Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]1[C:7](=[O:18])[C:8](=[O:17])[C:9]=1[NH:10][CH:11]([CH3:16])[C:12]([CH3:15])([CH3:14])[CH3:13])CCC.[Cl:19][C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23]>O1CCCC1>[Cl:19][C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[CH2:22][NH:23][C:6]1[C:7](=[O:18])[C:8](=[O:17])[C:9]=1[NH:10][CH:11]([CH3:16])[C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: CCCCOc1c(NC(C)C(C)(C)C)c(=O)c1=O
Solvent: C1CCOC1
Product: CC(Nc1c(NCc2ccc(Cl)cc2Cl)c(=O)c1=O)C(C)(C)C
Yield: 28.8 %

Procedure:
Tetrahydrofuran (10 mL), 3-butoxy-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione (1.01 g, 3.99 mmol, Example 1) and 2,4-dichlorobenzylamine (0.70 g, 4.0 mmol) were stirred together at room temperature for 14 hours. Following removal of solvent, the residue was triturated with diethyl ether and dried. The off-white solid product was recrystallized twice from nitromethane to yield 0.408 g (29%) of the title compound as a white solid: mp 234°-235° C.; 1H NMR: (DMSO-d6): δ 7.67 (m, br, 1H), 7.65 (m, br, 1H), 7.48 (m, 2H), 7.32 (m, br, 1H), 4.80 (m, 2H), 3.90 (m, 1H), 1.10 (d, 3H), 0.86 (s, 9H) ppm. IR (KBr): 3140, 1790, 1640 cm-1 ; MS (m/z): 354/356/358. HPLC indicates a major component (99%).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([NH:13][CH:14]([CH3:25])[CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:12])[CH2:5][CH2:4]1.[Cl:33][Si](C)(C)C.C(OCC)C>CC(CC)=O>[ClH:33].[CH3:32][N:2]([CH3:1])[C:3]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([NH:13][CH:14]([CH3:25])[CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:12])[CH2:5][CH2:4]1.[CH3:32][N:2]([CH3:1])[C:3]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([NH:13][CH:14]([CH3:25])[CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:12])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CC(Cc1c[nH]c2ccccc12)NC(=O)NCC1CCC(c2ccccc2)(N(C)C)CC1
Solvent: CCC(C)=O
Solvent: CCOCC
Product: Cl
Temperature: 25 °C

Procedure:
The more nonpolar diastereoisomer of 1-(4-dimethylamino-4-phenyl-cyclohexyl-methyl)-3-[2-(1H-indol-3-yl)-1-methyl-ethyl]-urea (157 mg, 0.36 mmole) was dissolved in ethyl methyl ketone (6 ml). Chlorotrimethylsilane (69 μl, 0.6 mmole) was added dropwise with stirring at RT. On stirring for one hour at RT, only a little precipitate formed. The reaction solution was combined with diethyl ether (25 ml). The mixture was then vigorously stirred at RT for 1 h. A colorless precipitate was formed. The solid was filtered out, washed with diethyl ether (3×2 ml) and dried under a vacuum. The hydrochloride of the more nonpolar diastereoisomer of 1-(4-dimethylamino-4-phenyl-cyclohexylmethyl)-3-[2-(1H-indol-3-yl)-1-methyl-ethyl]-urea (163 mg, m.p. 150-155° C., 97%; Example 25) was obtained in this manner as a colorless solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:49]1[C:53]2[CH:54]=[CH:55][C:56]([C:58]3[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=3)=[CH:57][C:52]=2[CH2:51][CH2:50]1>CN(C=O)C>[O:49]1[C:53]2[CH:54]=[CH:55][C:56]([C:58]3[CH:59]=[C:60]([NH:64][C:22]([C:17]4[C:18](=[O:21])[O:19][C:20]5[C:15]([CH:16]=4)=[CH:14][CH:13]=[CH:12][C:11]=5[OH:10])=[O:24])[CH:61]=[CH:62][CH:63]=3)=[CH:57][C:52]=2[CH2:51][CH2:50]1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(-c2ccc3c(c2)CCO3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccc3c(c2)CCO3)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 49.4 %

Procedure:
DIEA (0.014 mL, 0.078 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.015 g, 0.071 mmol) and HATU (0.030 g, 0.078 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2,3-dihydro-benzofuran-5-yl)-phenylamine (0.015 g, 0.071 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.014 g of product in 49% yield: LCMS (ESI) m/z 400 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[C:14]([CH3:28])([O:16]C3C=CC(C4NN=NN=4)=CC=3)[CH3:15])[C:11]3[CH:35]=[C:36]([F:40])[C:37]([F:39])=[CH:38][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[F:41][C:42]1[CH:43]=[C:44]([CH:47]=[C:48]([F:51])[C:49]=1F)[C:45]#[N:46].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[C:14]([CH3:15])([CH3:28])[O:16][C:49]3[C:48]([F:51])=[CH:47][C:44]([C:45]#[N:46])=[CH:43][C:42]=3[F:41])[C:11]3[CH:35]=[C:36]([F:40])[C:37]([F:39])=[CH:38][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(Oc1ccc(-c2nnn[nH]2)cc1)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: N#Cc1cc(F)c(F)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(Oc1c(F)cc(C#N)cc1F)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reaction time: 18 h

Procedure:
A solution of 0.10 g (0.24 mmol) (−)-1-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-1-cyclohexyl-2-methyl-propan-2-ol (Example 88, intermediate b) and 38 mg (0.24 mmol) 3,4,5-trifluorobenzonitrile in 2 ml anhydrous tetrahydrofuran was cooled down to 0° C. Then, 0.53 ml (0.26 mmol) potassium bis(trimethylsilyl)amide (0.5 M solution in toluene) were added dropwise to the reaction mixture. The cooling bath was removed and stirring was continued for 18 h. The reaction mixture was poured onto aqueous saturated ammonium chloride solution and the phases were separated. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with n-heptane for 5 min., then with a gradient of dichloromethane:ethyl acetate (100:0 to 95:5). Light brown foam (45%). MS (Turbo Spray): m/z=556.2 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[NH:4][CH2:5][CH2:6][CH:7]=[O:8].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:26][CH2:27][C:28](Cl)=[O:29]>O>[Cl:26][CH2:27][C:28]([N:4]([CH2:5][CH2:6][CH:7]=[O:8])[C:3]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=1[CH3:1])=[O:29]
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(Cl)ccc1NCCC=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: Cc1cc(Cl)ccc1N(CCC=O)C(=O)CCl
Temperature: 25 °C

Procedure:
The diethyl acetal of 3-(2-methyl-4-chloroanilino)propionaldehyde (0.2 mole), benzene (150 ml) and sodium carbonate (0.2 mole) dissolved in water (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The mixture is cooled in an ice bath and chloroacetyl chloride (0.2 mole) is added dropwise with stirring. After addition is completed stirring is continued and the reaction mixture is allowed to warm up to room temperature. After this time the mixture is filtered and the filtrate washed with dilute aqueous hydrochloric acid. The washed filtrate is dried over anhydrous magnesium sulphate and is stripped of solvent under reduced pressure to yield the desired product the diethyl acetal of 3-[N-(α-chloroacetyl)-2-methyl-4-chloroanilino]propionaldehyde.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Br:11]Br>C(Cl)Cl>[Br:11][C:2]1[C:1](=[O:10])[C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=C1C=Cc2ccccc21
Reactant: BrBr
Solvent: ClCCl
Product: O=C1C(Br)=Cc2ccccc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The indenone of formula 23 prepared in Step 2 is dissolved in CH2Cl2, 1M Br2 solution (dissolved in CH2Cl2) is added thereto. The resulting mixture is stirred for 2 to 3 h at room temperature, to obtain the 2-bromoindenone of formula 17.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6]([C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:10]=1[N:11]([CH3:14])[CH:12]=[O:13])(=[O:8])[CH3:7].O>ClCCl>[Cl:19][C:16]1[CH:17]=[CH:18][C:9]([C:6](=[O:8])[CH2:7][Cl:4])=[C:10]([CH:15]=1)[N:11]([CH3:14])[CH:12]=[O:13]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)c1ccc(Cl)cc1N(C)C=O
Solvent: ClCCl
Solvent: O
Product: CN(C=O)c1cc(Cl)ccc1C(=O)CCl
Reaction time: 0.08 h

Procedure:
A solution of sulphuryl chloride (9 ml) in dichloromethane (15 ml) was added dropwise to the solution of 2'-acetyl-5'-chloro-N-methylformanilide under nitrogen whilst maintaining the temperature at 0 to Water (40 ml) was then added dropwise whilst maintaining the temperature at 0 to 10°. The mixture was stirred for a further 5 minutes and then the dichloromethane layer was separated and dried over magnesium sulphate to give a solution of 5'-chloro-2'-(2-chloroacetyl)-N-methylformanilide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:9])[C:6]([OH:8])=[O:7].C(Cl)(=O)C(C)=C.[C:16]([N:21]=[C:22]=[O:23])(=[O:20])[C:17]([CH3:19])=[CH2:18]>C(N(CC)CC)C>[C:16]([NH:21][C:22]([O:1][CH2:2][CH2:3][NH:4][C:5](=[O:9])[C:6]([OH:8])=[O:7])=[O:23])(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: O=C(O)C(=O)NCCO
Reactant: C=C(C)C(=O)N=C=O
Agent: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)NC(=O)OCCNC(=O)C(=O)O

Procedure:
In example 1, when the reaction of a triethylamine salt of 2-hydroxyethyloxamic acid with methacrylic acid chloride was performed, 5.5 g (0.05 moles) of methacryloylisocyanate were used instead of methacrylic acid chloride with no use of TEA and the reaction was carried out at room temperature. Except the forementioned, the same procedure as for example 1 was carried out to get methacryloylcarbamoyloxyethyloxamic acid of the following structure. ##STR18##
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[C:25]([C:29]1[CH:33]=[CH:32][C:31](=[C:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:30]=1)([CH3:28])([CH3:27])[CH3:26].Cl>C(OCC)C>[C:25]([C:29]1[CH:33]=[CH:32][CH:31]([C:34]([C:1]2[C:13]3[CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[CH:4]=[CH:3][CH:2]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(C)(C)C1=CC(=C(c2ccccc2)c2ccccc2)C=C1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)C1=CC(C(c2ccccc2)(c2ccccc2)c2cccc3c2Cc2ccccc2-3)C=C1
Temperature: 25 °C

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 0.76 g of fluorene (4.57 mmol) was dissolved in 40 ml of dehydrated diethyl ether in a nitrogen atmosphere. To the solution, 3.1 ml of a n-butyl lithium/hexane solution (1.57M: 4.87 mmol) was gradually added dropwise in an ice bath and stirred at room temperature for over night. The solvent was distilled off under reduced pressure and thereby a reddish-orange solid was obtained. To the solid, a solution prepared by dissolving 2.40 g of 2-tert-butyl-6,6-diphenyl fulvene (8.38 mmol) in 150 ml of dehydrated diethyl ether was added and stirred under reflux for 7 days. The reaction mixture was added to 150 ml of a hydrochloric acid aqueous solution (2%) and then diethyl ether was added therein to separate an organic phase. The organic phase was washed with water and saturated brine. The organic phase was dried with anhydrous magnesium sulfate and the drying agent was filtered off. The solvent was distilled off under reduced pressure from the filtrate and thereby orange brown oil was obtained. The oil was re-crystallized using hexane and thereby the aimed compound was obtained in an amount of 1.03 g (2.28 mmol) as a pale yellow solid. The solid further was purified with a chromatography using 100 g of silica gel (developing solvent: n-hexane) and the developing solvent was distilled off under reduced pressure and thereby the aimed compound was obtained in an amount of 0.370 g (0.817 mmol) as a yellow solid (yield: 67%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[C:24]4=[N:25][CH:26]=[N:27][C:28]([NH2:29])=[C:23]4[C:22]([C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)=[CH:32][CH:31]=4)=[N:21]3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[C:24]4=[N:25][CH:26]=[N:27][C:28]([NH2:29])=[C:23]4[C:22]([C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)=[CH:32][CH:31]=4)=[N:21]3)[CH2:16][CH2:15]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC(n3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCN(C2CCNCC2)CC1
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
1-[1-(1-tert-butoxycarbonyl-4-piperidinyl)-4-piperidinyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (254 mg, 0.446 mmol) was stirred in 25 ml of 10% trifluoroacetic acid in dichloromethane overnight. The solvent was evaporated and the residue was dissolved in dichloromethane. Saturated sodium bicarbonate was added and the resulting mixture was stirred for 30 minutes. The layers were separated and the aqueous layer was extracted with dichloromathane. The combined organic layer was washed, dried and evaporated to give 108 mg of 1-[1-(4-piperidinyl)-4-piperidinyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate GG) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH:20][CH:21]4[CH2:23][CH2:22]4)[C:14]=3[S:13][CH:12]=2)=[O:10])[CH:7]=1.[CH3:25][C:26]1[N:27]=[CH:28][N:29]([C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][C:32]=2[C:40]([F:43])([F:42])[F:41])[CH:30]=1>>[CH:21]1([NH:20][C:19]2[C:14]3[S:13][CH:12]=[C:11]([C:9]([NH:8][C:6]4[CH:7]=[C:2]([NH:1][C:35](=[O:36])[C:34]5[CH:38]=[CH:39][C:31]([N:29]6[CH:30]=[C:26]([CH3:25])[N:27]=[CH:28]6)=[C:32]([C:40]([F:41])([F:43])[F:42])[CH:33]=5)[CH:3]=[CH:4][C:5]=4[CH3:24])=[O:10])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:22][CH2:23]1
Reactant: Cc1ccc(N)cc1NC(=O)c1csc2c(NC3CC3)ncnc12
Reactant: Cc1cn(-c2ccc(C(=O)O)cc2C(F)(F)F)cn1
Product: Cc1cn(-c2ccc(C(=O)Nc3ccc(C)c(NC(=O)c4csc5c(NC6CC6)ncnc45)c3)cc2C(F)(F)F)cn1

Procedure:
The procedure of Step 5 of Example 1 was repeated except for using N-(5-amino-2-methylphenyl)-4-(cyclopropylamino)thieno[3,2-d]pyrimidine-7-carboxamide and 4-(4-methyl-1H-imidazole-1-yl)-3-(trifluoromethyl)benzoic acid to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].S(Cl)(Cl)=O.[CH3:21][O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>>[C:1]([C:3]1([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:27][C:26]3[CH:28]=[CH:29][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)=[O:14])=[CH:15][CH:16]=2)[CH2:4][CH2:5][CH2:6][CH2:7]1)#[N:2]
Reactant: N#CC1(c2ccc(C(=O)O)cc2)CCCC1
Reactant: COc1ccc(N)cc1
Solvent: O=S(Cl)Cl
Product: COc1ccc(NC(=O)c2ccc(C3(C#N)CCCC3)cc2)cc1

Procedure:
5.8 g. (27 mMol) 4-(1-cyanocyclopentyl)-benzoic acid are reacted with thionyl chloride and subsequently with 4-methoxyaniline as described in Example 1 to give 5.1 g. of the title compound; m.p. 163°-168° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[I:16])([OH:8])[C:4]([F:7])([F:6])[F:5].[Br:19]N1C(=O)CCC1=O>CC(O)C>[Br:19][I:16]1[C:10]2[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=2[C:3]([C:4]([F:7])([F:6])[F:5])([C:2]([F:1])([F:17])[F:18])[O:8]1
Reactant: Cc1ccc(I)c(C(O)(C(F)(F)F)C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(C)O
Product: Cc1ccc2c(c1)C(C(F)(F)F)(C(F)(F)F)OI2Br
Temperature: 50 °C
Yield: 100 %

Procedure:
Compound 2 (100 mg, 0.26 mmol) was dissolved in 5 mL propan-2-ol and N-bromosuccinimide (48.7 mg, 0.273 mmol) is added. The reaction mixture was heated 30 min at 50° C. After removal of the solvent under vacuum, the residue was purified over silica gel column using dichloromethane as eluant to give 111 mg (0.26 mmol, 92% yield) of a yellow solid.
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].Cl[CH2:10][C:11]#[N:12]>CCCCCCC>[F:3][C:4]([F:8])([F:7])[CH2:5][O:6][CH2:10][C:11]#[N:12]
Reactant: OCC(F)(F)F
Reactant: N#CCCl
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCCC
Product: N#CCOCC(F)(F)F
Temperature: 25 °C

Procedure:
At about 50° C., 26.4 g (0.40 mole) of 85% potassium hydroxide are solubilized in 100 g (1.0 mole) of 2,2,2-trifluoroethanol. After cooling at 25° C. 37.8 g (0.50 mole) of chloroacetonitrile are added dropwise to this solution. The temperature rises slowly to 40° C. and a precipitate appears. The reaction mixture is then brought gradually to 60° C.; after the addition of 300 ml of heptane, it is then brought to reflux. The whole of the vapour is condensed by means of a Dean and Stark apparatus. The lower phase of the condensate is separated after settling has taken place and distilled at atmospheric pressure. Yld: 19.6 g (28%), b.p. 125°-140° C.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[CH2:48]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:50][CH:49]1[NH2:57]>>[CH2:48]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:50][CH:49]1[NH:57][C:41]([C:39]1[S:40][C:36]([N:33]2[CH2:34][CH2:35][N:31]([CH2:30][C:29]3[CH:46]=[CH:47][C:26]([F:25])=[CH:27][CH:28]=3)[C:32]2=[O:45])=[CH:37][C:38]=1[CH3:44])=[O:42]
Reactant: NC1Cc2ccccc2C1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NC1Cc2ccccc2C1
Yield: 84 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with 2,3-dihydro-1H-inden-2-amine, the title compound was obtained as an off-white solid in 84% yield: 1H NMR (300 MHz, CDCl3) δ 7.30-7.15 (m, 6H), 7.07-6.98 (m, 2H), 6.06 (s, 1H), 5.90 (d, J=7.2 Hz, 1H), 4.92-4.80 (m, 1H), 4.42 (s, 2H), 3.84-3.74 (m, 2H), 3.47-3.32 (m, 4H), 2.90 (d, J=4.7 Hz, 1H), 2.85 (d, J=4.7 Hz, 1H), 2.47 (s, 3H); MS (ES+) m/z 450.2 (M+1).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][C@@H:5]([CH:7]2[CH2:9][N@@:8]2[S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[O:4][C:3]1=[O:22].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][C:34]([CH3:37])([CH3:36])[NH:33][CH2:32][C:31]1=[O:38]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[C:31](=[O:38])[CH2:32][N:33]([CH2:9][C@H:7]([NH:8][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C@@H:5]2[CH2:6][C@@H:2]([CH3:1])[C:3](=[O:22])[O:4]2)[C:34]([CH3:37])([CH3:36])[CH2:35]1
Reactant: CC1(C)CN(c2ccccc2Cl)C(=O)CN1
Reactant: C[C@@H]1C[C@@H](C2C[N@@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Agent: C[C@@H]1C[C@@H](C2C[N@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Solvent: Cc1ccccc1
Product: C[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3Cl)CC2(C)C)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Yield: 94.1 %

Procedure:
A solution of 822 mg of (3R,5S)-3-methyl-5-[(S)-1-(2-nitrobenzenesulfonyl)aziridin-2-yl]dihydrofuran-2-one obtained in Example (76g) (2.52 mmol) and 722 mg of 1-(2-chlorophenyl)-5,5-dimethylpiperazin-2-one obtained in Example (1k) (3.02 mmol) in toluene (25 ml) was stirred at 110° C. for two hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/ethyl acetate=3/1-2/1) to obtain 1.34 g of the title compound (yield: 94%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:18]3[N:22]=[C:21]([CH3:23])[O:20][N:19]=3)([CH3:17])[C:14]([OH:16])=O)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(O)(=O)C(O)=O.[CH2:36]1[C:39]2([CH2:42][NH:41][CH2:40]2)[CH2:38][O:37]1>>[CH:1]1([C:4]2[C:5]([O:24][CH2:25][C:26]([F:29])([F:27])[F:28])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:18]3[N:22]=[C:21]([CH3:23])[O:20][N:19]=3)([CH3:17])[C:14]([N:41]3[CH2:42][C:39]4([CH2:36][O:37][CH2:38]4)[CH2:40]3)=[O:16])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)C(=O)O)no1
Reactant: C1NCC12COC2
Agent: O=C(O)C(=O)O
Product: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)C(=O)N2CC3(COC3)C2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]-2-(5-methyl-1,2,4-oxadiazol-3-yl)propanoic acid (Example 147c) and 2-oxa-6-azaspiro[3.3]heptane oxalate (2:1) (CAN 1045709-32-7) as starting materials and isolated (8 mg, 10%); MS (ESI, m/z): 496.5 (M+H+).
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:9][C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>C(Cl)Cl>[Cl:9][C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12]([O:14][C:1]1([N:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:13]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: ON=C1CCCCC1
Solvent: ClCCl
Product: O=NC1(OC(=O)c2ccc(Cl)cc2Cl)CCCCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1-Nitrosocyclohexyl 2,4-dichlorobenzoate was prepared according to General Method 3. A solution of cyclohexanone oxime (2.66 g, 23.5 mmol) in DCM (50 ml) was added dropwise to a solution of lead tetra acetate (10.42 g, 23.5 mmol) and 2,4 dichlorobenzoic acid (45.0 g, 235 mmol) in DCM (300 ml) at 0° C. A blue color gradually appears on addition of the oxime solution. Upon complete addition (1 hour) the reaction was allowed to warm to ambient temperature and stirring was continued for a further 2-3 hours. The reaction was quenched by the addition of water, the phases separated and the organics dried over Na2SO4 and concentrated in vacuo to afford 1-nitrosocyclohexyl 2,4-dichlorobenzoate which was purified by column chromatography on silica gel with hexane:EtOAc as the eluent to afford the title compound as a blue oil in 9% yield. δH (400MHz, DMSO-d6) δ 8.02 (1H, d, 8.4 Hz), 7.85 (1H, d, 2.0 Hz), 7.64 (1H, dd, 8.4, 2.0 Hz), 2.03-2.12(2H, m), 1.38-1.93 (8H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[O:5].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([S:28](Cl)(=[O:30])=[O:29])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>N1C=CC=CC=1>[Br:17][C:14]1[CH:15]=[CH:16][C:2]([NH:1][S:28]([C:22]2[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:20]([O:19][CH3:18])[CH:21]=2)(=[O:30])=[O:29])=[C:3]([CH:13]=1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[O:5]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1F
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(Br)cc2C(=O)c2ccccc2F)cc1OC

Procedure:
20 g of 2-amino-5-bromo-2'-fluorobenzophenone are heated at 85° C. for 48 hours in 120 ml of dry pyridine in the presence of 20 g of 3,4-dimethoxyphenylsulfonyl chloride. The mixture is cooled, poured into ice-cold water, the solid is filtered off, the solid is extracted with AcOEt, the organic phase is washed with water, a solution of hydrochloric acid (1N), water and then saline water. After drying over magnesium sulfate and evaporating the solvent under vacuum, a solid is obtained which is recrystallized from DCM/isopropyl ether.