Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([C:4]1[C:5]([O:24][CH3:25])=[C:6]([CH:13]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]2)[C:7]([C:11]#[N:12])=[C:8]([CH3:10])[CH:9]=1)[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:32][C:33]1[C:41]2[C:36](=[N:37][CH:38]=[N:39][C:40]=2[NH2:42])[NH:35][N:34]=1>CN(C)C=O.C(OCC)(=O)C>[NH2:42][C:40]1[N:39]=[CH:38][N:37]=[C:36]2[N:35]([CH:2]([C:4]3[C:5]([O:24][CH3:25])=[C:6]([CH:13]4[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]4)[C:7]([C:11]#[N:12])=[C:8]([CH3:10])[CH:9]=3)[CH3:3])[N:34]=[C:33]([CH3:32])[C:41]=12
Reactant: Cc1n[nH]c2ncnc(N)c12
Reactant: COc1c(C(C)Cl)cc(C)c(C#N)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(C)c(C#N)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 18 h
Yield: 49.9 %

Procedure:
The tert-butyl 3-[3-(1-chloroethyl)-6-cyano-2-methoxy-5-methylphenyl]azetidine-1-carboxylate (2.3 g, 6.3 mmol) was dissolved in N,N-dimethylformamide (68 mL) with cesium carbonate (4.1 g, 13 mmol) and 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.4 g, 9.4 mmol) and was heated in an oil bath to 80° C. The reaction was stirred for 18 hrs and allowed to cool to room temperature. The reaction mixture was taken up in ethyl acetate, filtered, washed with water, brine, dried over magnesium sulfate and concentrated to give the crude product. The product was purified by FCC on silica gel eluting a (hexane: 10% ethanol ethyl acetate) gradient to give tert-butyl 3-{3-[-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-methoxy-5-methylphenyl}azetidine-1-carboxylate as a semisolid (1.5 g, 50%). LCMS calculated for C25H32N7O3(M+H)+: m/z=478.2; found: 478.2. The enantiomers were separated by Chiral column HPLC using: Phenomenex LUX Cellulose Column, 21.1×250 mm, 5 micron, 15% ethanol in hexane, 18 mL/min ˜5 mg/injection to give: First peak retention time: 2.1 minutes, tert-butyl 3-{3-[-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-methoxy-5-methylphenyl}azetidine-1-carboxylate; Second peak retention time: 3.9 minutes, tert-butyl 3-{3-[-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-methoxy-5-methylphenyl}azetidine-1-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH3:18])[C:12]3[O:16][CH:15]=[CH:14][C:13]=3[CH:17]=2)=[CH:5][CH:4]=1.C1C(=O)N(Br)C(=[O:22])C1.OP([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:18]=[O:22])[C:12]3[O:16][CH:15]=[CH:14][C:13]=3[CH:17]=2)=[CH:5][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(-c2cc(C)c3occc3c2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(-c2cc(C=O)c3occc3c2)cc1
Temperature: 25 °C
Yield: 50.1 %

Procedure:
To a solution of 5-(4-methoxyphenyl)-7-methyl-benzofuran (1.60 g, 2.83 g 1:1 ratio with 4-methoxy-biphenyl 6.72 mmol) in carbon tetrachloride (190 ml) was added NBS (1.32 g, 7.40 mmol) and AIBN (50 mg). The solution was brought to reflux for 2 h, cooled to room temperature, and the solids were filtered off. The solution was then concentrated and anhydrous CH3CN (80 ml) was added. Then potassium benzeneselenite (2.14 g, 9.41 mmol), and K2HPO4 (1.17 g, 6.72 mmol) were added and then reaction was heated to reflux for 1 h after which it was allowed to cool to room temperature. The solution was then passed through a silica plug and concentrated under high vacuum. Chromatography (100% CH2Cl2) afforded 850 mg (50%) product as a white solid: mp 94–95° C.; 1H NMR (300 MHz, DMSO-d6): δ 3.82 (3H, s), 7.08 (2H, d, J=8.8 Hz), 7.14 (1H, d, J=2.2 Hz), 7.71 (2H, d, J=8.8 Hz), 8.10 (1H, d, J=1.9 Hz), 8.21 (1H, d, J=2.2 Hz), 8.25 (1H, d, J=1.9 Hz), 10.37 (1H, s); MS (ESI) m/z 253 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([C:16]#[N:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[CH2:8]Br.[C:18]([O-:21])(=[O:20])[CH3:19].[K+]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([C:16]#[N:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][O:21][C:18](=[O:20])[CH3:19]
Reactant: N#Cc1ccccc1-c1ccc(CBr)c(Br)c1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1ccc(-c2ccccc2C#N)cc1Br
Temperature: 50 °C
Yield: 64.1 %

Procedure:
To a solution of 662 mg (1.89 mmol) of 3'-bromo-4'-bromomethyl-1,1'-biphenyl-2-nitrile (Step D) in 10 mL of dry dimethyl formamide was added 925 mg (9.43 mmol) of potassium acetate. The reaction mixture was heated at 50° C. for 2 hours then diluted with 100 mL of water. The mixture was extracted with ethyl acetate (3×100 mL). The organic extracts were combined, washed with water (100 mL), saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL). The solution was dried over magnesium sulfate, filtered and the solvent removed under vacuum to give an oil which was purified by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (75:25), to afford 400 mg (64%) of the product as a white solid. 1H NMR (200 MHz, CDCl3): δ 2.14 (s, 3H), 5.22 (s, 2H), 7.4-7.8 (m, 7H). EI-MS: calculated for C16H12BrNO2 329; found 329, 331 (M+, 7%); 270, 272 (M-Br, 100%).
Reaction SMILES: [NH:1]1[C:6](=[O:7])[CH2:5][CH2:4][CH2:3][C:2]1=[O:8].[CH2:9]([C:12]1[C:20]2[O:19][N:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=2[CH:15]=[CH:14][C:13]=1[O:25][CH2:26][CH2:27][CH2:28]Br)[CH2:10][CH3:11]>>[CH2:9]([C:12]1[C:20]2[O:19][N:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[C:16]=2[CH:15]=[CH:14][C:13]=1[O:25][CH2:26][CH2:27][CH2:28][N:1]1[C:6](=[O:7])[CH2:5][CH2:4][CH2:3][C:2]1=[O:8])[CH2:10][CH3:11]
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Reactant: O=C1CCCC(=O)N1
Product: CCCc1c(OCCCN2C(=O)CCCC2=O)ccc2c(C(F)(F)F)noc12

Procedure:
1-(3-{[7-Propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-piperidin-2,6-dione was prepared as for Example 10 from piperidin-2,6-dione and the bromide from Example 7. After aqueous work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[Cl:13])[C@@H:2]1[O:4][CH2:3]1.[CH3:14][C:15]([NH2:26])([CH3:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>>[ClH:12].[OH:4][C@@H:2]([CH2:1][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[Cl:13])[CH2:3][NH:26][C:15]([CH3:25])([CH3:14])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1
Reactant: COc1ccc(CC(C)(C)N)cc1
Reactant: Clc1cccc(OC[C@H]2CO2)c1Cl
Product: COc1ccc(CC(C)(C)NC[C@@H](O)COc2cccc(Cl)c2Cl)cc1
Product: Cl
Yield: 103.6 %

Procedure:
Using the method of Example 6, supra, (R)-2,3-dichlorophenyl glycidyl ether (0.837 g, 3.82 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (0.75 g, 4.18 mmol) were used to prepare 860 mg of the title compound as a white solid: GC/EI-MS, m/z, (rel. int.) 382 (M−15,0.1), 280 (11), 278 (64), 277 (16), 276 (100), 163 (10), 121 (35), 77 (10), 71 (24), 70 (27), 58 (12).
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[O:6][CH2:5]1.C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>CN(C)C=O.C(=O)(O)[O-].[Na+]>[Br:13][CH2:2][CH2:3][CH:4]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[O:6][CH2:5]1
Reactant: CC1(C)OCC(CCO)CO1
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCC(CCBr)CO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
To an ice-cooled solution of 5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxan (6.08 g, 38 mmol) and carbon tetrabromide (18.90 g, 57 mmol) in N,N-dimethylformamide (110 ml); triphenylphosphine (14.95 g, 57 mmol) was added. The solution was stirred for 0.5 hour at 0° C. The solution was then diluted with saturated aqueous sodium bicarbonate (55 ml) followed by water (55 ml), and was extracted with hexane (2×150 ml). The combined organic layers were dried (magnesium sulphate) and the solvent removed. The residue was placed under high vacuum for 2 hours to remove bromoform. The residue was taken up in a small amount of hexane, filtered and the solvent removed to afford 5-(2-bromoethyl)-2,2-dimethyl-1,3-dioxan (7.40 g, 87%) as a colourless oil which crystallised on cooling, m.p. ca. 18° C.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]2[C:5]([C:6]([Cl:17])=[C:7]([O:13][CH2:14][CH2:15][CH3:16])[O:8][C:9]2=[O:10])=[CH:4][CH:3]=1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19]>C1COCC1>[CH2:18]([NH:20][C:21]([NH:1][C:2]1[CH:12]=[C:11]2[C:5]([C:6]([Cl:17])=[C:7]([O:13][CH2:14][CH2:15][CH3:16])[O:8][C:9]2=[O:10])=[CH:4][CH:3]=1)=[O:22])[CH3:19]
Reactant: CCCOc1oc(=O)c2cc(N)ccc2c1Cl
Reactant: CCN=C=O
Solvent: C1CCOC1
Product: CCCOc1oc(=O)c2cc(NC(=O)NCC)ccc2c1Cl
Temperature: 25 °C
Yield: 45 %

Procedure:
This compound was synthesized by the reaction of an equimolar amount of 7-amino-4-chloro-3-propoxyisocoumarin and ethyl isocyanate in small amount of dry THF. The reaction mixture was stirred at r.t. for a few days. During this time the yellow crystals slowly crystallized out. After filtration, the compounds were recrystallized once more from THF-pentane, yield 45%; mp 189°-191° C.; TLC, Rf =0.43 (CH3Cl:MeOH=9:1); MS, m/e 324 (M+). Anal. Calc. for C15H17O4N2Cl: C, 55.42; H, 5.23. Found: C, 55.31; H, 5.28.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][N:3]=1.N[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[NH:8]([C:6]1[CH:7]=[C:2]([Cl:1])[N:3]=[CH:4][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Product: Clc1cc(Nc2ccccc2)ccn1
Yield: 92 %

Procedure:
The title compound (3.8 g) was prepared by the same procedure as the preparation 4 except for using 2-chloro-4-nitropyridine (3.2 g) and aniline (5.7 g).
Reaction SMILES: N[C:2]1N=C(C(O)=O)C(C)=C[CH:3]=1.[NH2:12][C:13]1[N:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:14]=1[C:15]([OH:17])=[O:16]>>[CH3:22][C:18]1[CH:19]=[CH:20][N:21]2[CH:2]=[CH:3][N:12]=[C:13]2[C:14]=1[C:15]([OH:17])=[O:16]
Reactant: Cc1ccc(N)nc1C(=O)O
Reactant: Cc1ccnc(N)c1C(=O)O
Product: Cc1ccn2ccnc2c1C(=O)O

Procedure:
Prepared analogous to Example 82 substituting 6-amino-3-methylpicolinic acid with 2-amino-4-methylnicotinic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[F:44][C:45]1[CH:50]=[CH:49][C:48]([CH:51]([NH2:53])[CH3:52])=[CH:47][CH:46]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:53][CH:51]([C:48]2[CH:49]=[CH:50][C:45]([F:44])=[CH:46][CH:47]=2)[CH3:52])=[O:42])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(N)c1ccc(F)cc1
Reactant: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1NC(=O)NC(C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methoxyaniline (82 mg) was dissolved in chloroform (2 ml) and triethylamine (0.2 ml) to prepare a solution. A solution of triphosgene (70 mg) in chloroform (0.4 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(4-fluorophenyl)ethylamine (70 mg) in chloroform (0.4 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (58 mg, yield 47%).
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:32])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:11]1[CH:16]=[CH:15][C:14](B2OC(C)(C)C(C)(C)O2)=[CH:13][CH:12]=1.O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:9][C:10]([F:32])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:11]1[CH:16]=[CH:15][C:14]([C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:12]=1
Reactant: Nc1ncccc1Br
Reactant: CC1(C)OB(c2ccc(C(F)(F)c3ccccc3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncccc1-c1ccc(C(F)(F)c2ccccc2)cc1

Procedure:
Pd(dppf)Cl2 (19.4 mg) was added to a mixture of 1-bromo-4-(difluoro(phenyl)methyl)benzene (376 mg), potassium acetate (391 mg) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (506 mg) in DME (10 mL) and DMSO (0.5 mL). The mixture was stirred at 80° C. under nitrogen overnight. Activated-carbon powder was added and the mixture was stirred for 5 min. The insoluble material was removed by filtration. The filtrate was concentrated in vacuo to give a brown oil of 2-(4-(difluoro(phenyl)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Tetrakis(triphenylphosphine)palladium(0) (38.4 mg) was added to a suspension of 3-bromopyridin-2-amine (192 mg), the prepared 2-(4-(difluoro(phenyl)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and sodium carbonate decahydrate (634 mg) in DME (10 mL) and water (2 mL) and the mixture was stirred at 80° C. under nitrogen for 3 hr. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give the title compound (291 mg) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH2:11][C:12]([CH3:19])([CH3:18])S[C:14]([CH3:17])([CH3:16])[CH:15]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].O[O:21][S:22]([O-:24])=O.[K+]>CO.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH2:11][C:12]([CH3:19])([CH3:18])[S:22](=[O:24])(=[O:21])[C:14]([CH3:17])([CH3:16])[CH:15]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC1(C)C=C(c2ccc([N+](=O)[O-])cn2)CC(C)(C)S1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC1(C)C=C(c2ccc([N+](=O)[O-])cn2)CC(C)(C)S1(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of 5-nitro-2-(2,2,6,6-tetramethyl-3,6-dihydro-2H-thiopyran-4-yl)-pyridine (0.300 g, 1.08 mmol, as prepared in the previous step) in MeOH (15 mL) was cooled to 0° C. and treated with oxone (984 mg, 3.23 mmol based on KHSO5 content) as a solution in water (1.5 mL). The ice bath was removed, and the mixture was allowed to stir at RT for 1 h. The mixture was diluted with water and extracted with CH2Cl2 (2×). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 25-g Sepra Si 50 SPE column (Isco system: Flow rate=20 mL/min; Eluent=5% EtOAc-hexane for 0-3 min, then 5-15% EtOAc-hexane for 5-30 min) to afford the title product (322 mg, 96%) as an off-white solid. Mass spectrum (ESI, m/z): Calcd. for C14H18N2O4S, 311.1 (M+H), found 311.0.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:9]=[C:10]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH:7]2[CH:3]1[CH2:4][NH:5][CH2:6]2.C(=O)([O-])O.[Na+].Br[CH2:25][CH2:26][CH2:27][OH:28].C(OCC)C>CN(C)C=O.O>[NH3:5].[OH:28][CH2:27][CH2:26][CH2:25][N:5]1[CH2:6][CH:7]2[CH:3]([C:2]2([C:8]2[CH:9]=[C:10]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH3:1])[CH2:4]1
Reactant: OCCCBr
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(CCCO)CC21
Product: N
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 29.1 %

Procedure:
To a solution of the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 200 mg, 0.89 mmol) in N,N-dimethylformamide (8 ml) was added sodium hydrogen carbonate (3 g, 36 mmol) and 3-bromo-1-propanol (0.08 ml, 0.89 mmol), the reaction mixture was heated at 50° C. for 20 h. After cooling, diethyl ether (15 ml) and water (15 ml) were added and the reaction mixture was stirred vigorously for 5 min. The phases were separated and the aqueous layer was further extracted with diethyl ether (2×15 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residual oil was purified by flash column chromatography using a Sep-Pak™ cartridge packed with silica gel (10 g) eluting with dichloromethane:ethanol:0.88 ammonia solution (200:8:1) to afford the title compound as an oil (42 mg, 15%).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([OH:10])=O)[S:4][N:3]=1.S(Cl)([Cl:13])=O>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([Cl:13])=[O:10])[S:4][N:3]=1
Reactant: O=C(O)c1snc(Cl)c1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1snc(Cl)c1Cl

Procedure:
After thionyl chloride (10 ml) had been added to 3,4-dichloro-5-isothiazole-carboxylic acid (0.99 g), the mixture was refluxed by heating for 2 hours. The excess of thionylchloride was then distilled off under reduced pressure, and 3,4-dichloro-5-isothiazolecarboxylic acid chloride was obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[CH:26]=[CH:25][C:10]([CH2:11][CH:12]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])=[CH:9][CH:8]=1)=[O:6].Br[CH:28]([CH2:31][CH2:32][CH3:33])[C:29]#[N:30].O>CN(C=O)C>[C:29]([CH2:28][CH2:31][CH2:32][CH2:33][C:12]([CH2:11][C:10]1[CH:9]=[CH:8][C:7]([C:5]([O:4][CH3:3])=[O:6])=[CH:26][CH:25]=1)([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])#[N:30]
Reactant: CCCC(Br)C#N
Reactant: C=CCOC(=O)C(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)C(CCCCC#N)(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
1.88 g (78.23 mmol) of sodium hydride are added in portions to a solution of 20 g (60.18 mmol) of diallyl 2-(4-methoxycarbonylbenzyl)malonate from Example 12A in 140 ml of DMF at 0° C. The reaction solution is then warmed to 40° C. and is stirred at this temperature for 30 min. The reaction solution is then cooled to 0° C. again and, after addition of 10.73 g (66.20 mmol) of bromovaleronitrile in 140 ml of DMF, stirred at this temperature for 30 min. The mixture is then stirred at room temperature overnight. Water is added dropwise to the reaction mixture and, after extraction three times with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is concentrated to dryness in vacuo. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 9:1→4:1). 15.5 g (37.49 mmol, 62% yield) of a colorless solid are obtained.
Reaction SMILES: [Br-].[CH2:2]([O:9][C:10]([C:12]1[S:16][C:15]([CH2:17][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:14][CH:13]=1)=[O:11])C1C=CC=CC=1.[N+:37]([C:40]1[CH:47]=[CH:46][C:43]([CH:44]=O)=[CH:42][CH:41]=1)([O-])=O.C1COCC1.C[O-].[Na+].CO>O>[NH2:37][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][CH2:17][C:15]2[S:16][C:12]([C:10]([O:9][CH3:2])=[O:11])=[CH:13][CH:14]=2)=[CH:42][CH:41]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C(OCc1ccccc1)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)s1
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(CCc2ccc(N)cc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
To a mixture of 2.88 g of ({5-[(benzyloxy)carbonyl]-2-thienyl}methyl)(triphenyl)phosphonium bromide, 823 mg of 4-nitrobenzaldehyde and 30 mL of THF was added dropwise 1.0 mL of a 5.0 M sodium methoxide/methanol solution, followed by stirring overnight at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed sequentially with 1.0 M hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine and then dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:6). 10 mL of methanol and 10 mL of THF were added to the obtained residue, and 98 mg of 10% palladium carbon was added thereto under an argon flow, followed by stirring overnight at room temperature in a hydrogen atmosphere. The reaction mixture was filtered using celite, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), thereby obtaining 765 mg of methyl 5-[2-(4-aminophenyl)ethyl]thiophene-2-carboxylate.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>C(#N)C.CCOC(C)=O>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:2]([NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:14]([F:13])[CH:15]=2)[C:3]([OH:5])=[O:4])=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: O=C(O)C(Br)c1ccc(F)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(O)C(Nc1cccc(F)c1)c1ccc(F)cc1
Temperature: 100 °C
Yield: 90.1 %

Procedure:
A mixture of 2-bromo-2-(4-fluorophenyl)acetic acid (500 mg, 2.15 mmol) and 3-fluoroaniline (477 mg, 4.29 mmol) in acetonitrile (8 mL) is heated under microwave irradiation at 100° C. for 50 minutes. Then 3-fluoroaniline (238 mg, 2.15 mmol) is added again and reaction is heated at 120° C. for 45 minutes in a microwave oven (LC-MS monitoring: complete conversion). The organic solution is diluted with EtOAc and washed with 2N HCl and then with brine. The organic phase is dried over Na2SO4, filtered and the solvent is evaporated to give intermediate I131 as a white solid (510 mg, 90% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[C:11]([OH:17])(=[O:16])[CH2:12]C(O)=O.C([O-])(=O)C.[NH4+:22]>C(O)C>[NH2:22][CH:5]([C:4]1[CH:7]=[CH:8][C:9]([F:10])=[C:2]([F:1])[CH:3]=1)[CH2:12][C:11]([OH:17])=[O:16]
Reactant: [NH4+]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(F)c(F)c1
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC(CC(=O)O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
697 g of 3,4-difluorobenzaldehyde (4.76 mol, 1 equivalent) were stirred together with 495 g of malonic acid (4.76 mol, 1 equivalent) and 733 g of ammonium acetate (9.52 mol, 2 equivalents) in 2788 ml of ethanol at reflux under argon for 20 h. Then the mixture was cooled to RT and stirred at RT overnight. The precipitated crystals were filtered off with suction, washed with ethanol and diethyl ether, and dried under reduced pressure. 590 g (62% of theory) of rac-3-amino-3-(3,4-difluorophenyl)propanoic acid were obtained.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[N:9]=1.[Cl-:20].[NH4+:21]>>[ClH:20].[CH3:19][O:18][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][CH:8]2[NH:9][C:3](=[NH:21])[CH2:4][CH2:5][CH2:6][CH2:7]2)[CH:17]=[CH:16][CH:15]=1
Reactant: COC1=NC(CCc2cccc(OC)c2)CCCC1
Reactant: [NH4+]
Reactant: [Cl-]
Product: COc1cccc(CCC2CCCCC(=N)N2)c1
Product: Cl

Procedure:
The product of Example 167 is reacted with ammonium chloride by the method of Example 5 to generate the compound.