Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[CH:25][C:24]([Cl:28])=[CH:23][CH:22]=4)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Sn](CCCC)(CCCC)CCCC.C(OCC)(=O)C.N>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:28][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]([S:16]([N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:4]=[CH:3][C:2]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=4)=[CH:7][N:6]=3)=[O:9])[CH2:11][CH2:12]1)(=[O:18])=[O:17])=[CH:27]2
Reactant: O=C(c1ncc(Br)cn1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1ncc(-c2ccccn2)cn1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Temperature: 100 °C
Reaction time: 9 h
Yield: 51 %

Procedure:
At room temperature, 1-[(5-bromopyrimidin-2-yl)carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazine (500 mg) and (pyridin-2-yl)tributyltin (418 mg) were dissolved in N,N-dimethylformamide (10 ml). To the reaction mixture was added tetrakis(triphenylphosphine)palladium(0) (69 mg), followed by stirring at 100° C. for 9 hours. After cooling to room temperature, ethyl acetate and ammonia solution were added. The resulting mixture was separated by ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate. The filtrate was concentrated and the residue was purified by chromatography on a silica gel column (4% methanol—methylene chloride). The resulting fraction was added with ethanol, followed by concentration. Diethyl ether was then added to the concentrate. Colorless powder thus precipitated was collected by filtration and dried, whereby the free form (254 mg) of the title compound was obtained. The resulting free form was dissolved in methylene chloride, followed by the addition of 1N hydrochloric acid (in ethanol) to make the solution acidic. After concentration, ethyl acetate and diethyl ether were added, followed by concentration. Colorless powder thus precipitated was collected by filtration and dried, whereby the title compound was obtained.
Reaction SMILES: CS(O)(=O)=O.[N+:6]([C:9]1[CH:30]=[CH:29][C:12]([C:13]([O:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:26](=[NH:28])[NH2:27])[CH:22]=3)[CH:17]=2)=[O:14])=[CH:11][CH:10]=1)([O-])=O.CS(O)(=O)=O>[Pd].CN(C=O)C>[NH2:6][C:9]1[CH:30]=[CH:29][C:12]([C:13]([O:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:26](=[NH:27])[NH2:28])[CH:22]=3)[CH:17]=2)=[O:14])=[CH:11][CH:10]=1
Reactant: N=C(N)c1ccc2cc(OC(=O)c3ccc([N+](=O)[O-])cc3)ccc2c1
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CN(C)C=O
Product: N=C(N)c1ccc2cc(OC(=O)c3ccc(N)cc3)ccc2c1
Yield: 164.8 %

Procedure:
A mixture of 3.0 g of 6-amidino-2-naphthyl 4-nitrobenzoate methanesulfonate, 0.88 g of methanesulfonic acid, 0.3 g of 10% Pd-C and anhydrous DMF was subjected to catalytic hydrogenation. After absorption of a stoichiometric quantity of hydrogen, the reaction mixture was freed from Pd-C by filtration. After adding ethylether to the filtrate with stirring, the precipitate was collected by filtration and recrystallized from a DMF-ethylether mixture to obtain 3.5 g of a white powder of 6-amidino-2-naphthyl 4-aminobenzoate dimethanesulfonate.
Reaction SMILES: [CH:1]1([CH2:6][C:7]2[C:12]([F:13])=[C:11]([F:14])[CH:10]=[CH:9][C:8]=2OS(C(F)(F)F)(=O)=O)[CH2:5][CH:4]=[CH:3][CH2:2]1.C([O-])(=O)C.[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[F:14][C:11]1[CH:10]=[CH:9][C:8]2[CH:4]3[CH2:5][CH:1]([CH2:6][C:7]=2[C:12]=1[F:13])[CH:2]=[CH:3]3
Reactant: O=S(=O)(Oc1ccc(F)c(F)c1CC1CC=CC1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: Fc1ccc2c(c1F)CC1C=CC2C1
Temperature: 100 °C
Yield: 57.8 %

Procedure:
Trifluoro-methanesulfonic acid 2-cyclopent-3-enylmethyl-3,4-difluoro-phenyl ester (340 mg, 0.99 mmol), was dissolved in DMF (5 mL) under a N2 atmosphere and treated with dilsopropylethylamine (.026 mL, 1.5 mmol), potassium acetate (981 mg, 10.0 mmol) and tri-o-tolylphosphine (12 mg, 0.04 mmol). This mixture was stirred and degassed (3 vacuum/N2 purge cycles) and then treated with palladium acetate (5 mg, 0.02 mmol). After 20 min. the mbdure was warmed to 100° C. for 18 hours, cooled and poured into brin (50 mL). The resulting mixture was extracted with hexanes (4×25 mL) and the combined organic layer was washed with a sat. aq. NaHCO3 soln. (10 mL), water (H2O) (10 mL), brine (10 mL), dried (magnesium sulfate (MgSO4)), filtered and and chromatographed on silica gel to provide an oil (110 mg, 60%). (TLC hexanes Rf 0.58). 1H NMR (CDCl3) δ 6.80 (ddd, J=6.6,8.1,8.3 Hz, 1H), 6.68 (m, 1H), 6.17 (dd, J=5.5,2.8 Hz, 1H), 5.77 (dd, J=5.5,2.8 Hz, 1H), 3.29 (br s, 1H), 2.96 (br s, 1H), 2.84 (AB dd, J=17.9,5.0 Hz, 1H), 2.54 (AB d, J=17.9 Hz, 1H), 2.19 (m, 1H), 1.77 (d, J=10.5 Hz, 1H), GCMS m/e 192 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([NH2:7])=O.S(Cl)(Cl)=O.CN(C=O)C.[OH-].[Na+]>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]#[N:7]
Reactant: Cc1cc(C)cc(C(N)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: Cc1cc(C)cc(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
3,5-dimethylbenzamide (50 g, 0.3356M) was suspended in benzene (400 mL). Thionyl chloride (49 mL, 0.671M) and DMF (2 mL) were added and the mixture was refluxed for 2 hr. After cooling to room temperature, the mixture was poured into a crushed ice. After 1 hr., the solution was neutralized by the addition of 6N sodium hydroxide solution. The product was then extracted with ether, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a yellow solid. The crude product was then purified by silica gel column chromatography (eluent, EA:hexane (1:4)) to afford 42 g (95%) of 3,5-dimethylbenzonitrile as a yellow solid. m.p. 51-52° C. 1H NMR (300 MHz, CDCl3) δ 2.34 (6H, s), 7.21 (1H, s), 7.26 (2H, s).
Reaction SMILES: C(N(CC)CC)C.[N:8]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[CH:17]=O)=[N+:9]=[N-:10].[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:21]=1[NH2:22]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:8]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1/[CH:17]=[N:22]/[C:21]1[C:23]([F:27])=[CH:24][CH:25]=[CH:26][C:20]=1[Cl:19])=[N+:9]=[N-:10]
Reactant: Nc1c(F)cccc1Cl
Reactant: [N-]=[N+]=Nc1ccncc1C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=Nc1ccncc1/C=N/c1c(F)cccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triethylamine (7.1 mL, 51 mmol) was added to a cooled (0° C.) mixture of 4-azidopyridine-3-carbaldehyde (2.52 g, 17 mmol) and 2-chloro-6-fluoroaniline (2.47 g, 17 mmol) in DCM (60 mL) under nitrogen. Titanium tetrachloride (1 M, 10.2 mL, 10.2 mmol) was then added and the resulting mixture was stirred for 1 hour at 0° C. before warming to room temperature and stirring for a further 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was suspended in toluene and filtered through a pad of Celite®. The filtrate was concentrated to dryness under reduced pressure to afford the title compound as a yellow solid. This crude material was employed in the next step without further purification or analysis.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.N1C=CC=CC=1.[CH3:23][C:24]1[C:25](B(O)O)=[N:26][CH:27]=[CH:28][CH:29]=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CN(C)C=O>[Br:1][C:2]1[C:3]([O:16][C:25]2[C:24]([CH3:23])=[CH:29][CH:28]=[CH:27][N:26]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2
Reactant: CC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Reactant: Cc1cccnc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(Br)c(Oc3ncccc3C)c2CC[C@@H]1C
Temperature: 90 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
A 100-mL, round-bottom flask equipped with a balloon filled with air was charged with (S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.200 g, 0.70 mmol), pyridine (1 mL), copper (II) acetate (0.382 g, 2.10 mmol), 3-methylpyridin-2-ylboronic acid 0.190 g, 1.39 mmol) and N,N-dimethylformamide (8 mL). The resulting mixture stirred at 90° C. overnight. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluting with 1:8, ethyl acetate/petroleum ether) to afford (S)-1-(6-bromo-2-methyl-5-(3-methylpyridin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.129 g, 49%) as yellow oil. MS (ESI, pos. ion) m/z 375, 377 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8](F)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16].[CH3:19][NH2:20]>O1CCOCC1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([NH:20][CH3:19])[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16]
Reactant: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CN
Solvent: C1COCCO1
Product: CNc1cc(C(=O)OC)c([N+](=O)[O-])cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.4 %

Procedure:
5-Fluoro-2-nitro-4-trifluoromethyl-benzoic acid methyl ester (300 mg, 1.12 mmoles) is dissolved in dioxane and after addition of methylamine (0.490 ml, 3.5 eq.) the yellow mixture is stirred at room temperature for 2 days. The mixture is evaporated to dryness. Dichloromethane is added and the suspension is filtrated. Evaporation of the filtrate yielded 2-nitro-5-methylamino-4-trifluoromethyl-benzoic acid methyl ester as a yellow solid (291.3 mg, 95.4% yield). The product is used in the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]2[CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][NH:37][C:38]([NH2:40])=[S:39])[CH2:31][CH2:30]2)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]2[CH2:28][CH:29]2[CH2:30][CH2:31][N:32]([CH2:35][CH2:36][NH:37][C:38]3[S:39][CH:2]=[C:3]([C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:40]=3)[CH2:33][CH2:34]2)=[CH:16][CH:17]=1
Reactant: NC(=S)NCCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Fc1ccc(Cn2c(CC3CCN(CCNc4nc(-c5ccccc5)cs4)CC3)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
A mixture of 3.3 parts of 2-bromo-1-phenylethanone, 7 parts of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]thiourea, 4 parts of potassium carbonate and 90 parts of tetrahydrofuran was stirred for 2 hours at room temperature. The reaction mixture was filtered over Hyflo and the filtrate was evaporated. The reaction mixture was poured into water. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 2.8 parts (33.3%) of 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-N-(4-phenyl-2-thiazolyl)-1-piperidineethanamine; mp. 122.2° C. (454).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:14](O)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:14]([N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2)CC1
Yield: 95.7 %

Procedure:
General procedure A was followed using 1-Boc-piperazine (50 mg, 0.27 mmol), benzoic acid (43 mg, 0.35 mmol), HATU (0.14 g, 0.35 mmol), DIPEA (0.23 ml 1.4 mmol) and DMF (2 mL) to furnish the title compound as a beige solid (75 mg, 98%), m.p. 105-107° C.; umax (CHCl3)/cm−1 3011, 2930, 2866, 1691, 1626, 1421, 1249, 1158; m/z (ESI) C16H22N2NaO3 requires 313.1523, found [M+Na]+ 313.1528.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]([NH:14][C:15](=[O:38])[CH2:16][CH:17]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[NH:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)(=[O:21])=[O:20])[CH2:9][CH2:10][O:11]2)=[CH:6][CH:5]=1.[CH:39](=O)[CH:40]([CH3:42])[CH3:41].[BH4-].[Na+]>C(Cl)Cl.CC(O)=O>[CH2:39]([N:1]([CH2:3][CH:4]([CH3:13])[CH3:5])[CH2:2][CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]([NH:14][C:15](=[O:38])[CH2:16][CH:17]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=3)(=[O:21])=[O:20])[CH2:9][CH2:10][O:11]2)=[CH:6][CH:5]=1)[CH:40]([CH3:42])[CH3:41]
Reactant: CC(C)C=O
Reactant: NCCc1ccc2c(c1)OCCC2NC(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)CN(CCc1ccc2c(c1)OCCC2NC(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccccc1)CC(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-[7-(2-aminoethyl)-chroman-4-yl]-3-phenyl-3-(3-trifluoromethylbenzenesulfonylamino)-propionamide (Example 208, 50 mg, 0.09 mmol) in dry CH2Cl2 (8 mL) was added isobutyraldehyde (83 L, 0.9 mmol) and HOAc (1 drop). The resulting mixture was stirred at RT under N2 After 3 h, MS showed the formation of imine; NaBH4 (17 mg, 0.45 mmol) was then added. The resulting mixture was stirred for 18 h. Quenched with minimum amount of sat. NaHCO3. The organic layer was isolated, dried over MgSO4 and evaporated in vacuo. The crude product was purified by chromatography on silica gel. Elution with CH2Cl2:MeOH mixture (97:3) gave final compound. MS m/z: 660.31 (M+H). Calc'd. for Calc'd. for C35H44F3N3O4S-659.82.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])=[C:4]([CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:20]([CH3:33])[C@@H:19]2[CH3:34])[CH:3]=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:20]([CH3:33])[C@@H:19]2[CH3:34])[CH:3]=1
Reactant: C[C@@H]1[C@H](C)N(Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)CCN1C(=O)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1[C@H](C)N(Cc2cc(Cl)ccc2OCC(=O)O)CCN1C(=O)Cc1ccccc1

Procedure:
The product from example 71 part b) treated with TFA (10 ml) for 16 h. Concentration in vacuo and purification by RPHPLC gave the title product as a white foam (39 mg).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[C:34]([Br:35])=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[Br:35][C:34]1[C:29]([O:28][C:25]2[CH:24]=[CH:23][C:22]([CH2:21][C@H:17]([NH:16][C:2]3[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=4)[N:3]=3)[C:18]([OH:20])=[O:19])=[CH:27][CH:26]=2)=[N:30][CH:31]=[CH:32][CH:33]=1
Reactant: N[C@@H](Cc1ccc(Oc2ncccc2Br)cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2ncccc2Br)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(3-bromo-pyridin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH:5]2[CH2:15][CH2:16][N:2]1[CH2:3][CH2:4]2.Br[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][CH:22]=[CH:21]2>>[N:24]1[C:25]2[C:20](=[CH:19][C:18]([N:7]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:14]4[CH2:1][N:2]5[CH2:3][CH2:4][CH:5]([C:6]3=4)[CH2:15][CH2:16]5)=[CH:27][CH:26]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc2c3c([nH]c2c1)C1CCN(CC1)C3
Reactant: Brc1ccc2ncccc2c1
Product: c1cnc2ccc(-n3c4c(c5ccccc53)CN3CCC4CC3)cc2c1

Procedure:
The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (212 mg, 1.0 mmol; Example 187A) and 6-bromoquinoline (312 mg, 1.5 mmol; TCI-US) was performed as described in Example 68 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.95-2.22 (m, 4H) 2.94-2.99 (m, 1H) 3.09-3.28 (m, 4H) 4.36 (s, 2H) 7.06-7.13 (m, 3H) 7.39-7.47 (m, 1H) 7.64 (dd, J=8, 4 Hz, 1H) 7.74 (dd, J=9, 2 Hz, 1H) 7.96 (d, J=2 Hz, 1H) 8.23 (d, J=9 Hz, 1H) 8.47 (d, J=8 Hz, 1H) 8.95 (dd, J=4, 2 Hz, 1H); MS (DCI/NH3) m/z 340 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:12]([CH3:14])=[O:13])[C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.Cl>C(O)CCC>[CH2:3]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:12]([CH3:14])=[O:13])[C:10]=1[Cl:11])[C:5]([OH:7])=[O:6])[CH2:2][CH2:10][CH3:9]
Reactant: CS(=O)c1cc(C(=O)O)cc(N)c1Cl
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCCCO
Product: CCCCNc1cc(C(=O)O)cc(S(C)=O)c1Cl

Procedure:
A solution of 3-amino-4-chloro-5-methylsulfinylbenzoic acid (4.67 g.; 0.02 mole) in n-butanol (150 ml.) containing concentrated sulfuric acid (2 ml.) is refluxed for 48 hours in a Soxhlet extractor containing type 4A molecular sieves (100 g.). The solvent is distilled at reduced pressure and the residue is treated with water (50 ml.), 10N sodium hydroxide (20 ml.) and ethanol (20 ml.) and refluxed for 1 hour to hydrolyze any butyl ester which may have formed. The reaction mixture is cooled and acidified with dilute hydrochloric acid to give 3-n-butylamino-4-chloro-5-methylsulfinylbenzoic acid which melts at 158° C. after recrystallization from ethanol and water.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:14]=1[C:25]1[N:26]=[CH:27][NH:28][CH:29]=1)[CH3:12]>>[CH2:11]([C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:14]=1[C:25]1[N:26]=[CH:27][N:28]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:29]=1)[CH3:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCc1onc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Product: CCc1onc(-c2ccc(F)cc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Yield: 28 %

Procedure:
As described for 1f, 1-fluoro-4-nitro-benzene was converted, using 5-ethyl-3-(4-fluoro-phenyl)-4-(1H-imidazole-4-yl)-isoxazole (100 mg, 0.39 mmol) instead of 4-(1H-imidazol-4-yl)-3-phenyl-isoxazole was converted to the title compound (43 mg, 28%) which was obtained as an off-white solid. MS: m/e=379.1.1 [M+H]+.
Reaction SMILES: C([O:4][C:5](=[O:33])[CH2:6][CH2:7][NH:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[N:24][NH:25][O:26][C:27]([N:29]([CH3:31])[CH3:30])=[O:28])=[CH:19][CH:18]=2)[C:13]1=[O:32])=[O:10])CC.[CH3:34][CH:35](C)[CH2:36]OC(=O)CCN>>[CH3:34][CH:35]([O:4][C:5](=[O:33])[CH2:6][CH2:7][NH:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([CH:23]=[N:24][NH:25][O:26][C:27]([N:29]([CH3:31])[CH3:30])=[O:28])=[CH:21][CH:22]=2)[C:13]1=[O:32])=[O:10])[CH3:36]
Reactant: CC(C)COC(=O)CCN
Reactant: CCCOC(=O)CCNC(=O)N[C@H]1CCN(c2ccc(C=NNOC(=O)N(C)C)cc2)C1=O
Product: CC(C)OC(=O)CCNC(=O)N[C@H]1CCN(c2ccc(C=NNOC(=O)N(C)C)cc2)C1=O

Procedure:
N-[[[(3S)-1-[4-[[[[(dimethylamino)carbonyl]oxy]amino]iminomethyl]phenyl]-2-oxo-3-pyrrolidinyl]amino]carbonyl]-β-alanine propyl ester; N-[[[(3S)- l -[4-[[[[(dimethylamino)carbonyl]oxy]amino]iminomethyl]phenlyl]-2-oxo-3-pyrrolidinyl]amino]carbonyl]-β-alanine 2-methylpropyl ester;
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br[CH2:12][CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN(C)C=O>[CH2:12]([N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[CH2:13][CH2:14][CH3:15]
Reactant: C1CC2(CCN1)OCCO2
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN1CCC2(CC1)OCCO2
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 1,4-dioxa-8-azaspiro[4,5]decane (20.0 g, 140 mmol), 1-bromobutane (21,0 g, 154 mmol), potassium carbonate (19.3 g, 140 mmol) and dimethyl formamide (200 ml) was stirred for 5 h at 80° C. Sodium hydroxide (200 ml, 1 M) was added. The mixture was extracted three times with diethyl ether (200 ml). The product was isolated as an oil, in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:12]O.P(Br)(Br)[Br:15]>C(OCC)C.O>[Br:15][CH2:12][C:3]1[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=1[Cl:1]
Reactant: BrP(Br)Br
Reactant: CS(=O)(=O)c1ccc(CO)c(Cl)c1
Solvent: CCOCC
Solvent: O
Product: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Temperature: 0 °C

Procedure:
A cooled (0° C.), stirred suspension of (2-chloro-4-methanesulfonyl-phenyl)-methanol (19.1 g, 0.087 mol) in diethyl ether (250 ml) under an inert atmosphere, is treated with phosphorus tribromide (5.2 ml, 0.029 mol) and allowed to stir and warm to room temperature overnight. The resulting mixture is diluted with water (100 ml) and the organic portion is separated and dried over NaOH pellets for 5 minutes. The solvent is removed in vacuo and the resulting crude residue is loaded on a pre-packed Isolute™ silica column and eluted with iso-hexane/ethyl acetate (4:1) to yield the titled compound as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[C:21]3[C:16](=[N:17][CH:18]=[N:19][C:20]=3[NH2:22])[NH:15][N:14]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C:23]([C@@H:25]1[CH2:29][C@@H:28](O)[CH2:27][N:26]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])#[CH:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:22][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:15]([C@@H:28]3[CH2:27][N:26]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[C@H:25]([C:23]#[CH:24])[CH2:29]3)[N:14]=[C:13]([C:12]#[C:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)[C:21]=12
Reactant: COc1cc(C#Cc2n[nH]c3ncnc(N)c23)cc(OC)c1
Reactant: C#C[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C#C[C@@H]1C[C@H](n2nc(C#Cc3cc(OC)cc(OC)c3)c3c(N)ncnc32)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-((3,5-Dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (14 mg) obtained in Example 1 (Step 1), (2S,4R)-tert-butyl 2-ethynyl-4-hydroxypyrrolidine-1-carboxylate (15 mg) synthesized by the method disclosed in WO2005/007083, and triphenylphosphine (23 mg) were suspended in THF (1.0 ml). DIAD (18 μl) was added to the suspension, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and dissolved in a solution of DMSO. The resulting solution was purified by preparative reversed-phase HPLC purification (water/acetonitrile (0.1% formic acid)) to obtain the title compound as a colorless, amorphous substance (5.0 mg). Physical properties: m/z [M+H]+ 489.2