Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=2)[CH2:10][O:11][CH2:12][C:13]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[N:5]=[N:4][N:3]=1.Cl>C(OCC)(=O)C>[CH3:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:32]=[C:33]([C:35]([F:38])([F:36])[F:37])[CH:34]=2)[CH2:10][O:11][CH2:12][C:13]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)[N:5]=[N:4][N:3]=1
Reactant: Cc1nnnn1-c1cc(COCC2(c3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1nnnn1-c1cc(COCC2(c3ccccc3)CCNCC2)cc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
tert-Butyl 4-((3-(5-methyl-1H-tetrazol-1-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate (40.0 mg, 0.08 mmol) was dissolved in a minimum amount of ethyl acetate, followed by addition of 4 N hydrochloric acid (1.5 mL). The mixture was stirred under nitrogen for 1 h. After removing the solvents, the crude mixture was precipitated in diethyl ether and filtered to afford 30.0 mg (93%) as a white powder. 1H-NMR (CDCl3, 500 MHz) δ 7.58 (s, 1H), 7.53 (s, 1H), 7.31-7.35 (m, 3H), 7.22-7.26 (m, 1H), 7.08-7.11 (m, 2H), 4.49 (s, 2H), 3.43 (s, 2H), 2.86-2.90 (m, 2H), 2.71-2.75 (m, 2H), 2.52 (s, 3H), 2.17-2.20 (m, 2H), 1.84-1.87 (m, 2H). 13C-NMR (CDCl3, 126 MHz) δ 151.5, 143.9, 143.1, 134.5, 136.6 (q, J=33.6 Hz), 128.7, 128.3, 127.2, 126.3, 127.7, 125.1 (q, J=272.6 Hz), 120.4, 80.6, 71.3, 42.6, 41.9, 33.6, 33.3. Mass spec.: 432.22 (MH)+.
Reaction SMILES: [CH2:1]([N:4]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:5]([C:7]1[CH:26]=[CH:25][C:10]2[N:11]([CH3:24])[C:12]([CH2:14][NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=3)=[N:13][C:9]=2[CH:8]=1)=[O:6])[C:2]#[CH:3].[ClH:34].C(O)C.C(=O)([O-])[O-].[NH4+:42].[NH4+]>ClCCl.C(O)C>[ClH:34].[CH2:1]([N:4]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:5]([C:7]1[CH:26]=[CH:25][C:10]2[N:11]([CH3:24])[C:12]([CH2:14][NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22](=[NH:42])[NH2:23])=[CH:18][CH:17]=3)=[N:13][C:9]=2[CH:8]=1)=[O:6])[C:2]#[CH:3]
Reactant: [NH4+]
Reactant: C#CCN(CCC(=O)OCC)C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: C#CCN(CCC(=O)OCC)C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C
Yield: 81 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-propargyl-N-(2-ethoxycarbonylethyl)amide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 81% of theory, C25H28N6O3 (460.6); Rf value: 0.094 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=461; (M+H+Na)++=242; (M+2H)++=231.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:10]=[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[O:26])=[CH:21][CH:20]=3)[C:12]([C:15]([NH2:17])=[O:16])=[N:13][CH:14]=2)[CH2:4]1.CCN(C(C)C)C(C)C.[C:42]([C:46]1[CH:54]=[CH:53][C:49]([C:50](Cl)=[O:51])=[CH:48][CH:47]=1)([CH3:45])([CH3:44])[CH3:43]>CN1C(=O)CCC1.CCOC(C)=O>[C:42]([C:46]1[CH:47]=[CH:48][C:49]([C:50]([NH:2][C@@H:3]2[CH2:8][CH2:7][CH2:6][N:5]([C:9]3[N:10]=[C:11]([NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[O:26])=[CH:23][CH:24]=4)[C:12]([C:15]([NH2:17])=[O:16])=[N:13][CH:14]=3)[CH2:4]2)=[O:51])=[CH:53][CH:54]=1)([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: NC(=O)c1ncc(N2CCC[C@@H](N)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(C(=O)N[C@@H]2CCCN(c3cnc(C(N)=O)c(Nc4ccc(C(=O)N5CCOCC5)cc4)n3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To a solution of (R)-5-(3-aminopiperidin-1-yl)-3-(4-(morpholine-4-carbonyl)phenylamino)pyrazine-2-carboxamide hydrochloride (90) (120 mg, 0.27 mmol) in NMP (3 mL) was added DIEA (190 μL, 1.08 mmol) and then 4-tert-butylbenzoyl chloride (106 mg, 0.54 mmol). The mixture was stirred at RT for 1 h, diluted with 100 mL EtOAc, washed with water ×2, dried, and concentrated in vacuo. The residue was subjected to flash column chromatography with 0 to 5% MeOH in DCM to isolate the title compound (91) (yield 114 mg). MS found for C32H39N7O4 as (M+H)+ 586.2, (M−H)− 584.3. UV: λ=259, 276, 286, 314, 344, 369 nm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[C:20](I)[CH:21]=3)[N:16]=[CH:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(NC(C)C)(C)C.[CH2:34]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[C:35]#[CH:36]>CN(C)C=O.CCOC(C)=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:36]#[C:35][CH2:34][N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)[CH:21]=3)[N:16]=[CH:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCN1CCOCC1
Reactant: CC(C)(C)OC(=O)c1ccc(Cn2cnc3ccc(I)cc3c2=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(Cn2cnc3ccc(C#CCN4CCOCC4)cc3c2=O)cc1
Temperature: 50 °C

Procedure:
To a solution of 300 mg (0.648 mmol) of 4-(6-iodo-4-oxo-4H-quinazolin-3-ylmethyl)-benzoic acid tert-butyl ester (preparation described above) in 50 mL of dimethylformamide (“DMF”), was added diisopropylamine (4 mol eq.), a catalytic amount of CuI, 4-prop-2-ynyl-morpholine (4 mol eq.), and Pd(PPh3)2Cl2 (a catalytic amount). The reaction mixture was then heated to 50° C. for 15 hours. The reaction was then diluted with 200 mL of EtOAc, and washed with 2×200 mL water, and 1×200 mL brine. The organic layer was dried over MgSO4 and concentrated. The residue was then passed through a silica gel column, elution with 4:1 EtOAc:tetrahydrofuran (“THF”). The product is carried directly to the next step.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[C:15]([NH2:27])=[N:16][CH:17]=[C:18]([C:20]3=[CH:21][CH2:22][NH:23][CH2:24][CH2:25][CH2:26]3)[CH:19]=2)=[N:12][N:11]=[N:10]1.C(Cl)CCl.[F:32][C:33]([F:38])([F:37])[C:34](O)=[O:35].CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:27][C:15]1[N:16]=[CH:17][C:18]([C:20]2[CH2:26][CH2:25][CH2:24][N:23]([C:34](=[O:35])[C:33]([F:38])([F:37])[F:32])[CH2:22][CH:21]=2)=[CH:19][C:14]=1[C:13]1[N:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[N:10]=[N:11][N:12]=1
Reactant: Nc1ncc(C2=CCNCCC2)cc1-c1nnnn1-c1cccc(F)c1F
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Nc1ncc(C2=CCN(C(=O)C(F)(F)F)CCC2)cc1-c1nnnn1-c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
3-(1-(2,3-Difluorophenyl)-1H-tetrazol-5-yl)-5-((E)-2,5,6,7-tetrahydro-1H-azepin-4-yl)pyridin-2-amine (37 mg, 100 μmol, 1 eq.) was diluted in DCM (1.5 mL). EDC (34.4 mg, 150 μmol, 1.5 eq.), trifluoroacetic acid (17.1 mg, 150 μmol, 1 eq.), and DIEA (53 μL, 300 μmol, 3 eq.) were added. The reaction was stirred at room temperature overnight then concentrated. The product was purified by reversed-phase HPLC purification to give 1-((E)-5-(6-amino-5-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)pyridin-3-yl)-3,4-dihydro-2H-azepin-1(7H)-yl)-2,2,2-trifluoroethanone (13.6 mg, 30% yield); 1H NMR (300 MHz, DMSO-d6): 8.25 (m, 1H); 7.87 (m, 1H); 7.77 (m, 1H); 7.55 (m, 1H); 7.37 (m, 1H); 5.95-5.7 (m, 1H); 4.12 (m, 2H); 3.75-3.6 (m, 2H); 2.4 (m, 2H); 1.75 (m, 2H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[O:15][CH3:16])#[N:2].IC.[CH2:19](N(CC)CC)C>C(O)C.O>[C:1]([CH2:3][CH2:4][CH2:5][N:6]([CH3:19])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[O:15][CH3:16])#[N:2]
Reactant: COc1ccc(OC)c(NCCCC#N)c1
Reactant: CCN(CC)CC
Solvent: CCO
Solvent: CI
Solvent: O
Product: COc1ccc(OC)c(N(C)CCCC#N)c1
Temperature: 50 °C
Yield: 52 %

Procedure:
To a stirred solution of N-(3-cyanopropyl)-2,5-dimethoxyaniline (46.2 g; 0.22 mol) in absolute ethanol (400 ml) were added iodomethane (47.7 g; 0.34 mol) and triethylamine (34.0 g; 0.34 mol). After stirring at 50° C. for 24 hours a further portion of iodomethane (47.7 g; 0.34 mol) was added to the reaction mixture, which was then heated at 50° C. for a further 24 hours. The reaction mixture was then cooled, diluted with water (500 ml) and extracted with dichloromethane (3×200 ml) and washed with water (2×400 ml). The resulting organic extract was dried (MgSO4), the solvent was then removed under reduced pressure to give a brown oil. The crude product was purified by flash chromatography, eluting first with hexane and subsequently increasing the polarity with dichloromethane. This procedure afforded the product as a colourless oil (26.8 g; 54%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:18](Br)[CH:19]1[O:23][CH2:22][CH2:21][CH2:20]1.O>CN1CCCC1=O>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([O:1][CH2:18][CH:19]2[CH2:20][CH2:21][CH2:22][O:23]2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: BrCC1CCCO1
Reactant: COc1cc(O)ccc1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc(OCC2CCCO2)ccc1C=O
Temperature: 80 °C
Reaction time: 22 h
Yield: 62.3 %

Procedure:
In 160 mL of N-methylpyrrolidone was dissolved 24.5 g (161 mmol) of 4-hydroxy-2-methoxybenzaldehyde. To this solution were added 63 g (0.19 mol) of cesium carbonate and 40 g (0.24 mol) of tetrahydrofurfuryl bromide at room temperature and the mixture was stirred at 80° C. for 22 hours. Water (800 mL) was added to the resulting reaction mixture under ice-cooling, and extraction with diethyl ether (500 mL×3 times) was performed. The combined organic layer was washed with water and then with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The resulting crude product was purified on basic alumina (hexane/ethyl acetate=50/50 to 0/100) to give 23.7 g (62% yield) of the title compound as a light yellow powder with the following properties.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[C:16]2[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1.[Cl:23][C:24]1[C:29]([C:30](O)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:26][CH:25]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[C:29]([C:30]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[N:10]=[CH:9][CH:8]=[C:7]3[O:6][C:5]2[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=2)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:26][CH:25]=1
Reactant: Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)ccnc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4cccc(C(F)(F)F)c4)ccnc23)c1F
Yield: 21.3 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-(3-(trifluoromethyl)phenoxy)quinolin-8-amine (Intermediate-11, 100 mg, 0.327 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 200 mg, 0.699 mmol), oxalyl chloride (125 mg, 0.99 mmol), DMF (1 drop) and DIPEA (126 mg, 0.98 mmol) in CH2Cl2 (5 mL) to afford 40 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.77 (s, 1H), 8.79 (d, J=8.7 Hz, 1H), 8.73 (d, 1H), 8.17 (br t, 1H), 8.08 (d, J=8.7 Hz, 1H), 7.78-7.67 (m, 5H), 7.41-7.35 (m, 2H), 6.83 (d, 1H), 4.32 (d, 2H), 1.14 (s, 9H); MS [M+H]+: 574.31.
Reaction SMILES: [CH:1]([N:4]1[C:8](=[O:9])[CH2:7][NH:6][C:5]1=[O:10])([CH3:3])[CH3:2].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:13][N:14]([CH:16]=[C:7]1[NH:6][C:5](=[O:10])[N:4]([CH:1]([CH3:3])[CH3:2])[C:8]1=[O:9])[CH3:15]
Reactant: CC(C)N1C(=O)CNC1=O
Reactant: COC(OC)N(C)C
Product: CC(C)N1C(=O)NC(=CN(C)C)C1=O
Temperature: 100 °C

Procedure:
A mixture of 5 g of 3-isopropylimidazolidine-2,4-dione and 5 ml dimethylformamide dimethylacetal were heated at 100° C. for 3 s. The reaction mixture was cooled to rt and purified by flash chromatography to give 2 g of an orange solid. 1H NMR (400 MHz, deuteriochloroform): δ=1.42 (6H, d, J=7 Hz), 3.11 (6H, s), 4.40 (1H, septet, J=7 Hz), 6.64 (1H, s), 9.55 (1H, br s).
Reaction SMILES: [Br-].Br[CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:23][C:24]1[N:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]([CH3:31])=[CH:27][C:28]=1[CH:29]=O.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:23][C:24]1[N:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]([CH3:31])=[CH:27][C:28]=1[CH:29]=[CH2:3]
Reactant: BrC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C=O)c(C)n1-c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=Cc1cc(C)n(-c2ccccc2)c1C
Yield: 80 %

Procedure:
To a solution of bromomethyl(triphenyl)phosphonium bromide (2.2 g, 5 mmol) in dry THF (50 mL), n-Bu.Li (2.5 M, 2 mL, 5 mmol) was added dropwise at −78° C. under nitrogen. The reaction mixture was stirred 30 min at this temperature and compound 5 (1.0 g, 5 mmol) was added, then the cooling bath was removed. Stirring was continued for another hour. The solvent was completely removed under reduced pressure. The residue and Pd(OAc)2 (56 mg, 0.25 mmol), Na2CO3 (1.86 g, 17.5 mmol), n-Bu4NCl (8.34 g, 30 mmol) were dissolved in dried DMF (20 mL). The reaction mixture was stirred at 100° C. for 3 hrs. The reaction was quenched by adding 20 mL of water, and the aqueous phase was extracted with EtOAc (30 mL×3). The combined extracts were dried over Na2SO4, the mixture was filtered and the filtrate was concentrated in vacuo to give the desired product as a colorless oil (Purity: 90%, yield: 80%). MS [M++1]=198, LC-MS: tR=2.76 min.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[CH2:12]([O:14][C:15]([C:17]1[S:21][C:20]([NH2:22])=[N:19][C:18]=1[CH3:23])=[O:16])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]([C:17]1[S:21][C:20]2=[N:22][C:3]([C:5]3[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=3)=[CH:2][N:19]2[C:18]=1[CH3:23])=[O:16])[CH3:13]
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: CCOC(=O)c1sc(N)nc1C
Solvent: CCO
Product: CCOC(=O)c1sc2nc(-c3ccc(F)cc3)cn2c1C
Temperature: 95 °C
Yield: 28.9 %

Procedure:
2-Bromo-1-(4-fluoro-phenyl)-ethanone (200 mg, 0.92 mmol) and 2-amino-4-methyl-thiazole-5-carboxylic acid ethyl ester (186.2 mg, 0.92 mmol) were heated in 5 ml of ethanol at 95° C. for 5 hours. After addition of 80 mg of 2-bromo-1-(4-fluoro-phenyl)-ethanone and further heating for 9 hours at 95° C. the mixture was evaporated. Addition of potassium hydrogensulfate solution, extraction with ethyl acetate and purification by preparative HPLC (RP18, acetonitrile/water 0.1% TFA) yielded 81 mg (32%) of the desired product. MS (mass spectrum): M+H+=305.07.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.CN.ClCCl.[CH2:20]([N:22](CC)CC)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:22][CH3:20])=[O:5]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 60 h

Procedure:
A mixture of 2-chloro-5-nitro-benzoyl chloride (502 mg, 2.3 mmol), methylamine hydrochloride (213 mg, 3.1 mmol), dichloromethane (10 ml), and triethylamine (0.84 ml, 6.0 mmol) was stirred for 60 hours. The mixture was treated with ethyl acetate (25 ml). The solution was washed with a mixture of saturated aqueous sodium chloride solution and 1 M hydrochloric acid (1:1, 2×20 ml), washed with aqueous sodium carbonate solution (1 M, 20 ml), dried over sodium sulfate, and concentrated under reduced pressure to provide 2-chloro-N-methyl-5-nitro-benzamide.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH3:9])[CH:3]=1.[Br:10]N1C(=O)CCC1=O>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][NH:5][C:4]([Br:10])([CH3:9])[CH:3]=1
Reactant: Cc1cc(Cl)c(F)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClCCCl
Product: CC1(Br)C=C(Cl)C(F)=CN1
Temperature: 75 °C
Yield: 69 %

Procedure:
4-Chloro-5-fluoro-2-picoline (2.9 g, 20 mmol), the product of Example 66, was dissolved in 50 mL of 1,2-dichloroethane in a dry flask. The resultant solution was heated, with stirring, to 75° C. and 4.09 (23 mmol) of N-bromosuccinimide was added, followed by 100 mG (0.7 mmol) of 2,2-azobisisobutyronitrile (AIBN), a free radical initiator. After the reaction mixture was stirred at 75° C. for 24 hours, it was diluted with 450 mL of methylene chloride and washed with 3×400 mL of water. The organic layer was separated and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dried in vacuo to give 3.5 g (69% yield) of the title compound as an amber oil; 1H NMR (CDCl3) d 4.50 (s, 2H), 7.54 (d, 1H), 8.44 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]3[O:12][CH2:13][O:14][C:8]3=[CH:7][C:6]=2[N:5]=[CH:4][N:3]=1.[C:15]([C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])#[CH:16]>C(O)(C)C>[O:12]1[C:9]2=[CH:10][C:11]3[C:2]([NH:20][C:19]4[CH:21]=[CH:22][CH:23]=[C:17]([C:15]#[CH:16])[CH:18]=4)=[N:3][CH:4]=[N:5][C:6]=3[CH:7]=[C:8]2[O:14][CH2:13]1
Reactant: Clc1ncnc2cc3c(cc12)OCO3
Reactant: C#Cc1cccc(N)c1
Solvent: CC(C)O
Product: C#Cc1cccc(Nc2ncnc3cc4c(cc23)OCO4)c1
Temperature: 25 °C
Yield: 88.4 %

Procedure:
A mixture of 8-chloro-[1,3]dioxolo[4,5-g]quinazoline (0.200 g, 1.04 mmol) and 3-ethynylaniline (0.127 g, 1.09 mmol) in 5 mL isopropanol was heated to reflux overnight, then cooled to ambient temperature. Precipitate was collected and washed to give [1,3]dioxolo[4,5-g]quinazolin-8-yl-(3-ethynyl-phenyl)-amine (0.266 g, 78%): mp greater than 350° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[C:10]([CH2:13][CH:14]([NH2:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Cl:27][C:28]([Cl:35])([Cl:34])[CH2:29][O:30][C:31](Cl)=[O:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[C:10]([CH2:13][CH:14]([NH:20][C:31]([O:30][CH2:29][C:28]([Cl:35])([Cl:34])[Cl:27])=[O:32])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C(N)CC1=CCN(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(CC1=CCN(C(=O)OC(C)(C)C)C1)NC(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Yield: 92.8 %

Procedure:
To an ice-cooled solution of 214 mg (0.75 mmol) 3-(2-amino-2-ethoxycarbonyl-ethyl)-2,5-dihydropyrrole-1-carboxylic acid tert.-butylester and 119 mg (1.5 mmol) pyridine in 2 ml methylene chloride was added a small amount of DMAP followed by 212 mg (1mmol) 2,2,2-trichloroethoxycarbonyl chloride. The mixture was allowed to warm to room temperature overnight. The mixture was diluted with ether, washed with water, sat. CuSO4, water and brine, dried over MgSO4 and evaporated. Purification of the residue by flash-chromatography (elution with petrol ether/ethyl acetate 3:1) gave 320 mg (93%) 3 -[2-(2,2,2-trichloroethoxycarbonyl-amino)-2-ethoxycarbonyl-ethyl]-2,5-dihydropyrrole-1-carboxylic acid tert.-butylester as a colorless oil, which was immediately used for the next step.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].[Cl-].[CH:14](=[N+:21]([CH3:23])[CH3:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:22][N:21]([CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[C:10]([OH:12])=[O:11])[CH3:23]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: C[N+](C)=Cc1ccccc1
Agent: [Cl-]
Product: CN(C)C(c1ccccc1)c1c(C(=O)O)[nH]c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1H-indole-2-carboxylic acid and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 1.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[OH:14][C:15]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([NH:6][C:7]([NH:28][C:27]1[CH:26]=[CH:25][C:24]([C:15]([OH:14])([C:16]([F:17])([F:18])[F:19])[C:20]([F:21])([F:22])[F:23])=[CH:30][CH:29]=1)=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 50 °C
Yield: 88.2 %

Procedure:
0.055 mole of 2,6-difluorobenzoyl isocyanate is dripped into 0.05 mole of 4-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoroethyl)-aniline in 150 ml of absolute toluene. The temperature rises to 27° C. The mixture is heated for 3 hours at 50° C. and then filtered while hot, and the filter cake is dried under reduced pressure at 50° C. There is obtained 19.5 g (95% of theory) of N-(2,6-difluoro-benzoyl)-N'-[4-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoroethyl)-phenyl]-urea; m.p.: 205°-207° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[C:14](OS(C(F)(F)F)(=O)=O)[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[N:11][N:10]=1.[CH2:30]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[C:31]#[CH:32]>[Cu]I.C(NCC)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[C:14]([C:32]#[C:31][CH2:30][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[N:11][N:10]=1
Reactant: C#CCN1CCOCC1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1OS(=O)(=O)C(F)(F)F
Agent: [Cu]I
Solvent: CCNCC
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1C#CCN1CCOCC1
Yield: 38.5 %

Procedure:
Operating analogously to what described in example 74 starting from trifluoro-methanesulfonic acid 1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazin-5-yl ester (2 g, 4.27 mmoles), prepared as described in example 73, 4-prop-2-ynyl-morpholine (640 mg, 5.12 mmoles), prepared as described in example 137, diethylamine (40 ml), bis(triphenylphosphine)PdCl2 (60 mg, 0.0854 mmole) and CuI (16 mg, 0.0854 mmole), 728 mg of the title compound were obtained (yield: 38.6%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][C:14](=[O:28])[C@:15]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)([OH:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)=O)(C)(C)C.[ClH:29].CCOC(C)=O>O1CCOCC1>[ClH:29].[NH:8]1[CH2:12][CH2:11][C@@H:10]([O:13][C:14](=[O:28])[C@:15]([CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)([OH:22])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OC(=O)[C@](O)(c2ccccc2)C2CCCC2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(O[C@@H]1CCNC1)[C@](O)(c1ccccc1)C1CCCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(R)-3-((R)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy)pyrrolidine-1-carboxylic acid t-butyl ester (50 g) was dissolved in 150 ml of 1,4-dioxane. The solution was cooled to 0° C., then 75 ml of 4N HCl in 1,4-dioxane was slowly added. The mixture was stirred overnight at room temperature. The solution was concentrated to 100 ml, followed by the addition of 200 ml EtOAc. The solution was heated at 50° C. for 15 minutes, and allowed to cool to room temperature and stand for 72 hours. The white solid precipitate was isolated by filtration, and the isolated solid added to 100 ml EtOAc, stirred for half hour then filtered again to yield the title compound as a white solid (13 g).