Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[NH:10][C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1.C.[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]([OH:29])([C:27]#[CH:28])[CH3:26].N1CCCCC1>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:28]#[C:27][C:25]([OH:29])([C:21]4[S:20][CH:24]=[CH:23][N:22]=4)[CH3:26])[CH:15]=[CH:16][C:11]=3[NH:10][C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1
Reactant: C#CC(C)(O)c1nccs1
Reactant: Nc1nccc(-n2c(=O)[nH]c3ccc(Br)cc32)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: CC(O)(C#Cc1ccc2[nH]c(=O)n(-c3ccnc(N)n3)c2c1)c1nccs1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-(2-aminopyrimidin-4-yl)-6-bromo-2,3-dihydro-1H-1,3-benzodiazol-2-one (230 mg, 0.751 mmol) in EtOAc was added charcoal (5 mol %). The mixture was stirred at RT for 20 min then filtered and concentrated in vacuo. To the residue in a sealed tube was added 2-(1,3-thiazol-2-yl)but-3-yn-2-ol (230 mg, 1.50 mmol), piperidine (2 mL), tetrakis(triphenylphosphine)palladium (43.4 mg, 0.038 mmol) and copper(I) iodide (14.3 mg, 0.075 mmol). The reaction mixture was then heated at 75° C. for 18 hr then partitioned between EtOAc (15 mL) and water (2 mL). The organic layer was concentrated in vacuo and the residue purified by reverse phase preparative HPLC to afford the title compound: 1H NMR (500 MHz, DMSO) δ 1.90 (3 H, s), 6.92 (2H, s), 6.95 (1H, s), 7.04 (1H, d, J=8.04 Hz), 7.21 (1H, dd, J=8.04, 1.42 Hz), 7.40 (1H, d, J=5.52 Hz), 7.68 (1H, d, J=3.31 Hz), 7.77 (1H, d, J=3.15 Hz), 8.26-8.36 (2H, m), 11.57 (1H, br. s.); LC-MS: m/z=+379.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:7][CH:8]=1)([O-:3])=[O:2].[K].Br[CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.COCCOC>CN(C=O)C.[Cl-].[Na+].O>[CH:16]1([N:7]2[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]2[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: BrC1CCCC1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c[nH]1
Agent: [Cl-]
Agent: [K]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc([N+](=O)[O-])cn1C1CCCC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
Ethyl 4-nitro-1H-pyrrole-2-carboxylate (1.006 g, 5.432 mmol; see Example 1, step (i) above) was dissolved in DMF (20 mL, dry) to which was added potassium metal (0.492 g, 12.582 mmol) then it was heated to 80° C. and then it was left at that temperature for 1 h with stirring. The reaction mixture was cooled to 50-60° C. after which bromocyclopentane (1 mL, 1.390 g, 9.326 mmol) was added followed by KI (1.548 g, 9.326 mmol). The reaction mixture was heated again for 5 h with stirring at 80° C., after which time it was left stirring at room temperature under N2, overnight. The reaction mixture was diluted with brine under N2, at room temperature, and then it was extracted with ethyl acetate (3×100 mL). The combined organic extract was dried over MgSO4, filtered and the solvent removed under reduced pressure to give the crude product (containing some DME). The product was purified using column chromatography [silica gel, 1/10 ethyl acetate/n-hexane (RF=0.24)]. Fractions containing the pure material were collected and the solvent removed to give pale yellow oil (440 mg, 32% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:22][CH2:23][O:24][CH3:25]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:22][CH2:23][O:24][CH3:25])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Reactant: COCCBr
Product: CCOC(=O)N1CCC(c2cn(CCOC)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.4 %

Procedure:
This compound was prepared following the procedure described in example 1, part D, starting with 5.5 g (0.02 mol) of 4-(1H-indol-3-yl)-piperidine-carboxylic acid ethyl ester and 2.3 ml (0.0233 mol) of 1-bromo-2-methoxyethane. The reaction mixture was stirred at room temperature for 24 h and after standard work-up, 6.5 g (98% of yield) of 4-[1-(2-methoxyethyl)-1H-indol-3-yl]-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [NH2:1][C:2]([CH3:53])([CH3:52])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[N:11]=[C:10]2[C:17]1[N:22]=[C:21]2[C:23]([C:45]([NH:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[CH:24][N:25](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:20]2=[N:19][CH:18]=1.[F:54][C:55]([F:60])([F:59])[C:56]([OH:58])=[O:57]>ClCCl>[F:54][C:55]([F:60])([F:59])[C:56]([OH:58])=[O:57].[NH2:1][C:2]([CH3:53])([CH3:52])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[N:11]=[C:10]2[C:17]1[N:22]=[C:21]2[C:23]([C:45]([NH:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[CH:24][NH:25][C:20]2=[N:19][CH:18]=1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(OCCCC(C)(C)N)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2cc(OCCCC(C)(C)N)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
To a solution of 2-(5-(4-amino-4-methylpentyloxy)-1-methyl-1H-indazol-3-yl)-N-tert-butyl-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (88 mg, 0.12 mmol) in 3 mL of dichloromethane was added trifluoroacetic acid (3 mL). The reaction mixture was stirred overnight at 25° C. After solvent evaporation, the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 40% acetonitrile/60% water (0.1% trifluoroacetic acid V/V) initially, and then proceed to 50% acetonitrile/50% water (0.1% trifluoroacetic acid V/V) in a linear fashion after just 9 min) to afford 2-(5-(4-amino-4-methylpentyloxy)-1-methyl-1H-indazol-3-yl)-N-tert-butyl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide 2,2,2-trifluoroacetate as yellow solid (9 mg, 13%). LCMS: (M+H)+=464; 1H NMR (300 MHz, CD3OD): δ 9.01 (s, 1H), 8.26 (s, 1H), 7.85 (s, 1H), 7.56 (d, 1H, J=9.0 Hz), 7.24 (dd, 1H, J1=9.0 Hz, J2=2.4 Hz), 4.15-4.12 (m, 5H), 1.87-1.84 (m, 4H), 1.59 (s, 9H), 1.27 (s, 6H).
Reaction SMILES: [ClH:1].[N+]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH:11](N(CC3C=CC=CC=3)C)[CH2:12]2)=[CH:7][CH:6]=1)([O-])=O.CC(O)=[O:26].O>[Zn]>[CH3:6][CH:5]([OH:26])[CH3:14].[ClH:1].[CH2:12]1[C:13]2[C:8](=[CH:7][CH:6]=[CH:5][CH:14]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: CN(Cc1ccccc1)C1CCc2ccc([N+](=O)[O-])cc2C1
Reactant: CC(=O)O
Agent: Cl
Agent: [Zn]
Solvent: O
Product: CC(C)O
Product: c1ccc2c(c1)CCCC2
Reaction time: 0.08 h

Procedure:
To 7-nitro-2-((phenylmethyl)(methyl)amino)-1,2,3,4-tetrahydronaphthalene hydrochloride (0.89 g, 2.7 mmol) in 85% AcOH/H2O (75 ml) was added zinc metal (3.5 g, 54.0 mmol). The mixture was stirred for 5 min, filtered through celite, and evaporated to an oil. The oil was dumped into basic water and extracted with chloroform (3×20 ml). The combined extracts were washed with water, dried over MgSO4, filtered and concentrated to an oil. Treatment with IPA/HCl yielded 7-amino-2-((phenyl)methyl)(methyl)amino)-1,2,3,4-tetrahydronaphthalene: (0.81 g, 88%); M.S. (M+H)+ =267.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[C:26]1(C)C=CC=CC=1>CO>[F:1][C:2]([F:20])([F:21])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7]([O:9][CH3:26])=[O:8]
Reactant: O=C(O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Yield: 98 %

Procedure:
A solution of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid (20 g) and thionyl chloride (15.0 g) in methanol (100 ml) was stirred at 80° C. for 2 hours. The solvents were evaporated under vacuum to give an oil residue. Toluene (100 ml) was added to the residue and the solution was washed with saturated NaHCO3 (30 ml) solution followed by water (3×30 ml). The organic layer was concentrated under reduced pressure to give the product as a white solid (20.5 g, yield 98.0%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]C)=O)=[CH:6][N:5]=[CH:4][C:3]=1[CH3:12].[CH3:13][NH2:14]>>[NH2:1][C:2]1[C:7]([C:8]([NH:14][CH3:13])=[O:10])=[CH:6][N:5]=[CH:4][C:3]=1[CH3:12]
Reactant: CN
Reactant: COC(=O)c1cncc(C)c1N
Product: CNC(=O)c1cncc(C)c1N
Temperature: 100 °C
Yield: 91 %

Procedure:
Methyl 4-amino-5-methylnicotinate (100 mg, 0.60 mmol) and methylamine (2.0 M in MeOH, 2 mL) were mixed, and stirred under heat at 100° C. in a sealed tube for 24 hours. The solvent was evaporated off under reduced pressure, and the resulting residue was purified through silica gel column chromatography (chloroform/methanol=9/1) to obtain the intended compound (91 mg, 91%) as a yellow solid.
Reaction SMILES: [ClH:1].Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.Br[C:26]1[C:32]([OH:33])=[CH:31][C:29]([NH2:30])=[C:28]([F:34])[CH:27]=1>C(O)(C)C.CC(C)=O>[Cl:1][C:26]1[C:32]([OH:33])=[CH:31][C:29]([NH:30][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][N:4]=2)=[C:28]([F:34])[CH:27]=1
Reactant: Nc1cc(O)c(Br)cc1F
Reactant: COc1cc2c(Cl)ncnc2cc1OCCN1CCN(C)CC1
Reactant: Cl
Solvent: CC(C)O
Solvent: CC(C)=O
Product: COc1cc2c(Nc3cc(O)c(Cl)cc3F)ncnc2cc1OCCN1CCN(C)CC1
Yield: 32 %

Procedure:
1M Ethereal hydrogen chloride (0.34 ml, 0.34 mmol) was added to 4-chloro-6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazoline (115 mg, 0.34 mmol) and 4-chloro-2-fluoro-5-hydroxyaniline (61 mg, 0.38 mmol), (as described in EP 61741 A2), in isopropanol (5 ml) and the mixture was heated at reflux for 90 minutes and then allowed to cool. The mixture was diluted with acetone, and the solid product collected by filtration. The impure solid was treated with methylene chloride/methanol/ammonia (100/8/1) (5 ml), and water was added. The reprecipitated product was collected by filtration and dried to give 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazoline (32%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:18]2[CH:17]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:14][C:13]=2[S:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2.[Na+].[I-:24]>CC(C)=O>[I:24][CH2:2][CH2:3][CH2:4][N:5]1[C:18]2[CH:17]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:14][C:13]=2[S:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: [I-]
Reactant: FC(F)(F)c1ccc2c(c1)N(CCCCl)c1ccccc1S2
Agent: [Na+]
Solvent: CC(C)=O
Product: FC(F)(F)c1ccc2c(c1)N(CCCI)c1ccccc1S2
Temperature: 55 °C

Procedure:
A solution of 10-(3-chloropropyl)-2-(trifluoromethyl)-10H-phenothiazine was mixed with acetone (50 mL) and NaI (4.0 g, 26 mmol) and heated at 55° C. for 48 h. Once no starting material was observed by analytical LCMS, the reaction mixture was partitioned between CH2Cl2 (100 mL) and an aqueous solution of Na2S2O3 (20 ml). The organic layer is dried with MgSO4 and concentrated to afford the title compound.
Reaction SMILES: [C:1]([NH:18][CH2:19][C:20](O)=[O:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:56][C@H:57]([C:65]([NH:67][CH2:68][C:69]([OH:71])=[O:70])=[O:66])[CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>CN(C=O)C.C(OCC)(=O)C>[CH:7]1[C:6]2[CH:5]([CH2:4][O:3][C:1]([NH:18][CH2:19][C:20]([NH:56][C@H:57]([C:65]([NH:67][CH2:68][C:69]([OH:71])=[O:70])=[O:66])[CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[O:21])=[O:2])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: N[C@@H](Cc1ccccc1)C(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of Fmoc-glycine (297 mg, 1.00 mmol) in DMF (5 mL) at 0° C. was added DIEA (348 μL, 2.00 mmol) and HBTU (379 mg, 1.00 mmol). After stirring for 10 min at 0° C., the resulting activated ester solution was added to crude dipeptide 73 (1.00 mmol) and the reaction mixture was stirred for 2 h at 0° C. It was diluted with ethyl acetate, washed with H2O, 1N HCl solution, saturated NaHCO3 solution and saturated NaCl solution. The organic layer was dried over MgSO4, filtered and concentrated to dryness. The crude product was purified by silica gel chromatography on a Biotage™ flash chromatography system using a gradient of 0-75% ethyl acetate in CH2Cl2. Tripeptide 74 was obtained as a white solid (546 mg, 98%). 1H NMR (400 MHz, CDCl3) δ 1.44 (s, 9H), 3.10 (d, J=6.8 Hz, 2H), 3.74-3.95 (m, 4H), 4.21 (t, J=7.0 Hz, 1H), 4.40 (d, J=7.2 Hz, 2H), 4.70 (q, J=7.5 Hz, 1H), 5.36 (bs, 1H), 6.31 (bs, 1H), 6.53 (d, J=7.4 Hz, 1H), 7.17-7.22 (m, 3H), 7.24-7.28 (m, 2H), 7.30-7.34 (m, 2H), 7.41 (t, J=7.4 Hz, 2H), 7.59 (d, J=7.3 Hz, 2H), 7.77 (d, J=7.3 Hz, 2H).
Reaction SMILES: P([O-])(OCC)(SCC)=[S:2].[Cl:10][C:11]1[CH:12]=[C:13]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:14][NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=2)[C:19]([N:28]2[CH2:33]CCC[CH:29]2O)=[N:18][N:17]=1.[CH:40]([OH:43])([CH3:42])[CH3:41]>O>[Cl:10][C:11]1[CH:12]=[C:13]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:14][NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26](=[S:2])[NH2:27])[CH:24]=2)[C:19]([N:28]2[CH2:33][CH2:42][CH:40]([OH:43])[CH2:41][CH2:29]2)=[N:18][N:17]=1
Reactant: CC(C)O
Reactant: CCOP([O-])(=S)SCC
Reactant: COc1ccc(CNc2nnc(N3CCCCC3O)c3ccc(C#N)cc23)cc1Cl
Solvent: O
Product: COc1ccc(CNc2nnc(N3CCC(O)CC3)c3ccc(C(N)=S)cc23)cc1Cl

Procedure:
3.7 ml diethyl dithiophosphate was added to a mixture of 2.0 g 4-[(3-chloro-4-methoxybenzyl)amino]-1-(hydroxypiperidino)-6-phthalazine carbonitrile, 1 ml water and 2 ml isopropanol, and the mixture was heated under reflux for 1 hr. After cooling, water was added to the reaction solution and the resulting crystals were collected by filtration. The filtrate was extracted with ethyl acetate and washed with brine. It was dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated, and the resulting crystalline residue was combined with the crystals collected above by filtration, whereby 1.5 g of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[ClH:1].[C:12]1([C:2]2[C:7]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)Nc1cccnc1Cl
Reactant: OB(O)c1ccccc1
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccnc1-c1ccccc1
Product: Cl
Temperature: 25 °C
Yield: 857.7 %

Procedure:
To a mixture of N-(2-chloro-pyridin-3-yl)-acetamide (50,0 g, 29.3 mmol), phenylboronic acid (39.3 g, 32.2 mmol), sodium carbonate (49.7 g, 46.9 mmol), in toluene (400 mL), ethanol (100 mL), and water (200 mL) was added tetrakis(triphenylphosphine)palladium(0) (1.02 g, 0.883 mmol). The reaction mixture was heated to reflux for 8 hours, cooled to room temperature, and the layers were separated. The aqueous layer was extracted with ethyl acetate (500 mL) and the organic extracts were combined and concentrated to a yellow solid. The crude solid was dissolved in methanol (500 mL) and concentrated hydrochloric acid was added (10 mL). The solution was concentrated to a low volume and tetrahydrofuran (500 mL) was added. The solid was triturated, filtered and dried to afford N-(2-phenyl-pyridin-3-yl)-acetamide hydrochloride (62.5 g, 86%). M. p.=262-263° C. 1H NMR (300 MHz, DMSOd6) δ2.52 (s, 3), 6.30 (bs, 2), 7.64-7.72 (m, 6), 7.78 (dd, 1, J=1.2, 8.6), 8.06 (dd, 1, J=1.2, 5.2)
Reaction SMILES: Cl[C:2]1[C:3]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][S:14][C:4]=2[N:5]=[C:6]([CH2:8][C:9]([O:11]CC)=[O:10])[N:7]=1.Cl.[CH3:24][O:25][CH2:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)CC)C>C(O)C>[CH3:24][O:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:2]2[C:3]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:15][S:14][C:4]=3[N:5]=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[N:7]=2)[CH2:29][CH2:28]1
Reactant: COCC1CCNCC1
Reactant: CCOC(=O)Cc1nc(Cl)c2c(-c3ccccc3)csc2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COCC1CCN(c2nc(CC(=O)O)nc3scc(-c4ccccc4)c23)CC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
Ethyl 2-(4-chloro-5-phenyl-thieno[2,3-d]pyrimidin-2-yl)acetate (100 mg, 0.285 mmol), 4-(methoxymethyl)piperidine hydrochloride (52 mg, 0.314 mmol) and triethylamine (0.12 mL, 0.85 mmol) were dissolved in ethanol (4 mL) and heated to 65° C. for 6 hrs. The reaction was then heated to 150° C. in a microwave for 10 min. The reaction was poured over ice and extracted with DCM. The extracts were combined and concentrated in vacuo. The residue was dissolved in non-dry THF (2 mL) and lithium hydroxide monohydrate (48 mg) was added. The reaction was stirred at room temperature overnight then another portion of lithium hydroxide monohydrate was added (10 mg) and the reaction stirred for a further 2 hrs. The reaction mixture was purified on an Isolute NH2 SPE column (eluting ammonia in methanol) to give 2-[4-[4-(methoxymethyl)-1-piperidyl]-5-phenyl-thieno[2,3-d]pyrimidin-2-yl]acetic acid (107 mg).
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]([C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:6]N(C)C)C.Cl.[C:20]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)(=[NH:22])[NH2:21]>>[C:11]1([C:10]2[C:5]([C:4]([OH:18])=[O:3])=[CH:6][N:21]=[C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[N:22]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1
Reactant: N=C(N)c1cccnc1
Agent: Cl
Product: O=C(O)c1cnc(-c2cccnc2)nc1-c1ccccc1

Procedure:
In an analogous manner to that described in example 3b) starting from 2-benzoyl-3-dimethylamino-acrylic acid ethyl ester and 3-amidinopyridine hydrochloride, followed by saponification as described in example 3c) there was obtained 4-phenyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid, MS (EI): 277 (M+).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[F:17][C:18]([F:42])([F:41])[CH2:19][NH:20][C:21]([C:23]1([CH2:36][CH2:37][CH2:38][CH2:39]Br)[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22]>>[F:17][C:18]([F:41])([F:42])[CH2:19][NH:20][C:21]([C:23]1([CH2:36][CH2:37][CH2:38][CH2:39][N:12]2[CH2:13][CH2:14][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=3)[CH2:10][CH2:11]2)[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22]
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc(C(F)(F)F)cc3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-(4-trifluoromethyl-phenyl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[NH:32][CH2:33][CH3:34])=[O:26])[CH3:23].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[N:32]([CH2:33][CH3:34])[C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)=[O:26])[CH3:23]
Reactant: CCNC1CCCC1C(=O)OCC
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)C1CCCC1N(CC)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.1665 g, 0.5 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL). 2-Ethylamino-cyclopentanecarboxylic acid ethyl ester (0.0926 g, 0.5 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.1003 g, 0.525 mmol). Then N-methylmorpholine (115 μL, 1.05 mmol) was added. The mixture was stirred at 25° C. for 5 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product, 2-{ethyl-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid ethyl ester, as a yellow oil. LC-MS (ESI) calcd for C20H28N4O7S2 500.14, found 501.2 [M+H+].
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)=O)(C)(C)C.B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)(=O)C>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]([NH:15][C:10]2[C:9]([NH2:8])=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: COc1ccc(C(=O)Nc2ncccc2NC(=O)OC(C)(C)C)cc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2ncccc2N)cc1
Reaction time: 2 h
Yield: 49.2 %

Procedure:
A solution of N3-(tert-butoxycarbonyl)—N2-(4-methoxybenzoyl)-2,3-pyridinediamine (350 mg, 1.02 mmol) in acetic acid (2 mL) at 0° C. was treated with boron trifluoride etherate (0.50 mL, 4.1 mmol). After 2 h, the mixture was poured into aqueous sodium bicarbonate and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate and the combined extracts were dried (magnesium sulfate), filtered, and concentrated in vacuo. Purification of the residue by chromatography (silica gel, ethyl acetate/methylene chloride) yielded 122 mg (49%) of the title compound.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].[N:13]#[C:14][Br:15]>CO>[BrH:15].[NH2:13][C:14]1[N:4]2[C:5]3[C:10]([CH:11]=[CH:12][C:3]2=[N:1][N:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: NNc1ccc2ccccc2n1
Reactant: N#CBr
Solvent: CO
Product: Br
Product: Nc1nnc2ccc3ccccc3n12

Procedure:
2-Hydrazinoquinoline (25.0 grams) was placed in a 3-liter flask (three-necked, equipped with a condenser) containing 1500 milliliters of methanol. To this flask was added 17 grams of cyanogen bromide. The reaction mixture was refluxed for six hours, at which time it was cooled. The reaction mixture was then evaporated down to approximately 200 milliliters. This solution was then poured into 1 liter of absolute ether. The precipitate which formed was washed with an aliphatic naphtha solvent. This precipitate, the desired 1 -amino-s-triazolo(4,3-a)quinoline hydrobromide, was separated by filtration.