Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH:12]1([C:17]#[N:18])[CH2:16][CH2:15][CH2:14][CH2:13]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1(C)C=CC=CC=1>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:12]2([C:17]#[N:18])[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:3][CH:4]=1
Reactant: N#CC1CCCC1
Reactant: Fc1ccc(C(F)(F)F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#CC1(c2ccc(C(F)(F)F)cc2)CCCC1
Temperature: 70 °C
Reaction time: 14 h
Yield: 103.3 %

Procedure:
To a stirred solution of 4-fluorobenzotrifluoride (5.0 g, 30.47 mmol) in toluene (40 mL) was added cyclopentanecarbonitrile (10.5 mL, 100.55 mmol) followed by a solution of 0.5 M KHMDS in toluene (92 mL, 45.71 mmol). The reaction mixture was heated to 70° C. and stirred for 14 hours. After cooling to RT, the reaction mixture was quenched with 1 M HCl until pH<7. The layers were separated and the organic layer was washed with saturated NaHCO3, water, brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification via silica gel chromatography (6:1 hexanes:EtOAc) afforded 7.53 g of a mixture of compound A and residual cyclopentanecarbonitrile. Because these two compounds were not easily separable by chromatography, this mixture was carried directly to the next step.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:4][C:5]([O:8]C)=[CH:6][CH:7]=1.[I-].[Na+].[Si](Cl)(C)(C)C>C(#N)C.CCOC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[N:4][C:3]=1[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: COc1ccc(F)c(NCC2CCOCC2)n1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1ccc(F)c(NCC2CCOCC2)n1
Temperature: 95 °C
Reaction time: 20 h

Procedure:
To a solution of 3-fluoro-6-methoxy-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (4.6 g, 19.14 mmol) in acetonitrile (50 mL) was added sodium iodide (20.09 g, 134 mmol) and TMS-chloride (17.13 mL, 134 mmol). The resulting mixture was stirred at about 95° C. for 20 hr. The reaction mixture was cooled to ambient temperature and then diluted with EtOAc (80 mL) and water (40 mL). The diluted mixture was stirred vigorously for about 30 min. The organic layer was separated and washed with 0.1N aqueous HCl solution. The combined aqueous layers were carefully neutralized (pH ˜7) with solid NaHCO3 solution and extracted with EtOAc (1×100 mL) and DCM (2×50 mL). The combined organic layers were washed with saturated aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, 80 g, EtOAc/heptane=10/90 for 2 min, EtOAc/heptane=10/90 to 100/0 over 23 min, then EtOAc/heptane=100/0] providing 5-fluoro-6-((tetrahydro-2H-pyran-4-yl)methyl)aminopyridin-2-ol as a highly viscous oil which turned to purple upon standing at room temperature. Yield: 780 mg. LCMS (m/z): 227.1 [M+H]+; Retention time=0.42 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH2:22])[C:16]=3[C:15]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)=[CH:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:43])C(=O)C1>C(Cl)Cl>[NH2:22][C:21]1[C:16]2[C:15]([C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:27][CH:28]=3)=[C:14]([Br:43])[N:13]([C@@H:10]3[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]3)[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](n2c(Br)c(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a solution of (R)-tert-butyl 3-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (2) (330 mg, 0.70 mmol) in DCM (10.0 mL) was added NBS (124 mg, 0.70 mmol). After the mixture was stirred at r.t. for 30 min, the reaction solution was partitioned between DCM (20.0 mL) and water (20.0 mL). The layers were separated and the organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain the product (R)-tert-butyl 3-(4-amino-6-bromo-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (9) (375 mg, 98% yield) as a brown solid. LC-MS (ESI): m/z (M/M+2) 550.1/552.1.
Reaction SMILES: C(Cl)(Cl)Cl.[F:5][C:6]([F:24])([F:23])[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[C:18]([OH:19])=[C:17]([C:20]([CH3:22])=[O:21])[CH2:16][S:15]2)=[CH:10][CH:9]=1.S(Cl)(Cl)(=O)=O>O>[F:24][C:6]([F:5])([F:23])[O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[S:15][CH:16]=[C:17]([C:20]([CH3:22])=[O:21])[C:18]=2[OH:19])=[CH:12][CH:13]=1
Reactant: CC(=O)C1=C(O)C(c2ccc(OC(F)(F)F)cc2)SC1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: O=S(=O)(Cl)Cl
Product: CC(=O)c1csc(-c2ccc(OC(F)(F)F)cc2)c1O
Temperature: -15 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
A chloroform (45 mL) solution of 2-(4-trifluoromethoxyphenyl)-3-hydroxy-4-methylcarbonyl-2,5-dihydrothiophene (4.5 g, 12.6 mmol, purity: 85%) was cooled to −5° C., and to this solution, a chloroform (90 mL) solution of sulfuryl chloride (1.1 mL, 1.1 equivalent amounts) was dropwise added over a period of 30 minutes, followed by stirring at −15° C. for 1 hour. The temperature of the solution was raised to 0° C., and water (11 mL) was dropwise added, followed by liquid separation. The obtained chloroform solution was sequentially washed with water, a saturated salt solution, a sodium hydroxide aqueous solution, a saturated sodium thiosulfate aqueous solution and a saturated salt solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give the desired product as a yellow solid (3.15 g, yield: 83%).
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14](N)[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].N1C=CN=C1.[C:25]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26].CN(C)C=[O:36]>>[Si:29]([O:8][CH2:7][C@H:6]1[O:9][C@@H:1]([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([OH:36])[C:13]=3[N:12]=[CH:11]2)[C@H:2]([OH:3])[C@@H:4]1[OH:5])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:31])[CH3:30]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.7 %

Procedure:
A mixture of inosine 13 (15.0 g, 56 mmol) (dried by coevaporation with 70 ml of dimethylformamide (DMF)), imidazole (9.52 g, 140 mmol) and tertbutyldimethylsilyl chloride (10.1 g, 67 mmol) in DMF (125 ml) was stirred at room temperature for 12 h. The solvent was removed in vacuo and the residue was purified chromatographically using CHCl3 -methanol (15:2) as the eluent to obtain 16.4 g (76.7%) of 18: mp softening at 220° C., melting at 229°-231° C. (CHCl3 -diethyl ether); 1H NMR (DMSO-d6) δ 0.0 (6H, s, (CH3)2Si), 0.82 (9H, s, (CH3)3CSi), 3.52-4.00 (3H, m, 4' and 5'-H), 4.10 (1H, t, J=4.8 Hz, 2'(3')-H), 4.41 (1H, t, J=4.8 HZ, 3'(2')-H), 5.83 (1H, d, J=5.3 HZ, 1'-H), 8.00 (1H, s, 8-H), 8.18 (1H, s, 2-H).
Reaction SMILES: C([O:5][C:6]([NH:8][NH:9][C:10](=O)[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]([C:22](=[O:42])[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]2[CH:31]=[N:32][C:33]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:35]=2[C:36]#[N:37])[CH:24]=1)[CH3:21])=[O:7])(C)(C)C.CCN(C(C)C)C(C)C.C(Cl)(Cl)=O>Cl.O1CCOCC1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([N:20]([CH3:21])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH2:12][CH2:11][C:10]2[O:7][C:6](=[O:5])[NH:8][N:9]=2)=[O:42])=[CH:24][C:25]=1[C:30]1[CH:31]=[N:32][C:33]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:35]=1[C:36]#[N:37]
Reactant: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCCC(=O)NNC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C(Cl)Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCCc1n[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.1 %

Procedure:
N′-[3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionyl]-hydrazinecarboxylic acid tert-butyl ester (40.1 mg, 0.065 mmol) was stirred in 4N HCl in dioxane (5 mL) for 2 hrs and was concentrated. The residue was suspended in toluene (5 mL) containing DIPEA (25.2 mg, 0.19 mmol). Phosgene (20% in toluene, 8.2 μL, 0.077 mmol) was added and the mixture was stirred at rt for 24 hrs. The mixture was concentrated and purified via reverse phase preparative LCMS to give 4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methyl-N-{2-[2-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-ethoxy]-phenyl}-benzamide 31-1 (17 mg). MS [M+H]+: 544.1; tR=5.11 min. (method 3)
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][N:5]([CH3:8])[C:4](=[O:9])[C:3]=1[NH:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[CH2:15][CH2:14]1.[CH3:27][O-:28].[Na+]>CO>[CH3:27][O:28][C:2]1[CH:7]=[N:6][N:5]([CH3:8])[C:4](=[O:9])[C:3]=1[NH:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[CH2:15][CH2:14]1
Reactant: C[O-]
Reactant: COc1ccccc1N1CCN(CCNc2c(Cl)cnn(C)c2=O)CC1
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1N1CCN(CCNc2c(OC)cnn(C)c2=O)CC1

Procedure:
4.2 g (0.011 mol) of 5-chloro-2-methyl-4-((2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)amino)-3(2H)-pyridazinone are heated in methanol, in which 0.010 mol of sodium methylate is dissolved, under reflux for 50 hours and then concentrated in vacuo. The residue is taken up in water, when 1.6 g of 5-methoxy-2-methyl-4-((2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)amino)-3(2H)-pyridazinone (38.9% of theory) precipitate out. The solid is filtered off with suction, dried, dissolved in acetone and converted by addition of fumaric acid at the reflux temperature into 1.50 g (24.5% of theory) of fumarate, m.p. 144°-148° C.; C 54.0%, H 6.1%, N 12.5%, O 27.4%, UV in 0.1N H
Reaction SMILES: [C:1](=[N:23]O)([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[N:21]O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.N.[Ni]>[NH2:21][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([CH:1]([NH2:23])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: ON=C(c1ccccc1)c1ccc(C(=NO)c2ccccc2)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NC(c1ccccc1)c1ccc(C(N)c2ccccc2)cc1

Procedure:
The dioxime from Step 2 (30 g) is dissolved in ethyl alcohol (300 ml), saturated with ammonia gas and Raney nickel catalyst W-6 (2 g) added. The mixture is subjected to 700 psi hydrogen pressure and heated at 70° for 3 hours. The catalyst is removed by filtration and 220 ml of ethanol is removed by distillation. The pale yellow precipitate is filtered and dried. Yield 28 g (91% of theory) mp 123°-7° .
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[S:9][CH:10]=1)(=[O:5])[CH3:4].Br>C(Cl)(Cl)Cl>[Br:1][CH2:4][C:3]([C:6]1[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[S:9][CH:10]=1)=[O:5]
Reactant: BrBr
Reactant: COC(=O)c1cc(C(C)=O)cs1
Agent: Br
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(C(=O)CBr)cs1
Temperature: 40 °C
Yield: 63 %

Procedure:
Following the procedure of Japan Kokai Tokkyo Koho JP 60 11,487 CA 103:22580m (1985), a solution of bromine (4.29 g, 26.87 mmoles) in 40 ml of chloroform was added dropwise to a stirred solution of methyl 4-acetyl-2-thiophenecarboxylate, prepared according to Example 15 (4.95 g, 26.87 mmoles) in 150 ml of chloroform containing four drops of 50% (v/v) 48% hydrobromic acid/glacial acetic acid. After 10 minutes at 40° C. the solution was cooled to room temperature, concentrated in vacuo and the residue triturated with methanol (25 ml). Filtration furnished an off-white solid (4.96 g, 63%), m.p. 112°-4° C. EIMS (m/z): 264/262 (M+, 11%), 233/231 (M+ --CH3O, 11%), 171/169 (M+ --CH2Br, base); 1HNMR (CDCl3) delta, 8.31 (1H, d, J=1.5 Hz), 8.17 (1H, d, J=1.5 Hz), 4.29 (2H, s), 3.90 (3H, s).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[CH:13]=1.Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C>C(O)CCC.C(OCC)(=O)C>[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][N:9]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=[CH:17][CH:16]=3)[CH2:8][C:7]=2[CH:13]=1
Reactant: Clc1ccnc2ccccc12
Reactant: Brc1ccc2c(c1)CNCCO2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Brc1ccc2c(c1)CN(c1ccnc3ccccc13)CCO2
Yield: 84.4 %

Procedure:
A solution of 7-bromo-2,3,4,5-tetrahydro-1,4-benzoxazepine hydrochloride (1.50 g, 5.67 mmol) (example 2, step 1), 4-chloroquinoline (0.973 g, 5.95 mmol), diisopropylethylamine (2.93 g, 22.7 mmol) in 1-butanol (15 mL) was stirred at 170° C. for 1 hour in a microwave synthesizer. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate (50 mL) and brine (50 mL), dried over sodium sulfate. Filtration and concentration afforded a crude brown oil that was purified by silica gel chromatography (9:1 dichloromethane/methanol) to provide 7-bromo-4-quinolin-4-yl-2,3,4,5-tetrahydro-1,4-benzoxazepine (1.70 g, 84.6% yield) as a yellow oil. MS (EI) for C18H15BrN2O: 356 (MH+).
Reaction SMILES: [OH-].[Na+:2].[CH3:3][S:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:9]=[CH:8]2>CO>[CH3:3][S:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:15]([CH3:19])[C:16]([O-:18])=[O:17])[CH:9]=[CH:8]2.[Na+:2]
Reactant: CSc1ccc2cc(C(C)C(=O)O)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSc1ccc2cc(C(C)C(=O)[O-])ccc2c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a mixture of 4 g. of sodium hydroxide and 500 ml. of methanol are added 24.6 g. of 6-methylthio-2-naphthyl-α-methylacetic acid. The mixture is stirred for 18 hours at 50°C. The cooled mixture is then evaporated to give sodium 6-methylthio-2-naphthyl-α-methylacetate.
Reaction SMILES: C[N:2]1CCN(C2C=CC(NC3C4N(C=CN=4)C(C4SC=C(C(N)=O)C=4)=CN=3)=CC=2)CC1.C(OC(=O)[N:38]([C:61]1[CH:66]=[CH:65][C:64]([N:67]2[CH2:72][CH2:71][N:70]([CH3:73])[CH2:69][CH2:68]2)=[CH:63][CH:62]=1)[C:39]1[C:40]2[N:41]([CH:58]=[CH:59][N:60]=2)[C:42]([Sn](CCCC)(CCCC)CCCC)=[CH:43][N:44]=1)(C)(C)C.C(OC([N:82]1[C:86]([C:87]([F:90])([F:89])[F:88])=[C:85](Br)[CH:84]=[N:83]1)=O)(C)(C)C.C(Cl)Cl>CN(C=O)C.C(O)(C(F)(F)F)=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>[NH3:2].[CH3:73][N:70]1[CH2:71][CH2:72][N:67]([C:64]2[CH:65]=[CH:66][C:61]([NH:38][C:39]3[C:40]4[N:41]([CH:58]=[CH:59][N:60]=4)[C:42]([C:85]4[C:86]([C:87]([F:90])([F:89])[F:88])=[N:82][NH:83][CH:84]=4)=[CH:43][N:44]=3)=[CH:62][CH:63]=2)[CH2:68][CH2:69]1
Reactant: CN1CCN(c2ccc(Nc3ncc(-c4cc(C(N)=O)cs4)n4ccnc34)cc2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(N(C(=O)OC(C)(C)C)c2ccc(N3CCN(C)CC3)cc2)c2nccn12
Reactant: CC(C)(C)OC(=O)n1ncc(Br)c1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCN(c2ccc(Nc3ncc(-c4c[nH]nc4C(F)(F)F)n4ccnc34)cc2)CC1
Product: N
Yield: 1 %

Procedure:
In the same way as described for Compound 145, step 2 using [4-(4-methyl-piperazin-1-yl)-phenyl]-(5-tributylstannanyl-imidazo[1,2-a]pyrazin-8-yl)-carbamic acid tert-butyl ester (0.38 g, 0.78 mmol) in DMF (6mL), 4-bromo-5-trifluoromethyl-pyrazole-1-carboxylic acid tert-butyl ester (0.49 g, 0.15 mmol) and Pd(PPh3)4 (0.09 g, 0.15 mmol). The crude mixture is stirred in (1:1) TFA:DCM (2 mL) at room temperature for 3 hours. Purification by silica gel column chromatography eluting with DCM followed by a mixture of 99:1 and 95:5 DCM:NH3 (7M in MeOH) affords the title compound (2.79 mg, 1%). LCMS: Rt 1.90 min (96%) m/z (ES+) 443 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.26 (3H, s), 2.49-2.54 (4H, m), 3.09-3.14 (4H, m), 6.96 (2H, d), 7.31 (1H, s), 7.63 (2H, d), 7.89 (2H, d), 8.37 (1H, s), 9.44 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:18][CH3:19])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][CH2:13][O:14][CH3:15])[CH2:9][C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])[C:24]([Cl:38])=[CH:23][N:22]=1>>[Cl:38][C:24]1[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])=[N:26][C:21]([NH:1][C:2]2[C:3]([O:18][CH3:19])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][CH2:13][O:14][CH3:15])[CH2:9][C:8](=[O:16])[NH:7][C:6]=3[CH:17]=2)=[N:22][CH:23]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: COCCN1CC(=O)Nc2cc(N)c(OC)cc2C1
Product: COCCN1CC(=O)Nc2cc(Nc3ncc(Cl)c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)n3)c(OC)cc2C1
Yield: 15.2 %

Procedure:
In an analogous manner to procedure 1656g, 8-amino-7-methoxy-4-(2-methoxy-ethyl)-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (80 mg, 0.30 mmol) and (1S,2S,3R,4R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (90 mg, 0.30 mmol) were coupled to afford (1S,2S,3R,4R)-3-{5-chloro-2-[7-methoxy-4-(2-methoxy-ethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino]-pyrimidin-4-ylamino}-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (24 mg, 14%) as a tan foam following reverse-phase preparative chromatography; 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.77 (s, 1H), 6.96 (s, 1H), 6.32 (m, 1H), 6.09 (m, 1H), 4.38 (m, 1H), 4.22 (m, 1H), 4.16 (m, 1H), 3.84 (m, 5H), 3.77 (s, 2H), 3.44 (m, 4H), 3.41 (s, 3H), 3.04 (s, 1H), 2.80 (s, 1H), 2.53 (d, J=8 Hz, 1H), 1.57 (d, J=8 Hz, 1H); MS (m/e) 528 (M+1).
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[C:18]1([CH2:24][CH2:25][NH2:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[N+:15]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])[C:2]=1[NH:26][CH2:25][CH2:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]([OH:8])=[O:7])([O-:17])=[O:16]
Reactant: NCCc1ccccc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1NCCc1ccccc1

Procedure:
A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (22.4 g), β-phenylethylamine (29 g), and water (200 ml) was refluxed for 2.5 hours. After cooling, the reaction mixture was adjusted to a pH of 9.5 and extracted with diethyl ether. The aqueous layer was then acidified by addition of 4N hydrochloric acid, and the precipitated 3-nitro-4-(β-phenylethylamino)-5-sulphamyl-benzoic acid was collected by suction. After recrystallization from aqueous ethanol, the melting point was 208°-208.5° C.
Reaction SMILES: [CH2:1]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:36]=[CH:35][C:22]([O:23][C:24]3[N:29]=[CH:28][C:27](OS(C)(=O)=O)=[CH:26][CH:25]=3)=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[F:37][C:38]([F:47])([F:46])[C:39]1[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=1.[C:48](=O)(O)[O-].[Na+].C(OCC)(=O)C>C1COCC1>[F:37][C:38]([F:46])([F:47])[C:39]1[CH:40]=[CH:41][C:42]([NH:45][CH2:48][C:27]2[CH:26]=[CH:25][C:24]([O:23][C:22]3[CH:35]=[CH:36][C:19]([C:17]([N:14]4[CH2:15][CH2:16][N:11]([CH2:1][C:2]5[CH:10]=[CH:9][C:8]6[O:7][CH2:6][O:5][C:4]=6[CH:3]=5)[CH2:12][CH2:13]4)=[O:18])=[CH:20][CH:21]=3)=[N:29][CH:28]=2)=[CH:43][CH:44]=1
Reactant: O=C([O-])O
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)Oc1ccc(Oc2ccc(C(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)nc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1ccc(Oc2ccc(CNc3ccc(C(F)(F)F)cc3)cn2)cc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Methanesulfonic acid 6-[4-(4-piperonylpiperazine-1-carbonyl)phenoxy]pyridin-3-yl ester (0.433 g, 0.824 mmol) and 4-trifluoromethyl phenylamine (0.310 mL, 2.47 mmol) were mixed together, and the resulting mixture was stirred for 2 hours at 100° C. The formed yellow mass was stirred together with a saturated sodium bicarbonate solution, ethyl acetate and THF (20 ml of each). The organic layer was collected, washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=50:1), to thereby yield 0.236 g of the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][S:15]([C:18]1[CH:30]=[CH:29][C:21]([C:22]([NH:24][CH2:25][C:26]([OH:28])=O)=[O:23])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:32]([O:39][C:40](=[O:46])[C@@H:41]1[CH2:45][CH2:44][CH2:43][NH:42]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([O:39][C:40]([C@@H:41]1[CH2:45][CH2:44][CH2:43][N:42]1[C:26](=[O:28])[CH2:25][NH:24][C:22](=[O:23])[C:21]1[CH:20]=[CH:19][C:18]([S:15](=[O:17])(=[O:16])[NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:30][CH:29]=1)=[O:46])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: O=C(O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccccc2)cc1
Agent: Cl
Product: O=C(NCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccccc2)cc1

Procedure:
The title compound was prepared from [4-(2-phenoxy-phenylsulfamoyl)-benzoylamino]-acetic acid and L-proline benzyl ester hydrochloride according to the method described in Example 1.1/d. MS (EI) 614.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[F:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1ccc(F)cc1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Product: O=C(Nc1ccc(F)cc1)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-chloro-3-nitrobenzoyl chloride was reacted with 4-Fluoro-phenylamine to produce 4-Chloro-N-(4-fluoro-phenyl)-3-nitro-benzamide according to the procedure of Example 10A, which was treated sequentially using the procedures from Examples 22A and 22B to provide the title product.