Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C:10](=O)[CH2:9][CH2:8]2.[N+:14]([CH3:17])([O-:16])=[O:15]>C(N)CN>[CH3:1][O:2][C:3]1[C:12]2[CH:11]=[C:10]([CH2:17][N+:14]([O-:16])=[O:15])[CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: C[N+](=O)[O-]
Reactant: COc1cccc2c1CC(=O)CC2
Solvent: NCCN
Product: COc1cccc2c1C=C(C[N+](=O)[O-])CC2
Temperature: 25 °C

Procedure:
44.1 g of 8-methoxy-2-tetralone (0.25 mol) are stirred at 70° C. under argon for 3 h in 402 ml of nitromethane (7.50 mol) and 2.5 ml of ethylenediamine. After the mixture has cooled to room temperature, a yellow crystallisate is filtered off with suction. The nitromethane is distilled off from the solution in vacuo. The residue is dissolved in 500 ml of toluene. The solvent is again distilled off in vacuo in order to remove nitromethane residues. The residue is then dissolved in 200 ml of toluene again. An insoluble component is filtered off and the solution is concentrated to 50 ml. The concentrated solution is then chromatographed on 500 g of silica gel using toluene. After concentrating the main fraction, the final product is obtained as a yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:22]5[S:23][CH:24]=[N:25][N:26]=5)[CH:20]=4)[N:15](C(OC(C)(C)C)=O)[CH:14]=3)[CH:10]=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[S:23]1[CH:24]=[N:25][N:26]=[C:22]1[C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[C:11]1[N:12]=[C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cccc(N3CCOCC3)n2)c2cc(-c3nncs3)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc(-c2c[nH]c3ccc(-c4nncs4)cc23)nc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
To a solution of tert-butyl 3-(6-morpholinopyridin-2-yl)-5-(1,3,4-thiadiazol-2-yl)-1H-indole-1-carboxylate (86.0 mg, 0.186 mmol) in DCM (1.0 mL) was added TFA (1.0 mL) and the reaction was stirred at RT for 1 h, then solvent was removed. The residue was diluted with DCM (60 mL) and washed with sat. NaHCO3, dried, filtered and concentrated. The residue was purified with RP-HPLC to give 4-(6-(5-(1,3,4-thiadiazol-2-yl)-1H-indol-3-yl)pyridin-2-yl)morpholine (34.0 mg, 0.094 mmol, 50.4%) as a yellow solid. MS (ESI, pos. ion) m/z: 364 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.78 (1H, br. s.), 9.52 (1H, s), 9.17 (1H, d, J=1.4 Hz), 8.16 (1H, d, J=2.5 Hz), 7.92 (1H, dd, J=8.6, 1.6 Hz), 7.53-7.65 (2H, m), 7.24 (1H, d, J=7.6 Hz), 6.66 (1H, d, J=8.4 Hz), 3.78-3.90 (4H, m), 3.57-3.69 (4H, m).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:14](=[O:17])[S:15][CH:16]=2)=[CH:8][CH:7]=1.[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:19]1.C(=O)([O-])[O-].[Na+].[Na+]>[I-].[Na+].CC(CC(C)C)=O>[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([N:27]2[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3[CH:11]=[CH:10][C:9]([C:12]4[NH:13][C:14](=[O:17])[S:15][CH:16]=4)=[CH:8][CH:7]=3)[CH2:31][CH2:32]2)=[N:19]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: O=c1[nH]c(-c2ccc(CCCCCl)cc2)cs1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c(-c2ccc(CCCCN3CCN(c4nsc5ccccc45)CC3)cc2)cs1
Yield: 59.4 %

Procedure:
To a 125 ml round-bottomed flask equipped with condenser and N2 inlet were added 1.10 g (4.11 mmol) 4-(4-(4-chlorobutyl)phenyl)-thiazol-2-one, 0.90 g (4.11 mmol) N-(3-benzoisothiazolyl)piperazine, 0.87 g (8.22 mmol) sodium carbonate, 2 mg sodium iodide, and 40 ml methylisobutylketone. The reaction mixture was heated at reflux for 44 hours, cooled, filtered, and the filtrate was evaporated. The residue was chromatographed on silica gel using ethyl acetate as eluent, and the product fractions collected and evaporated. The residue was taken up in methylene chloride/methanol, treated with ether saturated with HCl, and evaporated. The resulting solid was triturated with acetone to afford 1.10 g (55%) of white solid, m.p. 140-145° C. NMR (DMSO-d6): 1.6-1.8 (m, 4H), 2.62 (t, 2H), 3.1-3.3 (m, 4H), 3.4-3.6 (m, 4H), 4.0-4.1 (m, 2H), 6.75 (d, 1H), 7.2-8.1 (m, 8H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][C:3]=1B(O)O.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O)#[N:14].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.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]>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[C:16]1[C:15]([C:13]#[N:14])=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#Cc1ccccc1B(O)O
Reactant: O=Cc1ccc(B(O)O)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1-c1ccc(CO)cc1F
Temperature: 100 °C
Reaction time: 72 h
Yield: 29.5 %

Procedure:
A mixture of (2-fluoro-4-formylphenyl)boronic acid (35.3 g), 2-cyano-phenylboronic acid (40.0 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (1.7 g), tetrabutylammonium bromide (0.68 g), 2M aqueous sodium carbonate solution (200 mL) and toluene (600 mL) was stirred at 100° C. for 72 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (150 mL) and methanol (150 mL), sodium borohydride (8.7 g) was added, and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (14.1 g, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][CH2:11][CH2:12][Cl:13]
Reactant: ClCCCBr
Reactant: Oc1ccccc1Cl
Product: ClCCCOc1ccccc1Cl

Procedure:
Prepared by Procedure U and Scheme AK using 2-chlorophenol and 1-bromo-3-chloropropane.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:9][C:10](=[O:12])[CH3:11])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:10]([NH:9][C:3]1[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][S:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:21])=[O:20])[N:4]=1)(=[O:12])[CH3:11]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(=O)Nc1nc(O)ncc1F
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(OS(=O)(=O)c2ccccc2)ncc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.6 %

Procedure:
N-(5-fluoro-2-hydroxypyrimidin-4-yl)-acetamide (200 mg, 1.17 mmol) was suspended in pyridine (5 mL) and stirred at ambient temperature. To the stirred suspension was added benzenesulfonyl chloride (226 mg, 1.29 mmol) and agitation was continued for 16 hours. The solvent was evaporated under a stream of nitrogen and the residue was suspended in dichloromethane (2-3 mL), placed directly onto a silica gel column, and eluted with ethyl acetate in petroleum ether (0-50% gradient) to isolate 180 mg, 0.58 mmol (49%) of the title compound as a white solid: mp 142-143° C.; 1H NMR (DMSO-d6) δ 10.96 (s, 1H), 8.67 (d, J=2.6 Hz, 1H), 8.12-8.06 (m, 2H), 7.86-7.79 (m, 1H), 7.73-7.65 (m, 2H), 2.98 (s, 3H); HPLC-MS (ESI) m/z 312 (M+H)+, 310 (M−H)−. *N-(5-fluoro-2-hydroxypyrimidin-4-yl)-acetamide can be prepared through known literature methods.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:18]3[S:23][C:22]([CH2:24][CH2:25][NH:26]C(=O)OC(C)(C)C)=[CH:21][C:19]=3[N:20]=2)[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)Cl.CO>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)[C:18]3[S:23][C:22]([CH2:24][CH2:25][NH2:26])=[CH:21][C:19]=3[N:20]=2)[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCc1cc2nc(-c3cccc(O[Si](C)(C)C(C)(C)C)c3)nc(N3CCOCC3)c2s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1cccc(-c2nc(N3CCOCC3)c3sc(CCN)cc3n2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-butyl 2-(2-(3-(tert-butyldimethylsilyloxy)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)ethylcarbamate (10.0 mg, 1.0 eq.) was solved in 3 ml of TFA:DCM (1:1). The reaction mixture was stirred at room temperature for 2 h. The silica column chromatography (DCM:MeOH/95:5) gave the title compound.
Reaction SMILES: Cl/[C:2](/[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([SH:28])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].Cl>CO>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([S:28]/[C:2](/[CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3]\[C:4]([O:6][CH3:7])=[O:5])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(S)cc1OC
Reactant: COC(=O)/C=C(\Cl)CCCCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)/C=C(/CCCCc1ccccc1)Sc1ccc(OC)c(OC)c1
Yield: 74.7 %

Procedure:
A mixture of methyl (Z)-3-chloro-7-phenyl-2-heptenoate (0.7 g, 2.77 mmol), 3,4-dimethoxythiophenol (0.47 g, 2.77 mmol) and potassium carbonate (0.38 g, 2.77 mmol) in methanol (30 mL) is heated under reflux for 3 hours. The mixture is added to aqueous HCl and is extracted with ether. The organic layer is washed with water and is dried over MgSO4. The solvent is removed in vacuo and the residue is chromatographed on silica gel (4:1 hexane:ethyl acetate) to produce methyl (Z)-3-[(3,4-dimethoxyphenyl)thio]-7-phenyl-2-heptenoate as an oil (0.8 g, 75% ): 1H-NMR (300 MHz, CDCl3) δ (TMS) 1.30-1.53 (m, 3H), 1.62-1.76 (m, 1H), 2.03-2.18 (m, 2H), 2.38-2.48 (m, 1H), 2.64-2.74 (m, 1H), 3.72 (s, 3H), 3.78-3.90 (m, 6H), 5.78 (s, 1H), 6.72-6.82 (m, 1H), 6.92-7.00 (m, 1H), 7.05-7.10 (m, 1H), 7.20-7.38 (m, 5H).
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:32]C(=O)OC(C)(C)C)([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][C:20]4[O:21][C:22]5[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH3:31])=[CH:25][C:23]=5[CH:24]=4)=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)[CH2:4][O:3]1.CC1(C)OCC(NC(=O)OCCCC)(CN2C3C(=C(C4N=C(C5C=NC(CCC)=CC=5)ON=4)C=CC=3)CC2)CO1>>[NH2:32][C:5]([CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:19][C:20]3[O:21][C:22]4[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH3:31])=[CH:25][C:23]=4[CH:24]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)([CH2:6][OH:7])[CH2:4][OH:3]
Reactant: CCCc1ccc2oc(COc3ccc4c(c3)CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2c1
Agent: CCCCOC(=O)NC1(CN2CCc3c(-c4noc(-c5ccc(CCC)nc5)n4)cccc32)COC(C)(C)OC1
Product: CCCc1ccc2oc(COc3ccc4c(c3)CCN4CC(N)(CO)CO)cc2c1
Yield: 45 %

Procedure:
When the product of Step D was substituted for tea-butyl 2,2-dimethyl-5-((4-(5-(6-propylpyridin-3-yl)-1,2,4-oxadiazol-3-yl)indolin-1-yl)methyl)-1,3-dioxan-5-ylcarbamate in Example 66, Step F, the identical process afforded the title compound in 45% yield, as colourless solid. 1H-NMR (CDCl3+CD3OD) 0.92 (tr, 3H, J=6 Hz); 1.56-1.67 (m, 2H+H2O); 2.55-2.65 (m, 2H); 2.91 (tr, 2H, J=(Hz); 2.98 (s, 2H); 3.39 (tr, 2H, J=6 Hz); 3.4-3.6 (m, 4H); 5.02 (s, 2H); 6.5 (d, 1H, J=9 Hz); 6.64 (s, 1H); 6.68-6.81 (m, 2H); 7.06 (dd, 1H, J=3, 9 Hz); 7.28-7.37 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][C@H:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.Cl.[CH3:22][C:23]1[N:24]=[N:25][N:26]([CH:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)[CH:27]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[F:1][C:2]1[C:3]([N:30]2[CH2:31][CH2:32][CH:28]([N:26]3[CH:27]=[C:23]([CH3:22])[N:24]=[N:25]3)[CH2:29]2)=[C:4]2[O:9][CH2:8][C@H:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23
Reactant: C[C@H]1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: Cc1cn(C2CCNC2)nn1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cn(C2CCN(c3c(F)cc4c(=O)c(C(=O)O)cn5c4c3OC[C@@H]5C)C2)nn1

Procedure:
A solution of 70.25 mg (0.25 mmol) of (-)-9,10-difluoro-3(S)-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid and 141 mg (0.75 mmol) of 3-(4-methyl-1,2,3-triazol-1-yl)pyrrolidine hydrochloride in 3 ml of acetonitrile in the presence of 152.24 mg (1 mmol) of DBU was refluxed for 3 days under nitrogen atmosphere. The suspension was then evaporated and water was added to the residue and solid collected and washed with methanol to yield after drying 50 mg of the desired product, m.p. 241°-242° C. 1H NMR (TFA) δ: 9.16 (s, 1H), 8.37 (s, 1H), 7.99 (d, 13.3Hz, 1H), 5.75-5.6 (m, 1H), 5.15-4.1 (m, 7H), 3-2.6 (m, 2H), 2.67 (s , 3H), 1.8 (d, 6.8Hz, 3H). Anal. calcd. for C20H20FN5O4 . 1/2 H2O: C, 56.87; H, 5.01; N, 16.58. Found: C, 57.30; H, 4.77; N, 16.75.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=S)[NH:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[O:3].N.OO>CO>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:11]2[NH:10][C:5]3[C:4]([C:2](=[O:3])[N:1]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:21])=[CH:15][CH:16]=1
Reactant: NC(=O)c1ccccc1NC(=S)NC(=O)c1ccc(Cl)cc1
Agent: N
Agent: OO
Solvent: CO
Product: O=C(Nc1nc(=O)c2ccccc2[nH]1)c1ccc(Cl)cc1
Reaction time: 0.17 h
Yield: 47.9 %

Procedure:
To a stirred mixture of 10 g of the above benzamide, 100 ml of methanolic ammonia and 100 ml of methanol was added dropwise 25 ml of 30% hydrogen peroxide, during 10 minutes. The mixture was stirred overnight, the solid was collected, and then partially dissolved in 500 ml of hot acetonitrile. The undissolved solid was collected, mixed with 100 ml of hot water and the solid collected, giving 4.3 g of the desired product as off-white crystals, mp 239°-241° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.O[CH:11]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH:11]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)=[CH:5][CH:4]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccccc3)CC2)c1
Reactant: COc1ccc(O)cc1
Product: COc1ccc(OC(CCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)cc1

Procedure:
Prepared by Procedure A and Scheme AN using 4-methoxyphenol and N-{3-[1-(5-hydroxy-5-phenylpentyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 515.6 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:25]=[C:24](B(O)O)[CH:23]=[CH:22][N:21]=1>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[CH:22][N:21]=1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: OB(O)c1ccnc(F)c1
Product: N#Cc1cc(-c2ccnc(F)c2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, white solid (51 mg, 64%), MS (ISP) m/z=321.4 [(M+H)+], mp 275° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 2-fluoro-pyridin-4-ylboronic acid (45.8 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.C[O:14][CH:15](OC)[CH2:16][CH2:17][CH2:18][CH:19]=O>CCOC(C)=O.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]/[C:9](/[N+:10]([O-:12])=[O:11])=[CH:19]\[CH2:18][CH2:17][CH2:16][CH:15]=[O:14])=[CH:6][CH:7]=1
Reactant: COC(CCCC=O)OC
Reactant: O=[N+]([O-])CCc1ccc(Cl)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=CCCC/C=C(\Cc1ccc(Cl)cc1)[N+](=O)[O-]
Yield: 45.1 %

Procedure:
Prepared according to the general procedure B from 1-chloro-4-(2-nitroethyl)benzene 112g (24 mmol) and 5,5-dimethoxypentanal 131 (16 mmol) to provide the title compound as yellow oil (1.93 g, 45% yield) after silica gel chromatography (EtOAc/Hexane).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH3:16])=[CH:10]2)C.Cl[CH2:22][C:23]1[N:24]=[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:26][CH:27]=1.[H-].[Na+]>CN(C)C=O.O>[CH2:18]([O:17][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:22][C:23]1[N:24]=[C:25]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[S:26][CH:27]=1)[C:11]([CH3:16])=[CH:10]2)[C:4]([OH:3])=[O:20])[CH3:19]
Reactant: CCOC(=O)C(Cc1ccc2[nH]c(C)cc2c1)OCC
Reactant: ClCc1csc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(Cc1ccc2c(c1)cc(C)n2Cc1csc(-c2ccccc2)n1)C(=O)O
Yield: 90.4 %

Procedure:
0.28 g (1.0 mmol) rac-2-ethoxy-3-(2-methyl-1H-indol-5-yl)-propionic acid ethyl ester (preparation 5) were reacted with 0.23 g (1.1 mmol) 4-chloromethyl-2-phenyl-thiazole in 5 ml N,N-dimethylformamide in the presence of 0.09 g (2.0 mmol) sodium hydride (55%) in mineral oil) at room temperature for 16 hours. The reaction mixture was then diluted with water and extracted with dichloromethane. The combined organic phases were dried over MgSO4 and evaporated. The residue formed was purified by flash-chromatography (silica gel; eluent: gradient of n-heptane and ethyl acetate) to give 0.38 g (90%) of rac-2-ethoxy-3-[2-methyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-indol-5-yl]-propionic acid as light brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:9])[C:5]([F:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:18]2[CH:19]=[N:20][N:21](C(OC(C)(C)C)=O)[CH:22]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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>[F:8][C:5]1[C:4]([F:9])=[CH:3][C:2]([C:18]2[CH:19]=[N:20][NH:21][CH:22]=2)=[CH:7][N:6]=1
Reactant: Fc1cc(Br)cnc1F
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: C1COCCO1
Product: Fc1cc(-c2cn[nH]c2)cnc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
5-bromo-2,3-difluoropyridine (2.0 g, 10.31 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (3.03 g, 10.31 mmol), Na2CO3 (2.186 g, 20.62 mmol) and Pd(Ph3P)4 (1.191 g, 1.031 mmol) were dissolved in dioxane (20 ml). The mixture was bubbled with Ar for 10 min. The reaction was stirred at 100° C. for overnight, cooled and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH=30/1) to afford the title compound as white solid (1.0 g, 53.5% yield). LCMS (method B): [M+H]+=182, tR=1.98 min.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:34]([N:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45]O)[CH2:39][CH2:38]1)[C:35]#[CH:36]>ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:45][CH2:44][CH2:43][N:40]3[CH2:39][CH2:38][N:37]([CH2:34][C:35]#[CH:36])[CH2:42][CH2:41]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: C#CCN1CCN(CCCO)CC1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C#CCN1CCN(CCCOc2cc3ncnc(Cl)c3cc2OC)CC1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 76.8 %

Procedure:
4-Chloro-7-hydroxy-6-methoxyquinazoline (300 mg, 1.42 mmol), (prepared as described for the starting material in Example 4), was suspended in dichloromethane (15 ml). Triphenylphosphine (523 mg, 2 mmol) and 3-(4-prop-2-yn-1-ylpiperazin-1-yl)propan-1-ol (267 mg, 1.46 mmol) were added. Diisopropyl azadicarboxylate (340 μl, 1.71 mmol) was then added dropwise. The reaction mixture was stirred for 1.25 hours at ambient temperature and then loaded directly onto a silica column, and eluted with methylene chloride/methanol (90/8 followed by 90/10) to give 4-chloro-6-methoxy-7-[3-(4-prop-2-yn-1-ylpiperazin-1-yl)propoxy]quinazoline (409 mg, 77%).
Reaction SMILES: [CH3:1][C:2]1[C:18]([C:19]2[S:23][C:22]([C:24]3[N:25]([CH3:29])[N:26]=[CH:27][N:28]=3)=[N:21][CH:20]=2)=[C:5]2[N:6]=[C:7]([CH3:17])[CH:8]=[C:9]([CH:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[N:4]2[N:3]=1.[Br:30]N1C(=O)CCC1=O>C(#N)C>[Br:30][C:20]1[N:21]=[C:22]([C:24]2[N:25]([CH3:29])[N:26]=[CH:27][N:28]=2)[S:23][C:19]=1[C:18]1[C:2]([CH3:1])=[N:3][N:4]2[C:9]([CH:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])=[CH:8][C:7]([CH3:17])=[N:6][C:5]=12
Reactant: CCCC(CCC)c1cc(C)nc2c(-c3cnc(-c4ncnn4C)s3)c(C)nn12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCCC(CCC)c1cc(C)nc2c(-c3sc(-c4ncnn4C)nc3Br)c(C)nn12
Temperature: 22 °C
Reaction time: 10 h
Yield: 76.9 %

Procedure:
To a solution of 2,5-dimethyl-3-[2-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiazol-5-yl]-7-(1-propyl-butyl)-pyrazolo[1,5-a]pyrimidine (6 g, 14.65 mmol) in acetonitrile (60 mL) add N-bromosuccinimide (2.74 g, 15.4 mmol) in one portion and stir at 22° C. for 10 h. Evaporate the solvent and dissolve the residue in a mixture of water (50 mL) and methyl-t-butyl ether (100 mL). Separate the organic layer and extract the aqueous layer with additional methyl-t-butyl ether (2×50 mL). Combine the organic portions and evaporate the solvent. Purify the resulting material by filtration through a silica gel pad, eluting with hexanes/ethyl acetate (3/1). Combine the product containing fractions and evaporate the solvent. Add heptanes (25 mL) and triturate the solid. Filter the solid and dry under vacuum to afford the title compound (5.5 g, 77%). ES/MS m/z (79Br/81Br) 488/490 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:11]([CH:12]=[O:13])=[CH:10][N:9]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][C:7]=1[Cl:8].S(=O)(=O)([OH:24])N.Cl([O-])=O.[Na+].P([O-])(O)(O)=O.[K+]>O.O1CCOCC1>[Br:1][C:2]1[N:3]=[C:4]2[C:11]([C:12]([OH:24])=[O:13])=[CH:10][N:9]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][C:7]=1[Cl:8]
Reactant: NS(=O)(=O)O
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(Br)c(Cl)nc21
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)c(Cl)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a stirred solution of 2-bromo-3-chloro-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (1.96 g, 5.03 mmol) in a (1:1) mixed solvent system of 1,4-dioxane:water (105 mL), were added sulfamic acid (2.93 g, 30.15 mmol), sodium chlorite (0.591 g, 6.53 mmol) and potassium dihydrogen phosphate (8.20 g, 60.3 mmol). The mixture was stirred overnight at room temperature The resulting mixture was diluted with water (50 mL) and extracted with ethyl acetate (150 mL×3). The combined organic phases were washed with brine, dried and concentrated in vacuo to a yellow solid which was thoroughly washed with hexane to give 2-bromo-3-chloro-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1.62 g, 79%) as off-white solid. LC-MS: 406.2 (M−H).