Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.Br[C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][N:42]=[C:41]2[C:47]1[CH:52]=[C:51]([CH:53]([CH3:55])[CH3:54])[CH:50]=[C:49]([CH:56]([CH3:58])[CH3:57])[C:48]=1[O:59][CH2:60][CH3:61]>CN(C=O)C.[Cl-].[Na+].O.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]>[CH3:7][O:6][C:1](=[O:5])[CH:2]=[C:3]([C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][N:42]=[C:41]2[C:47]1[CH:52]=[C:51]([CH:53]([CH3:55])[CH3:54])[CH:50]=[C:49]([CH:56]([CH3:58])[CH3:57])[C:48]=1[O:59][CH2:60][CH3:61])[CH3:4]
Reactant: CCOc1c(-c2n[nH]c3ccc(Br)cc23)cc(C(C)C)cc1C(C)C
Reactant: C/C=C/C(=O)OC
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1c(-c2n[nH]c3ccc(C(C)=CC(=O)OC)cc23)cc(C(C)C)cc1C(C)C
Temperature: 120 °C

Procedure:
Methyl crotonate (0.017 mL, 0.17 mmol), tris(dibenzylideneacetone)-dipalladium(0) (1.3 mg, 0.001 mmol), tri-o-tolylphosphine (18.2 mg, 0.06 mmol), and triethyl amine (0.042 mL, 0.30 mmol) were added to a solution of 5-bromo-3-(2-ethoxy-3,5-diisopropyl-phenyl)-1H-indazole (60 mg, 0.15 mmol) in DMF (1 mL). The reaction mixture was then heated to 120° C. under an atmosphere of nitrogen for 12 hrs., then cooled, poured into brine and extracted with ethyl acetate (2×5 mL). The organic was dried over MgSO4 and evaporated to give 3-[3-(2-ethoxy-3,5-diisopropyl-phenyl)-1H-indazol-5-yl]-but-2-enoic acid methyl ester as a clear oil which was used without further purification. MS [EI+] 421 (M+H)+ MS [EI−] 419 (M−H)−.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11](Cl)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20]([C:22]1([CH3:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])[CH3:18].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH2:17]([O:19][C:20]([C:22]1([CH3:28])[CH2:27][CH2:26][N:25]([C:11]2[N:10]=[N:9][C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:13]([CH3:14])[C:12]=2[CH3:15])[CH2:24][CH2:23]1)=[O:21])[CH3:18]
Reactant: Cc1c(Cl)nnc(Cc2ccccc2)c1C
Reactant: CCOC(=O)C1(C)CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1(C)CCN(c2nnc(Cc3ccccc3)c(C)c2C)CC1
Temperature: 210 °C
Yield: 40.5 %

Procedure:
To a solution of 3-benzyl-6-chloro-4,5-dimethyl-pyridazine (1.0 g, 4.3 mmol) in NMP (10 mL) is added 4-methyl-piperidine-4-carboxylic acid ethyl ester (2.0 g, 8.6 mmol) and DIPEA (3.7 mL, 21.6 mmol). The mixture is heated in microwave at 210° C. for 1.5 h. The mixture is concentrated at 80° C. by rotovaporation. The crude product is purified by HPLC (CH3CN/H2O: 22%˜45% with 0.1% TFA) to give 1-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-4-methyl-piperidine-4-carboxylic acid ethyl ester (0.64 g, 41%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.O.O.[Sn](Cl)Cl>CCO>[CH3:1][C:2]1[C:6]2[C:7]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: Cc1noc2cccc(Oc3ccc([N+](=O)[O-])cc3)c12
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Cc1noc2cccc(Oc3ccc(N)cc3)c12
Temperature: 90 °C
Reaction time: 5 h
Yield: 33.7 %

Procedure:
3-methyl-4-[(4-nitrophenyl)oxy]-1,2-benzisoxazole (Intermediate 11, 100 mg) was dissolved under nitrogen atmosphere in 5.0 ml of EtOH. Tin(II) chloride dihydrate (417 mg, 1.85 mmol) was added. The reaction mixture was then stirred at 90° C. for 5 hours. After removal of the volatiles, water was added and the reaction mixture was extracted two times with ethyl acetate. The collected organic layers were washed with a 5% aqueous solution of NaHCO3, dried over sodium sulphate, filtered and evaporated. The crude obtained was purified by a NH column and eluted with DCM/MeOH (100/0, then a gradient from 100/0 to 90/10, then 90/10) to afford 30 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]([CH3:15])=[CH:5]2.[C:16]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.II.Cl>CN(C=O)C.O>[C:16]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=[CH:18][C:19]([S:22][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[CH3:15])=[CH:20][CH:21]=1
Reactant: Cc1cc2cc(F)ccc2n1CC(=O)O
Reactant: Sc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: II
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Sc2ccc(-c3ccccc3)cc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
To a solution of (5-fluoro-2-methyl-indol-1-yl)-acetic acid (0.5 g) and biphenyl-4-thiol (0.19 g) in DMF (5 ml) was added iodine (0.25 g). After stirring at RT overnight the mixture was poured into water, the pH adjusted to 3 using 1M HCl and the organics extracted with EtOAc. The EtOAc extractions were combined, washed with brine, dried (MgSO4) and evaporated under reduced pressure to give crude material. Purification using RPHPLC gave the title compound as a pink solid (0.1 μg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CCO>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[CH2:16][CH2:15][CH2:14][NH:13][C:12]=2[N:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCc1ccc2cccnc2n1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCc1ccc2c(n1)NCCC2

Procedure:
A mixture of 10-5 (5.0 g, 20.4 mmol), 10% Pd/C (2.5 g), and EtOH (200 mL) was stirred under a balloon of hydrogen for 15 h. The mixture was filtered, and the filtrate concentrated to give 10-6 as a yellow oil.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:22]#[N:23].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][C@H:8]4[C:7](=[O:16])[NH:6][C:5]=3[CH:4]=2)[CH2:29][CH2:28]1)[C:22]#[N:23]
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: N#Cc1ccc(N2CCNCC2)c(Cl)c1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)c(Cl)c1
Temperature: 90 °C
Yield: 70.2 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), 3-chloro-4-(piperazin-1-yl)benzonitrile hydrochloride (118 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propionitrile (2 ml) and heated in a closed vial at 90° C. for 2 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo and purified using flash column chromatography on silica gel (80 g SiO2, dichloromethane-methanol 100:0-95:5). The resulting solid was suspended in ether (7 mL), stirred until a fine suspension resulted, filtered and the solid was dried in vacuum to afford (S)-3-chloro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile (135.4 mg, 0.320 mmol, 70.2% yield) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.80-2.03 (m, 3H) 2.10-2.25 (m, 1H) 2.39-2.61 (m, 4H) 2.94-3.19 (m, 4H) 3.35-3.46 (m, 3H) 3.51-3.65 (m, 1H) 3.91-4.05 (m, 1H) 6.97 (d, J=1.77 Hz, 1H) 7.22 (d, J=8.59 Hz, 1H) 7.62 (d, J=1.52 Hz, 1H) 7.74 (dd, J=8.46, 1.89 Hz, 1H) 7.93 (d, J=1.77 Hz, 1H) 10.44 (s, 1H); [M+H] calc'd for C22H23ClN6O, 423. found, 423; melting point 213-215° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:15]([NH2:17])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[Cl:18][C:19]1[N:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[C:21]([CH3:28])[N:20]=1>>[Cl:18][C:19]1[N:24]=[C:23]([C:25]([NH:17][CH:15]([C:5]2[CH:6]=[N:7][C:8]([O:9][CH2:10][C:11]([F:14])([F:12])[F:13])=[C:3]([CH3:2])[CH:4]=2)[CH3:16])=[O:26])[CH:22]=[C:21]([CH3:28])[N:20]=1
Reactant: Cc1cc(C(=O)O)nc(Cl)n1
Reactant: Cc1cc(C(C)N)cnc1OCC(F)(F)F
Agent: Cl
Product: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(C)c2)nc(Cl)n1
Yield: 69 %

Procedure:
The title compound is prepared in 69% yield (296 mg, clear colorless oil) from 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (300 mg, 1.1 mmol, Amine-17, single enantiomer) and 2-chloro-6-methylpyrimidine-4-carboxylic acid (191 mg, 1.1 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[C:12]1([Mg]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(OCC)C>C1COCC1>[OH:5][C:4]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:1][C:2]1=[O:3]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1Nc2ccccc2C1(O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
Dissolve isatin (1.47 g, 10 mmol) in anhydrous THF (40 mL) in an oven-dried flask under nitrogen. Cool in an ice bath and add slowly a 3M solution of phenylmagnesium bromide in diethyl ether (7.4 mL, 22 mmol). After 5 min remove the ice bath and stir at room temperature for 18 h. Pour the reaction over saturated NH4Cl solution and extract with ethyl acetate (200 mL, 2×100 mL). Wash combined organic portions with brine and dry (Na2SO4), filter, and concentrate in vacuo to give a yellow solid. Triturate in diethyl ether, filter and dry under house vacuum to give 1.77 g (79%) of the title compound as a yellow solid. MS (ES): m/z=208 (M+1−H2O), 224 (M−1); 1H NMR(DMSO-d6): δ10.39 (s, 1H), 7.32-7.23 (m, 6H), 7.09 (d, J=7.3 Hz, 1H), 6.96 (dt, J=0.9 Hz, J=7.5 Hz, 1H), 6.90 (d, J=7.7 Hz, 1H), 6.61 (s, 1H).
Reaction SMILES: [CH:1](=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH2:14](I)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:11][O:10][C:9]1[CH:12]=[C:2]([CH:3]=[C:4]([O:5][CH3:6])[C:7]=1[O:8][CH2:14][CH3:15])[CH:1]=[O:13]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1c(OC)cc(C=O)cc1OC
Yield: 102.1 %

Procedure:
A mixture of syringaldehye (50 g, 0.275 mole), ethyl iodide (85.5 g, 0.55 mol) and potassium carbonate (151.7 g. 1.09 mol) in DMF (60 ml) was stirred and heated at 60°-70° for 6 h. The mixture was cooled and evaporated in vacuo then treated with water and extracted with diethyl ether. The extracts were dried (Na2SO4) and evaporated to give the title compound (59 g) as a white solid, pure by tlc, and used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CO>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.C1(C)C=CC=CC=1>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:18])=[CH:15][CH:16]=2)=[C:6]([C:7]#[N:8])[CH:9]=1
Reactant: COc1ccccc1B(O)O
Reactant: CN1CCN(C(=O)c2ccc(Nc3ccc(Br)cc3C#N)cc2)CC1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccccc1-c1ccc(Nc2ccc(C(=O)N3CCN(C)CC3)cc2)c(C#N)c1
Temperature: 105 °C
Yield: 84.5 %

Procedure:
5-Bromo-2-(4-(4-methylpiperazine-1-carbonyl)phenylamino)benzonitrile (100 mg, 0.250 mmol), Pd(Ph3P)4 (14.47 mg, 0.013 mmol), 2-methoxyphenylboronic acid (53.3 mg, 0.351 mmol), aqueous Na2CO3 (0.28 mL, 0.560 mmol), MeOH (0.5 mL) and Toluene (1 mL) were combined in a 2 ml microwave vial, sealed, the vial flushed with nitrogen and heated to 105° C. for 5 hrs in an oil bath. The reaction was poured into a separating funnel loaded with dichloromethane and 0.1 N aq. KOH. The aqueous layer was extracted one more time with dichloromethane, the organic layers combined and washed once with brine, then dried over MgSO4, filtered and concentrated in vacuum. Purification by chromatography on silica Solvent A: 500 ml ethyl acetate+500 ml CH2Cl2+10 ml Et3N; Solvent B: 500 ml ethyl acetate+500 ml CH2Cl2+10 ml Et3N+100 ml MeOH, Gradient from 100% A to 100% B, product elutes at ˜25% Solvent B. Combine product containing fractions and evaporate volatiles. 90.1 mg 2′-methoxy-4-(4-(4-methylpiperazine-1-carbonyl)phenylamino)-biphenyl-3-carbonitrile were isolated as a colorless film. MS (ESI) m/z 427 (M+H). 1H NMR (CDCl3) δ ppm 7.74 (d, 1H, J=2.2), 7.60 (dd, 1H, J=8.9, 1.9), 7.42 (d, 2H, J=8.5), 7.34 (d, 1H, J=8.9), 7.32 (dt, 1H, J=1.5, ˜8, ˜8), 7.26 (dd, 1H, J=1.6, ˜8), 7.20 (d, 2H, J=8.2), 7.02 (t, 1H, J=7.5), 6.98 (d, 1H, J=8.2), 6.49 (s, 1H), 3.83 (s, 3H), 3.85-3.45 (b, 4H), 2.43 (bs, 4H), 2.32 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH3:12])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Br:20]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH3:12])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:20])[N:6]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrBr
Reactant: CNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CNc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
6-Amino-9-benzyl-2-methylaminopurine (75 mg, 0.30 mmol) and bromine (0.5 ml) were dissolved in 50 ml of methylene chloride and the solution was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and filtered. The solvent of the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (73 mg, yield 74%).
Reaction SMILES: [C:1]([O:23][CH:24]1[CH2:29][C:28]([CH3:31])([CH3:30])[N:27]([OH:32])[C:26]([CH3:34])([CH3:33])[CH2:25]1)(=[O:22])[C:2]1[CH:21]=[CH:20][CH:19]=[C:4]([C:5]([O:7][CH:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[N:11]([OH:16])[C:10]([CH3:18])([CH3:17])[CH2:9]2)=[O:6])[CH:3]=1.C(OO[C:41]([CH3:44])([CH3:43])C)(C)(C)C>C1CCCCC1>[C:5]([O:7][CH:8]1[CH2:13][C:12]([CH3:14])([CH3:15])[N:11]([O:16][CH:43]2[CH2:41][CH2:44][CH2:13][CH2:8][CH2:9]2)[C:10]([CH3:18])([CH3:17])[CH2:9]1)(=[O:6])[C:4]1[CH:19]=[CH:20][CH:21]=[C:2]([C:1]([O:23][CH:24]2[CH2:25][C:26]([CH3:34])([CH3:33])[N:27]([O:32][CH:2]3[CH2:21][CH2:20][CH2:19][CH2:4][CH2:3]3)[C:28]([CH3:31])([CH3:30])[CH2:29]2)=[O:22])[CH:3]=1
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: CC1(C)CC(OC(=O)c2cccc(C(=O)OC3CC(C)(C)N(O)C(C)(C)C3)c2)CC(C)(C)N1O
Solvent: C1CCCCC1
Product: CC1(C)CC(OC(=O)c2cccc(C(=O)OC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)c2)CC(C)(C)N1OC1CCCCC1

Procedure:
A solution of 34.2 g of di-(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl) isophthalate and 54 ml of di-tert-butyl peroxide in 250 ml of cyclohexane is heated for 22 hours in a nitrogen atmosphere in a Fisher-Porter bottle (bath temperature of 140° C.). Solvent is evaporated under reduced pressure. The product is recrystallized from pentane to give a white solid, mp 140°-42° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH2:4][CH2:3]1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1.Cl.C(=O)([O-])[O-].[K+].[K+].[C:37]1([CH:43](Br)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1C=CCCC1>[C:37]1([CH:43]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[N:2]2[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH2:4][CH2:3]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: OCCCCC1CCNCC1
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Product: OCCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 3 h

Procedure:
120 g (620 mmol) 4-piperidin-4-yl-butan-1-ol hydrochloride are suspended in 400 ml 3,4-dihydro-2H-pyran and added to 1.5 g pyridinium tosylate and 5 ml 8 M methaneolic hydrochloric acid. This is stirred for three hours and left to stand at RT overnight. After addition of 5 g potassium carbonate, this is concentrated under vacuum to dryness. The resulting 4-[4-Tetrahydro-pyran-2-yloxy)-butyl]-piperidine is. dissolved in 500 ml acetonitrile without further purification and added to 193 g (742 mmol) diphenylmethyl bromide (95%) and 160 g (1157 mmol) potassium carbonate and stirred for three days at RT. The mixture is filtered and the filtrate is stirred with a further 20 g (76.8 mmol) diphenylmethyl bromide (95%) and 16 g (115.8 mmol) potassium carbonate for one day at RT. The mixture is filtered and the solvent is removed under vacuum. The resulting 1-diphenylmethyl-4-[4-(tetrahydro-pyran-2-yloxy)-butyl]-piperidine is dissolved in 700 ml methanol without further purification, added to 120 ml conc. hydrochloric acid and the mixture is left to stand for two days at RT. Subsequently, the solvent is drawn off under vacuum, the residue is taken up with 1500 ml water and extracted with 1500 ml acetic acid ethyl ester. The organic phase is discarded and the aqueous phase is made alkaline with 95 g sodium hydroxide and extracted with 700 ml acetic acid ethyl ester. After washing the organic phase with 200 ml water, this is dried over sodium sulfate and the solvent is removed under vacuum. The brown oil is dried under high-vacuum and further processed without additional purification. Yield 145 g (72%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](OS(C(F)(F)F)(=O)=O)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:26]([O:28][CH2:29][CH3:30])=[CH2:27])CCC.[Li+].[Cl-]>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>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:26]([O:28][CH2:29][CH3:30])=[CH2:27])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=c1cc(OS(=O)(=O)C(F)(F)F)c2ccc(Br)cc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=C(OCC)c1cc(=O)oc2cc(Br)ccc12

Procedure:
To a solution of 7-bromo-4-trifluoromethanesulfonyloxycoumarin (5.1 g, 13.7 mmol) in dioxane is added tributyl(1-ethoxyvinyl)tin (4.8 mL, 14.2 mmol), (Ph3P)4Pd (0.790 g, 0.7 mmol) and LiCl (1.74 g, 41 mmol). The mixture is refluxed for 4 h, cooled and partitioned between aqueous NH4Cl and EtOAc. The layers are separated and the aqueous phase is extracted with EtOAc. The combined organic layers are washed with brine and dried over anhydrous Na2SO4. The solvent is evaporated and the residue is chromatographed on silica gel (CH2Cl2/EtOAc; 95:5) and triturated in hexane/Et2O to give the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][N:13]([C:18]3[CH:23]=[C:22]([C:24]([NH:26][CH:27]4[CH2:29][CH2:28]4)=[O:25])[CH:21]=[CH:20][C:19]=3[CH3:30])[C:14]2=[O:17])=[CH:9][CH:8]=1)(=O)=O.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:85][N:86]1[CH2:91][CH2:90][NH:89][CH2:88][CH2:87]1>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH:27]1([NH:26][C:24](=[O:25])[C:22]2[CH:21]=[CH:20][C:19]([CH3:30])=[C:18]([N:13]3[CH:12]=[CH:11][C:10]4[C:15](=[CH:16][C:7]([N:89]5[CH2:90][CH2:91][N:86]([CH3:85])[CH2:87][CH2:88]5)=[CH:8][CH:9]=4)[C:14]3=[O:17])[CH:23]=2)[CH2:29][CH2:28]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(OS(=O)(=O)C(F)(F)F)cc2c1=O
Reactant: CN1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(N3CCN(C)CC3)cc2c1=O
Temperature: 95 °C
Reaction time: 16 h

Procedure:
2-{5-[(Cyclopropylamino)carbonyl]-2-methylphenyl}-1-oxo-1,2-dihydroisoquinolin-7-yl trifluoromethanesulfonate (58 mg), palladium acetate (3 mg), BINAP (16 mg) and cesium carbonate (101 mg) were placed in a reaction tube under an atmosphere of argon. Toluene (0.5 ml) was added followed by N-methylpiperazine (0.041 ml) and the reaction mixture was stirred in a sealed tube at 95° C. for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with water (2×), brine, dried (magnesium sulfate) and concentrated. Purification by RP-HPLC (5-95% MeCN: 1% NH4OH in H2O, 21 ml/min using a Waters Xterra Prep RP18 5 micron, 19×100 mm column) gave N-cyclopropyl-4-methyl-3-[7-(4-methylpiperazin-1-yl)-1-oxoisoquinolin-2(1H)-yl]benzamide (17 mg) as a pale yellow solid; NMR Spectrum: (DMSOd6) 0.55 (m, 2H), 0.69 (m, 2H), 2.09 (s, 3H), 2.29 (s, 3H), 2.56 (m, 4H), 2.85 (m, 1H), 3.29 (m, 4H), 6.65 (d, 1H), 7.11 (d, 1H), 7.48 (d, 1H), 7.52 (d, 1H), 7.61 (m, 2H), 7.74 (s, 1H), 7.87 (d, 1H), 8.43 (d, 1H); Mass Spectrum: M+H+ 417.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:32]([O:36][C:37]([NH:39][C@H:40]([C:45]([NH:47][C@H:48]([CH2:53]O)[CH2:49][CH:50]([CH3:52])[CH3:51])=[O:46])[C:41]([CH3:44])([CH3:43])[CH3:42])=[O:38])([CH3:35])([CH3:34])[CH3:33].[C:55]([OH:58])(=[S:57])[CH3:56]>C1COCC1>[C:32]([O:36][C:37]([NH:39][C@H:40]([C:45]([NH:47][C@H:48]([CH2:53][S:57][C:55](=[O:58])[CH3:56])[CH2:49][CH:50]([CH3:52])[CH3:51])=[O:46])[C:41]([CH3:42])([CH3:43])[CH3:44])=[O:38])([CH3:33])([CH3:35])[CH3:34]
Reactant: CC(O)=S
Reactant: CC(C)C[C@@H](CO)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SC[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a solution triphenylphosphine (373 mg, 1.42 mmol) and diethyl azodicarboxylate (225 μL, 1.42 mmol) in THF (6 mL) at 0° was added a solution of N-tert-butyloxy carbonyl-L-tert-butylglycyl-L-leucinol 10 (313 mg, 0.950 mmol) and thioacetic acid (100 μL, 1.42 mmol) in THF (4 mL). The mixture was stirred at 0° for 2 h and the solvent was removed under vacuum. The residue was purified by flash chromatography (SiO2, 10-30% EtOAc-hexane) to give the corresponding title compound 11 in 63% yield (232 mg).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:15][C:14]1=[O:26].[Br:27][C:28]1[CH:29]=[N:30][C:31](Cl)=[N:32][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Br:27][C:28]1[CH:29]=[N:30][C:31]([N:23]2[CH2:24][CH2:25][CH:20]([O:19][C:16]3[CH:17]=[CH:18][N:13]([C:4]4[CH:5]=[CH:6][C:7]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:8][C:3]=4[F:2])[C:14](=[O:26])[CH:15]=3)[CH2:21][CH2:22]2)=[N:32][CH:33]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CS(=O)(=O)c1ccc(-n2ccc(OC3CCNCC3)cc2=O)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-n2ccc(OC3CCN(c4ncc(Br)cn4)CC3)cc2=O)c(F)c1
Temperature: 160 °C
Yield: 53.9 %

Procedure:
A mixture of 1-(2-fluoro-4-(methylsulfonyl)phenyl)-4-(piperidin-4-yloxy)pyridin-2(1H)-one hydrochloride (100 mg, 0.248 mmol, prepared according to the procedures described in Example 9), 5-bromo-2-chloropyrimidine (144 mg, 0.745 mmol) and cesium carbonate (324 mg, 0.993 mmol) in DMF (3 mL) was placed in a microwave and heated at 160° C. for 20 min. The reaction mixture was diluted with EtOAc (30 mL) and washed with water 3 times. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a crude yellow solid. The residue was purified by flash chromatography (SiO2, 0-100% EtOAc/Hexanes) to give a white solid (70 mg, 53.9%). MS (ESI) 523 (M+H).