Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:25][CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[C:28]1([CH2:34][C:35]([N:37]=[C:38]=[O:39])=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1.CCCCCC>[N:22]1([CH:19]2[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]3[CH:8]=[C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:38]([NH:37][C:35](=[O:36])[CH2:34][C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)=[O:39])=[CH:27][CH:26]=4)[CH:12]=[CH:11][N:10]=3)=[O:15])[CH2:21][CH2:20]2)[CH2:25][CH2:24][CH2:23]1
Reactant: O=C=NC(=O)Cc1ccccc1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC4)CC3)c2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC4)CC3)c2)cc1
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(azetidin-1-yl)piperidin-1-yl]carbonylamino}pyridine (62.8 mg) in tetrahydrofuran (4.0 ml) was added a solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 1.71 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2) to provide the titled compound (50.0 mg, 55%) as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=O)[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=1.[C:23]1([NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH2:29]>[N+](C1C=CC=CC=1)([O-])=O>[NH:29]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:30]=[C:21]1[C:4]1[C:5]2[O:10][CH:9]([C:11]([F:12])([F:14])[F:13])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=[C:2]([Cl:1])[CH:3]=1
Reactant: Nc1ccccc1N
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(C=O)c2OC1C(F)(F)F
Solvent: O=[N+]([O-])c1ccccc1
Product: CCOC(=O)C1=Cc2cc(Cl)cc(-c3nc4ccccc4[nH]3)c2OC1C(F)(F)F
Yield: 43 %

Procedure:
A solution of the aldehyde (Example 76, Step 3) (0.33 g, 0.99 mmol) and 1,2-phenylenediamine (0.11 g, 1.02 mmol) in nitrobenzene (20 mL) was heated to 150° C. for 1.8 hours. The reaction mixture was extracted with ethyl acetate, washed with brine, dried over MgSO4, and concentrated in vacuo and purified by flash chromatography over silica gel (with 1:9 ethyl acetate/hexane as eluant) to give the ester as a brown solid (0.18 g, 43%) which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[N:15][N:16]3[CH:21]=[CH:20][CH:19]=[N:18][C:17]=23)=[O:12])=[C:6]([O:22][CH3:23])[CH:5]=1.[OH-].[NH4+:26].N>C(#N)C.CS(C)=O>[C:3]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[N:15][N:16]3[CH:21]=[CH:20][CH:19]=[N:18][C:17]=23)=[O:12])=[C:6]([O:22][CH3:23])[CH:5]=1)(=[O:2])[NH2:26]
Reactant: [NH4+]
Reactant: COC(=O)c1ccc(NC(=O)c2cnn3cccnc23)c(OC)c1
Agent: N
Agent: [OH-]
Solvent: CC#N
Solvent: CS(C)=O
Product: COc1cc(C(N)=O)ccc1NC(=O)c1cnn2cccnc12
Temperature: 50 °C
Yield: 35 %

Procedure:
A mixture of 3-methoxy-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-benzoic acid methyl ester (5 mg) and an aqueous solution of ammonium hydroxide (concentrated, 1 mL) and a mixture of 3-methoxy-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-benzoic acid methyl ester (5 mg) and a solution of ammonia (2 M in MeOH, 1 mL) were stirred at room temperature for 2 days. The two mixtures were then combined and dimethyl sulfoxide (1 mL) was added followed by acetonitrile (1 mL). A solution of ammonia (2 M in MeOH, 1 mL) and an aqueous solution of ammonium hydroxide (concentrated, 2 mL) were then added and the resulting mixture was heated to 50° C. for 24 hours. A second portion of 3-methoxy-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-benzoic acid methyl ester (35 mg) was added followed by dimethyl sulfoxide (5 mL), acetonitrile (5 mL), a solution of ammonia (2 M in MeOH, 5 mL) and an aqueous solution of ammonium hydroxide (concentrated, 5 mL) and the resulting mixture was heated to 85° C. for 3 days. The white precipitate which formed was collected by filtration, washed with water, methanol and diethyl ether to afford after drying 15 mg (35% yield) of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (4-carbamoyl-2-methoxy-phenyl)-amide as light yellow solid. MS=312 [M+H]+.
Reaction SMILES: O1CCC(=CC[C@H](C(OC(C)(C)C)=O)[C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11](O)=[O:12])CC1.C([NH:29][NH2:30])C(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>O1CCOCC1>[CH3:16][CH:15]([CH3:17])[CH2:14][CH2:10][C:11]([NH:29][NH2:30])=[O:12]
Reactant: CC(C)CNN
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](CC=C1CCOCC1)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: C1COCCO1
Product: CC(C)CCC(=O)NN

Procedure:
In a manner analogous to that described in Example 2, parts (iii)-(v), starting from 4-tert-butyl hydrogen 3(S)-[(tetrahydro-2H-pyran-4-ylidene)ethyl]-2(R)-isobutylsuccinate and isobutylhydrazine and using trimethylsilyl trifluoromethanesulphonate in 1,4-dioxane instead of trifluoroacetic acid to deprotect the tertiary butyl ester there was obtained 2(R)-[3-(tetrahydro-2H-pyran-4-ylidene)-1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-propyl]-2′-isobutyl-2′-methanesulphonyl)-4-methylvalerohydrazide in the form of an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[S:16]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:26][O:25][C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([S:16](=[O:17])(=[O:18])[NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(S(=O)(=O)Nc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.4 %

Procedure:
A solution of 4-fluoroaniline (484 μL, 5.11 mmol) and pyridine (688 μL, 8.52 mmol) in DCM (20 mL) was treated with methyl 4-(chlorosulfonyl)benzoate (1.00 g, 4.26 mmol) and stirred at room temperature for 3 hours. The mixture was diluted with DCM, washed with 1 N aqueous HCl, saturated aqueous NaHCO3, water and brine, dried over Na2SO4 and concentrated under vacuum. Triturating with pentane gave 4-(4-fluoro-phenylsulfamoyl)-benzoic acid methyl ester (1.02 g, 77%). 1H NMR (300 MHz, CDCl3) δ 8.10 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.4 Hz, 2H), 7.07-6.99 (m, 2H), 6.98-6.88 (m, 2H), 6.75 (br s, 1H), 3.94 (s, 3H). LCMS (m/z, Method A) ES+ 310.0 [M+1]+.
Reaction SMILES: [NH2:1][C:2](=[N:19][OH:20])[C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:5]([F:18])[CH:4]=1.[CH3:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][N:23]1[C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=O)=[CH:30][C:29]=1[C:37]([F:40])([F:39])[F:38]>>[F:18][C:5]1[CH:4]=[C:3]([C:2]2[N:1]=[C:32]([C:31]3[CH:35]=[CH:36][C:28]([N:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH:22]4[CH3:21])=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:30]=3)[O:20][N:19]=2)[CH:17]=[CH:16][C:6]=1[O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10]
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)COc1ccc(C(N)=NO)cc1F
Product: CC1CCCCN1c1ccc(-c2nc(-c3ccc(OCC(=O)OC(C)(C)C)c(F)c3)no2)cc1C(F)(F)F

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 49 (142.14 mg; 0.50 mmol) and Intermediate 15 (172.37 mg; 0.60 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/EtOAc: 9.5/0.5), affording the title compound as a white solid. LC/MS (Method B): 536.4 (M+H)+. HPLC (Method A) Rt 7.2 min (Purity: 99.4%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:38]=[CH:37][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:14](=[O:36])[N:15]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[C:16]([CH3:25])=[C:17]([C:19]3[O:20][CH:21]=[C:22]([CH3:24])[N:23]=3)[CH:18]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[CH:40](C)C(=O)C.C([O-])([O-])=O.[Ca+2].CN1C(=O)CCC1>C(#N)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:14](=[O:36])[N:15]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=3)[C:16]([CH3:25])=[C:17]([C:19]3[O:20][C:21]([CH3:40])=[C:22]([CH3:24])[N:23]=3)[CH:18]=2)=[O:12])=[CH:37][CH:38]=1)(=[O:3])=[O:4]
Reactant: CC(=O)C(C)Br
Reactant: Cc1coc(-c2cc(C(=O)NCc3ccc(S(C)(=O)=O)cc3)c(=O)n(-c3cccc(C(F)(F)F)c3)c2C)n1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC#N
Solvent: CN1CCCC1=O
Product: Cc1nc(-c2cc(C(=O)NCc3ccc(S(C)(=O)=O)cc3)c(=O)n(-c3cccc(C(F)(F)F)c3)c2C)oc1C
Temperature: 140 °C
Yield: 12.8 %

Procedure:
6-Methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dicarboxylic acid 5-amide 4-methanesulfonyl-benzylamide (see Example 60, 0.05 g, 0.098 mmol), 3-bromo-2-butanone (0.020 g, 0.20 mmol), CaCO3 (0.015 g, 0.15 mmol), NMP (1.5 ml) and a magnetic stirrer bar were placed in a tube designed for microwave synthesis. The vial was sealed and the mixture was heated in a CEM Discover Microwave apparatus (100 W, 140° C.) for 2 h. The reaction was stopped and the crude mixture was dissolved in acetonitrile (2 ml) and water (2 ml) and was purified directly on preparative HPLC, giving the title compound (0.007 g, 13%) as a slightly brownish solid after freeze-drying the pure fractions.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7](NC2SC=CN=2)[CH:6]=C[CH:4]=1.Cl[C:16]1[C:17](F)=C(C=C[CH:29]=1)C(N1CCNCC1)=O>CN(C)C=O>[CH:16]([N:8]([CH2:7][CH3:6])[CH:3]([CH3:2])[CH3:4])([CH3:17])[CH3:29]
Reactant: O=C(c1cccc(Cl)c1F)N1CCNCC1
Reactant: ClCc1cccc(Nc2nccs2)n1
Solvent: CN(C)C=O
Product: CCN(C(C)C)C(C)C

Procedure:
A mixture of 2.70 g of 6-(chloromethyl)-N-thiazol-2-ylpyridin-2-amine, 4.00 g of 1-(3-chloro-2-fluorobenzoyl)piperazine obtained in Reference Example 1, 6.25 ml of N,N-diisopropylethylamine and 30 ml of dimethylformamide was stirred at 90° C. for 2 hours. The reaction solution was diluted with ethyl acetate and then washed with water and brine. The resulting organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The resulting residue was purified by a silica gel column chromatography (eluent: chloroform to chloroform/methanol=10/1). Then, the obtained compound was suspended in ethyl acetate, and filtered and collected to give the title compound as a colorless amorphous substance.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H][H].C(OC(C)C)(C)C>[Pd].CCOC(C)=O>[C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(Cc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: CN(Cc1ccc(N)cc1)C(=O)OC(C)(C)C
Yield: 66.4 %

Procedure:
A Parr bottle was charged with (4-nitrobenzyl)-methy-carbarnic acid tert-butyl ester (30.0 g, 113 mmol), 150 mL EtOAc, and 10% Pd/C (3.0 g, 10 wt %), and shaken under 40 psi hydrogen for 90 min. When hydrogen uptake ceased, the reaction vessel was purged with nitrogen, filtered through celite, and concentrated to provide a tan solid, which was granulated with 300 mL of isopropyl ether to provide the title compound as an off-white solid (17.7 g in two crops, 75 mmol, 66% yield):
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S].S1C2C=CC=CC=2N=C1.[C:18](=[S:20])=[S:19]>>[SH:20][C:18]1[S:19][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: S=C=S
Reactant: Nc1ccccc1
Agent: [S]
Agent: c1ccc2scnc2c1
Product: Sc1nc2ccccc2s1

Procedure:
reacting starting materials comprising (1) aniline, carbon disulphide and sulphur, (2) benzothiazole and sulphur or (3) aniline, carbon disulphide, benzothiazole and sulphur, to form crude 2-mercaptobenzothiazole,
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl(O)(=O)(=O)=[O:14].C(=O)(O)[O-].[Na+]>O>[CH2:1]([O:8][CH2:9][CH:10]([OH:12])[CH2:11][OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][Cl+3]([O-])([O-])O
Reactant: c1ccc(COCC2CO2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: OCC(O)COCc1ccccc1
Reaction time: 18 h
Yield: 90 %

Procedure:
3-Benzyloxy-1,2-epoxypropane (263 g, 1.60 mol), water (1,300 mL) and 70% perchloric acid (1.5 mL) were placed in a 2.0 L 3-necked flask equipped with condenser and thermometer. The mixture was heated to 80° for 18 hours. After heating and stirring for 18 hours at 80° the reaction mixture was neutralized with 5% sodium bicarbonate solution. The water was removed by rotary evaporation. Final removal of residual water was accomplished by azeotropic distillation using 300 mL of benzene. After evaporation of the benzene the product was distilled to yield 264 g (90%) of 3-benzyloxy-1,2-propanediol: bp 127°-136° C. (0.04 mm).
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH2:10][CH2:9]2.O>CS(C)=O>[CH2:11]1[C:12]2[C:8](=[CH:7][C:6]([CH2:5][C:1]#[N:2])=[CH:14][CH:13]=2)[CH2:9][CH2:10]1
Reactant: ClCc1ccc2c(c1)CCC2
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, partial solution of NaCN (11.4 g, 0.232 mol) in DMSO 75 mL) was added 5-chloromethylindan (35.2 g, 0.211 mol) dropwise over 45 minutes. (The internal temperature was maintained below 65° C.). The resulting mixture was stirred at room temperature overnight. H2O (250 mL) was added and the mixture was extracted with ether. The organic phase was washed with H2O (200 mL), 6N HCl (100 mL), H2O (200 mL), saturated aqueous NaHCO3 (100 mL), and saturated aqueous NaCl, dried (MgSO4), and concentrated. The crude product was distilled under reduced pressure (0.6 mm) to give 28.1 g (85%) as a colorless oil, b.p. 131°) C.
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([N:8]2[CH2:11][C:10]([CH2:34][C:35]#[N:36])([N:12]3[CH:16]=[C:15]([C:17]4[C:18]5[CH:25]=[CH:24][N:23](COCC[Si](C)(C)C)[C:19]=5[N:20]=[CH:21][N:22]=4)[CH:14]=[N:13]3)[CH2:9]2)[CH2:6][CH2:5][NH:4][CH2:3]1.[F:37][C:38]([F:49])([F:48])[C:39]1[N:44]=[C:43]([C:45](O)=[O:46])[CH:42]=[CH:41][N:40]=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.C(N(CC)CC)C>CN(C=O)C>[F:1][C@H:2]1[C@@H:7]([N:8]2[CH2:11][C:10]([CH2:34][C:35]#[N:36])([N:12]3[CH:16]=[C:15]([C:17]4[C:18]5[CH:25]=[CH:24][NH:23][C:19]=5[N:20]=[CH:21][N:22]=4)[CH:14]=[N:13]3)[CH2:9]2)[CH2:6][CH2:5][N:4]([C:45]([C:43]2[CH:42]=[CH:41][N:40]=[C:39]([C:38]([F:49])([F:37])[F:48])[N:44]=2)=[O:46])[CH2:3]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN([C@H]5CCNC[C@H]5F)C4)c3)ncnc21
Reactant: O=C(O)c1ccnc(C(F)(F)F)n1
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(CC)CC
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN([C@H]2CCN(C(=O)c3ccnc(C(F)(F)F)n3)C[C@H]2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
To a solution of {1-[cis-3-fluoropiperidin-4-yl]-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (200 mg, 0.4 mmol) and 2-(trifluoromethyl)pyrimidine-4-carboxylic acid (83 mg, 0.43 mmol) in DMF (10 mL) were added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (5.20E2 mg, 1.17 mmol) and triethylamine (0.14 mL, 0.98 mmol). The mixture was stirred at room temperature overnight and purified with prep-LCMS to give 100 mg (36% yield) of the desired compound as a white solid.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C([Mg]Cl)(C)C.[CH2:12]([O:19][CH:20]1[CH2:25][CH2:24][C:23]([N:28]([CH3:30])[CH3:29])(C#N)[CH2:22][CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:12]([O:19][CH:20]1[CH2:25][CH2:24][C:23]([N:28]([CH3:30])[CH3:29])([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)[CH2:22][CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Ic1cccs1
Reactant: CN(C)C1(C#N)CCC(OCc2ccccc2)CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)C1(c2cccs2)CCC(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.67 g of 2-iodothiophene were dissolved in 20 ml of tetrahydrofuran, and 7.26 ml of two molar isopropylmagnesium chloride solution in tetrahydrofuran were added dropwise under a nitrogen atmosphere, while cooling with an ice bath. After one hour, 2.50 g of 4-benzyloxy-1-dimethylaminocyclohexanecarbonitrile were added dropwise, dissolved in 10 ml of tetrahydrofuran. After stirring overnight at room temperature, the mixture was again cooled in an ice bath and 25 ml of cold ammonium chloride solution (20 wt. %) were added. The phases were separated and extracted three times using 40 ml of diethyl ether each time, and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The resulting crude product (3.82 g) was separated on silica gel with diethyl ether. 1.59 g of the non-polar and 260 mg of the polar diastereoisomer of (4-benzyloxy-1-thiophen-2-yl-cyclohexyl)dimethylamine were obtained and, as described for Example 1, were converted into 1.11 g (Example 11) and 210 mg (Example 12) of the corresponding hydrochlorides using chlorotrimethylsilane and water in 2-butanone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:3]=1.[Cl-].[NH4+].C(OCC)(=O)C>C(O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Oc1ccc(F)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(Cl)cc1Oc1ccc(F)cc1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a solution of 4-chloro-2-(4-fluorophenoxy)-1-nitrobenzene (4.56 g, 17.0 mmol) and iron powder (3.07 g, 55.0 mmol) in ethanol (20 mL), a saturated aqueous ammonium chloride solution (aq., 8.0 mL) was added, and the mixture was stirred at 90° C. for 30 minutes. After the reaction, the reaction mixture was cooled to room temperature, and ethyl acetate (30 mL) was added. After the organic phase was washed with water (30 mL), 1N sodium hydroxide (aq., 30 mL) and saturated brine (20 mL), it was dried with sodium sulfate. The solvent was distilled off under reduced pressure to give the title compound (3.62 g, 90%). The obtained compound was used for the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][C:2]#[C:3][CH3:4].CN1C(=O)N(C)CCC1.N#N.C([Li])CCC.I[CH2:22][CH2:23][C@@H:24]1[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]1.CC1(C)O[C@H](CCO)CO1>C1COCC1>[CH2:23]([C@@H:24]1[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]1)[CH2:22][C:1]#[C:2][CH2:3][CH3:4]
Reactant: CC#CC
Reactant: CC1(C)OC[C@@H](CCI)O1
Agent: CC1(C)OC[C@@H](CCO)O1
Agent: N#N
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCC#CCC[C@@H]1COC(C)(C)O1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a flask cooled to −78° C. under N2 was added 2-butyne gas via syringe needle until approximately ˜3 mL of liquid had condensed in the flask. THF (120 mL) was then added followed by DMPU (18.9 ml, 156 mmol). The flask was purged with N2 and n-butyllithium (2.5M hexanes, 18.7 ml, 46.9 mmol) was added via syringe over 5 min and stirred for an additional 15 min at which time (R)-4-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolane (10.0 g, 39.1 mmol) was added as a solution in THF (30 mL) [preparation of enantiopure (R)-4-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolane from commercially available (R)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol was performed using the procedure described by: Taber. D. F.; Xu, M.; Hartnett, J. C. J. Am. Chem. Soc. 2002, 124, 13121]. The reaction was slowly warmed to rt and stirred a total of 3 h. The mixture was quenched with sat. NH4Cl, and extracted with Et2O (2×). The organics were washed with H2O, and brine, dried over MgSO4, filtered, and concentrated. The material was purified by silica gel chromatography (5% EtOAc in hexanes gradient to 15% EtOAc in hexanes) to give (R)-4-(hex-3-ynyl)-2,2-dimethyl-1,3-dioxolane as a clear oil. 1H NMR (400 MHz, CDCl3): δ 4.19 (1H, m), 4.08 (1H, dd, J=8.0, 6.0 Hz), 3.58 (1H, dd, J=7.6, 6.8 Hz), 2.26 (2H, m), 2.15 (2H, qt, J=5.2, 2.4 Hz), 1.81 (1H, m), 1.68 (1H, m), 1.40 (3H, s), 1.36 (3H,s), 1.11 (3H, t, J=7.6 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[CH3:18])[CH:6]=[CH:7][CH:8]=1>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[C:10]([CH3:18])[CH:11]=1
Reactant: COc1cccc(-c2ccc([N+](=O)[O-])cc2C)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cccc(-c2ccc(N)cc2C)c1
Yield: 101.6 %

Procedure:
1-(3-Methoxyphenyl)-2-methyl-4-nitrobenzene(23.4 gm, 96 mmol) was dissolved in a mixture of ethanol and ethyl acetate (3:1, 470 mL) and hydrogenated over 10% palladium on charcoal (2.3 gm) at 3 bar and 20° C. for 2 h. The mixture was filtered through Arbocel filter aid, washing with ethyl acetate. The filtrate was concentrated under reduced pressure to give 4-amino-1-(3-methoxyphenyl)-2-methylbenzene (20.8 gm, 100%) as a pinkish-brown oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[O:15][C:16]([CH3:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:19])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][Br:20])=[CH:10][C:9]=1[O:15][C:16]([CH3:18])=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1cc(C)ccc1CC(=O)OC(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1cc(CBr)ccc1CC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 38.9 %

Procedure:
To a solution of 2-(2-acetoxyl-4-methylphenyl)acetic acid tert-butyl ester (4.9 g, 18.5 mmol) in CCl4 (50 ml) was added N-bromosuccinimide (3.29 g, 18.5 mmol, 1 equivalents) and benzoyl peroxide (100 mg), the reaction mixture was refluxed under argon for 3 hr. The reaction mixture was then cooled to room temperature. The solid precipitate was filtered off, and washed with hexanes, the combined organic was taken to dryness, and the residue obtained was purified by chromatography (Hexanes—EtOAc, 50:1 to 40:1) to give (2-acetoxyl-4-bromomethylphenyl)acetic acid tert-butyl ester 2.467 g (38.8% yield) as an oil. 1H NMR (CDCl3) δ: 7.290 (1H, d, J=7.81 Hz), 7.230 (1H, dd, J=1.71, 7.81 Hz), 7.158 (1H, d, J=1.71 Hz), 4.467 (2H, s), 3.462 (2H, S), 2.320 (3H, s), 1.430 (9H, s) ppm. FABMS (+Ve), m/z 345 [MH+, 81Br], 343 [MH+, 79Br], 389 [MH+—C4H8, 81Br], 387 [MH+—C4H8, 79Br]. Anal. calcd. for C15H19BrO4: C, 52.5; H, 5.6; Br, 23.3. Found: C, 52.30; H, 5.50; Br, 23.44.