Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH3:16][O:17][CH2:18][CH2:19][N:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[C:28]([NH2:31])[CH:29]=[CH:30][C:23]=2[CH2:22][CH2:21]1.Cl[C:33]1[N:38]=[C:37]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[S:46]([N:49]([CH3:51])[CH3:50])(=[O:48])=[O:47])[C:36]([Cl:52])=[CH:35][N:34]=1.C(=O)([O-])[O-]>C(O)(C)C>[Cl:52][C:36]1[C:37]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[S:46]([N:49]([CH3:51])[CH3:50])(=[O:48])=[O:47])=[N:38][C:33]([NH:31][C:28]2[CH:29]=[CH:30][C:23]3[CH2:22][CH2:21][N:20]([CH2:19][CH2:18][O:17][CH3:16])[CH2:26][CH2:25][C:24]=3[CH:27]=2)=[N:34][CH:35]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N(C)C)n3)cc2CC1
Reaction time: 1 h

Procedure:
10-Camphorsulfonic acid (53 mg, 0.23 mmol) was added to 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (48 mg, 0.22 mmol) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide (72 mg, 0.21 mmol) in Isopropyl alcohol (2 mL). The mixture was irradiated in a CEM microwave (140° C., 30 min). MP-Carbonate (2.69 mmol/g loading; 0.18 g, 0.47 mmol) was added and the mixture stirred for 1 h and filtered, washing with DCM. The filtrate was conc. in vacuo. The residue was taken up in DCM with a few drops of MeOH and chromatographed (ISCO, 2×12 g, 0-12% MeOH:DCM) to afford 2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N,N-dimethyl-benzenesulfonamide as a colorless wax (83 mg, 75%). LCMS 531 (M+H), 1H-NMR (CDCl3): 9.42 (s, 1H), 8.54 (d, 1H, J=8.4 Hz), 8.12 (s, 1H), 7.86 (d, 1H, J=7.5 Hz), 7.55 (dd, 1H, J=7.5, 8.2 Hz), 7.24 (m, 3H), 7.02 (d, 1H, J=7.8 Hz), 6.90 (s, 1H), 3.55 (m, 2H), 3.37 (s, 3H), 2.90 (m, 4H), 2.74 (m, 12H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10](=NNC(N)=O)[CH2:11][P:12](=[O:17])([O:15][CH3:16])[O:13][CH3:14])=[N:6][CH:7]=1.Cl.[OH-:24].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10](=[O:24])[CH2:11][P:12](=[O:17])([O:15][CH3:16])[O:13][CH3:14])=[N:6][CH:7]=1
Reactant: [OH-]
Reactant: COP(=O)(CC(COc1ccc(Cl)cn1)=NNC(N)=O)OC
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COP(=O)(CC(=O)COc1ccc(Cl)cn1)OC
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A mixture of dimethyl 3-(5-chloropyrid-2-yloxy)-2-semicarbazonopropylphosphonate (400 mg.), toluene (5 ml.) and 6N hydrochloric acid (1.0 ml.) was stirred at room temperature for 4.5 hours, and the pH of the reaction mixture was adjusted to about 4 by the dropwise addition of 5N sodium hydroxide solution. The organic layer was separated and the aqueous layer was washed with ethyl acetate (6 ml). The combined organic extracts were washed with a 1:1 v/v mixture of saturated brine and water (4 ml. then 2 ml.) and dried, and the solvents were evaporated under reduced pressure to give dimethyl 3-(5-chloropyrid-2-yloxy)-2-oxopropylphosphonate, RF = 0.43 (5% v/v methanol in ethyl acetate). The n.m.r. spectrum in deuteriochloroform showed the following characteristic peaks (δ values):
Reaction SMILES: C(=O)(O)[O-].[Na+].[C:6]1(O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](O)=[N:8][N:7]=1.[CH2:18]([S:26][S:27]C(=N)N)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>O.CO>[CH2:18]([S:26][S:27][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([S:27][S:26][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[N:8][N:7]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCSSC(=N)N
Reactant: Oc1nnc(O)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCCCSSc1nnc(SSCCCCCCCC)c2ccccc12
Temperature: 25 °C
Yield: 91 %

Procedure:
A solution of sodium bicarbonate (4.30 g, 0.05 mole) in water (60 ml) was added dropwise to a stirred suspension of the phthalazine-1,4-diol prepared as above (2.91 g, 0.015 mole) and S-n-octylthioisothiourea obtained in step (A) (7.695 g, 0.03 mole) in methanol (70 ml) at 60°-65° C. over 30 minutes. The mixture was stirred at room temperature for a further hour, then filtered giving a yellow solid, which was washed with water and dried giving the product as yellow crystals (6.56 g, 91%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+].Cl[C:14]1[N:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=1.O>CS(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:14]2[N:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C)nc(Oc2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
27.8 g (0.2 mole) of 4-nitro-phenol were dissolved in 100 ml of dimethylsulphoxide. After addition of 11.2 g (0.2 mole) of powdered potassium hydroxide, the mixture was stirred at room temperature for 30 minutes and 28.5 g (0.2 mole) of 2-chloro-4,6-dimethyl-pyrimidine were then added. The mixture was heated at 120° C. for 6 hours and then cooled, stirred with one liter of water and filtered off with suction. The crystals filtered off with suction were dried in air. 38 g (77.5% of theory) of 2-(4-nitrophenoxy)-4,6-dimethyl-pyrimidine were obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([NH2:12])[CH:9]=[N:8]2)[CH:2]=1.[F:13][C:14]([F:22])([F:21])[CH2:15][CH:16]([CH3:20])[C:17](O)=[O:18].Cl.CN(C)CCCN=C=NCC>ClC(Cl)C>[F:13][C:14]([F:22])([F:21])[CH2:15][CH:16]([CH3:20])[C:17]([NH:12][C:10]1[CH:9]=[N:8][N:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:11]=1)=[O:18]
Reactant: Nc1cnn(-c2cccnc2)c1
Reactant: CC(CC(F)(F)F)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Product: CC(CC(F)(F)F)C(=O)Nc1cnn(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a solution of 1-(pyridin-3-yl)-1H-pyrazol-4-amine (0.150 g, 0.93 mmol) in dichloroethane (1.8 ml) was added 4,4,4-trifluoro-2-methylbutanoic acid (0.14 g, 0.93 mmol) and 4-N,N-dimethylaminopyridine (0.23 g, 1.87 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.36 g, 1.87 mmol). The reaction stirred at room temperature overnight. The reaction mixture was concentrated and the crude product was purified by silica gel chromatography eluting with 0-5% MeOH/dichloromethane to give a white solid (0.15 g, 55%); mp 140-145° C.; 1H NMR (400 MHz, CDCl3) δ 9.00 (d, J=2.4 Hz, 1H), 8.62-8.47 (m, 2H), 8.01 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.68 (s, 1H), 7.53 (bs, 1H), 7.40 (ddd, J=8.3, 4.8, 0.6 Hz, 1H), 2.92-2.61 (m, 2H), 2.32-2.05 (m, 1H), 1.38 (d, J=6.6 Hz, 3H); ESIMS m/z 300 ([M+2]).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([N+:20]([O-:22])=[O:21])[C@H:9]([C:17]([OH:19])=O)[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[NH:16])[NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH3:39][O:40][C:41](=[O:59])[C@H:42]([CH2:51][C:52]1[CH:57]=[CH:56][C:55]([OH:58])=[CH:54][CH:53]=1)[NH:43][C:44](=[O:50])[C@H:45]([CH:47]([CH3:49])[CH3:48])[NH2:46]>C(Cl)Cl>[CH3:39][O:40][C:41](=[O:59])[C@H:42]([CH2:51][C:52]1[CH:57]=[CH:56][C:55]([OH:58])=[CH:54][CH:53]=1)[NH:43][C:44](=[O:50])[C@H:45]([CH:47]([CH3:49])[CH3:48])[NH:46][C:17](=[O:19])[C@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14](=[NH:16])[NH2:15])[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[N+:20]([O-:22])=[O:21]
Reactant: CC(C)(C)OC(=O)N([C@@H](CCCNC(=N)N)C(=O)O)[N+](=O)[O-]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)C(C)C
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)N)N(C(=O)OC(C)(C)C)[N+](=O)[O-])C(C)C
Temperature: -70 °C
Reaction time: 0.08 h

Procedure:
21.5 g of t-butoxycarbonylnitroarginine is dissolved in 200 ml of methylene chloride. 15.0 ml of N-methylmorpholine is added to the solution. The solution is cooled to -70° C. 8.8 ml of isobutyl chloroformate is then added. The reaction mixture is warmed up to -15° C. and stirred for 5 minutes. The reaction mixture is again cooled to -70° C. 22.3 g of valyltyrosine methyl ester hydrochloride is added to the reaction mixture. The reaction mixture is allowed to warm to room temperature, and then is stirred for 16 hours. The reaction mixture is extracted three times with 0.5 M potassium bisulfate and once with brine. The methylene chloride solution is dried over anhydrous sodium sulfate, filtered and stripped of solvent. The residue is dissolved in 200 ml of ethyl ether. The ether solution is added to cold rapidly stirring Skellysolve B. The white precipitate is filtered and dried to afford the product t-butoxycarbonylnitroarginylvalyltyrosine methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][C:12]=3[C:13](=[O:16])[C:14]=2[OH:15])=[CH:5][CH:4]=1>C(Cl)(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][C:11]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][C:12]=3[C:13](=[O:16])[C:14]=2[O:15][CH2:9][C:6]2[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2oc3ccc(NC(C)=O)cc3c(=O)c2O)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2oc3ccc(NC(C)=O)cc3c(=O)c2OCc2ccccc2)cc1
Yield: 95 %

Procedure:
Prepared analogously to Example 5d) starting from 2-(4-methoxyphenyl)-3-hydroxy-6-acetamido-4H-1-benzopyran-4-one. Yield: 95%; TLC (9/1 Chloroform/Methanol) Rf: 0.51; 1H-NMR (d6-DMSO): 10.31 (s broad, 1H), 8.40 (d, 1H), 8.02 (m, 3H), 7.70 (d, 1H), 7.32 (m, 5H), 7.11 (d, 2H), 5.08 (s, 2H), 3.86 (s, H), 2.11 (s, 3H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].FC1C([O:38][C:39](=O)[CH2:40][CH2:41][CH2:42][O:43][N+:44]([O-:46])=[O:45])=C(F)C(F)=C(F)C=1F>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:7]([CH2:11][O:12][C:39]([CH2:40][CH2:41][CH2:42][O:43][N+:44]([O-:46])=[O:45])=[O:38])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: O=C(CCCO[N+](=O)[O-])Oc1c(F)c(F)c(F)c(F)c1F
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(COC(=O)CCCO[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.3 %

Procedure:
To a solution of 2-butyl-4-chloro-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol (0.48 g, 1.1 mmol), TEA (0.16 ml, 1.1 mmol) and DMAP (0.14 mg, 1.1 mmol) in DMF (3 ml), cooled to 0° C., a solution of 4-nitrooxybutyric acid pentafluorophenyl ester (0.36 g, 1.1 mmol) in DMF (3 ml) was added. The reaction was slowly warmed to room temperature and stirred for 3 hours. Then the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc (10 ml) and washed with a buffer solution (pH=3) then with brine. The organic layer was dried over Na2SO4, concentrated and purified by flash chromatography (CH2Cl2/MeOH 98:2) to afford the title compound (0.41 g, 66%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:20]2[CH:21]=[CH:22][O:23][C:19]=2[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[O:23][CH:22]=[CH:21][C:20]=4[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2occc21
Product: CC1c2ccoc2CCN1C(=O)c1cc2ncc(Br)cn2n1
Yield: 39 %

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4-Methyl-4,5,6,7-tetrahydro-furo[3,2-c]pyridine to provide the title compound.
Reaction SMILES: Cl.[O:2]=[C:3]1[N:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:6][C:5]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:4]1.C([BH3-])#N.[Br:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[O:35][C:36]([F:39])([F:38])[F:37])[CH:30]=O.CC(O)=O>CN(C=O)C>[Br:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[O:35][C:36]([F:37])([F:38])[F:39])[CH2:30][N:20]1[CH2:21][CH2:22][C:5]2([O:4][C:3](=[O:2])[N:7]([C:8]3[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=3)[CH2:6]2)[CH2:18][CH2:19]1
Reactant: COC(=O)c1ccc(N2CC3(CCNCC3)OC2=O)cc1
Reactant: O=Cc1ccc(OC(F)(F)F)c(Br)c1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(N2CC3(CCN(Cc4ccc(OC(F)(F)F)c(Br)c4)CC3)OC2=O)cc1
Yield: 66.2 %

Procedure:
To methyl 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoate hydrochloride salt (300 mg, 0.918 mmol; Example 1, Step 2), MP-cyanoborohydride (1192 mg, 2.75 mmol), 3-bromo-4-trifluoromethoxybenzaldehyde (272 mg, 1.01 mmol) and AcOH (79 μl, 1.38 mmol) was added 5 mL of DMF. The reaction mixture was filtered, the resin was washed with DMF and the solvent was evaporated. The residue was dissolved in saturated aqueous NaHCO3 and extracted with DCM. The combined organic layers were evaporated to yield the title compound as a light yellow solid (330 mg) that was used without any further purification.
Reaction SMILES: Cl.[F:2][CH2:3][C:4]([C:8]1[O:12][N:11]=[C:10]([NH:13][C:14](=[O:38])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[CH:26][N:25]=3)=[CH:18][CH:17]=2)[CH:9]=1)([CH3:7])[CH2:5][F:6].CCN(C(C)C)C(C)C.FC(F)(F)S(O[CH2:54][C:55]([F:58])([F:57])[F:56])(=O)=O>CC#N>[F:2][CH2:3][C:4]([C:8]1[O:12][N:11]=[C:10]([NH:13][C:14](=[O:38])[NH:15][C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:32][CH2:33][N:34]([CH2:54][C:55]([F:58])([F:57])[F:56])[CH2:35][CH2:36]4)=[CH:26][N:25]=3)=[CH:20][CH:21]=2)[CH:9]=1)([CH3:7])[CH2:5][F:6]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(CF)(CF)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNCC4)cn3)cc2)no1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(CF)(CF)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCN(CC(F)(F)F)CC4)cn3)cc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a stirred solution of N-(4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(piperidin-4-yloxy)picolinamide hydrochloride (50 mg, 0.091 mmol) from Step 4 of Example 17 in 3 mL of CH3CN was added DIEA (32 mL, 0.18 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (21 mg, 0.18 mmol). The resulting mixture was then stirred at rt for 1 h, heated at 85° C. for 1 h. CH3CN was then evaporated under reduced pressure and the residue was taken up in 2 mL of DMF. To the reaction mixture was then added DIEA (32 μL, 0.18 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (21 mg, 0.18 mmol), and heated at 85° C. for 2 h. LC-MS indicated that the reaction was complete. Purification by reverse phase HPLC yielded N-(4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(1-(2,2,2-trifluoroethyl)piperidin-4-yloxy)picolinamide (40 mg, 74%) as a white solid. LC-MS (ESI) m/z 597 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.59 (s, 1H), 8.77 (s, 1H), 8.36 (d, J=2.83 Hz, 1H), 8.08 (d, J=8.85 Hz, 1H), 7.81 (d, J=8.85 Hz, 2H), 7.67 (dd, J=2.83, 8.85 Hz, 1H), 7.42 (d, J=8.85 Hz, 2H), 6.79 (s, 1H), 4.73 (s, 2H), 4.65 (td, J=3.93, 8.15 Hz, 1H), 4.57 (s, 2H), 3.23 (q, J=10.24 Hz, 2H), 2.80-2.96 (m, 2H), 2.62 (t, J=9.42 Hz, 2H), 1.97 (br. s., 2H), 1.60-1.76 (m, 2H), 1.34 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C.C(OCC)C>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([Br:7])[CH:9]=1)[CH3:22])[CH3:21]
Reactant: Oc1cccc(Br)c1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C(C)Oc1cccc(Br)c1
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 91.7 %

Procedure:
Cesium carbonate (57.8 g, 177.4 mmol) was added to a solution of 3-bromophenol (10.23 g, 59.1 mmol) in anhydrous DMF (500 mL) at room temperature under an atmosphere of nitrogen. After five minutes, ethyl 2-bromopropionate (7.7 mL, 59.1 mmol, d=1.394) was added rapidly dropwise and the resultant mixture was allowed to stir at 90° C. for 18 h. The reaction mixture was diluted with diethyl ether and extracted twice with 1N HCl and three times with water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (25% ether in hexanes) to provide the titled compound (14.8 g, 97%) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.13-7.07 (m, 3H), 7.02-7.13 (m, 1H), 6.79 (dt, 1H, J=7.63 Hz, 2.35 Hz), 4.70 (q, 1H, J=6.75 Hz), 4.23 (q, 2H, J=3.52 Hz), 1.60 (d, 3H, J=7.04 Hz), 1.24 (t, 3H, J=7.04 Hz). Rf=0.36 in 25% ether in hexanes.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]1.C(O[C@@H:14]1[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]1[O:16][C:17](=[O:19])[CH3:18])(=O)C.P([O-])(OC1C=CC([N+]([O-])=O)=CC=1)(OC1C=CC([N+]([O-])=O)=CC=1)=O>C1C=CC=CC=1>[CH3:9][O:8][C:6]([C:3]1[N:4]=[CH:5][N:1]([C@@H:14]2[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]2[O:16][C:17](=[O:19])[CH3:18])[N:2]=1)=[O:7]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COC(=O)c1nc[nH]n1
Agent: O=[N+]([O-])c1ccc(OP(=O)([O-])Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: c1ccccc1
Product: COC(=O)c1ncn([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)n1
Reaction time: 0.29 h

Procedure:
A mixture of methyl 1,2,4-triazole-3-carboxylate (12.7 g., 0.10 mol) and 1,2,3,5-tetra-O-acetyl-β -D-ribofuranose (31.8 g., 0.10 mol) was heated in an oil bath maintained at 160-165° until the sugar had melted. Bis(p-nitrophenyl) phosphate (250 mg.) was added and heating at 160-165° was continued with stirring under diminished pressure for 15-20 min. The residue was dissolved in hot benzene, the solution was filtered and cyclohexane was added to the filtrate to give the crystalline product (30.0 g., 77.8%) with M.P. 107-109°.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:3]=1.CN([C:23]([CH:25]=[CH2:26])=O)C.FC(F)(F)C(O)=O>>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][N:6]1[C:2]2=[N:1][CH:23]=[CH:25][CH:26]=[C:3]2[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:5]1
Reactant: CCOC(=O)c1cc(N)n(Cc2ccccc2F)n1
Reactant: C=CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nn(Cc2ccccc2F)c2ncccc12
Reaction time: 72 h

Procedure:
The solution obtained from 3A) is treated with 61.25 ml (60.77 g, 0.613 mol) of dimethylaminoacrolein and 56.28 ml (83.88 g, 0.736 mol) of trifluoroacetic acid and boiled under argon for 3 days. The solvent is then evaporated in vacuo, the residue is added to 2 l of water and the mixture is extracted three times with 1 l of ethyl acetate each time. The combined organic phases are dried using magnesium sulphate and concentrated in a rotary evaporator. The residue is chromatographed on 2.5 g of silica gel and eluted with a toluene/toluene-ethyl acetate=4:1 gradient. Yield: 91.6 g (49.9% of theory over two steps).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:9]=[CH:10][CH:11]=1
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C=Cc1cccc(OC(F)(F)F)c1
Temperature: 15 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
A mixture of 3-(trifluoromethoxy)benzaldehyde 158a (10.0 g, 52.6 mmol) and ethyl 2-(triphenylphosphoranylidene)acetate 158b (27.5 g, 78.9 mmol) in DCM (200 mL) was stirred at 15° C. for 2 h. See FIG. 4. The resulting mixture was concentrated under reduced pressure, and the crude was purified by column chromatography on silica gel (ethyl acetate:petroleum ether=1:8) to afford ethyl 3-(3-(trifluoromethoxy)phenyl)acrylate 158c (12.0 g, 88%) as yellow oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:19])[CH:16]=3)[N:11]([CH2:20][CH2:21][OH:22])[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH2:23]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:19])[CH:16]=3)[N:11]([CH2:20][CH2:21][O:22][S:32]([CH3:31])(=[O:34])=[O:33])[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:24]
Reactant: CCN(CC)C(=O)C1CCCc2c1c1cc(F)ccc1n2CCO
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN(CC)C(=O)C1CCCc2c1c1cc(F)ccc1n2CCOS(C)(=O)=O
Temperature: 0 °C
Yield: 28.9 %

Procedure:
To a solution of 6-fluoro-9-(2-hydroxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (37) (460 mg, 1.4 mmol) in dichloromethane (20 mL) was added pyridine (1.11 g, 14.0 mmol, 1.1 mL). The reaction was cooled to 0° C. and methanesulfonyl chloride (722 mg, 6.3 mmol, 0.5 mL) was added. The reaction was allowed to warm to room temperature overnight. The mixture was washed with 2 N HCl (2×30 mL) and water (2×30 mL), dried and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (0-100% (B), 10 g, 45 CV, 30 mL/min) then triturated with diethyl ether to afford 166 mg (30%) of methanesulfonic acid 2-(4-diethylcarbamoyl-6-fluoro-1,2,3,4-tetrahydro-carbazol-9-yl)-ethyl ester (precursor compound 9) as a white solid. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 12.9, 15.0, 21.1, 27.7, 36.1, 36.7, 40.6, 41.7, 67.8, 103.3 (d, JCF=23 Hz), 108.7, 109.0, 109.1, 109.4 (d, JCF=5 Hz), 126.9 (d, JCF=10 Hz), 132.4, 138.4, 156.1, 159.2, and 173.3.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH2:3][CH2:2]2.[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:24]([NH:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])=[CH:12][CH:11]=1)[CH2:3][CH2:2]2
Reactant: Nc1ccc(N2CCN3CCC2CC3)cc1
Reactant: O=C=Nc1ccccc1
Solvent: CO
Product: O=C(Nc1ccccc1)Nc1ccc(N2CCN3CCC2CC3)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-phenylamine (0.43 g, 2.0 mmol), phenylisocyanate (0.29 ml, 2.5 mmol) and methanol (60 ml) was stirred at room temperature for hours. The mixture was evaporated and diethylether (30 ml) was added, the precipitate was filtered. The product was isolated. Yield 0.23 g (34%). Mp. 145° C. (dec).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH3:8][C:9]1[O:10][C:11]([CH3:14])=[CH:12][CH:13]=1>C(OCC)C>[CH3:8][C:9]12[O:10][C:11]([CH3:14])([CH:12]=[CH:13]1)[CH:3]1[CH:2]2[C:1](=[O:7])[O:6][C:4]1=[O:5]
Reactant: O=C1C=CC(=O)O1
Reactant: Cc1ccc(C)o1
Solvent: CCOCC
Product: CC12C=CC(C)(O1)C1C(=O)OC(=O)C12
Reaction time: 18 h
Yield: 71.9 %

Procedure:
A 100 mL 3-necked RBF is fitted with a mechanical stirrer, a condenser and a subaseal, and placed under nitrogen. Maleic anhydride (25.5 g, 0.260 mol) and anhydrous diethyl ether (35 mL) are charged to the RBF. 2,5-Dimethylfuran (27.7 mL, 0.260 mol) is added via syringe over a period of 20 mins to the suspension at 22° C. The reaction mixture is stirred for 18 h. The product is filtered off, washed with cold diethyl ether (100 mL), and dried under vacuum to yield the product 1 as a cream solid (36.32 g, 72%): 1H-NMR (300 MHz, CDCl3) δ6.35 (s, 2H), 3.16 (s, 2H), 1.76 (s, 6H).