Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([S:17][CH2:18][CH3:19])[N:14]3[CH:20]=[CH:21][N:22]=[C:13]3[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9]C.B(Br)(Br)Br>C(Cl)Cl>[CH2:18]([S:17][C:15]1[N:14]2[CH:20]=[CH:21][N:22]=[C:13]2[CH:12]=[C:11]([C:5]2[CH:4]=[C:3]([OH:2])[C:8]([OH:9])=[CH:7][CH:6]=2)[N:16]=1)[CH3:19]
Reactant: CCSc1nc(-c2ccc(OC)c(OC)c2)cc2nccn12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCSc1nc(-c2ccc(O)c(O)c2)cc2nccn12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To 7-(3,4-Dimethoxy-phenyl)-5-ethylsulfanyl-imidazo[1,2-c]pyrimidine (1.1 g, 3.5 mmol) in CH2Cl2 (25 ml) at 0° C., was added dropwise 1M solution of BBr3 in CH2Cl2 (25 ml, 25.0 mmol). The reaction mixture was stirred at 0° C. for 15 min and then at room temperature overnight. The mixture was then cooled using ice bath and ice-water was added, the precipitate was collected by filtration and then suspended in CH2Cl2 to give 4-(5-Ethylsulfanyl-imidazo[1,2-c]pyrimidin-7-yl)-benzene-1,2-diol. (875 mg, 87%)
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[Cl:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[C:42]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:42]2[C:43]([C:47]([F:49])([F:50])[F:48])=[CH:44][CH:45]=[CH:46][C:41]=2[Cl:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: OB(O)c1c(Cl)cccc1C(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3c(Cl)cccc3C(F)(F)F)sc2N)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6S)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 95), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-chloro-6-(trifluoromethyl)phenyl)boronic acid gave 329. 1H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.59-8.53 (m, 1H), 7.99-7.96 (m, 1H), 7.85 (s, 1H), 7.75-7.70 (m, 1H), 7.61 (s, 2H), 4.85 (dd, J=10.4, 3.6 Hz, 1H), 4.57-4.39 (m, 1H), 4.37-4.24 (m, 1H), 4.16-3.97 (m, 2H), 3.76 (s, 3H), 2.11-2.03 (m, 1H), 1.89-1.67 (m, 4H). LCMS (ES+) m/z 433 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][CH:5]=2.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[SH:29].II.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=2)[N:3]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:2]=1[CH3:1]
Reactant: CCOC(=O)Cn1c(C)cc2cc(NS(C)(=O)=O)ccc21
Reactant: Sc1ccccc1Cl
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C)c(Sc2ccccc2Cl)c2cc(NS(C)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-acetic acid, ethyl ester (0.31 g) and 2-chlorobenzenethiol (0.27 g) were dissolved in dimethyl formamide (3 ml) followed by addition of iodine 0.30 g) for the whole to be stirred at room temperature overnight. The mixture was poured into aqueous sodium thiosulphate (50 ml) and the resultant white precipitate collected by filtration and rinsed with water, dried under vacuum to be recrystallised from ethanol. The crystals were harvested and rinsed with isohexane and dried under vacuum to give the sub-title compound (0.20 g)
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:20]=[C:21]([N:26]=[C:27]=[O:28])[CH:22]=[CH:23][C:24]=1[CH3:25]>>[CH3:18][C:19]1[CH:20]=[C:21]([NH:26][C:27](=[O:28])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]3)[CH:22]=[CH:23][C:24]=1[CH3:25]
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Reactant: Cc1ccc(N=C=O)cc1C
Product: Cc1ccc(NC(=O)Oc2ccc3c(c2)CCN3Cc2ccccc2)cc1C

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (15.0 mg, 66.6 μmol) using the same procedure employed for Example 2 (2), but with 3,4-dimethylphenylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a sticky oil (10.5 mg, 42%) having the following characteristics.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[CH2:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[CH:7]=[CH2:8].C1(O)C=CC=CC=1>N1C=CC=CC=1>[CH2:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])[CH:7]=[CH2:8]
Reactant: ClCC1CO1
Reactant: C=CCc1ccccc1O
Solvent: Oc1ccccc1
Solvent: c1ccncc1
Product: C=CCc1ccccc1OCC(O)CCl
Temperature: 90 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
In a flask are placed 92.5 g (1 mol) of epichlorohydrin, 33.5 g (0.25 mol) of o-allylphenol and 0.3 ml of pyridine is added. The mixture is taken to 80° C. in about 1 hour then the temperature is raised to 90° C. and maintained for about 6 hours until the phenol has disappeared completely. The mixture is then cooled and the excess of epichlorohydrin evaporated. The remaining oil is taken up in 100 ml chloroform and 50 ml of HCl (d415 -1.19) are slowly added. The organic phase is then washed two to three times in water then dried over Na2SO4. After evaporation of the chloroform, 56.6 g (yield: about 100%) are obtained of 1-(o-allylphenoxy)-3-chloro-2-propanol in the form of an oil, dark brown in colour.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=1[O:18][CH3:19])[CH2:7][CH2:8][CH3:9].[C:20]([O-])(=[O:22])C.[Na+]>CN(C)C=O>[CH3:19][O:18][C:11]1[CH:12]=[C:13]([CH3:17])[C:14]([CH:20]=[O:22])=[C:15]([CH3:16])[C:10]=1[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CC(=O)[O-]
Reactant: CCCCc1c(C)cc(C)cc1OC
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCc1c(OC)cc(C)c(C=O)c1C

Procedure:
5.5 ml. of phosphorous oxychloride are added dropwise while stirring to 4.6 ml. of dimethylformamide. The temperature rises to 30° C. The mixture is treated dropwise with 9.6 g. of 2-butyl-3,5-dimethylanisole, poured onto ice water after the addition of 30 to 35 percent aqueous solution of sodium acetate, stirred for 1 hour and extracted with benzene. The benzene extract is washed with water, dried over sodium sulfate and evaporated. There is obtained 4-methoxy-3-butyl-2,6-dimethyl-benzaldehyde, which is purified by absorption on silica gel, using hexane/methylene chloride 1:1 parts by volume as the eluent, before the condensation with 1-ethoxycarbonyl-2,6-dimethyl-hepta-1,3,5-trien-7-triphenylphosphonium bromide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](N2N=CC=N2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:16][C:17]1[CH:18]=[N:19][NH:20][CH:21]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:19]2[CH:18]=[C:17]([CH3:16])[CH:21]=[N:20]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1cn[nH]c1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Product: Cc1ccc(-n2cc(C)cn2)c(C(=O)O)c1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A11 using 4-methyl-1H-pyrazole. MS (ESI) 217 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[NH:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1.[Br:16]Br>C(Cl)Cl>[Br:16][C:6]1[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][NH:9][C:5]=1[CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCc1cc(-c2ccccc2)n[nH]1
Reactant: BrBr
Solvent: ClCCl
Product: COCCc1[nH]nc(-c2ccccc2)c1Br
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a solution of 5-(2-methoxyethyl)-3-phenyl-1H-pyrazole (2.0 g, 9.89 mmol) in DCM (100 mL) was added bromine (4.74 g, 29.7 mmol) dropwise at 0° C. The reaction was stirred at that temperature for 1 h and continued at room temperature for 2 h before quenched with Na2SO3 (10% aq.). The organics were separated, and the aqueous layer was extracted with DCM (2×50 mL). The combined organics were washed with brine, dried over MgSO4, and concentrated to give the title compound (2.5 g). LCMS m/z=281.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 187 (t, J=6.82 Hz, 2H), 3.27 (s, 3H), 3.62 (t, J=6.82 Hz, 2H), 5.75 (s, 1H), 7.35-7.51 (m, 3H), 7.75-7.82 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH3:19])[CH:16]=2)[C:11]1=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:19][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:20])[N:10]([CH:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:2][O:1][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:18]2
Reactant: Cc1ccc2c(c1)CN(C(CO)c1ccccc1)C2=O
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(c1)CN(C(COS(C)(=O)=O)c1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(2-Hydroxy-1-phenyl-ethyl)-5-methyl-2,3-dihydro-isoindol-1-one (4.72 g, 17.66 mmol) and triethylamine (5.36 g, 53.97 mmol, 7.38 mL) were taken up in anhydrous DCM (50 mL), under argon and cooled to 0EC. Methanesulfonyl chloride (2.22 g, 19.43 mmol, 1.5 mL) was added to the reaction over 10 min. The reaction was stirred for 1 h at 0EC then allowed to slowly warm to room temp and stirred for 4 h. The reaction was slowly poured into saturated sodium bicarbonate and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with 1N HCl, water, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed under reduced pressure. The product was used in the next step without further purification. Yield 5.61 g. 1H NMR (CDCl3, 300 MHz): δ 2.44 (s, 3H), 3.01 (s, 3H), 4.15 (d, J=16 Hz, 1H), 4.43 (d, J=17 Hz, 1H), 4.77 (dd, J=5, 11 Hz, 1H), 5.03 (dd, J=9, 11 Hz, 1H), 5.76 (dd, J=5, 9 Hz, 1H), 7.20-7.38 (, 7H), 7.76 (d, J=8, 1H).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][C@@H:33]([CH3:37])[CH2:34][NH:35][CH3:36])[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][C@@H:33]([CH3:37])[CH2:34][N:35]([CH3:36])[C:1](=[O:5])[CH2:2][OH:3])[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: CNC[C@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O=C(O)CO
Product: C[C@@H](CN(C)C(=O)CO)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 53 %

Procedure:
The procedure described in Example 1 was repeated using glycolic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(1S)-1-methyl-2-(methylamino) ethoxy]quinazolin-4-amine (obtained as described for the R-antipode in Example 2.3, preparation of starting materials) to give the title compound in 53% yield; NMR spectrum (DMSO-d6) 1.39 (d, 3H), 2.96 (s, 3H), 3.36 (dd, 1H), 4.04 (d, 2H), 4.21 (m, 1H), 4.37 (t, 1H), 5.09 (m, 1H), 5.29 (s, 1H), 7.25 (m, 2H), 7.35 (m, 2H), 7.57 (d, 1H), 7.65 (dd, 1H), 7.70 (t, 1H), 7.87 (dt, 1H), 8.12 (d, 1H), 8.46 (s, 1H), 8.58 (d, 1H), 9.93 (s, 1H); Mass Spectrum MH+ 508.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([CH2:9][CH2:10][OH:11])[CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[CH2:4]1.[H][H]>[Pd].CO>[CH3:1][O:2][C@H:3]1[C@@H:8]([CH2:9][CH2:10][OH:11])[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: [H][H]
Reactant: CO[C@@H]1CN(Cc2ccccc2)CC[C@@H]1CCO
Agent: [Pd]
Solvent: CO
Product: CO[C@@H]1CNCC[C@@H]1CCO
Yield: 100 %

Procedure:
A mixture of 25.9 parts of cis-3-methoxy-1-(phenylmethyl)-4-piperidineethanol (prepared as in EP-A-0,320,032) and 198 parts of methanol was hydrogenated at normal pressure and 50° C. with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 16.5 parts (100%) of cis-3-methoxy-4-piperidineethanol (interm. 45).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@H:9]([F:10])[CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1)=[N+]=[N-].[H][H]>C(O)C.[Pt](=O)=O>[NH2:1][CH2:4][C@@H:5]1[C@H:9]([F:10])[CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1
Reactant: [H][H]
Reactant: [N-]=[N+]=NC[C@H]1CN(Cc2ccccc2)C[C@H]1F
Agent: O=[Pt]=O
Solvent: CCO
Product: NC[C@H]1CN(Cc2ccccc2)C[C@H]1F
Yield: 99.9 %

Procedure:
(3R,4S)-3-Azidomethyl-1-benzyl-4-fluoropyrrolidine (215 mg) was dissolved in ethanol (3 mL) and platinum (IV) oxide (30.0 mg) was added. The mixture was stirred at room temperature for 5 hours under a stream of hydrogen gas (blown by a balloon). The catalyst in the reaction mixture was filtered through a Celite pad, and the catalyst and the Celite pad were washed with ethanol. The filtrate and the washings were then combined and concentrated under reduced pressure to give (3S,4S)-3-aminomethyl-1-benzyl-4-fluoropyrrolidine as a pale brown oil (191 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:33])=[CH:23][C:24]([O:31]C)=[C:25]([CH:30]=4)[C:26]([O:28][CH3:29])=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.B(Cl)(Cl)Cl.CO>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:33])=[CH:23][C:24]([OH:31])=[C:25]([CH:30]=4)[C:26]([O:28][CH3:29])=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)OC)c(OC)cc3C)cc12
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)OC)c(O)cc3C)cc12
Yield: 77.9 %

Procedure:
To a 100 mL round-bottomed flask was added methyl 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoate (350.5 mg, 0.783 mmol) in DCM (8 mL). To this solution was then added, under nitrogen, a 1M solution of boron trichloride (3.92 mL, 3.92 mmol) and the mixture was stirred overnight at room temperature. The reaction mixture was cooled in an ice bath and 10 mL of methanol was slowly added. The solvent was removed under vacuum. The flask was again cooled, 25 mL of ice cold methanol was added and the resulting solid was filtered to give 264.5 mgs (78% yield) of methyl 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-hydroxy-4-methylbenzoate as an ivory colored solid. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. 1H NMR (400 MHz, DMF-d7) δ ppm 2.30 (s, 3H), 2.95 (d, J=4.77 Hz, 3H), 3.98 (s, 3H), 7.02 (s, 1H), 7.38-7.48 (m, 3H), 7.68-7.73 (m, 2H), 7.76 (d, J=8.53 Hz, 1H), 8.08-8.15 (m, 2H), 8.33 (br. s., 1H). LCMS Rt=3.636, m/z 434.3 (M+H), 100% purity.
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])(C)(C)C.[CH2:20]([S:27]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32](Br)[CH:31]=1)(=[O:29])=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([S:27]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([C:18]#[C:17][C:10]2[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]([OH:5])=[O:19])[CH:31]=1)(=[O:29])=[O:28])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Cc2ccccc2)cc1Br
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(S(=O)(=O)Cc2ccccc2)cc1C#Cc1cc(C#N)ccc1OCC(=O)O

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-cyano-2-ethynyl phenoxy)acetate (Intermediate 46) and 4-(benzylsulfonyl)-2-bromo-1-methylbenzene (Intermediate 69), the title compound was obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]3)=[O:13])[C:6]=2[CH:21]=1.[CH3:22][N:23]=[C:24]=[O:25]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][CH:17]([O:20][C:24](=[O:25])[NH:23][CH3:22])[CH2:18][CH2:19]3)=[O:13])[C:6]=2[CH:21]=1
Reactant: O=C(Cn1c(=O)sc2ccc(Cl)cc21)N1CCC(O)CC1
Reactant: CN=C=O
Solvent: c1ccncc1
Product: CNC(=O)OC1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Temperature: 30 °C
Reaction time: 15 h
Yield: 71.8 %

Procedure:
5-Chloro-3-(4-hydroxypiperidinocarbonylmethyl)benzothiazolin-2-one (3.2 g) was dissolved in dry pyridine (15 ml) and the solution was cooled. After methyl isocyanate (0.9 g) was dropwise added to the solution, the resultant was stirred for 15 hours at 30° C. Pyridine was evaporated off under vacuum from the reaction mixture and the residue was recrystallized from methanol to yield the title compound as colorless crystals (2.7 g). mp 202°-203° C.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Cl)=[C:11]([Cl:16])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O-:18].[Na+]>O1CCOCC1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([O:18][CH3:17])=[C:11]([Cl:16])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: O=c1c(Cl)c(Cl)cnn1Cc1ccccc1
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1c(Cl)cnn(Cc2ccccc2)c1=O
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a stirring solution of 2-benzyl-4,5-dichloropyridazin-3(2H)-one (22.9 g, 89.8 mmol) in 1,4-dioxane (300 mL) at RT under argon was added NaOMe (22.4 mL, 25% solution in MeOH, 97.9 mmol) over 10 min by syringe. After 2 h, TLC indicated the reaction was completed. The reaction mixture was concentrated under reduced pressure. A saturated solution of NaCl (200 mL) was added and the resulting solution was extracted with CH2Cl2 (2×100 mL). The combined organic layers were dried (Na2SO4), concentrated under vacuum and purified by silica gel column chromatography eluting with CH2Cl2 to give the title compound, 2-benzyl-5-chloro-4-methoxypyridazin-3(2H)-one (20.3 g, 90%) as a colorless oil. TLC (CH2Cl2, Rf=0.4); MS [M+H]+ 251; HPLC retention time=2.74 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.[NH2-].[Na+].Br[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[C:15]1([CH2:14][CH2:13][CH:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:8]#[N:9])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCCc1ccccc1
Reactant: N#CCc1cccnc1
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(CCc1ccccc1)c1cccnc1
Temperature: -35 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
A solution of 3-pyridylacetonitrile (23 g) in tetrahydrofuran (75 ml) was added dropwise to a stirred suspension of sodium amide (8 g) in tetrahydrofuran (175 ml) under a nitrogen atmosphere at 0° C. After complete addition of the solution, the resultant mixture was stirred at 0-10° C. for 1 hour, then cooled to -35° C. and a solution of 2-(bromoethyl)benzene (36 g) in tetrahydrofuran (100 ml) was added dropwise over 30 minutes. The resultant new mixture was stirred between -35° C. to ambient temperature overnight, then quenched with water and neutralized with 10% hydrochloric acid. After the removal of of tetrahydrofuran, the residue was dissolved in methylene chloride and washed with saturated sodium bicarbonate solution. The organic extract was then dried over magnesium sulfate, filtered and evaporated to give an oil. The oil was then distilled to provide 30 g of α-(2-phenylethyl)-3-pyridineacetonitrile, b.p.=170-173° C./0.5 mmHg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]([CH3:12])([CH3:11])[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[K+]>C(O)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]([CH3:12])([CH3:11])[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)C(=O)O

Procedure:
25 g 2,2-Dimethyl-malonic acid diethyl ester, 7.8 g potassium hydroxide and 500 ml ethanol were mixed in a round-bottomed flask and refluxed for 3 hours. Then again 2.2 g potassium hydroxide were added and the mixture was refluxed overnight. The solvent was removed on a rotovap, 250 ml H2O were added and the mixture was washed with ether. The aqueous phase was acidified with HCl to pH 3-4 followed by two extractions with dichloromethane. The organic solvent was dried and evaporated and the resulting product was characterized by 1H-NMR.
Reaction SMILES: CC([N:5]([C@@H:9]([CH3:16])[CH2:10][CH2:11][NH:12][CH:13]1[CH2:15][CH2:14]1)[C:6](=[O:8])[O-:7])(C)C.[CH3:17][C:18](N([C@@H](C)CC=O)C(=O)[O-])([CH3:20])[CH3:19].C1(N)CC1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH:13]1([NH:12][CH2:11][CH2:10][C@@H:9]([NH:5][C:6](=[O:8])[O:7][C:18]([CH3:20])([CH3:19])[CH3:17])[CH3:16])[CH2:14][CH2:15]1
Reactant: C[C@@H](CC=O)N(C(=O)[O-])C(C)(C)C
Reactant: C[C@@H](CCNC1CC1)N(C(=O)[O-])C(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: NC1CC1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: C[C@@H](CCNC1CC1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
1,1-Dimethylethyl[(1S)-1-methyl-3-oxopropyl]carbamate. To a stirred solution of 1,1-dimethylethyl[(1S)-2-cyano-1-methylethyl]carbamate (0.656 g, 3.56 mmol) in anhydrous ether cooled to −40° C. was added dropwise a 1.0 M solution of diisobutylaluminum hydride in hexanes (14.2 mL, 14.2 mmol) over 20 minutes. Stirring was continued at this temperature for an additional 20 minutes. The yellow solution was quenched with Rochelle's salt and the resultant stirred at room temperature for 1 hour. The solids were filtered off through celite and rinsed with EtOAc. The organics were washed with brine, concentrated, and flash chromatographed (10-100% EtOAc/hexanes) to give 1,1-dimethylethyl [(1S)-1-methyl-3-oxopropyl]carbamate (0.193 g, 30%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 1.22 (d, J=6.8 Hz, 3H), 1.41 (s, 9H), 2.53-2.65 (m, 2H), 4.08-4.13 (m, 1H), 4.63 (m, 1H), 9.74-9.75 (m, 1H). b) 1,1-Dimethylethyl[(1S)-3-(cyclopropylamino)-1-methylpropyl]carbamate. The protected diamine was prepared using a modified procedure as described in example Z-32. A solution of 1,1-dimethylethyl[(1S)-1-methyl-3-oxopropyl]carbamate (0.178 g, 0.95 mmol) and cyclopropylamine (197 μL, 2.85 mmol) in anhydrous dichloroethane (10 mL) was treated with acetic acid (272 μL, 4.8 mmol) and stirred for 30 minutes. Sodium triacetoxyborohydride (0.444 g, 2.1 mmol) was added and the solution was stirred for 20 hours. The resultant was subjected to a workup and purification procedure as described in example Z-32 to give 1,1-dimethylethyl [(1S)-3-(cyclopropylamino)-1-methylpropyl]carbamate (0.136 g, 63%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 0.32-0.42 (m, 4H), 1.12 (d, J=6.8 Hz, 3H), 1.39-1.51 (m, 10H), 1.58-1.92 (m, 2H), 2.05-2.10 (m, 1H), 2.67-2.80 (m, 2H), 3.71 (m, 1H), 4.78 (m, 1H). c) [(3S)-3-Aminobutyl]cyclopropylamine dihydrochloride was prepared in a similar manner as described in example Z-29. 1H NMR (400 MHz, CDCl3/CD3OD) δ 0.70-0.75 (m, 2H), 0.90-0.94 (m, 2H), 1.18 (d, J=6.8 Hz, 3H), 1.84-1.94 (m, 1H), 1.97-2.05 (m, 1H), 2.49-2.54 (m, 1H), 2.99-3.04 (m, 2H), 3.23-3.28 (m, 1H), d)