 100° C. for 3 hours, cooled to ambient temperature, diluted with 40 ml of dichloromethane and poured into 300 ml of a saturated aqueous sodium carbonate solution. The aqueous phase is extracted twice with 100 ml of dichloromethane, and the combined organic phases are dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of chloroform, methanol and aqueous ammonia in the proportions 90/10/1. 0.04 g of the expected product is obtained in the form of a beige powder.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]12.C([Sn](CCCC)(CCCC)[C:24]([O:26][CH2:27][CH3:28])=[CH2:25])CCC>O1CCOCC1.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>[CH2:27]([O:26][C:24]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]12)=[CH2:25])[CH3:28]
Reactant: O=C1C=C2c3cccc(I)c3CCN2C(=O)CN1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=C(OCC)c1cccc2c1CCN1C(=O)CNC(=O)C=C21
Temperature: 150 °C
Yield: 57 %

Procedure:
111-1. A mixture of 9-iodo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (2.5 g, 7.06 mmol) in dioxane (15 mL) was treated with tributyl(1-ethoxyvinyl)stannane (2.98 mL, 8.82 mmol) and Pd(PPh3)4 (408 mg, 0.35 mmol) under Ar, and the mixture was heated to 150° C. for 90 min in a microwave reactor. The mixture was then filtered and the filtrate concentrated in vacuo. Purification by flash chromatography (SiO2, DCM/MeOH 99:1 to 90:10) gave the title compound (1.20 g) as a beige solid. UPLC-MS: MS 299.2 (M+H+); UPLC rt 0.85 min.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C@H:10]2[O:15][CH2:14][C@@H:13]([CH2:16][CH3:17])[N:12](C(OC(C)(C)C)=O)[CH2:11]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCOCC1.[ClH:31]>>[ClH:31].[CH:1]1([NH:7][C:8]([C@H:10]2[O:15][CH2:14][C@@H:13]([CH2:16][CH3:17])[NH:12][CH2:11]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC[C@@H]1CO[C@H](C(=O)NC2CCCCC2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@@H]1CO[C@H](C(=O)NC2CCCCC2)CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl(2S,5R)-2-[(cyclohexylamino)carbonyl]-5-ethyl-4-morpholinecarboxylate (0.2963 g, 0.870 mmol) was taken up in HCl in 1,4-dioxane (4 M, 5 ml, 165 mmol) and stirred at room temperature overnight. The reaction was concentrated to afford a HCl salt of the title compound (0.256 g). LC-MS (ES) m/z=241 [M+H]+.
Reaction SMILES: O.Cl.[F:3][C:4]([F:26])([F:25])[C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[C:10]2[NH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=1.CN(C)C=O.[CH2:32]([N:34]([CH2:40][CH3:41])[CH2:35][CH2:36][NH:37][CH2:38][CH3:39])[CH3:33].C(=O)([O-])[O-].[Na+].[Na+]>S(Cl)(Cl)=O.C(Cl)(Cl)Cl.O.CCOCC>[CH2:32]([N:34]([CH2:40][CH3:41])[CH2:35][CH2:36][N:37]([CH2:38][CH3:39])[C:20](=[O:22])[C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:10]2[C:9]3[C:14](=[C:5]([C:4]([F:25])([F:3])[F:26])[CH:6]=[CH:7][CH:8]=3)[N:13]=[CH:12][CH:11]=2)=[CH:24][CH:23]=1)[CH3:33]
Reactant: CCNCCN(CC)CC
Reactant: O=C(O)c1ccc(Nc2ccnc3c(C(F)(F)F)cccc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCN(CC)CCN(CC)C(=O)c1ccc(Nc2ccnc3c(C(F)(F)F)cccc23)cc1
Reaction time: 1 h
Yield: 64 %

Procedure:
11.6 Grams (0.03 mole) of 4-(8-trifluoromethyl-4-quinolylamino)benzoic acid hydrochloride monohydrate were refluxed in 80 milliliters of thionyl chloride containing two drops of dimethyl formamide for 11/2 hours. The thionyl chloride was evaporated off and 50 milliliters of benzene were added and evaporated. The resulting acid chloride hydrochloride was added in portions with stirring to a cooled mixture of 4.32 grams (0.03 mole) of N,N,N'-triethyl ethylenediamine in 80 milliliters of chloroform and 31.8 grams (0.3 mole) of sodium carbonate in 100 milliliters of water. The mixture was stirred for one hour, and allowed to stand overnight. The chloroform layer was separated and dried and the chloroform evaporated to give a gummy solid, which was largely taken up in ether. On concentration of this solution a colourless solid crystallised out, which was collected to give 8.8 grams (63% yield) of N-(2-diethylaminoethyl)-N-ethyl-4-(8-trifluoromethyl-4-quinolylamino)benzamide quarter hydrate, m.p. 151°-152° C.
Reaction SMILES: Br[C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([Si:11]([CH3:14])([CH3:13])[CH3:12])#[CH:10]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH3:12][Si:11]([CH3:14])([CH3:13])[C:9]1[O:8][C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:10]=1
Reactant: C#C[Si](C)(C)C
Reactant: Oc1cccnc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1COCCO1
Product: C[Si](C)(C)c1cc2ncccc2o1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A sealed pressure flask was charged with 2-bromopyridin-3-ol (10.0 g, 57.5 mmol), ethynyltrimethylsilane (15.9 ml, 115 mmol), copper (I) iodide (1.09 g, 5.75 mmol), bis(triphenylphosphine)palladium(II) chloride (2.02 g, 2.87 mmol) and 7.5 mL of dioxane. Ethynyltrimethylsilane (15.9 ml, 115 mmol) and TEA (40.0 ml, 287 mmol) were added, the vial was flushed with nitrogen, and the reaction was stirred at 50° C. for 18 h. The reaction was concentrated and purified via column chromatography (gradient elution 0-40% EtOAc:Hex) to afford 2-(trimethylsilyl)furo[3,2-b]pyridine as a brown oil. MS Found M+H+=192.3
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>CN(C=O)C>[Si:14]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: Oc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
To an ice-cooled solution of hydroquinone (Compound 17; 3.3 g, 30 mmol) in DMF (60 ml), a solution of imidazole (3.1 g, 45 mmol) and tert-butyldimethylsilyl chloride (4.5 g, 30 mmol) in DMF (30 ml) was added; the ice bath was removed, and this was followed by overnight stirring at room temperature. This was poured over water to stop the reaction, after which extraction from ether was conducted. The combined organic phases were washed with saturated brine, thereafter dried with sodium sulfate. After filtration and concentration under reduced pressure, the residue obtained was purified by silica gel column chromatography [Biotage, eluent (9:1 n-hexane:ethyl acetate)] to yield Compound 18 (white solid 3.6 g, 53%).
Reaction SMILES: [CH3:1][N:2]([CH3:36])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:35])/[C:14](/[C:25]2[CH:30]=[CH:29][C:28]([O:31]COC)=[CH:27][CH:26]=2)=[C:15](/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)\[CH:16]([CH3:18])[CH3:17])=[CH:8][CH:7]=1.Cl.C([O-])(O)=O.[Na+]>CO.O1CCOCC1.O>[CH3:36][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:35])/[C:14](/[C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[C:15](/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)\[CH:16]([CH3:18])[CH3:17])=[CH:10][CH:11]=1
Reactant: COCOc1ccc(/C(C(=O)Nc2ccc(OCCN(C)C)cc2)=C(\c2ccccc2)C(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CC(C)/C(=C(\C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of 5b (90 mg, 0.184 mmol) in MeOH (3 ml) was added 4N HCl in 1,4-dioxane (0.5 ml) under ice cooling, and the mixture was stirred at room temperature for 2 h. A solution of NaHCO3 in H2O was poured into the reaction mixture under ice cooling, and the whole was extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, and then concentrated. The residue was crystallized with Et2O to give 6b (84%). 6b: colorless powder; 1H-NMR (CD3OD) δ 1.07 (6H, d, J=6.8 Hz), 2.37 (6H, s), 2.79 (2H, t, J=5.4 Hz), 3.12 (1H, sep, J=5.4 Hz), 4.11 (2H, t, J=5.4 Hz), 6.46 (2H, d, J=8.8 Hz), 6.94 (2H, d, J=9.1 Hz), 6.95 (2H, d, J=8.8 Hz), 7.10 (2H, m), 7.16-7.25 (3H, m), 7.52 (2H, d, J=9.1 Hz). HRMS calcd for C28H33N2O3 [M+H]+: 445.2491. Found: 445.2510.