Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)CCCOC1C=CC=C(CCCCCCOC2C=C(C3C=CC(F)=C(F)C=3)C=C(C(=O)N(C)C)C=2)C=1CCC(OCC)=O)C.[CH2:49]([O:51][C:52](=[O:98])[CH2:53][CH2:54][CH2:55][O:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][O:69][C:70]2[CH:75]=[C:74]([C:76](=[O:89])[NH:77][CH2:78][C:79]3[CH:84]=[CH:83][CH:82]=[CH:81][C:80]=3[O:85][CH:86]([F:88])[F:87])[CH:73]=[C:72](Br)[CH:71]=2)[C:58]=1[CH2:91][CH2:92][C:93]([O:95][CH2:96][CH3:97])=[O:94])[CH3:50].[S:99]1[CH:103]=[CH:102][C:101](B(O)O)=[CH:100]1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.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.Cl[Pd]Cl.[Fe+2]>[CH2:49]([O:51][C:52](=[O:98])[CH2:53][CH2:54][CH2:55][O:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][O:69][C:70]2[CH:71]=[C:72]([C:101]3[CH:102]=[CH:103][S:99][CH:100]=3)[CH:73]=[C:74]([C:76](=[O:89])[NH:77][CH2:78][C:79]3[CH:84]=[CH:83][CH:82]=[CH:81][C:80]=3[O:85][CH:86]([F:88])[F:87])[CH:75]=2)[C:58]=1[CH2:91][CH2:92][C:93]([O:95][CH2:96][CH3:97])=[O:94])[CH3:50]
Reactant: OB(O)c1ccsc1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)NCc3ccccc3OC(F)F)c2)c1CCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N(C)C)cc(-c3ccc(F)c(F)c3)c2)c1CCC(=O)OCC
Solvent: COCCOC
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)NCc3ccccc3OC(F)F)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Yield: 90.7 %

Procedure:
The title compound was prepared by the same method as 4-{3-[6-(5-dimethylcarbamoyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester starting from 4-[3-{6-[3-bromo-5-(2-difluoromethoxy-benzylcarbamoyl)-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (200 mg, 0.262 mmol), 3-thiophenylboronic acid (67 mg, 0.524 mmol), PdCl2(dppf) (29 mg, 0.04 mmol) and cesium carbonate (171 mg, 0.524 mmol) in 1,2-dimethoxyethane (5.0 mL) to obtain 4-[3-{6-[3-(2-difluoromethoxy-benzylcarbamoyl)-5-thiophen-3-yl-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (182 mg, 91%) as a colorless oil.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=2[N:10]([CH:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH3:21])[C:9]1=[O:29])=O)(C)(C)C>C(Cl)Cl>[C:25]([O:24][C:22](=[O:23])[CH:19]([N:10]1[C:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[CH:13][C:12]=2[NH:8][C:9]1=[O:29])[CH2:20][CH3:21])([CH3:26])([CH3:27])[CH3:28]
Reactant: CCC(C(=O)OC(C)(C)C)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(C#N)cc21
Solvent: ClCCl
Product: CCC(C(=O)OC(C)(C)C)n1c(=O)[nH]c2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.4 %

Procedure:
To a stirred solution of 3-(1-tert-butoxycarbonyl-propyl)-5-cyano-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester (55 mg, 0.14 mmol) in CH2Cl2 (5 mL) trifluoroacetic acid (0.10 mL) was added. The reaction mixture was stirred at room temperature for 4 hours, concentrated in vacuo and co-evaporated the solvent with toluene (3×). The residue was purified by flash chromatography in silical gel using 40% ethyl acetate in n-heptane as eluent to afford 2-(6-cyano-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-butyric acid tert-butyl ester (28 mg, 68%) as a white solid.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[N:9][N:10]([CH3:15])[C:11]=2[C:12]([OH:14])=O)=[O:6])[CH2:4][CH2:3][CH2:2]1.[F:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]3[CH:30]=[C:29]([NH2:31])[N:28]=[CH:27][N:26]3[CH:32]=2)[CH:20]=[CH:21][CH:22]=1>>[F:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:27]3[N:28]=[C:29]([NH:31][C:12]([C:11]4[N:10]([CH3:15])[N:9]=[CH:8][C:7]=4[C:5]([N:1]4[CH2:2][CH2:3][CH2:4]4)=[O:6])=[O:14])[CH:30]=[CH:25][N:26]3[CH:32]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cc2nc(-c3cccc(F)c3)cn2cn1
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)O
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2cc(-c3cccc(F)c3)nc2n1

Procedure:
The title compound was prepared in analogy to example 82 from 4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (91.7 mg, 438 μmol) and 2-(3-fluorophenyl)imidazo[1,2-c]pyrimidin-7-amine (100 mg, 438 μmol). Yellow solid (6.5 mg, 3.5%). MS (m/z)=420.1 [M+H+].
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[C:6]([O:10][C:11]([N:13]1CCC[C:16](=O)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:6]([O:10][C:11]([N:13]1[CH2:14][CH2:15][CH2:16][C:3](=[CH2:4])[CH2:2][CH2:1]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 1 g methyltriphenylphosphoniumbromide (MW: 357.22, 2.79 mmol) in 20 ml of tetrahydrofurane was treated at −78° C. with 1.22 ml of a 2.3 M n-butyl lithium solution in N-hexane (2.8 mmol). The reaction mixture was stirred at −78° C. for ten minutes, then at 0° C. for one hour. The yellow suspension was cooled to −78° C. and treated with a solution of 595 mg 4-oxo-azepane-1-carboxylic acid tert-butyl ester (WO 2000044376) (MW: 213.279, 2.78 mmol) in 10 ml tetrahydrofurane. The reaction mixture was stirred at room temperature for one and half hour. The reaction mixture was quenched with 30 ml of a saturated aqueous solution of ammonium chloride, diluted with 30 ml of ethyl acetate. The organic layer was successively washed with 30 ml water and 30 ml brine, dried over magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure and the residue purified by chromatography over silica. (cyclohexane:ethyl acetate 1:1). Yield: 487 mg, 83%. NMR (CDCl3): 1.35 ppm (s, 9H, tert-but.); 1.6 ppm (m, 2H, —CH2—), 2.14 ppm (m, 2H), 2.33 ppm (m, 2H); 3.29 ppm (m, 4H, N—CH2); 4.67 ppm (m, 2H, vinyl-CH2).
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:24]1[S:28][C:27]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([S:42]([NH2:45])(=[O:44])=[O:43])=[CH:38][CH:37]=3)[N:30]=2)=[CH:26][CH:25]=1.CN(C)C=O.[C:51]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=1)#[CH:52]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[N:54]1[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=1[C:51]#[C:52][C:24]1[S:28][C:27]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([S:42]([NH2:45])(=[O:44])=[O:43])=[CH:38][CH:37]=3)[N:30]=2)=[CH:26][CH:25]=1
Reactant: NS(=O)(=O)c1ccc(Nc2nccc(-c3ccc(Br)s3)n2)cc1
Reactant: C#Cc1ccccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccc(Nc2nccc(-c3ccc(C#Cc4ccccn4)s3)n2)cc1
Temperature: 180 °C
Yield: 11.5 %

Procedure:
A 10 mL glass microwave reaction vessel with stir bar contained palladium acetate (5 mg, 22 μmol), tri-o-tolylphosphine (13 mg, 44 μmol), and 4-[4-(5-bromo-thiophen-2-yl)-pyrimidin-2-ylamino]-benzenesulfonamide (80 mg, 200 μmol). Anhydrous dimethylformamide (DMF) (3.5 mL), 2-ethynylpyridine (46 mg, 450 μmol), and triethylamine (50 μL) is added to the reaction vessel. The reaction vessel is sealed and heated to 180° C. for 660 seconds in a microwave reactor (Emrys Microwave Reactor, personal Chemistry AB, Uppsala, Sweden). The reaction is filtered through celite, concentrated, redissolved in dimethylsulfoxide (DMSO), and purified by reverse phase (RP) HPLC to obtain 10 mg of the title compound. LC/MS data (Condition A; molecular ion and retention time): m/z 434 (M+H); 2.52 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[NH4+].[Cl-].[CH2:17](O)C>C(=O)(O)[O-].[Na+].[Fe]>[NH2:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([Br:1])[CH:11]=1)[C:5]([O:7][CH2:8][CH3:17])=[O:6]
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Reactant: CCO
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Cl-]
Product: CCOC(=O)c1cc(N)cc(Br)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 99.14 %

Procedure:
To a stirred solution of methyl 3-bromo-5-nitrobenzoate (17 g, 62.04 mmol) in ethanol (85 mL), was added NH4Cl solution (17 g in 85 mL water, 317.8 mmol) followed by Fe powder (27.82 g, 498.12 mmol). Resulting reaction mass was stirred at 90° C. for 1 h. On completion, reaction mass was filtered and filtrate concentrated till dryness to get solid which was dissolved in sat. sodium bicarbonate solution. Aqueous layer was extracted with ethyl acetate (3×50 mL). Combined organic layers were dried over sodium sulfate and concentrated to afford the desired compound (15 g, 99.14%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[C:4]([C:11](O)=O)=[CH:3]1.ClS([N:18]=C=O)(=O)=O.CN(C)C=O.O>C(#N)C.C(OCC)(=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[C:4]([C:11]#[N:18])=[CH:3]1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cn1cc(C(=O)O)c(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: Cn1cc(C#N)c(C(F)(F)F)c1
Temperature: 40 °C
Reaction time: 48 h

Procedure:
A mixture of 1-methyl-4-(trifluoromethyl)pyrrole-3-carboxylic acid (1.93 g, 0.01 mol) in acetonitrile at 40°-45° C. is treated dropwise with chlorosulfonylisocyanate (1.41 g, 0.01 mol), heated at 40° C. for 24 hours, cooled to room temperature, treated with dimethylformamide (1.46 g, 0.02 mol), heated at 40° C. for 8 hours, cooled to room temperature, stirred for 48 hours at room temperature and poured into water. The resultant mixture is extracted with ethyl acetate. The extracts are combined, washed sequentially with water and brine, dried (MgSO4) and concentrated in vacuo to afford an oily solid residue. The residue is taken up in ethyl acetate, washed with 1% aqueous sodium hydroxide, dried (MgSO4) and concentrated in vacuo to give a yellow oil residue. Kugelrohr distillation at 100°-110° C./2 mm Hg yields the title product as a white solid, 0.95 g (54%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([C:15]([OH:17])=O)[N:12]=[CH:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:19][NH:20][CH3:21].C(NC(C)C)(C)C.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH3:19][N:20]([CH3:21])[C:15]([C:13]1[N:12]=[CH:11][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:14]=1)=[O:17]
Reactant: CNC
Reactant: O=C(O)c1cn(-c2cccc([N+](=O)[O-])c2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CN(C)C(=O)c1cn(-c2cccc([N+](=O)[O-])c2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.8 %

Procedure:
1-(3-Nitro-phenyl)-1H-imidazole-4-carboxylic acid 2 (0.1 g, 0.4 mmol) was dissolved in DMF (5 mL) and dimethyl amine hydrochloride (33 mg, 0.4 mmol), diisopropyl amine (366 uL, 2.1 mmol), 1-hydroxy-7-azabenzotriazole (HOAt, 68 mg; 0.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride (EDC HCl, 96 mg, 0.5 mmol) were added. The mixture was stirred at room temperature for 16 h. The solvent was evaporated and the residue was extracted with hot ethyl acetate. The solvent was evaporated and crystallization from MeOH afforded 30 mg (29%) pure product as white needles. HRMS (ESI+): m/z=260.2518 [M+H]
Reaction SMILES: [C:1]([NH:6][C:7](=[O:12])[O:8][CH:9]([CH3:11])[CH3:10])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C@@H:3]([CH3:4])[CH2:2][C:1]([NH:6][C:7](=[O:12])[O:8][CH:9]([CH3:11])[CH3:10])=[O:5])=[CH:16][CH:15]=1
Reactant: C/C=C/C(=O)NC(=O)OC(C)C
Reactant: Nc1ccc(Br)cc1
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)NC(=O)C[C@H](C)Nc1ccc(Br)cc1
Reaction time: 0.33 h

Procedure:
Similarly a second batch of 1-methylethyl (2E)-2-butenoylcarbamate (Intermediate 49, 8.51 g, 49.7 mmol) was stirred in Toluene (255 ml) under nitrogen and (R-BINAP)ditriflatebis(acetonitrile)palladium(II) (3.04 g, 2.73 mmol) added. The catalyst formed a gummy ball, the solution turned to an opaque yellow mixture and was stirred for 20 mins. 4-bromoaniline (12.83 g, 74.6 mmol) was added, the solution turned a clear light brown and the gummy catalyst dissolved further. The mixture was stirred overnight. The two reaction mixtures were combined and loaded on to a 1.5 kg Isco silica Redisep column. The column was eluted with DCM:MeOH (0%−>0.5%, 19 CV). The clean, product containing fractions were evaporated to a pale brown oil. The mixture was dried in a vacuum oven overnight at 40° C. to give a white solid (24.2 g, 67% overall).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([CH:7]([CH3:9])[CH3:8])[N:3]=1.FC(F)(F)C(O)=O.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([NH:26][C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:28])=[N:18]1.C(N(CC)CC)C.O>CN(C)C=O>[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([NH:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([C:2]3[S:6][N:5]=[C:4]([CH:7]([CH3:9])[CH3:8])[N:3]=3)[CH2:31][CH2:30]2)=[O:28])=[N:18]1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Reactant: CC(C)c1nsc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nsc(N2CCN(C(=O)Nc3noc4ccccc34)CC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.3 %

Procedure:
To a solution of 5-chloro-3-isopropyl-1,2,4-thiadiazole (90.3 mg, 0.555 mmol) and N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) in N,N-dimethylformamide (2 ml) was added triethylamine (0.389 ml, 2.78 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured to water, and the precipitated solid was separated by filtration, which was recrystallized from a mixed solvent of ethyl acetate and tetrahydrofuran to give 42.0 mg (20.3%) of the desired product. mp 178-179° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:19]([O-])=[O:20].[Na+]>C(O)=O>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][CH:19]=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C[O-]
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Agent: [Na+]
Solvent: O=CO
Product: O=CNCCCOc1cccc(CN2CCCCC2)c1
Yield: 39.2 %

Procedure:
A mixture of 1 g of 3-[3-(1-piperidinylmethyl)phenoxy]propylamine, 1 g of sodium formate and 3 ml of formic acid was refluxed for 1 hour, and a greater portion of the solvent was distilled off under reduced pressure, and water was added to the residue. The mixture was alkalized with 4% sodium hydroxide solution. The product was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was separated and purified by thin-layer chromatography (TLC) (developing solvent: chloroform/methanol=9/l) to afford 436 mg of N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]formamide as an oil.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH:21]([CH2:25][OH:26])[CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:19]2[CH2:24][CH2:23][O:22][CH:21]([CH2:25][OH:26])[CH2:20]2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Oc2nc3ncccc3s2)cc1
Reactant: OCC1CNCCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: OCC1CN(Cc2ccc(Oc3nc4ncccc4s3)cc2)CCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.5 %

Procedure:
To a solution of 4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzaldehyde (150 mg, 0.585 mmol) and morpholin-2-yl-methanol (82 mg, 0.702 mmol, 1.2 equiv.) in DCE (3.1 mL) was added sodium triacetoxyborohydride (211 mg, 0.995 mmol, 1.7 equiv.) in two portions over 5 min. The mixture was then allowed to stir at rt for 4 h. The mixture was then filtered and purified using preparative reverse phase HPLC to afford the desired product as a light yellow oil (116 mg, 56%). 1H NMR (600 MHz, CDCl3): 8.56 (dd, J=4.8, 1.6, 1H), 8.01 (dd, J=7.9, 1.6, 1H), 7.42-7.35 (m, 4H), 7.20 (dd, J=7.9, 4.8, 1H), 3.95-3.87 (m, 1H), 3.75-3.61 (m, 3H), 3.60-3.48 (m, 3H), 2.70 (t, J=12.8, 2H), 2.22 (dt, J=11.5, 3.5, 1H), 2.07-1.99 (m, 1H), 1.93-1.86 (m, 1H). MS (ESI): mass calcd. for C18H19N3O3S, 357.12; m/z found, 358.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[O:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=3)[C:25]#[N:26])[CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]>CO.N.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[O:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=3)[CH2:25][NH2:26])[CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(-c2cc3nccc(-c4cccc(C#N)c4)c3o2)cc(OC)c1OC
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1cc(-c2cc3nccc(-c4cccc(CN)c4)c3o2)cc(OC)c1OC
Reaction time: 15 h
Yield: 67 %

Procedure:
3-[2-(3,4,5-Trimethoxy-phenyl)-furo[3,2-b]pyridin-7-yl]-benzonitrile (0.067 mmol) is dissolved in methanol/NH3 (10%, 10 ml) and sponge nickel catalyst (70%, 0.1 g) is added. The mixture is hydrogenated at 5.6 bar at 50° C. for 15 h. The suspension is filtrated and the solvent removed in vacuo. The precipitate is suspended in diethylether and filtrated. The product is obtained after drying in vacuo as slight green solid (67% yield). HPLC (method A): Rt 2.41 min (purity 97.3%); LCMS (ESI+) (method E): Rt 1.527 min, M+H+ 391.1 m/z; 1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.56 (d, J=4.8, 1H), 8.25 (s, 1H), 7.93 (d, J=7.1, 1H), 7.74 (s, 1H), 7.65-7.45 (m, 3H), 7.34 (s, 2H), 3.92 (s, 6H), 3.88 (s, 2H), 3.81-3.68 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[C:9]([Cl:16])=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:17].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:28]([O:35][C:36]1[C:41]([CH2:42]Cl)=[C:40]([CH3:44])[CH:39]=[C:38]([CH3:45])[N:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCOCC1>[CH2:28]([O:35][C:36]1[C:41]([CH2:42][N:6]2[CH2:5][CH2:4][C:3]3[C:8](=[C:9]([Cl:16])[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:11][C:2]=3[Br:1])[C:7]2=[O:17])=[C:40]([CH3:44])[CH:39]=[C:38]([CH3:45])[N:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)Oc1cc(Br)c2c(c1Cl)C(=O)NCC2
Reactant: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc(C)c(CN2CCc3c(Br)cc(OC(C)C)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
To a solution of 5-bromo-8-chloro-7-(propan-2-yloxy)-3,4-dihydroisoquinolin-1(2H)-one (77d, 188 mg, 0.590 mmol) in anhydrous 1,4-dioxane (10 mL) was added KHMDS (2.00 mL, 2.00 mmol). Upon addition, a dark red paste was formed. After stirring at room temperature for 30 minutes, 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd Z, 170 mg, 0.649 mmol) was added. The resulting reaction mixture was stirred at 100° C. for 5 hours. After cooling to room temperature, the reaction mixture was quenched with water, and extracted with ethyl acetate (2×50 mL). The combined organic phases were dried over sodium sulfate, concentrated under vacuum, and purified by column chromatography (0-40% EtOAc/heptanes) to give 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-5-bromo-8-chloro-7-(propan-2-yloxy)-3,4-dihydroisoquinolin-1(2H)-one (77e, 140 mg, 44%).
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[Cl:9][C:10]1[N:15]=[N:14][C:13]([O:16]C(O)C)=[C:12]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:11]=1>Br>[Cl:9][C:10]1[N:15]=[N:14][C:13]([OH:16])=[C:12]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:11]=1
Reactant: CC(O)Oc1nnc(Cl)cc1N1CCNCC1
Agent: Br
Agent: O=C(O)/C=C/C(=O)O
Product: Oc1nnc(Cl)cc1N1CCNCC1
Reaction time: 1 h
Yield: 221.2 %

Procedure:
15 g (6-chloro-4-piperazin-1-yl-pyridazin-3-yloxy)-ethanol fumarate are suspended in 90 ml hydrogen bromide (48%). The reaction mixture is stirred for 1 hour at reflux temperature and evaporated to dryness. 19 g product are obtained as the hydrobromide. M.p.=35° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH:5]=[CH:4][N:3]=[CH:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[S:42]1C=C[CH:44]=[C:43]1CC(O)=O>>[N:1]1([CH2:6][CH2:7][O:8][C:43](=[S:42])[CH3:44])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)Cc1cccs1
Reactant: OCCn1ccnc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=S)OCCn1ccnc1

Procedure:
2-(1-Imidazolyl)ethanethiolacetate can be prepared by a method similar to that described in Example 11 for the preparation of the starting material, but starting from 2-(1-imidazolyl)ethanol (15 g), triphenylphosphine (70.2 g), diisopropyl azodicarboxylate (55.8 cc) and thiolacetic acid (21 cc). After purification by "flash" chromatography [eluent: methylene chloride (1500 c), followed by ethyl acetate-methanol (80-20 by volume)], 100-cc fractions being collected, and concentrating fractions 21 to 35 to dryness under reduced pressure (2.7 kPa) at 30° C., 2-(1-imidazolyl)ethylthioacetate (21.14 g) is obtained in the form of an orange-yellow oil which is used without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)=[O:3].[C:5]([NH:8][CH2:9][CH2:10][N:11]1[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]1[CH3:17])(=[O:7])[CH3:6].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:5]([NH:8][CH2:9][CH2:10][N:11]1[C:12]([CH3:17])=[CH:13][C:14]([S:2]([CH3:1])=[O:3])=[C:15]1[CH3:16])(=[O:7])[CH3:6]
Reactant: CS(=O)Cl
Reactant: CC(=O)NCCn1c(C)ccc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCn1c(C)cc(S(C)=O)c1C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
19.7 g (0.2 mol) of methylsulphinyl chloride are dissolved in 500 ml of methylene chloride. 36.0 g (0.2 mol) of 1-(2-acetylaminoethyl)-2,5-dimethylpyrrole and 27.6 ml (0.2 mol) of triethylamine in 500 ml of methylene chloride are added dropwise at 0° C. and the mixture is stirred at 0° C. for 45 minutes and poured onto aqueous sodium bicarbonate solution. The organic phase is separated off and discarded. The aqueous phase is concentrated and the residue is boiled up with isopropanol and, after the mixture has been concentrated, the product is chromatographed.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:25])=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CC([O-])(C)C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)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]>[CH3:24][C:22]1[NH:21][N:20]=[C:19]([NH:18][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:25])[N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:3][CH:4]=3)[N:17]=2)[CH:23]=1
Reactant: Cc1cc(Nc2nn(-c3ccc(Cl)cc3)c(=O)c3ccccc23)n[nH]1
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Product: Cc1cc(Nc2nn(-c3ccc(Nc4ccccc4)cc3)c(=O)c3ccccc23)n[nH]1
Temperature: 25 °C
Yield: 1.7 %

Procedure:
2-(4-Chloro-phenyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-phthalazin-1-one (B-1, 0.10 g, 0.28 mmol), aniline (0.034 g, 0.37 mmol), NaOtBu (0.041 g, 0.43 mmol), tris-(dibenzylideneacetone)-dipalladium (0.026 g, 0.028 mmol) and 2-(di-t-butylphosphino)-biphenyl (0.017 g, 0.057 mmol) under argon were heated to 100° C. for 17 hours, and then allowed to cool to RT. The solvent was evaporated in vacuum, the residue was diluted in H2O (50 ml) and the resulting solid was collected by filtration. Purification of the raw product by chromatography over silica gel with DCM:MeOH (20:1) gave the title compound (0.002 g, 2% yield) as a white solid (example U-1). 1H-NMR: (400 MHz, D6-DMSO) 12.0 (1H, s), 9.23 (1H, s), 8.49 (1H, d), 8.33-8.37 (2H, m), 7.88-7.97 (2H, m), 7.54 (2H, d), 7.28 (2H, t), 7.15 (4H, m), 6.86 (1H, t), 6.25 (1H, s), 2.19 (3H, s); MS (API+)=409.0 (M+H)+.