Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][O:23]C2CCCCO2)[CH:17]=[CH:16][C:15]=1[N:30]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]1>CO>[F:13][C:14]1[CH:19]=[C:18]([CH:17]=[CH:16][C:15]=1[N:30]1[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]1)[O:20][CH2:21][CH2:22][OH:23]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(OCCOC3CCCCO3)cc2F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: OCCOc1ccc(N2CCNCC2)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
p-Toluenesulfonic acid monohydrate (45.2 mmol) is added to 4-{2-fluoro-4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-piperazine-1-carboxylic acid, tert.-butyl ester (22.6 mmol) in MeOH (50 ml) at room temperature. The reaction mixture is stirred at room temperature for 1.5 h. After the mixture is extracted with AcOEt, the organic layer is washed with brine, dried over magnesium sulfate and filtered. The solvent is evaporated. To the residue in CH2Cl2 (9 ml), TFA (17.5 ml) is added at 0° C. The reaction mixture is stirred at room temperature for 1 h. The solvent is removed by evaporation and dried to give brown crude oily product, 2-(3-fluoro-4-piperazin-1-yl-phenoxy)-ethanol. To the crude product in DMF (100 ml), potassium carbonate (113 mmol) is successively added at 0° C. The mixture is stirred at 0° C. for 15 min. 6-Bromomethyl-7-(2,2-dimethyl-propyl)-7.H.-pyrrolo[2,3-.d.]pyrimidine-2-carbonitrile (22.6 mmol) is added to the mixture at 0° C. The reaction mixture is stirred at room temperature for 3 h and quenched with saturated ammonium chloride. The mixture is extracted with AcOEt. The combined extracts are washed with H2O, brine and dried over magnesium sulfate. The solvent is evaporated and the residue is purified by column chromatography on silica gel using n-hexane:AcOEt=3:2 (v/v).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5]2.[CH3:18][O:19][CH2:20]Cl>CN(C)C=O>[CH3:18][O:19][CH2:20][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5]2
Reactant: COCCl
Reactant: COC(=O)C(C)c1ccc2cc(O)ccc2c1
Solvent: CN(C)C=O
Product: COCOc1ccc2cc(C(C)C(=O)OC)ccc2c1
Reaction time: 12 h

Procedure:
A mixture of 23 g. of methyl 6-hydroxy-2-naphthyl-α-methylacetate, 25 g. of chlorodimethyl ether, and 500 ml. of dimethylformamide is allowed to stand at room temperature for 12 hours. The reaction mixture is evaporated under reduced pressure to give methyl 6-methoxymethyloxy-2-naphthyl-α-methylacetate.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.[CH3:15][C:16]1([CH3:24])[O:20][C@@H:19]([CH2:21][O:22][NH2:23])[CH2:18][O:17]1.C(N(CC)CC)C>O1CCOCC1>[Cl:11][C:6]1[C:7]([NH:8][CH:9]=[O:10])=[C:2]([NH:23][O:22][CH2:21][C@H:19]2[CH2:18][O:17][C:16]([CH3:24])([CH3:15])[O:20]2)[N:3]=[C:4]([NH:12][CH:13]=[O:14])[N:5]=1
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC1(C)OC[C@H](CONc2nc(NC=O)nc(Cl)c2NC=O)O1
Temperature: 100 °C
Reaction time: 4 h
Yield: 20.2 %

Procedure:
A mixture of 4,6-dichloro-2,5-diformamidopyrimidine (3.5 g, 15 mmol), (R)-(2,2-dimethyl-1,3-dioxolan-4-ylmethoxy)amine (2.65 g, 18 mmol) and triethylamine (20 ml, 150 mmol) in dioxan (80 ml) was stirred at 100° C. for 4 hours. The reaction was cooled, filtered and evaporated under reduced pressure. The residue was chromatographed on silica, eluting with chloroform-methanol (10:1), affording slightly impure (R)-4-chloro-2,5-diformamido-6-(2,2-dimethyl-1, 3-dioxolan-4-ylmethoxyamino)pyrimidine (1.05 g, 20%) as pale orange solid. IR: υmax (nujol) 3400, 3300, 3180, 1690, 1650 cm-1 ;
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[F:30][C:31]([F:46])([F:45])[C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[C:35]([OH:37])=O>>[F:45][C:31]([F:30])([F:46])[C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[C:35]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:29])=[O:3])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:37]
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 3,5-bis(trifluoromethyl)benzoic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-[3,5-bis(trifluoromethyl)benzoyl]-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 606 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(C(C)=O)C>[CH2:27]([O:26][CH2:25][CH2:24][CH2:23][O:14][C:11]1[CH:10]=[N:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]2[OH:1])=[N:13][CH:12]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCCCOCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncc(O)cn2)C(O)C1
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ncc(OCCCOCc3ccccc3)cn2)C(O)C1
Temperature: 80 °C
Reaction time: 48 h
Yield: 41 %

Procedure:
A mixture of 65 mg (0.22 mmol) of tert-butyl (3RS,4RS)-3-hydroxy-4-(5-hydroxy-pyrimidin-2-yl)-piperidine-1-carboxylate and 151.2 mg (0.66 mmol) of (3-bromo-propoxymethyl)-benzene in 10 ml of methyl ethyl ketone was stirred at 80° C. for 48 hours under argon. For the working-up, the reaction mixture was evaporated under reduced pressure, the residue was taken up in methylene chloride and the solution was chromatographed directly on silica gel using a 1:4 mixture of methylene chloride and ethyl acetate as the eluent. There were obtained 40 mg (41% of theory) of tert-butyl (3RS,4RS)-4-[5-(3-benzyloxy-propoxy)-pyrimidin-2-yl]-3-hydroxy-piperidine-1-carboxylate as a foam; Rf : 0.43 (silica gel; methylene chloride:ethyl acetate=1:4 v/v).
Reaction SMILES: [CH3:1][C:2]1[S:9][C:8]2[CH:7]=[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:5][C:4]=2[CH:3]=1.[Br:15]N1C(=O)CCC1=O.O>O1CCCC1>[Br:15][C:7]1[C:8]2[S:9][C:2]([CH3:1])=[CH:3][C:4]=2[NH:5][C:6]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc2sc(C)cc2[nH]1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1[nH]c2cc(C)sc2c1Br
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To a solution of ethyl 2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate (1.0 g) in tetrahydrofuran (10 mL) was added N-Bromosuccinimide (0.94 g) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added water and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=97/3−76/24) to give the title compound (0.96 g).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[C:12]([C:13]([C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1>>[Cl:6][C:7]1[C:12]([C:13]([C:15]2[NH:16][CH:17]=[C:18]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:19]=2)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: O=S(=O)(O)Cl
Reactant: O=C(c1ccc[nH]1)c1cccnc1Cl
Product: O=C(c1cc(S(=O)(=O)Cl)c[nH]1)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
Chlorosulfonic acid (6.6 mL, 100 mL) was added dropwise to (2-chloro-pyridin-3-yl)-(1H-pyrrol-2-yl)-methanone (from Example 2, 2.06 g, 10 mmol) at 0° C. After stirring at 0° C. for 24 hours, the reaction was poured slowly into ice water. The precipitate was collected by vacuum filtration, washed with water and dried to give 2.9 g (95%) of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-3-sulfonyl chloride as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH3:31])[C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]3[CH:27]=[N:26][C:25]([C:28]#[N:29])=[C:24](Cl)[N:23]=3)[CH2:17]2)=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH:32]1([NH2:35])[CH2:34][CH2:33]1>CN1C(=O)CCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH3:31])[C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]3[CH:27]=[N:26][C:25]([C:28]#[N:29])=[C:24]([NH:35][CH:32]4[CH2:34][CH2:33]4)[N:23]=3)[CH2:17]2)=[O:14])[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: NC1CC1
Reactant: CN(C(=O)N[C@@H]1CCCN(c2cnc(C#N)c(Cl)n2)C1)c1cc(Cl)cc(C(F)(F)F)c1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CN(C(=O)N[C@@H]1CCCN(c2cnc(C#N)c(NC3CC3)n2)C1)c1cc(Cl)cc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
(R)-1-(3-Chloro-5-(trifluoromethyl)phenyl)-3-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1-methylurea (521, 50 mg, 0.10 mmol) was dissolved in 2 mL NMP in a sealed tube. To it was added cyclopropylamine (210 μL, 3.0 mmol), and the mixture was stirred in 70° C. bath for overnight. It was diluted with 50 mL EtOAc, washed with saturated NH4Cl (aq) solution and water ×2, concentrated in vacuo to give crude (R)-1-(3-chloro-5-(trifluoromethyl)phenyl)-3-(1-(5-cyano-6-(cyclopropylamino)pyrazin-2-yl)piperidin-3-yl)-1-methylurea (522). It was dissolved in 10 mL MeOH and 2 mL DMSO. To it were added one NaOH solid pellet (about 50-100 mg) and then 0.5 mL 30% H2O2. The mixture was stirred at RT for 1 hour, diluted with 10 mL MeCN, stirred for 5 min, concentrated on rotavap. The residue was treated with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate (R)-5-(3-(3-(3-chloro-5-(trifluoromethyl)phenyl)-3-methylureido)piperidin-1-yl)-3-(cyclopropylamino)pyrazine-2-carboxamide (523 as HCl salt (32 mg, 62% yield). LC-MS (ESI): m/z (M+1) 512.2 (chloro pattern). UV: λ=282, 318, 369 nm. Proton NMR (CD3OD): δ 7.53 (1H, m), 7.51 (1H, broad s), 7.48 (1H, broad s), 7.46 (1H, s), 3.98 (1H, dd, J=13.5; 3.5 Hz), 3.90 (1H, m), 3.81 (1H, m), 3.66 (1H, m), 3.52 (1H, m), 3.25 (3H, s), 2.71 (1H, m), 1.96 (1H, m), 1.78 (2H, m), 1.62 (1H, m), 0.76 (2H, m), 0.45 (2H, m) ppm.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:13][C:14]([CH3:20])([CH2:17][C:18]#[CH:19])[CH2:15][OH:16]>N1CCCCC1.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>[CH3:13][C:14]([CH3:20])([CH2:17][C:18]#[C:19][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1)[CH2:15][OH:16]
Reactant: FC(F)(F)Oc1ccc(I)cc1
Reactant: C#CCC(C)(C)CO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CC(C)(CO)CC#Cc1ccc(OC(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A mixture of 1-iodo-4-trifluoromethoxy-benzene (3.56 g, 12 mmol), Pd(PPh3)4 (578 mg, 0.5 mmol) and cuprous iodide (95 mg, 0.5 mmol) in piperidine (40 ml) was degassed (Ar) and stirred for 30 min at 50° C. under an argon atmosphere. 2,2-Dimethyl-pent-4-yn-1-ol (1.25 g, 10 mmol, 90% purity) [Magnus, Philip; Slater, Martin J.; Principe, Lawrence M. Journal of Organic Chemistry (1989), 54(21), 5148-5153] in piperidine (20 ml) was added within 60 min at 50° C. During the addition the oil bath temperature was slowly raised to 80° C. starting after 30 min. The mixture was stirred for 2 h at this temperature. The reaction mixture was cooled to ambient temperature, poured into a solution of aqueous 10% KHSO4/ice water 1/1 and extracted two times with ether. The combined extracts were washed with aqueous 10% KHSO4 and aqueous 10% NaCl and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography (silica gel, heptane/AcOEt 2:1 to 1:1) to give 1.91 g (7 mmol, 70%) of the title compound as yellow oil.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[N:8]2[N:16]=[N:17][N:18]=[C:7]12)[CH2:2][CH2:3][CH2:4][CH3:5].C1C(=O)N([Br:26])C(=O)C1>C1COCC1>[Br:26][C:12]1[NH:11][C:10]2[C:9](=[O:15])[N:8]3[N:16]=[N:17][N:18]=[C:7]3[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2nnnc12
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2nnnc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
The mixture of 4-pentyl-4,7-dihydro-8H-tetrazolo[1,5-a]purin-8-one (94.6 mg, 0.38 mmol) and NBS (75 mg, 0.42 mmol) in THF (20 ml) was stirred at 70° C. for 1 hour. After evaporation of solvent, the residue was purified by preparative LC-MS to yield the desired product (17.1 mg, 13.7%). LCMS calculated for C10H13BrN7O (M+H): 326.0. found: 326.0.
Reaction SMILES: [F:1][C:2]1([F:21])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=O)[NH:4][C@@:3]1([C:13]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:14]=1[F:20])[CH3:12].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>>[F:1][C:2]1([F:21])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=[S:31])[NH:4][C@@:3]1([C:13]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:14]=1[F:20])[CH3:12]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(I)ccc2F)C1(F)F
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(I)ccc2F)C1(F)F
Yield: 95.3 %

Procedure:
In a manner analogous to that described for the preparation of intermediate B7, the reaction of (R)-6,6-difluoro-5-(2-fluoro-5-iodo-phenyl)-5,7,7-trimethyl-[1,4]oxazepan-3-one (intermediate B6″.1) (1.455 g, 3.52 mmol) with Lawesson's reagent (1.42 g, 3.52 mmol), yielded the title compound (1.44 g, 95% yield) as a colorless oil. MS (ISP): m/z=430.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH:19]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[CH2:20][CH2:21][C:22]([OH:24])=O)[C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1.[CH3:33][O:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:33][O:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH:38][C:22](=[O:24])[CH2:21][CH2:20][CH:19]([N:2]([CH3:1])[C:3](=[O:18])[C:4]1[CH:5]=[C:6]([C:14]([F:15])([F:17])[F:16])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1)[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CCC(=O)O)Cc1ccc(Cl)cc1
Reactant: COc1ccccc1CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccccc1CNC(=O)CCC(Cc1ccc(Cl)cc1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
This is the compound of Example 3. It can be prepared also by the following synthesis method: a mixture of 0.495 g of 4-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(4-chlorophenyl)-pentanoic acid, 0.137 g of 2-methoxy-benzylamine, 0.21 g of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride, 0.134 g of 4-dimethylaminopyridine and 10 ml of methylene chloride is stirred at room temperature for 16 hours and then concentrated by evaporation. The residue is chromatographed (silica gel, hexane/ethyl acetate 1:1). In this way the title compound is obtained in the form of a colourless amorphous solid. 1H-NMR, 400 MHz, DMSO, 150°, delta (ppm): 7.95(s, 1H), 7.50(s, 2H), 7.43(s, 1H), 7.3-7.1(m, 6H), 6.95(d, 1H), 4.23(d,2H), 3.80(s, 3H), 2.9-2.7(m, 5H), 2.25(m, 2H), 1.92(m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)c(C)c1C(=O)NCCN1CCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.9 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (54.9 mg, 45%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][CH:25]([F:37])[O:26][C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[C:19]([NH:21][S:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH:25]([F:24])[F:37])[CH:28]=3)(=[O:35])=[O:34])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(N)cc1N1CCCN(C(=O)OC(C)(C)C)CC1
Reactant: O=S(=O)(Cl)c1cccc(OC(F)F)c1
Product: COc1ccc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCCN(C(=O)OC(C)(C)C)CC1

Procedure:
0.5 g of 4-(5-amino-2-methoxy-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.556 mmol) was reacted as described for Preparation example 1 with 3-(difluoromethoxy)-benzene-sulfonylchloride to yield 0.64 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][C:10]2[O:9][CH2:8][CH2:7][N:6]3[CH:13]=[C:14]([C:16]4[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=4)[N:15]=[C:5]3[C:4]=2[CH:3]=1.C(#N)C.O.C([O-])(=O)C.[K+].[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][N:35]=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>[F:33][C:34]1[N:35]=[CH:36][C:37]([C:2]2[N:12]=[CH:11][C:10]3[O:9][CH2:8][CH2:7][N:6]4[CH:13]=[C:14]([C:16]5[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=5)[N:15]=[C:5]4[C:4]=3[CH:3]=2)=[CH:38][CH:39]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Cl)ncc1OCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(-c3ccc(F)nc3)ncc1OCC2
Temperature: 25 °C

Procedure:
10-Chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine (85.0 mg, 0.257 mmol) dissolved in Acetonitrile (2 mL, 50 mmol) and Water (2 mL, 100 mmol) with dissolved Potassium acetate (85.5 mg, 0.871 mmol). Degas by bubbling nitrogen for 5 min. 2-Fluoropyridine-5-boronic acid (47.1 mg, 0.334 mmol) was added, then Tetrakis(triphenylphosphine)palladium(0) (4.0E1 mg, 0.035 mmol). The reaction was microwaved at 145 C 35 min, cooled to RT, and extracted with ethyl acetate. Combined organics were concentrated to give fluoro intermediate, 10-(6-fluoropyridin-3-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine, which was dissolved in 1,2-Dimethoxyethane (3.00 mL, 28.9 mmol). 10% aqueous HCl (3 mL) was added. The reaction was allowed to stir and heat at 80° C. overnight. The reaction was allowed to cool to room temperature and concentrated under reduced pressure to give 306, analyzed by rHPLC. MS: (ESI+)=390.1
Reaction SMILES: [CH:1](NC(C)C)(C)C.[CH2:8]([C@H:10]1[C@@H:14]([OH:15])[CH2:13][C:12](=[O:16])[N:11]1[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=1)[CH3:9].IC.[Cl-].[NH4+]>O1CCCC1>[CH2:8]([C@H:10]1[C@@H:14]([OH:15])[C@H:13]([CH3:1])[C:12](=[O:16])[N:11]1[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:26])[F:27])[CH:18]=1)[CH3:9]
Reactant: CC(C)NC(C)C
Reactant: CC[C@H]1[C@@H](O)CC(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CC[C@H]1[C@@H](O)[C@H](C)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 1 h
Yield: 13 %

Procedure:
To a solution of diisopropylamine (0.603 mL) in tetrahydrofuran (8 mL) was added dropwise n-butyllithium-hexane solution (2.56 mL, 1.6 mol/L) at −78° C., the mixture was stirred for 1 hr, and a solution of 4-[(2S,3S)-2-ethyl-3-hydroxy-5-oxopyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (490 mg) in tetrahydrofuran (6 mL) was added dropwise. The mixture was stirred at −78° C. for 30 min, iodomethane (0.510 mL) was added dropwise at −78° C., and the mixture was stirred at 0° C. for 1 hr. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30/1→1/4) and further purified by basic silica gel chromatography (eluent: hexane/ethyl acetate=30/1→1/4) to give the title compound as a colorless solid (yield: 66.5 mg, 13%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:24])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:24])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)=[O:10])[CH:18]=1)[CH3:12]
Reactant: O=C(O)c1cccc(Br)n1
Reactant: CCOC(=O)CCc1cccc(N)c1
Product: CCOC(=O)CCc1cccc(NC(=O)c2cccc(Br)n2)c1

Procedure:
6-Bromo-pyridine-2-carboxylic acid (261 mg, 1.29 mmol) was coupled to aniline (124) (250 mg, 1.29 mmol) using Method C to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[N:5][N:4]([CH2:9][CH2:10][CH2:11][CH2:12]Cl)[C:3]1=[O:14].[Cl:15][C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.C(O)CCC>C(N(CC)CC)C>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[N:5][N:4]([CH2:9][CH2:10][CH2:11][CH2:12][N:25]2[CH2:24][CH2:23][N:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=3)[CH2:27][CH2:26]2)[C:3]1=[O:14]
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: Cn1c(=O)cnn(CCCCCl)c1=O
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Cn1c(=O)cnn(CCCCN2CCN(c3cccc(Cl)c3)CC2)c1=O
Yield: 44.9 %

Procedure:
The compound 4c (5.5 g; 0.025 mol) and 4-(3-chlorophenyl)piperazine (9.83 g; 0.05 mol) are heated for 3 hours in refluxing butanol (150 ml) in the presence of triethylamine (10 ml). The mixture is concentrated to dryness under vacuum, taken up in water and then extracted with ethyl ether (2×50 ml). The dried organic phases (Na2SO4) are concentrated to dryness under vacuum to give an oil which crystallizes from isopropyl ether (70 ml). After recrystallization from 2-propanol and drying under vacuum at 40° C., the compound 4 (4.24 g) is obtained.