Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N+:9]([CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15])=[CH:8][CH:7]=[CH:6]2.BrCC(C1C=CC=CC=1)=O.ClC1C=C2C(=CC=1)[N:39]=[CH:38][CH:37]=[CH:36]2>C(#N)C>[C:14]([C:13]1[N:9]2[C:10]3[C:5]([CH:6]=[CH:7][C:8]2=[C:37]([C:38]#[N:39])[CH:36]=1)=[CH:4][C:3]([Cl:2])=[CH:12][CH:11]=3)(=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(C[n+]1cccc2cc(Cl)ccc21)c1ccccc1
Reactant: Clc1ccc2ncccc2c1
Agent: O=C(CBr)c1ccccc1
Agent: [Br-]
Solvent: CC#N
Product: N#Cc1cc(C(=O)c2ccccc2)n2c1ccc1cc(Cl)ccc12

Procedure:
6-Chloro-1-phenacyl-quinolinium bromide: The title compound was prepared from 2-bromo-1-phenyl-ethanone (483 mg, 2.43 mmol), 6-chloro-quinoline (312 mg, 1.91 mmol) and acetonitrile (5 mL), similar to Example 1a, and yielded 433 mg (63%) as an off white solid: 1H NMR (CDCl3) 10.40 (d, J=5.7 Hz, 1H), 8.95 (d, J=8.7 Hz, 1H), 8.31 (m, 1H), 8.29 (m 1H), 8.24 (d, J=2.1 Hz, 1H), 8.19–8.14 (m, 2H), 7.99 (dd, J=2.1, 9.3 Hz, 1H), 7.70–7.65 (m, 3H), 7.53 (t, J=7.8 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CC([O-])(C)C.[K+].Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][N:20]=[C:19]2[O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-amino-3-nitrophenol (0.8 g, 5.34 mmol, 1.2 eq) in DMSO (3.8 mL, 5×) was treated with KOt-Bu (0.6 g, 5.34 mmol, 1.2 eq), and the mixture was stirred at RT for 2 h. The contents were treated with 4-chloro-6,7-dimethoxyquinazoline (1.0 g, 4.45 mmol, 1.0 eq) and K2CO3 (0.33 g, 2.4 mmol, 0.53 eq) then heated at 110° C. for 16 h. The mixture was cooled to RT, diluted with EtOAc and washed with NaHCO3 (sat). To remove the emulsion, the mixture was filtered through Celite, then the organic layer was washed with brine, 1N NaOH, then brine again. The organic portion was dried with Na2SO4, filtered and evaporated to give the title compound as a brown solid. MS(MH+)=343.1; Calc'd 342.31 for C16H14N4O5.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][C:14]=1[Cl:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH2:5]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([Cl:3])=[O:18])=[CH:15][C:14]=1[Cl:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(OCc2ccccc2)c(Cl)c1
Product: O=C(Cl)c1ccc(OCc2ccccc2)c(Cl)c1

Procedure:
In a mixed solvent of methanol and tetrahydrofuran was dissolved 5.17 g of 4-hydroxy-3-chlorobenzoic acid, and a solution of 2.4 g of sodium hydroxide in 5 ml of water was added to the solution. Then, 10 ml of benzyl chloride was added to the mixture and the liquid was refluxed for 4 hours. Then, 1.2 g of sodium hydroxide was further added to the mixture, the liquid was refluxed for 2 hours, and the reaction liquid was put into 1N hydrochloric acid, and the precipitate was recovered by filtration, washed with water, methanol and n-pentane in succession and recrystallized from a mixed solvent of benzene and tetrahydrofuran to obtain 2.7 g of 4-benzyloxy-3-chlorobenzoic acid. Then, 15 g of thionyl chloride was added to 2.7 g of this 4-benzyloxy-3-chlorobenzoic acid, and the mixture was reacted under reflux and reacted for 3 hours. Unreacted thionyl chloride was removed by distillation under reduced pressure. Thus, 4-benzyloxy-3-chlorobenzoic acid chloride was quantitatively obtained.
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1F>CN(C=O)C.C(Cl)Cl>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][C:18]=1[N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Reactant: c1c[nH]cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(Br)c(-n2ccnc2)c1
Temperature: 150 °C
Yield: 60 %

Procedure:
A microwave vial charged with a solution of potassium tert-butoxide (0.462 g, 4.12 mmol), imidazole (0.280 g, 4.12 mmol), and 1-bromo-2-fluoro-4-(trifluoromethyl)benzene (1.000 g, 4.12 mmol) in 2 mL DMF was heated to 150° C. in an oil bath overnight. The reaction mixture was diluted with DCM, filtered through a syringe filter, and concentrated. Purification of the resulting residue by silica gel column chromatography (0 to 100% EtOAc/heptane) gave 1-(2-bromo-5-(trifluoromethyl)phenyl)-1H-imidazole (0.720 g, 2.474 mmol). [M+H]+=291.0
Reaction SMILES: C1N2CCN(CC2)C1.[Li]CCCC.[F:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.CN([CH:24]=[O:25])C>CCOCC.O.CCOC(C)=O>[F:14][C:15]1[C:16]([CH:24]=[O:25])=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: Fc1cccnc1
Reactant: CN(C)C=O
Agent: C1CN2CCN1CC2
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=Cc1ncccc1F
Temperature: -70 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of DABCO (262.4 g, 2342 mmol) in anhydrous Et2O (2.1 L) at −25° C. in a 10 L 3-neck round bottom flask was added n-BuLi (2.5 M in hexane, 938 mL, 2342 mmol). The mixture was stirred between −25° C. to −10° C. for 45 min. and then cooled to −70° C. To the above solution was added 3-fluoropyridine (206.7 g, 2129 mmol) dropwise, and the reaction was stirred between −70° C. to −60° C. for 1.5 h before DMF (344 mL, 4258 mmol) was added. The progress of the reaction was monitored by TLC (5% EtOAc in Petroleum ether). After 1 h stirring at −70° C., water (800 mL) was added, and the reaction was allowed to warm to rt. The layers were separated, and the aqueous layer was extracted with DCM (5×1 L). The combined organic layers were washed with brine and dried over sodium sulfate. After removal of solvent the initially obtained product was purified by silica gel chromatography using a gradient of EtOAc in hexane to give the title compound as pale yellow oil. 1H-NMR (400 MHz, CDCl3): δ ppm 10.21 (s, 1H), 8.63 (t, J=2.2 Hz, 1H), 7.54-7.57 (m, 2H). MS (ESI pos. ion) m/z: 126.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH2:10][CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21]([CH3:26])[CH:20]=[C:19]2[NH2:27])=[O:14].C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:10][CH2:11][CH2:12][C:13]([NH:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21]([CH3:26])[CH:20]=[C:19]3[NH2:27])=[O:14])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(N)c2cc(NC(=O)CCN)ccc2n1
Reactant: Cc1cc(Cl)nc(N)n1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NCCC(=O)Nc2ccc3nc(C)cc(N)c3c2)nc(N)n1
Yield: 36.6 %

Procedure:
A solution of 0.05 g (0.35 mmol) 2-amino-4-chloro-6-methylpyrimidine, 0.204 mg (0.35 mmol) 3-amino-N-(4-amino-2-methyl-quinolin-6-yl)-propionamide and 0.18 mg (1.39 mmol) diisopropyl ethylamine in 5 ml dimethylacetamide was stirred at 100° C. for 2 h. After evaporation of the solvent the residue was purified by HPLC and lyophilized to yield 45 mg of the title compound. MS 352.3 (M+H)+, 1H-NMR (DMSO-d6) δ 2.20 (s, 3H), 2.55 (s, 3H), 2.70 (m, 2H), 3.65 (m, 2H), 6.1 (s, NH), 7.70-7.90 (m, 5H), 8.60-8.80 (br.s., NH), 13.85 (br.s., NH).
Reaction SMILES: C(O[C:6]([NH:8][CH:9]1[CH2:14][C:13]([CH3:19])([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C.Cl.CCN(C(C)C)C(C)C.[Cl:30][C:31]1[N:36]=C(Cl)[C:34]([F:38])=[CH:33][N:32]=1>CO>[Cl:30][C:31]1[N:36]=[C:6]([NH:8][C@H:9]2[CH2:10][CH2:11][CH2:12][C@@:13]([CH3:19])([C:15]([O:17][CH3:18])=[O:16])[CH2:14]2)[C:34]([F:38])=[CH:33][N:32]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COC(=O)C1(C)CCCC(NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@]1(C)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of methyl 5-(tert-butoxycarbonylamino)-1-methylcyclohexanecarboxylate, 52g, (5.63 g, 20.75 mmol) in MeOH (20 mL) was treated with HCl gas for 10 minutes. The resulting solution was stirred at room temperature for 1 hour, then concentrated to dryness and redissolved in THF (50 mL). To the reaction mixture was added iPr2NEt (10.84 mL, 62.25 mmol) and 2,4-dichloro-5-fluoro-pyrimidine (5.20 g, 31.12 mmol) sequentially. The reaction was stirred at reflux overnight, concentrated in vacuo and resulting residue was purified by silica gel chromatography (1:1 Hexane:EtOAc), yielding 2.2 g of the racemic product as a yellow oil. 300 mg of the racemic methyl 3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanecarboxylate was submitted for SFC chiral separation, yielding 100 mg of the desired product, 52h, as a yellow oil.
Reaction SMILES: S(=O)(=O)(O)O.O.[O:7]=[C:8]1[CH:17]([NH:18]C(=O)C)[CH2:16][C:15]2[C:10](=[C:11]([N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:27])[CH:12]=[CH:13][CH:14]=2)[N:9]1[CH2:28][C:29]1[CH:33]=[CH:32][S:31][CH:30]=1.[OH-].[Na+]>C(OCC)(=O)C>[NH2:18][CH:17]1[CH2:16][C:15]2[C:10](=[C:11]([N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:27])[CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:28][C:29]2[CH:33]=[CH:32][S:31][CH:30]=2)[C:8]1=[O:7]
Reactant: CC(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Temperature: 86 °C
Reaction time: 0.08 h
Yield: 77.8 %

Procedure:
Sulfuric acid (470.6 mL) was added to water (5.65 L) at room temperature, and N-(2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-yl)acetamide (561.5 g) was added thereto at an internal temperature of 41-43° C. The mixture was heated at an internal temperature of 80 to 92° C. for four hours while being stirred. Under cooling on ice, 25% sodium hydroxide (2,715 g) was added dropwise to the reaction mixture at an internal temperature of 50° C. or lower, to thereby adjust the pH of the mixture to 7. Ethyl acetate (1.0 L) was added to the resultant mixture while being stirred, and 25% sodium hydroxide (300 g) was added thereto at an internal temperature of 50° C. or lower, to thereby adjust the pH of the mixture to 10. An additional ethyl acetate (1.83 L) was added to the mixture, and stirring was performed for five minutes, to thereby partition the mixture. Ethyl acetate (2.83 L) was added to the aqueous layer at an internal temperature of 30° C. or lower, and stirring was performed for five minutes, to thereby partition the mixture. An additional ethyl acetate (2.83 L) was added to the aqueous layer, and the above-described extraction procedure was repeated. The ethyl acetate layers were combined, and the combined ethyl acetate layer was concentrated under reduced pressure, to thereby evaporate ethyl acetate (6.8 L). The reaction mixture was left to stand overnight in a refrigerator, and the crystals that precipitated were recovered through filtration. The thus-recovered crystals were washed with ethyl acetate (566 mL). The thus-obtained solid was dried in air overnight and then at 60° C. under reduced pressure, whereby the title compound (389.2 g) was yielded as pale yellow crystals.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3](=O)[CH2:4][C:5]([C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:10]=2[N:11]=1)=O.Cl.[S:22]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][NH2:33])=[CH:28][CH:27]=1)(=[O:25])(=[O:24])[NH2:23]>>[CH3:17][O:16][C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[C:7]([C:5]3[N:32]([C:29]4[CH:28]=[CH:27][C:26]([S:22]([NH2:23])(=[O:25])=[O:24])=[CH:31][CH:30]=4)[N:33]=[C:3]([C:2]([F:20])([F:19])[F:1])[CH:4]=3)[S:8][C:9]=2[CH:15]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: COc1ccc2nc(C(=O)CC(=O)C(F)(F)F)sc2c1
Agent: Cl
Product: COc1ccc2nc(-c3cc(C(F)(F)F)nn3-c3ccc(S(N)(=O)=O)cc3)sc2c1

Procedure:
The procedure of Example 9 was repeated using 4,4,4-trifluoro-1-(6-methoxybenzothiazol-2-yl)butane-1,3-dione and 4-sulfamoylphenylhydrazine hydrochloride as the starting materials to obtain 4-[5-(6-methoxybenzothiazol-2-yl)-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide. NMR(CDCl3) δ: 3.88 (3H, s), 5.03 (2H, bs), 7.11 (1H, dd, J=2.3 Hz, 8.9 Hz), 7.20 (1H, s), 7.31 (2H, d, J=2.3 Hz), 7.68 (2H, d, J=8.6 Hz), 7.83 (1H, d, J=8.9 Hz), 8.01 (2H, d, J=8.6 Hz); mp 236-237° C. (ethyl acetate-isooctane)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]#[N:10])=[O:7].[ClH:11].[CH2:12]([O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[ClH:11].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]([NH:24][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:26][CH:25]=1)=[NH:10])=[O:7]
Reactant: N#CNC(=O)c1cccs1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: Cl
Product: N=C(NC(=O)c1cccs1)Nc1ccc(OCc2ccccc2)cc1
Yield: 61 %

Procedure:
Synthesis of this compound was achieved by the method set forth in Example 1, Part II above with the use of N-(2-thiophenecarbonyl)cyanamide in place of N-(4-methylbenzoylcyanamide) and using 4-benzylcyanamide and using 4-benzyloxyaniline hydrochloride instead of 4-isopropylaniline hydrochloride respectively. Yield 61%; m.p. 198–202° C.; Purity 93% (HPLC); 1H-NMR (CD3OD) δ 5.18 (s, 2H, CH2), 7.18 (d, 2H), 7.22–7.4 (m, 6H), 7.44 (d, 2H), 7.9 (d, 1H), 8.18 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[CH2:29][C@:28]3([CH3:43])[C@@H:30]([CH3:42])[CH2:31][CH2:32][C@H:33]4[C:34]([CH3:41])([CH3:40])[C@@H:35]([OH:39])[C@@H:36]([OH:38])[CH2:37][C@@:27]34[O:26][C:11]=2[C:12]2[CH2:13][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:15](=[O:18])[C:16]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[N+:53]([C:56]1[CH:61]=[CH:60][C:59]([S:62](Cl)(=[O:64])=[O:63])=[CH:58][CH:57]=1)([O-:55])=[O:54].O>ClCCl>[CH2:1]([O:8][C:9]1[C:10]2[CH2:29][C@:28]3([CH3:43])[C@@H:30]([CH3:42])[CH2:31][CH2:32][C@H:33]4[C:34]([CH3:41])([CH3:40])[C@@H:35]([OH:39])[C@@H:36]([O:38][S:62]([C:59]5[CH:58]=[CH:57][C:56]([N+:53]([O-:55])=[O:54])=[CH:61][CH:60]=5)(=[O:63])=[O:64])[CH2:37][C@@:27]34[O:26][C:11]=2[C:12]2[CH2:13][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:15](=[O:18])[C:16]=2[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)[C@@H](O)C[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: O
Product: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)[C@@H](OS(=O)(=O)c3ccc([N+](=O)[O-])cc3)C[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Reaction time: 6 h
Yield: 69.7 %

Procedure:
To a solution of Compound (48a) (200 mg, 0.34 mmol) in 15 ml of dichloromethane were added 83 mg (0.68 mmol) of dimethylaminopyridine and 112 mg (0.51 mmol) of p-nitrobenzenesulfonyl chloride under ice-cooling, and the mixture stirred for 6 hours at the same temperature. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed sequentially with 1N HCl, water, an aqueous saturated sodium hydrogen carbonate solution, and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by a column chromatography (Merck, Lobar column, size B; toluene:ethyl acetate=4:1) to give 184 mg (70%) of Compound (48f).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[NH:13][C:14](=[O:16])[CH3:15].Cl[CH2:18][C:19]([CH3:21])=[CH2:20]>CN(C)C=O.O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[N:13]([CH2:20][C:19]([CH3:21])=[CH2:18])[C:14](=[O:16])[CH3:15]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1Br
Reactant: C=C(C)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)CN(C(C)=O)c1cc([N+](=O)[O-])ccc1Br
Temperature: 60 °C

Procedure:
To a suspension of 1.34 g of sodium hydride in 10 mL of dimethylformamide under argon is added dropwise, at 0° C., a solution of 5.8 g of N-(2-bromo-5-nitrophenyl)acetamide obtained in stage c) below in 90 mL of dimethylformamide and the reaction medium is stirred at this temperature for 1 hour. 3.3 mL of 3-chloro-2-methylprop-1-ene are then added and the mixture is then heated at 60° C. for 2 hours. After cooling to room temperature, the mixture is diluted with one litre of water and extracted with four times 80 mL of ethyl acetate. The combined organic phases are washed with three times 50 mL of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of heptane and ethyl acetate (80/20 by volume) to give 5.2 g of N-(2-bromo-5-nitrophenyl)-N-(2-methylprop-2-en-1-yl)acetamide in the form of a yellow solid, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:5]=[C:6]([CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[S:7][CH:8]=1.[CH:15]1([N:18]([CH2:32][C:33]2[O:34][CH:35]=[C:36]([C:38]([OH:40])=O)[N:37]=2)[S:19]([C:22]2[C:27]([CH3:28])=[CH:26][C:25]([O:29][CH3:30])=[CH:24][C:23]=2[CH3:31])(=[O:21])=[O:20])[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O>CN(C=O)C>[CH:15]1([N:18]([CH2:32][C:33]2[O:34][CH:35]=[C:36]([C:38]([N:2]([CH3:1])[CH2:3][C:4]3[N:5]=[C:6]([CH2:9][N:10]4[CH2:14][CH2:13][CH2:12][CH2:11]4)[S:7][CH:8]=3)=[O:40])[N:37]=2)[S:19]([C:22]2[C:23]([CH3:31])=[CH:24][C:25]([O:29][CH3:30])=[CH:26][C:27]=2[CH3:28])(=[O:21])=[O:20])[CH2:17][CH2:16]1
Reactant: CNCc1csc(CN2CCCC2)n1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)O)co2)C2CC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N(C)Cc3csc(CN4CCCC4)n3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AH using N-methyl-1-[2-(pyrrolidin-1-ylmethyl)-1,3-thiazol-4-yl]methanamine (40 mg, 189 μmol), 2-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3-oxazole-4-carboxylic acid (72 mg, 189 μmol), DIPEA (0.1 mL, 575 μmol), EDCI (72 mg, 378 μmol), HOBt monohydrate (58 mg, 378 μmol) and DMF (1.5 mL). The resulting crude compound was purified by FCC eluting with 99:1 DCM:7N NH3 in MeOH.
Reaction SMILES: C(O[C:4](=[O:9])[C:5]([F:8])([F:7])[CH3:6])C.[CH2:10]([CH2:12][NH2:13])[OH:11]>>[F:8][C:5]([F:7])([CH3:6])[C:4]([NH:13][CH2:12][CH2:10][OH:11])=[O:9]
Reactant: NCCO
Reactant: CCOC(=O)C(C)(F)F
Product: CC(F)(F)C(=O)NCCO

Procedure:
2,2-Difluoro-propionic acid ethyl ester I-3a (10.1 g, 70 mmol) was added dropwise to stirred, cooled (0° C.) ethanolamine (4.4 ml, 70 mmol) and the resulting solution was allowed to stir at ambient temperature for 4 hours. Concentration of the reaction mixture in vacuo afforded the title compound (I-3b) as a solid, 11.2 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.Cl.[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH2:24])=[CH:19][CH:18]=1>>[CH3:6][O:8][C:9]([C:4]1[N:24]([CH2:23][C:20]2[CH:21]=[CH:22][C:17]([C:16]([O:15][CH3:14])=[O:25])=[CH:18][CH:19]=2)[C:6](=[O:8])[C:5]2[C:4]([C:9]=1[OH:10])=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=2)=[O:10]
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Product: COC(=O)c1ccc(Cn2c(C(=O)OC)c(O)c3cc(Cl)ccc3c2=O)cc1

Procedure:
The present compound was synthesized according to the method shown in Reference Example 8 and using 4-chloro phthalic anhydride and 4-(aminomethyl)benzoic acid methyl ester hydrochloride.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][C:8]([OH:22])=[C:9]([CH:21]=1)[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]([S:19][CH3:20])=[S:18])[CH2:13][CH2:12]1)(=O)C.[ClH:23]>C(O)C>[ClH:23].[OH:22][C:8]1[CH:7]=[CH:6][C:5]([OH:4])=[CH:21][C:9]=1[CH2:10][N:11]1[CH2:12][CH2:13][N:14]([C:17]([S:19][CH3:20])=[S:18])[CH2:15][CH2:16]1
Reactant: CSC(=S)N1CCN(Cc2cc(OC(C)=O)ccc2O)CC1
Agent: Cl
Solvent: CCO
Product: CSC(=S)N1CCN(Cc2cc(O)ccc2O)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In 38 ml of ethanol was suspended 10.6 g of methyl 4-(5-acetoxy-2-hydroxybenzyl)-1-piperazinecarbodithioate (compound prepared in Example 6). In a nitrogen atmosphere, 53 ml of conc. hydrochloric acid was added to the suspension at room temperature. After the solid was dissolved, insolubles were removed by filtration, and further the insolubles were washed with 4 ml of ethanol. The filtrate and washing were combined to give a pale brown solution. The solution was stirred for 20 hours at room temperature to give a suspension. The suspension was further stirred at 80° C. for 3 hours, and then stirred for 8 hours at room temperature. The crystalline solid was collected by filtration and washed with ethanol to give 6.34 g of the desired compound as a pale brown crystalline powder, m.p. 200°-202° C. (decomp.).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:24])(=O)=O)=CC=1.Cl>C1COCC1.C(OCC)C>[F:24][C:3]1[CH:4]=[CH:5][S:1][C:2]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cccs1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)c1sccc1F
Temperature: -78 °C
Yield: 40 %

Procedure:
2-Thiophene-carboxylic acid (1.7 g, 13.3 mmol) was dissolved in anhydrous THF (30 mL) and the solution was cooled to −78° C. under Ar, with stirring. n-Butyllithium (18.3 mL, 29.3 mmol) in hexanes was added to the above solution and the mixture was stirred for 30 min. A solution of N-fluorobenzenesulfonimide (5 g, 15.9 mmol) in THF (30 mL) was then added and the resulting solution was stirred at −78° C. for 4 h and allowed to warm to ambient temperature over a period of 6 h. The reaction was diluted with diethyl ether (100 mL), cooled to 0° C., and 1 N HCl (15 mL) was added to give a biphasic mixture. The aqueous layer was isolated and washed with diethyl ether (3×50 mL). The combined ethereal layers were dried over MgSO4, filtered, and concentrated in vacuo to yield an orange oil. The oil was subjected to column chromatography on silica gel using 1:1 hexanes/ethyl acetate as the eluent. (14) was obtained as a slightly brown solid (0.777 g) in 40% yield. TLC (1:1 ethyl acetate/hexanes) Rf 0.17; 1H NMR (CDCl3) δ 10.7 (s, 1H), 7.53 (dd, J=5.4, 3.6 Hz, 1H), 6.89 (d, J=5.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 166.2 (d, J=3.5 Hz), 161.5 (d, J=278 Hz), 132.0 (d, J=10 Hz), 118.9 (d, J=24.7 Hz), 113.6; 19FNMR (282 MHz, CDCl3, CFCl3) δ-65.2 (d, J=6 Hz); EI-MS m/e 145.9838 (M+ calcd 145.9838 for C5H3FO2S).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31]>>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1
Reactant: COc1ccccc1Br
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Product: COc1ccccc1N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
The title compound was prepared in analogy to example 1 step D from a mixture of 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 1 step C) and 2-bromoanisole. Light yellow solid. MS (ESI): 421.0 (MH+)