Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH:25]1([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37][O:38]S(C3C=CC(C)=CC=3)(=O)=O)[N:35]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37][O:38][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([O:15][C:16]4[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=4)([CH3:14])[C:4]([OH:24])=[O:3])=[CH:12][CH:11]=3)[N:35]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(F)c(F)c1
Product: Cc1oc(C2CCCCC2)nc1CCOc1ccc(CC(C)(Oc2ccc(F)c(F)c2)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(3,4-difluoro-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyloxazol-4-yl)-ethyl ester using the method of Example 56. 1H NMR (400 MHz, CDCl3) δ 9.37 (bs, 1H), 7.16 (d, 2H, J=8.4 Hz), 6.99 (dd, 1H, J=9.5 Hz), 6.78 (d, 2H, J=8.4 Hz), 6.77-6.72 (m, 1H), 6.63-6.58 (m, 1H), 4.12 (t, 2H, J=6.4 Hz), 3.21 and 3.08 (d of ABq, 2H, J=14.0 Hz), 2.97 (t, 2H, J=6.4 Hz), 2.91 (tt, 1H, J=12.0, 3.6 Hz), 2.32 (s, 3H), 2.04-1.98 (m, 2H), 1.85-1.78 (m, 2H), 1.76-1.68 (m, 1H), 1.62-1.49 (m, 2H), 1.41-1.19 (m, 3H), 1.37 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH2:9][CH2:10][CH3:11])=[O:8])[CH:2]=1.[Br:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(CCN2CCCC(C(C)=O)=C2)C=CC=CC=1>>[Br-:12].[CH2:13]([N+:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[O:8])[CH2:9][CH2:10][CH3:11])[CH:2]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCC(=O)c1cccnc1
Reactant: CCCCBr
Agent: CC(=O)C1=CN(CCc2ccccc2)CCC1
Product: CCCC[n+]1cccc(C(=O)CCC)c1
Product: [Br-]

Procedure:
Propyl 3-pyridyl ketone was reacted with 1-bromobutane according to the procedure of Part (a) of Example 6 to give 1-butyl-3-butyryl pyridinium bromide as a tan coloured crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].O>CN(C)C=O>[CH2:33]([O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: Nc1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1ccc(N)cc1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 40.8 %

Procedure:
To a solution of 15.0 g of 4-aminophenol dissolved in 300 ml of N,N-dimethylformamide, was added 28.5 g of anhydrous potassium carbonate. Subsequently, 46.0 g of 1-bromooctadecane was added thereto at 80° C., and the mixture was stirred for 3.5 hours at 80° C. Water was added to the reaction mixture, and the whole was extracted with ethyl acetate. The organic layer was washed with saturated brine, and was dried over anhydrous magnesium sulfate. The crude product obtained by removal of the solvent under reduced pressure was purified by silica gel column chromatography (eluent: hexane—ethyl acetate—chloroform=5:1:1 to 1:1:1), followed by recrystallization from chloroform—methanol, to yield 20.28 g of 4-octadecyloxyaniline (melting point: 95-97° C.) (Reaction Scheme (58) described below).
Reaction SMILES: [CH3:1][C@H:2]([C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=C)[C@H:3]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C[N+]1([O-])CC[O:30]CC1.O>C1COCC1.CCOC(C)=O.O=[Os](=O)(=O)=O>[CH3:1][C@@H:2]([C:18](=[O:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@H:3]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: C=C(c1ccccc1)[C@@H](C)[C@H](NC(=O)C(F)(F)F)C(=O)OC(C)(C)C
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](C(=O)c1ccccc1)[C@H](NC(=O)C(F)(F)F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To olefin 16 (903.4 mg, 2.53 mmol) in THF (25 mL) under N2 was added NMO (60% wt solution in H2O, 0.90 mL, 5.06 mmol) and OsO4 (4% wt solution in H2O, 1.50 mL, 0.25 mmol). The solution was stirred at ambient temperature for 16 h, and NaIO4 (2.16 g, 10.12 mmol) was then added, followed by H2O (2.7 mL). Stirring was continued for 4 h, and the reaction mixture was then diluted with EtOAc (200 mL) and washed with 10% Na2S2O3 (4×50 mL). The combined washings were extracted with EtOAc (50 mL). The organic solutions were combined and washed with 5 M NaCl (20 mL) and dried, and the solvent was evaporated. The residue was separated by chromatography (silica gel, 30 g; 9:1 hexane-EtOAc) and led to 0.632 g (70%) of 18 as a colorless solid: mp 127-128° C.; Rf0.19 (95:5 hexane-EtOAc); [α]23D−39.0 (c 1.05, CH3OH); 1H NMR δ 7.92 (2H, dd, J=7.5 and 1.3 Hz), 7.60 (1H, tt, J=7.5 and 1.3 Hz), 7.49 (2H, t, J=7.6 Hz), 7.03 (1H, br d, J=6.7 Hz), 4.72 (1H, dd, J=7.4 and 4.8 Hz), 4.13 (1H, m), 1.49 (9H, s), 1.36 (3H, d, J=7.2 Hz); 13C NMR δ 200.0, 168.3, 156.9 (q), 135.5, 133.6, 128.8, 128.4, 83.8, 55.0, 42.9, 27.8, 14.2; MS APCI+ m/z 360.1417 [M+H]+ (calcd for C17H21F3NO4, 360.1423); anal. C, 56.39%, H, 5.60%, N, 3.96%, calcd for C17H20F3NO4, C, 56.82%, H, 5.61%, N, 3.90%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][CH:28](C(O)=O)[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[C:4]([CH3:34])[CH:3]=1.Cl.[NH2:36][OH:37].[C:38](=[O:41])([O-])[OH:39].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:20]=[CH:21][C:22]([N:25]3[CH2:30][CH2:29][CH:28]([C:38]([OH:39])=[O:41])[CH2:27][CH2:26]3)=[CH:23][CH:24]=2)[CH2:9]/[C:10](=[N:36]\[OH:37])/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[C:4]([CH3:34])[CH:3]=1
Reactant: O=C([O-])O
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@@H](c2ccc(N3CCC(C(=O)O)CC3)cc2)c2ccc(Cl)cc2C)ccn1
Agent: Cl
Agent: [Na+]
Product: Cc1cc(/C(C[C@@H](c2ccc(N3CCC(C(=O)O)CC3)cc2)c2ccc(Cl)cc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from 1-{4-[(S)-1-(4-chloro-2-methyl-phenyl)-3-(2-methyl-pyridin-4-yl)-3-oxo-propyl]-phenyl}-piperidine-4-carboxylic acid and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a light yellow foam, MS (ESI−): m/z=490.3 ([M−H]−).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[S:7])[CH3:6].[Cl:8][C:9]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:10]=1[O:11][C:12]1[CH:13]=[C:14]([C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1)[CH2:15]Cl>O1CCCC1>[Cl:8][C:9]1[CH:26]=[C:25]([C:27]([F:28])([F:30])[F:29])[CH:24]=[CH:23][C:10]=1[O:11][C:12]1[CH:13]=[C:14]([C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1)[CH2:15][CH2:6][C:5]([O:4][CH3:3])=[S:7]
Reactant: COC(C)=S
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=S)CCc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 73 %

Procedure:
1.44 parts by weight of 80% strength sodium hydride were suspended in 25 parts by volume of absolute tetrahydrofuran, and a solution of 5.31 parts by weight of methylthioacetate in 50 parts by volume of absolute tetrahydrofuran was added a little at a time at room temperature. Stirring was continued for half an hour and a solution of 18.3 parts by weight of 3-(2'-chloro-4'-trifluoromethylphenoxy)-6-nitrobenzyl chloride in 50 parts by volume of absolute tetrahydrofuran was then added. The reaction mixture was then stirred under reflux for a further 3 hours, was cooled, and was concentrated under reduced pressure. The residue was taken up in ether, the solution was extracted with water, the organic phase was separated off, dried with magnesium sulfate and filtered, and the ether was evaporated. The oily residue crystallized when triturated and was recrystallized from diisopropyl ether. 16 parts by weight (73% of theory) of methyl 3-(2'-chloro-4'-trifluoromethylphenoxy)-6-nitrobenzylthioacetate (compound No. 13) of melting point 61°-63° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.[CH3:22][C:23]1[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=1>>[ClH:1].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:19][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([N:24]3[C:23]([CH3:22])=[CH:27][C:26]([CH3:28])=[N:25]3)[N:11]=2)=[CH:16][CH:15]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Cc1cc(C)[nH]n1
Reactant: NCc1ccc(Cl)cc1
Product: Cc1cc(C)n(-c2nc(NCc3ccc(Cl)cc3)c3ccccc3n2)n1
Product: Cl

Procedure:
Was prepared according to Method A from 2,4-dichloroquinazoline, 4-chlorobenzylamine and 3,5-dimethylpyrazole. LC-ESI-HRMS [M+H]+ 364.1319 Da. Calc. 364.132898 Da.
Reaction SMILES: N1CCOCC1.[C:7]([OH:11])(=[O:10])[CH:8]=O.[CH3:12][CH2:13][CH2:14][CH2:15][CH:16]=[O:17].Cl>CCCCCCC>[OH:17][CH:16]1[O:11][C:7](=[O:10])[CH:8]=[C:15]1[CH2:14][CH2:13][CH3:12]
Reactant: O=CC(=O)O
Reactant: CCCCC=O
Agent: Cl
Solvent: CCCCCCC
Solvent: C1COCCN1
Product: CCCC1=CC(=O)OC1O
Temperature: 0 °C

Procedure:
Heptane (394 mL) and morpholine (127.5 mL) are introduced in a reactor while stirring. The mixture is cooled to 0° C. and glyoxylic acid (195 g, 150 mL, 50 wt % in water) is added. The mixture is heated to 20° C. during 1 hour and then n-valeraldehyde (148.8 mL) is added. The reaction mixture is heated at 45° C. during 20 hours. After cooling down to 20° C., a 37% aqueous solution of hydrochloric acid (196.9 mL) is slowly added to the mixture, which is then stirred during 2 hours.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[F:5][C:6]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:7]=1[C:8]([Cl:10])=[O:9].[CH2:19]([NH:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:29]=1Cl)[CH2:20][CH2:21][CH3:22]>O1CCCC1>[ClH:10].[CH2:19]([N:23]1[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][C:29]=2[S:1]/[C:2]/1=[N:3]\[C:8](=[O:9])[C:7]1[CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=[CH:14][C:6]=1[F:5])[CH2:20][CH2:21][CH3:22]
Reactant: N#C[S-]
Reactant: CCCCNc1cnccc1Cl
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)sc2ccncc21
Product: Cl
Temperature: 50 °C
Yield: 93.5 %

Procedure:
To a three-necked flask were charged potassium thiocyanate (200.0 g, 2.03 mol), and tetrahydrofuran (6.78 L). 2-Fluoro-5-(trifluoromethyl)benzoyl chloride (471.0 g, 2.07 mol) was added into the flask slowly at room temperature. The reaction mixture was stirred at room temperature for 5 hours or until less than 1% of the acid chloride remains. The reaction mixture was filtered to remove potassium chloride by-product, and rinsed with tetrahydrofuran (about 0.5 L). The combined solution of 2-fluoro-5-(trifluoromethyl)benzoyl isothiocyanate was charged back to the three-necked flask, followed by addition of N-butyl-4-chloropyridin-3-amine (266.0 g, 1.44 mol). The reaction mixture was heated to approximately 50° C., and stirred vigorously overnight or until less than 1% of N-butyl-4-chloropyridin-3-amine remains. The product suspension was then cooled to room temperature, and the product collected by filtration. The wet cake was washed with tetrahydrofuran (1.0 L), and dried under vacuum at 60° C. to give the desired product (584.0 g, 93% isolated yield). MS-ESI: 398 (M+1); 1H-NMR (CDCl3-DMSO-d6) δ 0.96 (3H, t, J=7.4 Hz), 1.45 (2H, m), 1.84 (2H, m), 4.58 (2H, d, J=7.6 Hz), 7.49 (1H, t, J=9.0 Hz), 7.92 (1H, m), 8.42 (1H, d, J=5.8 Hz), 8.46 (1H, dd, J=6.6, 2.5 Hz), 8.65 (1H, d, J=6.6 Hz), 9.37 (1H, s); 13-NMR (CDCl3-DMSO-d6) δ 13.50, 19.47, 29.12, 46.08, 118.07 (d, J=23 Hz), 119.70, 122.90 (q, J=269 Hz, CF3), 123.96 (d, J=10 Hz), 124.84 (q, J=33 Hz, C—CF3), 128.21, 128.78, 130.70, 134.50, 137.03, 141.20, 162.78 (d, J=262 Hz, C—F), 165.79, 170.06 (d, J=4.0 Hz).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:17][C@H:18]3[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:44](Br)[CH:45]=[CH2:46].CN(C)C=O>C(OCC)C>[F:37][C:2]([F:36])([F:1])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[N:22]([CH2:46][CH:45]=[CH2:44])[C@@:16]2([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:17][C@H:18]3[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCN1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)C[C@H]2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 79 %

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 25; 424 mg, 0.8 mmol), potassium carbonate (770 mg), allyl bromide (0.5 ml) and N,N-dimethylforamide (3 ml) was stirred at room temperature for 3 days. The reaction mixture was treated with 1:1 mixture diethyl ether:iso-hexane, washed with water, dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether) to give the title compound (362 mg, 79%).
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH:12]1([CH2:15][NH:16][CH2:17][CH:18]2[CH2:20][CH2:19]2)[CH2:14][CH2:13]1.C1(CNCC)CCCC1>>[CH:12]1([CH2:15][N:16]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:2]2[C:9]([F:10])=[CH:8][C:7]([F:11])=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:14][CH2:13]1
Reactant: O=Cc1cc(F)cc(F)c1F
Reactant: C1CC1CNCC1CC1
Agent: CCNCC1CCCC1
Product: O=Cc1cc(F)cc(F)c1N(CC1CC1)CC1CC1

Procedure:
By using 2,3,5-trifluorobenzaldehyde instead of 2-fluoro-5-(trifluoromethyl)benzaldehyde, and N,N-bis(cyclopropylmethyl)amine synthesized by the method described in International Patent Publication WO2006/073973 instead of N-(cyclopentylmethyl)-N-ethylamine, reactions and treatments were performed in the same manner as those of Step 3 of Example 1 to obtain 2-[bis(cyclopropylmethyl)amino]-3,5-difluorobenzaldehyde as a yellow oil.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10][CH2:11]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[Li+].[Br-:34]>ClCCl.O>[Si:1]([O:8][C@H:9]([CH2:10][CH2:11][Br:34])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H](CCO)CCc1ccccc1
Reactant: [Br-]
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H](CCBr)CCc1ccccc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 85.5 %

Procedure:
(S)-3-(t-butyldimethylsilyloxy)-5-phenyl-pentan-1-ol (10.6 g, 36 mmol) was dissolved in dichloromethane (80 ml), triethylamine (12.6 ml, 90.5 mmol) was added, and the mixture was cooled to 0° C. Methane sulfonyl chloride (4.2 ml, 54.3 mmol) was slowly added dropwise and the resulting mixture was stirred for 12 hours. After completion of the reaction, the reaction mixture was diluted with water (50 ml). The organic layer was separated and the aqueous layer was extracted with dichloromethane (50 ml×2). The organic layers were combined, washed with saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated. Without further purification, the residue was dissolved in THF (60 ml). LiBr (7.86 g, 90.5 mmol) was added thereto and the mixture was refluxed for 4 hours. After completion of the reaction, water (80 ml) was added to the reaction solution which was then extracted with diethylether. The organic layers were combined, washed with saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to give colorless and transparent (S)-3-(t-butyldimethylsilyloxy)5-bromo-1-phenyl pentane (11 g, Yield 86%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].[O-][Si]([O-])=O.[Mg+2]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[N:13]=[C:14]1[C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)[CH3:2]
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(Br)cc1
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CCOC(=O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21

Procedure:
N-[3-[(4-bromobenzoyl)amino]-2-pyridinyl]glycine ethyl ester (4.6 g, 0.012 mole) was heated in glass in a 190° C. oil bath for 1/2 hour. The melt was cooled and methylene chloride (150 ml) added. The solution was twice treated with 25 g of Florisil® and filtered. The filtrate was concentrated vacuo and the residue recrystallized from isopropyl ether-ethanol to give 2.1 g (49%) of a white flocculent solid, mp 138°-139° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[Cl:16])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Nc1ccccc1Cl
Reactant: O=C1CCCc2c1[nH]c1ccc(Br)cc21
Product: Clc1ccccc1NC1CCCc2c1[nH]c1ccc(Br)cc21

Procedure:
6-Bromo-N-(2-chlorophenyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (200 mg, 0.76 mmol) and 2-chloroaniline (193 mg, 1.51 mmol) in a similar manner as described above to give 43 mg (15%) of a white solid; 1H-NMR (DMSO-d6): δ 11.08 (s, 1H), 7.57 (d, 1H), 7.27-7.23 (m, 2H), 7.16-7.12 (m, 2H), 6.92 (d, 1H), 6.64-6.60 (m, 1H), 5.12 (d, 1H), 4.95-4.90 (m, 1H), 2.71-2.56 (m, 2H), 2.04-1.76 (m, 4H); MS m/z (M−1) 373, 375.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26](F)([F:28])[F:27])[CH:21]=3)[C:11](=[O:30])[N:10]2[C:31]([NH:33][CH3:34])=[O:32])=[C:5]([S:35]([CH3:38])(=[O:37])=[O:36])[CH:4]=1)#[N:2].C(C1C=CC(C2C3C(=O)CCCC=3N(C3C=CC=C(C(F)F)C=3)C(=O)N2C(OC2C=CC([N+]([O-])=O)=CC=2)=O)=C(S(C)(=O)=O)C=1)#N>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([F:27])[F:28])[CH:21]=3)[C:11](=[O:30])[N:10]2[C:31]([NH:33][CH3:34])=[O:32])=[C:5]([S:35]([CH3:38])(=[O:36])=[O:37])[CH:4]=1)#[N:2]
Reactant: CNC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1S(C)(=O)=O
Agent: CS(=O)(=O)c1cc(C#N)ccc1C1C2=C(CCCC2=O)N(c2cccc(C(F)F)c2)C(=O)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Product: CNC(=O)N1C(=O)N(c2cccc(C(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1S(C)(=O)=O

Procedure:
The title compound is prepared in analogy to 4-(4-cyano-2-(methylsulfonyl)-phenyl)-N-methyl-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazoline-3(4H)-carboxamide (example 47), using 4-nitrophenyl 4-(4-cyano-2-(methylsulfonyl)-phenyl)-1-(3-(difluoromethyl)phenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinazoline-3(4H)-carboxylate (intermediate 39, 16 mg, 25 μmol), as starting material. Yield: 9 mg, ESI mass spectrum [M+H]+=529; Retention time HPLC: 0.97 min (Z017_S04).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][CH:8]([F:12])[C:9](O)=[O:10].[CH3:13][C:14]([SH:17])([CH3:16])[CH3:15]>C(#N)C.[Co](Cl)Cl>[F:7][CH:8]([F:12])[C:9](=[O:10])[S:17][C:14]([CH3:16])([CH3:15])[CH3:13]
Reactant: O=C(O)C(F)F
Reactant: CC(C)(C)S
Agent: Cl[Co]Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CC#N
Product: CC(C)(C)SC(=O)C(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.2 %

Procedure:
To a solution of oxaloyl chloride (9.08 mL, 104 mmol) in acetonitrile (ACN) (50 mL) at 25 ° C. was added dropwise difluoroacetic acid (6.55 mL, 104 mmol). After 3 hours, 2-methyl-2-propanethiol (11.74 mL, 104 mmol) was added dropwise followed by cobalt(II) chloride (10 mg). After being stirred at room temperature for 18 hours, additional 2-methyl-2-propanethiol (4.0 mL, 35.4 mmol) was added. After 2 hours, the solution was poured onto Et2O (500 mL) and washed with saturated NaHCO3 (2×300 mL) and H2O(2×300 mL). The organic layer was dried over Na2SO4, and the solvent was removed under reduced pressure to give a red oil. Vacuum distillation at 30 mm Hg gave S-tert butyl difluoroethane-thioate (8.26 g, 47% yield) as a colorless oil: bp 59-63° C. (30 mm Hg); 1H NMR (CDCl3) δ 1.48 (s, 9H), 5.67 (t, 1H, J=54 Hz); 13C NMR (CDCl3) δ 29.45, 49.32, 108.94 (t, J=255 Hz), 191.23 (t, J=28 Hz); 19F NMR (CDCl3) δ -123.65 (d, J=55 Hz); IR (film, cm-1) 2969, 1684, 1154, 1093, 1064. Anal. Calcd for C6H10F2OS: C, 42.84; H, 5.99. Found: C, 43.06; H, 6.15.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][NH:6][CH:7]=1.[C:14]1([C:20]2(CCC)C=CC=C(SSCCC)[CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.BrC1C(C2C=NC=CC=2)=NNC=1>C(OCC)(=O)C>[C:14]1([CH2:20][CH2:21][CH2:1][S:2][C:3]2[C:4]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)=[N:5][NH:6][CH:7]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCSSC1=CC=CC(CCC)(c2ccccc2)C1
Reactant: CSc1c[nH]nc1-c1cccnc1
Agent: Brc1c[nH]nc1-c1cccnc1
Solvent: CCOC(C)=O
Product: c1ccc(CCCSc2c[nH]nc2-c2cccnc2)cc1
Yield: 22 %

Procedure:
Compound 21I was prepared following the procedure as described for the synthesis of compound 21A (see Scheme 3) using 3-phenyl-propyldisulfanyl-3-propylbenzene as the disulfide (prepared according to the methodology described in Tetrahedron Letters, 42, 2001, 6741-6743) and 3-(4-bromo-1H-pyrazol-3-yl)-pyridine (compound 20A). (conditions flash chromatography (ethyl acetate)) Yield: 22% (oil). 1H-NMR (400 MHz, CDCl3): δ 9.18 (d, J=2 Hz, 1H), 8.62 (dd, J=5 Hz, 2 Hz, 1H), 8.31 (dt, J=8 Hz, 2 Hz, 1H), 7.69 (s, 1H), 7.40-7.36 (m, 1H), 7.24 (bt, J=7 Hz, 2H), 7.17 (bt, J=7 Hz, 1H), 7.04 (bd, J=7 Hz, 2H), 2.65-2.57 (m, 4H), 1.84-1.75 (m, 2H).