Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:17]=[CH:16][S:15][C:10]=2[NH:11][C:12](=[O:14])[N:13]=1.[H-].[Na+].[CH3:20]I.O>CN(C)C=O>[CH3:20][O:14][C:12]1[N:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:9]2[CH:17]=[CH:16][S:15][C:10]=2[N:11]=1
Reactant: O=c1nc(-c2ccccc2F)c2ccsc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(-c2ccccc2F)c2ccsc2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 9.49 g of 4-(o-fluorophenyl)-1,2-dihydrothieno[2,3-d]pyrimidin-2-one in 200 ml of dimethylformamide is added 1.76 g of 63% sodium hydride. The mixture is stirred at 60°C for 1 hour. The mixture is cooled to room temperature and 10.93 g of methyl iodide in 33 ml of dimethylformamide is added dropwise thereto. The mixture is stirred for 2 hours at room temperature. The reaction mixture is poured into water and extracted with chloroform. The chloroform extracts are washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure. The residue is chromatographed on silica gel, using chloroform as an eluent. From the first fraction, 2-methoxy-4-(o-fluorophenyl)-thieno[2,3-d]pyrimidine is obtained as crystals having a melting point of 175° - 176.5°C (after recrystallization from ethanol). From the second fraction, 1-methyl-4-(o-fluorophenyl)-1,2-dihydrothieno[2,3-d]pyrimidin-2-one is obtained as crystals having a melting point of 222° - 223°C (after recrystallization from ethanol). From the third fraction, 3-methyl-4-(o-fluorophenyl)-3H-thieno[2,3-d]pyrimidin-2-one is obtained as crystals having a melting point of 191° - 192.5°C (after recrystallization from ethanol).
Reaction SMILES: [CH:1]1([N:7]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:17]C#N)=[C:14]([CH3:16])[N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:1]1([N:7]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:17][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[C:14]([CH3:16])[N:15]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1nc(NC(=O)N(C2CCCCC2)C2CCCCC2)sc1SC#N
Reactant: ClCCN1CCCC1
Product: Cc1nc(NC(=O)N(C2CCCCC2)C2CCCCC2)sc1SCCN1CCCC1

Procedure:
Prepared as described in general procedure (H) using 1,1-dicyclohexyl-3-(4-methyl-5-thiocyanato-thiazol-2-yl)-urea and N-(2-chloroethyl)pyrrolidine.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:32][CH2:31][N:30]([C:33](=[O:35])C)[CH2:29][CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH2:36]([N:38]=C=O)[CH3:37]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:28][CH2:29][N:30]([C:33]([NH:38][CH2:36][CH3:37])=[O:35])[CH2:31][CH2:32]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CC(=O)N1CCC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)CC1
Reactant: CCN=C=O
Product: CCNC(=O)N1CCC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)CC1

Procedure:
4-(8-Amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl)-N-ethylpiperidine-1-carboxamide was synthesized using the same procedure as 1-{4-[8-amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]piperidin-1-yl}ethanone except ethylisocyanate was used instead of acetic anhydride; yellow powder; MS (ES+): m/z 492.10 (70) [MH+], 493.11 (45) [MH+2], 211.41 (100) [MH-280]; HPLC: tR=2.08 min (polar-5 min/openlynx).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1[CH:9]=[C:10]2[C:16](I)=[N:15][N:14]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]2=[CH:12][N:13]=1)([CH3:4])([CH3:3])[CH3:2].[F:38][C:39]1[CH:46]=[CH:45][C:42]([CH:43]=[CH2:44])=[CH:41][CH:40]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1[CH:9]=[C:10]2[C:16](/[CH:44]=[CH:43]/[C:42]3[CH:45]=[CH:46][C:39]([F:38])=[CH:40][CH:41]=3)=[N:15][N:14]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]2=[CH:12][N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)Nc1cc2c(I)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cc2c(/C=C/c3ccc(F)cc3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cn1
Temperature: 80 °C
Reaction time: 6 h
Yield: 68.2 %

Procedure:
To a solution of 400 mg of (3-iodo-1-trityl-1H-pyrazolo[3,4-c]pyridin-5-yl)carbamic acid tert-butyl ester and 162 mg of 4-fluorostyrene in 2.0 mL of N,N-dimethylformamide were added 15 mg of palladium acetate, 40 mg of 2-(di-tert-butylphosphino)biphenyl and 0.46 mL of triethylamine at room temperature, and stirred at 80° C. for 6 hours. After diluting with ethyl acetate, the organic layer was washed successively with saturated aqueous ammonium chloride and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:10-dichloromethane:n-hexane=1:1-ethyl acetate:n-hexane=1:3). The resultant crystals were washed with diethyl ether, to afford 270 mg of the title compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:32]=[CH:31][C:21]([O:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[C:20]([O:33][CH3:34])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:32]=[CH:31][C:21]([O:22][CH2:23][C:24]([OH:26])=[O:25])=[C:20]([O:33][CH3:34])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC(=O)O
Yield: 88 %

Procedure:
A solution of tert-butyl 2-(4-(6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)acetate Example 14 (370 mg; 0.741 mmol) in 1:1 TFA/CH2Cl2 (6 mL) was stirred at rt for 1 h. After concentration under reduced pressure and azeotroping with toluene, the residue was triturated with MeOH to afford the title compound (290 mg; 88%) as a white solid. 1H NMR (DMSO-d6) δ 3.79 (s, 3H), 4.75 (s, 2H), 6.99-7.04 (m, 2H), 7.22 (d, J=2.20 Hz, 1H), 7.57 (d, J=8.80 Hz, 2H), 7.91 (d, J=8.25 Hz, 2H), 7.97 (s, 1H), 8.40 (s, 1H), 13.06 (s, 1H); 13C NMR (DMSO-d6) δ 55.76, 64.86, 111.95, 112.70, 119.41, 121.70, 121.98, 127.83, 129.26, 130.21, 131.18, 134.26, 147.36, 148.80, 149.44, 149.79, 156.06, 157.39, 169.9; HPLC (Method #1): 3.44 min retention time; MS (ES): m/z 443 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][C:10]1[N:15]=[C:14]2[S:16][C:17]([NH:19][CH:20]([CH3:22])[CH3:21])=[N:18][C:13]2=[CH:12][CH:11]=1.NN.C[N:27]([CH:29]=O)C.CC([N:34](C)C)=O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][CH:20]([CH3:22])[CH3:21])=[N:18][C:13]3=[CH:12][CH:11]=2)=[CH:29][NH:27][N:34]=1
Reactant: CN(C)C=O
Reactant: CC(=O)N(C)C
Reactant: CC(C)Nc1nc2ccc(CC(=O)c3ccccc3F)nc2s1
Agent: NN
Product: CC(C)Nc1nc2ccc(-c3c[nH]nc3-c3ccccc3F)nc2s1
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 29 %

Procedure:
A solution of 1-(2-fluorophenyl)-2-(2-(isopropylamino)thiazolo[5,4-b]pyridin-5-yl)ethanone (0.0403 g, 0.122 mmol, 1.0 eq.) in DMF/DMA (1.0 mL) was heated under nitrogen at 80° C. for 2 hr. After cooling to room temperature, the reaction mixture was concentrated in vacuo and dissolved in EtOH (0.5 mL). Hydrazine (0.1 mL, 3.19 mmol, 26.1 eq.) was added, and the reaction was allowed to stand for 2.75 hr and then concentrated in vacuo. MeOH was added to the residue, and the mixture was subjected to autoprep. The appropriate fractions were collected, and NaHCO3 (s) was added. The solution was then concentrated in vacuo not to dryness and extracted with CH2Cl2 (3×). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo to give 5-(3-(2-fluorophenyl)-1H-pyrazol-4-yl)-N-isopropylthiazolo[5,4-b]pyridin-2-amine as a light yellow solid (0.0125 g, 29% yield). LC/MS (MH)=354.26.
Reaction SMILES: CO[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH:9]([NH2:15])[CH2:8][C:7]=2[CH:6]=1)=[O:4].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([S:26](Cl)(=[O:28])=[O:27])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].[OH:30][NH2:31].[OH-].[K+]>ClCCl>[OH:30][NH:31][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH:9]([NH:15][S:26]([C:20]3[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([O:17][CH3:16])[CH:19]=3)(=[O:28])=[O:27])[CH2:8][C:7]=2[CH:6]=1)=[O:4]
Reactant: NO
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: COC(=O)c1ccc2c(c1)CC(N)CC2
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NC2CCc3ccc(C(=O)NO)cc3C2)cc1OC

Procedure:
The title compound was prepared in two steps according to Scheme 6 by (1) treating amine VII with 3,4-dimethoxybenzenesulfonyl chloride and TEA in dichloromethane, and (2) treating the ester intermediate with aqueous HONH2 and KOH. MS: calc'd (MH+) 407, exp (MH+) 407.5. 1H NMR (CD3OD, 400 MHz), 7.51 (dd, 1H, J1=8.4 Hz, J2=2.0 Hz), 7.46 (d, 1H, J=8.0 Hz), 7.42 (d, 1H, J=1.6 Hz), 7.35 (s, 1H), 7.11 (m, 2H), 3.92 (s, 3H), 3.88 (s, 3H), 3.55 (m, 1H), 2.95 (m, 2H), 2.82 (m, 1H), 2.69 (m, 1H), 1.95 (m, 1H) 1.73 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][C@@H:19]5[CH2:23][CH2:24][CH2:25][C@@H:18]45)=[N:16][C:12]=3[CH:11]=[C:10]([C:34]#[N:35])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[Cl-].[Li+].CC1(C)CCCC(C)(C)N1[Mg]Cl.[Br:50]N1C(C)(C)C(=O)N(Br)C1=O>C1COCC1>[Br:50][C:11]1[C:12]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][O:20][C@@H:19]4[CH2:23][CH2:24][CH2:25][C@@H:18]34)[N:14]([CH2:26][C@H:27]3[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]3)[C:13]=2[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[N:9][C:10]=1[C:34]#[N:35]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: CC1(C)CCCC(C)(C)N1[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3c(Br)c(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a −78° C. solution of 4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Example 3.2, Step 3; 300 mg, 0.611 mmol) in THF (8 mL) was added 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex (Aldrich, 1M in THF/toluene) (1.22 mL, 1.22 mmol). The resulting yellow solution was stirred at −78° C. for 45 minutes, and then 1,3-dibromo-5,5-dimethylhydantoin (437 mg, 1.527 mmol) was added as a solid in one portion. The reaction was allowed to warm slowly to 0° C. over 90 minutes and then quenched with saturated NH4Cl (10 mL). EtOAc (75 ml) was added, and the organic layer was washed with water and brine (25 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue on a silica gel column eluting with 0 to 50% EtOAc/DCM afforded 7-bromo-4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd for C27H30BrClN6O [M+H]+=571. found=571.
Reaction SMILES: [CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[C:7](=O)[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[CH3:2].[NH2:24][OH:25]>CO.[OH-].[K+]>[CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[C:7](=[N:24][OH:25])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[CH3:2]
Reactant: NO
Reactant: CCC1(C)CC(=O)C(C)C(C)(CC)N1OC(C)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCC1(C)CC(=NO)C(C)C(C)(CC)N1OC(C)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.1 %

Procedure:
2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-4-oxopiperidine prepared according to DE 199 09 767 A1 is dissolved in methanol containing 10% by weight of KOH and stirred for 5 hours at room temperature. Methanol is evaporated, the residue is washed with water and dried in vacuo. A solution of 95.24 g (0.3 mol) of 2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-4-oxopiperidine and 29.7 g (0.45 mol) 50% aqueous hydroxylamine solution in 150 ml of methanol is stirred under reflux during 5 h. The suspension is then cooled to −8° C. and filtered. The solid is washed with 100 ml of a cold (−20° C.) methanol and dried to afford 64 g (64.1%) of the title compound as a white, microcrystalline powder, mp 130–145° C. C20H32N2O2 (332.49) calculated C, 72.25%; H, 9.70%; N, 8.43%. found 72.19% C; 9.54% H; 8.43 % N.
Reaction SMILES: [O:1]=[C:2]([N:14]1[CH2:26][CH2:25][C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]=2[CH:15]1[C:27]1[CH:32]=[CH:31][C:30]2[O:33][CH2:34][O:35][C:29]=2[CH:28]=1)/[CH:3]=[CH:4]/[C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1.[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCN(CC)CC.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[CH2:36]([NH:43][C:9](=[O:10])[C:8]1[CH:7]=[CH:6][C:5](/[CH:4]=[CH:3]/[C:2](=[O:1])[N:14]2[CH2:26][CH2:25][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][C:16]=3[CH:15]2[C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)=[CH:13][CH:12]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(O)c1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Reactant: NCc1ccccc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)c1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Yield: 13 %

Procedure:
This product was prepared by stirring a solution of Example 31 (0.2 g, 0.43 mmol) in 50 mL of THF with benzylamine (0.5 mL, 9 equiv.), Et3N (1 mL) and diphenylphosphoryl azide (0.5 mL). After two days the reaction mixture was concentrated in vacuo. The residue was taken up in 100 mL of DCM and washed with 3×50 mL of water. Drying over Na2SO4 and evaporation of the solvent gave a residue which was purified via flash chromatography with cyclohexane and Et2O. Evaporation in vacuo and recrystallization from EtOH gave the title compound (0.03 g, 13%) as white crystals.
Reaction SMILES: [C:1]1([N:11]2[C:15]([C:16]3[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=3[O:24][CH3:25])=[CH:14][C:13]([C:26]([NH:28][C:29]3([C:39]([OH:41])=[O:40])[CH:36]4[CH2:37][CH:32]5[CH2:33][CH:34]([CH2:38][CH:30]3[CH2:31]5)[CH2:35]4)=[O:27])=[N:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O.[C:43](=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.CN(C)C=O>[C:1]1([N:11]2[C:15]([C:16]3[C:17]([O:24][CH3:25])=[CH:18][CH:19]=[CH:20][C:21]=3[O:22][CH3:23])=[CH:14][C:13]([C:26]([NH:28][C:29]3([C:39]([O:41][CH3:43])=[O:40])[CH:36]4[CH2:35][CH:34]5[CH2:33][CH:32]([CH2:31][CH:30]3[CH2:38]5)[CH2:37]4)=[O:27])=[N:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COc1cccc(OC)c1-c1cc(C(=O)NC2(C(=O)O)C3CC4CC(C3)CC2C4)nn1-c1cccc2ccccc12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)c2cc(-c3c(OC)cccc3OC)n(-c3cccc4ccccc34)n2)C2CC3CC(C2)CC1C3
Reaction time: 1 h

Procedure:
0.5 g of the compound prepared in Example 11 is dissolved in 34.6 ml of anhydrous tetrahydrofuran and 4 ml of dimethylformamide. 3.5 ml of water and 0.028 g of caesium carbonate are added and the reaction mixture is left at room temperature for 1 hour. It is concentrated under vacuum and treated azeotropically with toluene. The residue is taken up in 5 ml of tetrahydrofuran. 0.6 ml of methyl iodide is added and the reaction mixtureis left for 1 hour at room temperature. It is concentrated under vacuum, the residue is taken up in water, the mixture is stirred and the precipitate is separated by filtration. The precipitate is washed with water and with pentane.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]([O:14][CH:15]2[CH2:32][CH:31]3[CH:17]([C:18](=[O:38])[N:19]([CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34](O)=[O:35])([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)[C:11]2[C:6](=[C:7]([CH3:41])[C:8]([O:39][CH3:40])=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:54]1([S:57]([NH2:60])(=[O:59])=[O:58])[CH2:56][CH2:55]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]([O:14][CH:15]2[CH2:32][CH:31]3[CH:17]([C:18](=[O:38])[N:19]([CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([NH:60][S:57]([CH:54]5[CH2:56][CH2:55]5)(=[O:59])=[O:58])=[O:35])([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)[C:11]2[C:6](=[C:7]([CH3:41])[C:8]([O:39][CH3:40])=[CH:9][CH:10]=2)[N:5]=1)[CH3:2]
Reactant: NS(=O)(=O)C1CC1
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (2) (182 mg, 0.32 mmol) and CDI (139 mg, 0.29 mmol) in dry THF (10 mL) was heated at reflux for 1.5h under nitrogen. LCMS analysis showed one peak of the intermediate (2-1) (a stable intermediate, which can be isolated by purification on silica gel). The reaction mixture was cooled to room temperature and cyclopropyl-sulfonamide (93 mg, 0.76 mmol) was added. Then, DBU (138 mg, 0.91 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, then heated at 55° C. for 12 h. Next, the solvent was evaporated, and the residue partitioned between ethyl acetate and acidic water (pH=3). The organic layer was dried (Na2SO4) and evaporated. The crude material was purified by column chromatography (ethyl acetate/CH2Cl2, 1:9). The residue was sonicated in water for 1 h, filtered off and washed with isopropylether to give the title product (3) as a white powder: m/z=669 (M+H)+. 1H NMR (CDCl3): 0.90-1.30 (m, 5H), 1.31-1.52 (m, 6H), 1.61-1.72 (m, 1H), 1.73-1.99 (m, 3H), 2.09-2.20 (m, 1H), 2.30-2.42 (m, 2H), 2.48-2.62 (m, 5H), 2.70-2.83 (m, 1H), 3.01 (s, 3H), 3.30-3.41 (m, 2H), 3.94 (s, 3H), 4.50-4.73 (m, 3H), 5.05 (t, J=10.0 Hz, 2H), 5.62-5.69 (m, 1H), 5.95 (s, 1H), 6.35 (br s, 1H), 7.01 (d, J=9.1 Hz, 1H), 7.85 (d, J=9.1 Hz, 1H), 10.8 (br s, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6]([CH2:8][CH2:9][NH2:10])[CH2:5][CH:4]([CH3:11])[O:3]1.Br[CH:13]=[CH:14]Br.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]2[C@:25]3([C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][C:26]3=[O:34])[CH2:24]2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C@H:23]2[C@@:25]3([C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]([CH2:13][CH2:14][NH:10][CH2:9][CH2:8][N:6]4[CH2:7][CH:2]([CH3:1])[O:3][CH:4]([CH3:11])[CH2:5]4)[C:26]3=[O:34])[CH2:24]2)=[CH:21][CH:22]=1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Reactant: BrC=CBr
Reactant: CC1CN(CCN)CC(C)O1
Product: CC1CN(CCNCCN2C(=O)[C@@]3(C[C@H]3c3ccc(Cl)cc3)c3ccccc32)CC(C)O1

Procedure:
The title compound was prepared in analogy to Example 81 starting from 2-(2,6-dimethylmorpholino)ethanamine, dibromo ethylene (commercially available), (1R,2S) and (1S, 2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C26H32ClN3O2: 453, observed (M+H)+: 454.1 1HNMR (400 MHz, MeOD-d4) δppm 1.22 (dd, J=6.32, 2.27 Hz, 2 H) 1.26-1.37 (m, 6 H) 2.15-2.32 (m, 3 H) 2.43-2.67 (m, 1 H) 2.88 (br. s., 3 H) 3.26 (d, J=8.59 Hz, 2 H) 3.40-3.62 (m, 4 H) 3.70-3.96 (m, 1 H) 4.13 (br. s., 4 H) 6.05-6.21 (m, 1 H) 6.81 (t, J=7.58 Hz, 1 H) 7.06-7.18 (m, 1 H) 7.24 (d, J=8.34 Hz, 3 H) 7.29-7.38 (m, 2 H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([CH3:19])[C:3]=1[NH2:4].[CH3:20][O:21][C:22]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[C:27]([O:34][CH3:35])[C:23]=1[C:24](O)=[O:25].C(N(CC)CC)C.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>ClCCl>[CH3:19][C:5]1[CH:6]=[C:7]([C:9]([F:18])([C:10]([F:12])([F:13])[F:11])[C:14]([F:15])([F:16])[F:17])[CH:8]=[C:2]([CH3:1])[C:3]=1[NH:4][C:24](=[O:25])[C:23]1[C:27]([O:34][CH3:35])=[CH:28][CH:29]=[C:30]([N+:31]([O-:33])=[O:32])[C:22]=1[O:21][CH3:20]
Reactant: COc1ccc([N+](=O)[O-])c(OC)c1C(=O)O
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc([N+](=O)[O-])c(OC)c1C(=O)Nc1c(C)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C
Temperature: 25 °C
Yield: 89.1 %

Procedure:
To a solution of 2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-aniline (145 mg, 0.5 mmol) and 2,6-dimethoxy-3-nitrobenzoic acid (136 mg, 0.6 mmol) in dichloromethane (10 ml) was added triethylamine (210 μl, 1.5 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride “BOP-Cl” (153 mg, 0.6 mmol). The reaction mixture was heated to reflux for 48 hours. The reaction mixture was cooled to ambient temperature and quenched by the addition of a saturated sodium bicarbonate solution (10 ml). The phases were separated, the organic phase was dried over sodium sulfate and concentrated. Purification by chromatography over silica gel (eluent: hexane/ethyl acetate 2:1) gave N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-2,6-dimethoxy-3-nitrobenzamide (222 mg, 89% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12](=[O:15])([O-])[O-:13].[Cs+].[Cs+].O>CN(C=O)C>[CH3:8][C:7]1[C:2]([NH:1][C:12](=[O:15])[O:13][C:7]([CH3:8])([CH3:2])[CH3:6])=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1N
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cnc1NC(=O)OC(C)(C)C

Procedure:
2-Amino-3-methyl-5-nitropyridine (1 g, 6.5 mmol) and di-tert-butyl Bicarbonate (2.2 g, 9.8 mmol) were added in DMF (33 mL), then cesium carbonate (6.4 g, 19.6 mmol) at room temperature for 6 hours. Water (200 mL) was added, extracted with ethyl acetate (200 mL), second wash with brine (100 mL). The organic phase was dried by magnesium sulfate, filtered, concentrated and purified by column chromatography through a 25 gram Biotage SNAP KP-Sil™ silica gel cartridge eluting with 13% ethyl acetate/hexanes to give the title compound as a pale yellow solid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[N:24][N:23]=[N:22]4)=[N:19][CH:20]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.[CH:26]([S:29](Cl)(=[O:31])=[O:30])([CH3:28])[CH3:27]>>[CH:26]([S:29]([N:2]1[CH2:3][CH2:4][CH:5]([N:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[N:24][N:23]=[N:22]4)=[N:19][CH:20]=3)[CH:10]=[N:9]2)[CH2:6][CH2:7]1)(=[O:31])=[O:30])([CH3:28])[CH3:27]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: c1cc(-n2cnnn2)ncc1OCc1cnn(C2CCNCC2)n1
Agent: Cl
Product: CC(C)S(=O)(=O)N1CCC(n2ncc(COc3ccc(-n4cnnn4)nc3)n2)CC1

Procedure:
The title compound was synthesized using Intermediate 15 and isopropylsulfonyl chloride in a similar manner as described in Example 39. 1H NMR (DMSO-d6): δ 10.08 (1H, s), 8.41 (1H, d), 8.01 (1H, d), 7.95 (1H, s), 7.86 (1H, dd), 5.35 (2H, s), 4.75 (1H, m), 3.69 (2H, m), 3.31 (1H, m), 3.13 (2H, m), 2.17 (2H, m), 1.97 (2H, m), 1.20 (6H, d).