Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1.BrN1C(=O)CCC1=O.[CH3:28][O:29][C:30](=[O:43])[CH2:31][NH:32][S:33]([C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=1)(=[O:35])=[O:34]>>[CH3:1][O:2][C:3](=[O:19])[C:4]1[C:9]([CH2:10][N:32]([CH2:31][C:30]([O:29][CH3:28])=[O:43])[S:33]([C:36]2[CH:37]=[CH:38][C:39]([CH3:42])=[CH:40][CH:41]=2)(=[O:35])=[O:34])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)c1c(C)cccc1Oc1ccc(F)cc1
Agent: O=C1CCC(=O)N1Br
Product: COC(=O)CN(Cc1cccc(Oc2ccc(F)cc2)c1C(=O)OC)S(=O)(=O)c1ccc(C)cc1

Procedure:
The crude title compound was synthesized from 2-(4-fluoro-phenoxy)-6-methyl-benzoic acid methyl ester, N-bromosuccinimide, and (toluene-4-sulfonylamino)-acetic acid methyl ester in analogy to example 18c and was used in the following step without further purification; MS-(+)-ion: M+23=524.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH3:13])[CH:7]=[CH:6]2.[Br:14]C(Br)(Br)C=O.C(OCC)(=O)C>N1C=CC=CC=1.CN(C)C=O>[Br:14][CH2:13][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: COc1ccc2nc(C)ccc2c1
Reactant: O=CC(Br)(Br)Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1ccc2nc(CBr)ccc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 30.6 %

Procedure:
A solution of 10 g (57.7 mmol) of 6-methoxy-2-methylquinoline and 30 drops of pyridine in 40 mL of N,N-dimethylformamide was stirred at 60° C. while a solution of 16.21 g (57.7 mmol) of tribromoacetaldehyde in 20 mL of N,N-dimethylformamide was added over 15 min. The reaction mixture was stirred for another 2 hr and then cooled and poured onto 600 mL of ice-water. Work-up with ethyl acetate was carried out in the usual manner. The crude product was purified by flash chromatography on 800 g of silica gel, eluting with hexane-ethyl acetate (4:1) afforded 4.45 g (30.6%) of the title compound as a violet solid. An analytical sample was obtained by recrystallization from ethanol to give colorless crystals, mp 103° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.CCN(C(C)C)C(C)C.[CH3:25][C:26]1[N:31]=[CH:30][C:29]([C:32]2([CH2:38][NH2:39])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[Cl:1][C:2]1[C:6]([C:7]([NH:39][CH2:38][C:32]2([C:29]3[CH:30]=[N:31][C:26]([CH3:25])=[CH:27][CH:28]=3)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)=[O:9])=[CH:5][N:4]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: Cc1ccc(C2(CN)CCCCC2)cn1
Reactant: O=C(O)c1cn(-c2ncccn2)nc1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(C2(CNC(=O)c3cn(-c4ncccn4)nc3Cl)CCCCC2)cn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 3-chloro-1-pyrimidin-2-yl-1H-pyrazole-4-carboxylic acid (75 mg, 0.33 mmol) in 1.0 mL of DMF is added sequentially DIEA (0.11 mL, 0.66 mmol), 1-[1-(6-methylpyridin-3-yl)-cyclohexyl]methanamine (67 mg, 0.33 mmol), and BOP (177 mg, 0.40 mmol). The resulting mixture is stirred at RT for 20 h. Water (3 mL) is added, and the mixture is extracted with EtOAc (5 mL). The EtOAc layer is dried (Na2SO4), filtered, and evaporated in vacuo. The residue is purified by preparative chromatography (2% MeOH/CH2Cl2) to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.18 (1H, s), 8.90 (2H, d, J 4), 8.43 (1H, s), 8.03 (1H, s), 7.64 (1H, d, J 8), 7.56 (1H, s), 7.18 (1H, d, J 7.6), 2.41 (3H, s), 2.13 (2H, m), 1.56 (5H, m), 1.22 (5H, m). MS (M+1)=411.18; RT=1.08 min. *IC50.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([CH3:41])[C:17]2[C:18]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[CH3:40])=[CH:19][C:20]([C:23]3[CH2:24][CH2:25][C@:26]([CH3:32])([C:28](OC)=[O:29])[N:27]=3)=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH3:46]>CO>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([CH3:41])[C:17]2[C:18]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[CH3:40])=[CH:19][C:20]([C:23]3[CH2:24][CH2:25][C@:26]([CH3:32])([C:28]([NH2:46])=[O:29])[N:27]=3)=[N:21][CH:22]=2)=[O:15])[CH:4]=[C:3]([C:2]([F:44])([F:45])[F:1])[CH:8]=1
Reactant: N
Reactant: COC(=O)[C@@]1(C)CCC(c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)=N1
Solvent: CO
Product: Cc1cc(F)ccc1-c1cc(C2=N[C@@](C)(C(N)=O)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Methyl (2R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)pyridin-2-yl]-2-methyl-3,4-dihydro-2H-pyrrole-2-carboxylate (Intermediate 23 1.06 Kg) was suspended in 20.44 L of 7M ammonia in methanol. The mixture was gently stirred for at least 5 days at 20° C. The mixture was concentrated by half by distillation at atmospheric pressure. The solution obtained was then cooled to 40° C. and stirred for 1 h. The slurry obtained was then cooled to 0° C. over 3 h and aged at 0° C. for 2 h. The title compound was then isolated by filtration and the cake washed with ice cold methanol (1.1 L). The wet cake was dried at 40° C./vacuum to yield the title compound (841.3 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[N:14][C:15]([O:19][CH3:20])=[C:16]([CH3:18])[CH:17]=1)(=[O:10])=[O:9].Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[CH3:20][O:19][C:15]1[N:14]=[CH:13][C:12]([N:11]2[C:22](=[O:24])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]2(=[O:9])=[O:10])=[CH:17][C:16]=1[CH3:18]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ncc(NS(=O)(=O)c2ccccc2N)cc1C
Solvent: C1COCCO1
Product: COc1ncc(N2C(=O)Nc3ccccc3S2(=O)=O)cc1C
Yield: 385.5 %

Procedure:
The title compound was prepared from 2-amino-N-(6-methoxy-5-methylpyridin-3-yl)benzenesulfonamide (2.60 g) and triphosgene (815 mg, 2.75 mmol) in anhydrous 1,4-dioxane (160 mL) using the methods of (IntA1) step 3. Concentration in vacuo after completion of the reaction yielded the title compound (3.38 g, 10.6 mmol, approximately 80% purity by LCMS) which was used without further purification.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:11][C:12]([C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2C(OC(C)(C)C)=O)=[O:13])[C:9]#[N:10])=[CH:3][CH:2]=1>C(O)=O>[C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]([NH:11][C:12]([C@@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[O:13])[C:9]#[N:10])=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](C#N)Cc1ccc(-c2ccccc2)cc1
Solvent: O=CO
Product: N#C[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)[C@@H]1CCCN1
Temperature: 50 °C
Yield: 67.9 %

Procedure:
A solution of (S)-tert-butyl 2-((S)-2-(biphenyl-4-yl)-1-cyanoethylcarbamoyl)pyrrolidine-1-carboxylate (178 mg) in formic acid (5 mL) was stirred and heated at 50° C. for 10 min. The solvent was evaporated. The crude material was dissolved in methanol (2 mL) and loaded on to a 10 g SCX cartridge. The impurities were washed through with methanol (20 mL) and discarded. The product was eluted with 0.7 N methanolic ammonia (15 mL) and evaporated in vacuo. The residue was triturated with ethyl acetate (3 mL) and the solid collected, washed with a little ethyl acetate and dried to afford the title compound (92 mg).
Reaction SMILES: C[Si](C)(C)[C:3]1[C:4]([NH:9]C#C)=[N:5][CH:6]=[CH:7][CH:8]=1.[F-].[CH2:15]([N+](CCCC)(CCCC)CCCC)[CH2:16]CC.O>O1CCCC1>[C:15]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:16]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C#CNc1ncccc1[Si](C)(C)C
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cccnc1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-trimethylsilanyl ethinyl-pyridin-2-ylamine described in Preparation Example 1-1-4 (28.1 g, 148 mmoL) in tetrahydrofuran (300 mL) was added tetrabutyl ammonium fluoride (1M tetrahydrofuran solution, 20 mL, 20 mmol), which was stirred at room temperature for 15 minutes. To the reaction solution was added water and extracted four times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent thereof was evaporated under a reduced pressure. The residue was purified by silica gel chromatography (heptane:ethyl acetate=1:1 then 1:2) to obtain the title compound (16.4 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]1([CH3:28])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH:19]C(=O)C2C=CC=CC=2)=[N:10]1.CO.C1CCN2C(=NCCC2)CC1>CCOC(C)=O.CCCCCC>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]1([CH3:28])[CH2:14][C@@H:13]([C:15]([F:18])([F:16])[F:17])[O:12][C:11]([NH2:19])=[N:10]1
Reactant: C[C@@]1(c2cccc(F)c2Cl)C[C@@H](C(F)(F)F)OC(NC(=O)c2ccccc2)=N1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: C[C@@]1(c2cccc(F)c2Cl)C[C@@H](C(F)(F)F)OC(N)=N1
Yield: 82.6 %

Procedure:
A solution of N-((4S,6S)-4-(2-chloro-3-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (1.73 g, 4.17 mmol), methanol (25 mL) and DBU (0.798 mL, 5.30 mmol) was stirred at 55° C. overnight. The mixture was concentrated in vacuo, diluted with water and EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude was purified by silica gel chromatography: 0-100% EtOAc-hexane to give (4S,6S)-4-(2-chloro-3-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine as a white solid (1.07 g, 82% yield). MS m/z=415 [M+H]+. Calculated for C19H15ClF4N2O2: 414.8.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>>[CH2:13]([O:12][P:11]([CH2:7][C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)(=[O:18])[O:15][CH2:16][CH3:17])[CH3:14]
Reactant: CCOP(OCC)OCC
Reactant: N#Cc1ccc(CBr)cc1
Product: CCOP(=O)(Cc1ccc(C#N)cc1)OCC
Yield: 96.8 %

Procedure:
A mixture of 4-cyano-benzyl bromide (41.8 g, 0.213 mol) and triethyl phosphite (42 mL, 0.244 mol) was stirred in a flask equipped with a Dean-Stark trap at 150° C. for 6 h, then the reaction mixture was submitted to distillation in vacuo to yield 52.2 g (97%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([NH:23][CH2:24][CH:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1)#[N:2].I[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([N:23]([CH2:24][CH:25]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(CCC(=O)N2CCCc3cc(NCC(c4ccccc4)c4ccccc4)ccc32)cc1
Reactant: CCOC(=O)CI
Product: CCOC(=O)CN(CC(c1ccccc1)c1ccccc1)c1ccc2c(c1)CCCN2C(=O)CCc1ccc(C#N)cc1

Procedure:
Prepared from 1-[3-(4-cyano-phenyl)-propionyl]-6-(2,2-diphenyl-ethylamino)-1,2,3,4-tetrahydro-quinoline (see Example 14(4)) and ethyl iodoacetate
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.[C:19]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:12]1[C:13]2[C:4]([N:5]=[C:6]3[C:11]=1[CH:10]=[C:9]([O:17][CH3:18])[CH:8]=[CH:7]3)=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=2)([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Reactant: CC(C)(C)NCCCCN
Product: COc1ccc2nc3cc(Cl)ccc3c(NCCCCNC(C)(C)C)c2c1

Procedure:
Following the general procedure of Example 1 and making non-critical variations, but using 6,9-dichloro-2-methoxyacridine and commercially available N1-tert-butylbutane-1,4-diamine, the title compound was obtained; MS (Found M+1=386).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH2:14][C@H:15]3[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]3)[CH:13]=2)[N:3]=1.C(N(C(C)C)CC)(C)C.[Br:37][C:38]1[CH:39]=[N:40][C:41]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)=[N:42][CH:43]=1>O1CCOCC1>[Br:37][C:38]1[CH:39]=[N:40][C:41]([N:44]2[CH2:45][CH2:46][N:47]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:10]=[N:11][N:12]([CH2:14][C@H:15]5[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]5)[CH:13]=4)[N:3]=3)[CH2:48][CH2:49]2)=[N:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(Cl)n3)cn2)C1
Reactant: Brc1cnc(N2CCNCC2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(N4CCN(c5ncc(Br)cn5)CC4)n3)cn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a solution of (S)-tert-butyl 2-((4-(4-chloro-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate (1.8 g, 4.5 mmol) in dioxane (50 mL) was added diisopropylethylamine (4 mL) and 5-bromo-2-(piperazin-1-yl)pyrimidine (1.3 g, 5.5 mmol). The reaction mixture was stirred at room temperature for 2 hours. The solvents were removed, and the residue was washed with methanol (10 mL) to afford (S)-tert-butyl 2-((4-(4-(4-(5-bromopyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)-morpholine-4-carboxylate as a white solid (2.4 g, 89%), which was directly used in the next step without further purification. MS (ES+) C24H32BrN11O3 requires: 601, 603, found: 602, 604 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:9]([C:12]2[N:13]=[N:14][N:15]([CH3:17])[N:16]=2)[CH:10]=O)=[CH:4][CH:3]=1.C1(P(=[CH:44][CH:45]=[O:46])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:9]([C:12]2[N:13]=[N:14][N:15]([CH3:17])[N:16]=2)[CH:10]=[CH:44][CH:45]=[O:46])=[CH:19][CH:20]=1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1nnc(C(C=O)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Product: Cn1nnc(C(C=CC=O)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Yield: 8.9 %

Procedure:
The general procedure of Example 8 was repeated, except that the 3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-proenal utilized therein was replaced by 0.67 g (21.0 mmoles) of 3,3-bis(4-fluorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)-2-propenal [prepared in Example 7]. The reaction was carried out with 0.64 g (21.0 mmoles) of triphenylphosphoranylidene acetaldehyde to yield 0.66 g (90.5%) of the title compound.
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:14]=[C:13]([Cl:15])[C:9]2=[CH:10][O:11][N:12]=[C:8]2[C:7]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)[CH3:5])=[N+]=[N-].CP(C)C>O1CCCC1.O>[Cl:15][C:13]1[C:9]2=[CH:10][O:11][N:12]=[C:8]2[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:6]([CH:4]([NH2:1])[CH3:5])[CH:14]=1
Reactant: CC(N=[N+]=[N-])c1cc(Cl)c2conc2c1-c1cccc(F)c1
Agent: CP(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(N)c1cc(Cl)c2conc2c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 6-(1-azidoethyl)-4-chloro-7-(3-fluorophenyl)-2,1-benzisoxazole (90. mg, 0.28 mmol) in tetrahydrofuran (2 mL) and water (0.3 mL) was added 1.0 M trimethylphosphine in THF (0.35 mL, 0.35 mmol). The mixture was stirred at room temperature for 1 hour. After degassing with nitrogen, the reaction mixture was extracted with dichloromethane. The extracts were washed with brine, dried over magnesium sulfate and evaporated to dryness. The crude residue was used directly in the next step (68 mg, 82%). LCMS calculated for C15H10ClFNO (M−NH2)+: m/z=274.1; Found: 274.0.
Reaction SMILES: C(=O)=O.CCO.[CH2:7]([N:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23](=[O:26])[CH2:24][CH3:25])=[CH:22][C:17]=2[O:16][C:15]1=[O:27])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.I[CH:29]([CH2:34][CH2:35][CH3:36])[C:30]([O:32][CH3:33])=[O:31].Cl>C1COCC1>[CH2:7]([N:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23](=[O:26])[CH:24]([CH:29]([CH2:34][CH2:35][CH3:36])[C:30]([O:32][CH3:33])=[O:31])[CH3:25])=[CH:22][C:17]=2[O:16][C:15]1=[O:27])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCC(=O)c1ccc2c(c1)oc(=O)n2Cc1ccccc1
Reactant: CCCC(I)C(=O)OC
Agent: Cl
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CCO
Product: CCCC(C(=O)OC)C(C)C(=O)c1ccc2c(c1)oc(=O)n2Cc1ccccc1
Temperature: -2 °C
Reaction time: 0.5 h

Procedure:
200 mL (0.5 mol/l in toluene, 100 mmol) bis-(trimethylsilyl)-potassium amide in 1.50 L THF are placed under protective gas and cooled to −60° C. with dry ice/EtOH. 20 g (71 mmol) of 3-benzyl-6-propionyl-3H-benzoxazol-2-one dissolved in 500 mL THF are slowly added dropwise. The reaction mixture is stirred for 30 min at −2° C. and then cooled to −60° C. again. 20 g (83 mmol) methyl 2-iodo-pentanoate are added and the mixture is stirred for 45 min at −60° C. Then the reaction mixture is combined with 500 mL of 2M HCl and extracted at RT with diethyl ether. The organic phase is washed with saline solution, suction filtered through cellulose and the solv. is eliminated i.V. The residue is purified through silica gel (DCM/MeOH)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[C:6]([NH2:14])[CH:5]=1.C([O-])([O-])=O.[K+].[K+].CNCCNC.Br[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH:35]=[CH:36]Br>[Cu]I.CC(=O)OCC.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[C:6]([N:14]2[C:31]3[C:30](=[CH:29][CH:34]=[CH:33][CH:32]=3)[CH:35]=[CH:36]2)[CH:5]=1
Reactant: COC(=O)c1ccc(C(F)(F)F)c(N)c1
Reactant: BrC=Cc1ccccc1Br
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(F)(F)F)c(-n2ccc3ccccc32)c1
Temperature: 110 °C
Reaction time: 14 h
Yield: 44 %

Procedure:
690 mg of 3-Amino-4-trifluoromethyl-benzoic acid methyl ester, 650 mg of K2CO3, 30 mg of CuI, and 28 mg of N,N′-dimethylethylendiamine were suspended using 4.1 ml of anhydrous toluene. 410 mg of o-bromo-(2-bromo)vinylbenzene were added and the reaction mixture stirred at 110° C. for 14 h. The reaction mixture was allowed to cool to room temperature, 50 ml of EA added, filtrated, and evaporated. Chromatography on silica gel using EA/HEP (gradient) yielded 220 mg of the title compound, viscous oil.
Reaction SMILES: C(S[C:9]1[NH:10][CH:11]=[C:12]([C:14]2[CH:15]=[C:16]([C:20]3([CH3:33])[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:22][CH:21]3[CH3:32])[CH:17]=[CH:18][CH:19]=2)[N:13]=1)C1C=CC=CC=1.[OH-].[Na+]>C(O)C.[Ni]>[CH2:26]([N:23]1[CH2:24][CH2:25][C:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:12]3[N:13]=[CH:9][NH:10][CH:11]=3)[CH:15]=2)([CH3:33])[CH:21]([CH3:32])[CH2:22]1)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCN1CCC(C)(c2cccc(-c3c[nH]c(SCc4ccccc4)n3)c2)C(C)C1
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCN1CCC(C)(c2cccc(-c3c[nH]cn3)c2)C(C)C1
Reaction time: 0.08 h

Procedure:
To a solution of 4-(3-(2-(benzylsulfanyl)-1H-imidazol-4-yl)phenyl)-1-hexyl-3,4-dimethylpiperidine (Example 51, 98 mg, 0.21 mmol) in ethanol (2 mL) at room temperature was added 1 N NaOH (1.5 mL) and Raney® nickel (0.5 g, 50% slurry in water). The reaction was stirred for 5 minutes and then filtered through Celite®, washing with ethanol. The filtrate was concentrated in vacuo and the residue was dissolved in ethyl acetate (5 mL). The organic layer was washed with saturated aqueous sodium hydrogencarbonate (5 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was then purified by column chromatography on silica gel eluting with ethyl acetate:0.88 ammonia (100:1) and then ethyl acetate:methanol:0.88 ammonia (70:30:1). The title compound was obtained as a clear oil (13 mg, 19%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([C:24]([F:27])([F:26])[F:25])[C:21]=1[O:22]C)[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])#[N:2].[Cl-].[Li+].Cl>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([C:24]([F:27])([F:25])[F:26])[C:21]=1[OH:22])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:17])(=[O:18])[CH2:9]1)=[O:7])#[N:2]
Reactant: COc1c(C#N)cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc1C(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(C(F)(F)F)c1O
Temperature: 70 °C
Reaction time: 2 h
Yield: 5640.8 %

Procedure:
3-(3-cyano-4-methoxy-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (4.08 g) was dissolved in N,N-dimethylformamide (40 mL), and lithium chloride (1.74 g) was added to the solution, and then the mixture was stirred at 70° C. for 2 hours. To the reaction solution, 1N hydrochloric acid was added, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was crystallized from n-hexane-ethyl acetate to obtain the title compound (222 g) as a colorless crystal.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[CH2:14]([N:17]=[C:18]=[O:19])[CH2:15][CH3:16]>CN(C)C=O.C(OCC)(=O)C>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:18]([NH:17][CH2:14][CH2:15][CH3:16])=[O:19])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: CCCN=C=O
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCNC(=O)Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Yield: 44.6 %

Procedure:
A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (150 mg, 0.67 mmol) and propyl isocyanate (76 μL, 0.81 mmol) in 1 mL of N,N-dimethyl-formamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude. Purification upon column chromatograph on silica gel, eluting with ethyl acetate/hexane (50/50, v/v), followed by recrystallization from acetone and hexane, gave the desired product (92 mg, 44%). LC-MS (m/z) 308.2 (M+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[S:14][CH2:13][C:12]1([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH3:23].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41].O>ClCCl>[CH3:39][S:40]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[S:14][CH2:13][C:12]1([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH3:23])(=[O:42])=[O:41]
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 71.4 %

Procedure:
4-(9-Hydroxynonyl)-7-methoxy-3-(4-methoxyphenyl)-3-methyl thiochroman (882 mg, 1.99 mmol) was dissolved in dichloromethane (60 ml) and triethylamine (1.38 ml, 9.96 mmol), to which was added methanesulfonylchloride (0.77 ml, 9.96 mmol). The reaction mixture was stirred at room temperature for 40 minutes. After the reaction was completed, water was added to the reaction solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The residue was subjected to flash chromatography on silica gel (n-hexane:ethyl acetate=7:3) to give the title compound (0.74 g, yield 72%) as a colorless oil.