Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH2:8])[O:4][N:3]=1.[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19])([O-:11])=[O:10]>N1C=CC=CC=1>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N+:9]([O-:11])=[O:10])(=[O:19])=[O:20])[O:4][N:3]=1
Reactant: Cc1noc(N)c1C
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1noc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of 4.04 g (36 mmol) of 3,4-dimethyl-5-isoxazolamine in 15 mL of pyridine, 8.0 g (36 mmol) of 2-nitrobenzenesulfonyl chloride was added and the solution was stirred at room temperature overnight. The mixture was poured into 100 mL of ice water and filtered. The filtrate was acidified to pH 2 using 6N aqueous hydrochloric acid and the mixture was extracted with 4×125 mL of ethyl acetate. The combined organic extracts were washed with 75 mL of brine, dried and evaporated to provide 9.1 g of a dark brown residue. This material was chromatographed on silica gel using hexanes/ethyl acetate (2:1) to provide 0.5 g of Example 9 as a light yellow solid. Melting point: 91°-94° C. Analysis for C11H11N3O5S Calc'd: C, 44.44; H, 3.73; N, 14.13; S, 10.78. Found: C, 44.75; H, 3.69; N, 14.01; S, 11.06.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:10][C:11](=[O:24])[N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:13]=2)[CH:8]=1.[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>C1COCC1>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:8][C:7]=1[C:9]1[NH:10][C:11](=[O:24])[N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[CH:15]=2)[N:13]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1ccc(Cl)c(-c2nn(-c3cccc(C(F)(F)F)c3)c(=O)[nH]2)c1
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3cccc(C(F)(F)F)c3)c(=O)[nH]2)c1

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chlorophenyl)-2-(3-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-96, 0.250 g, 0.678 mmol), pivaloyl chloride (0.3 mL), TEA (2.0 mL), and dry THF (5 mL) to afford 0.150 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.13 (s, 9H), 4.30 (d, J=6.0 Hz, 2H), 7.41-7.43 (m, 1H), 7.59-7.62 (m, 3H), 7.71-7.76 (m, 1H), 8.19-8.29 (m, 3H), 12.68 (s, 1H); MS (m/z): 453.38 (M+H)+.
Reaction SMILES: [N:1]1C=CC=C[CH:2]=1.[CH3:7][C:8]1([CH3:20])[CH:10](/[CH:11]=[CH:12]/[C:13](OC)=O)[CH:9]1[C:17](O)=O.[CH:21]1C=CC=CC=1.Cl>O>[CH3:21][C:9]1[CH2:17][CH2:20][C:8](=[CH:7][C:2]#[N:1])[C:10]=1[CH2:11][CH:12]=[CH2:13]
Reactant: c1ccccc1
Reactant: c1ccncc1
Reactant: COC(=O)/C=C/C1C(C(=O)O)C1(C)C
Agent: Cl
Solvent: O
Product: C=CCC1=C(C)CCC1=CC#N
Reaction time: 2 h

Procedure:
1.5 ml of pyridine were added at 5° C. to a mixture of 3 g of the product of Step A, 3 g of (1R, trans) 2,2-dimethyl-3-(2-methyl-1-propenyl)-cyclopropane-carboxylic acid chloride and 50 ml of benzene and the mixture was held at 5° C. for 15 minutes, at 20° C. for 2 hours and was then poured into a mixture of 18 ml of 2 N hydrochloric acid and 100 ml of water at 5° C. The mixture was extracted with ether and the organic phase was washed with water, dried and evaporated to dryness. The 6.5 g of residue was chromatographed over silica gel and was eluted with a 97-3 toluene-ethyl acetate mixture to obtain 4.93 g of (1S) 2-methyl-3-allyl-4-cyanomethylene-cyclopent-2-ene-1-yl (1R, trans) 2,2-dimethyl-3-(2-methyl-1-propenyl)-cyclopropane-carboxylate with a specific rotation of [α ]D20 =-162.5°±3.5° (c=0.6% in benzene).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([O:13][C:14]([NH:16][C@@H:17]([CH2:20][CH2:21][S:22][CH3:23])[CH:18]=O)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:9]([O:13][C:14]([NH:16][C@@H:17]([CH2:20][CH2:21][S:22][CH3:23])[CH2:18][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=1)=[O:15])([CH3:10])([CH3:12])[CH3:11]
Reactant: CSCC[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: Nc1cccc(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CSCC[C@@H](CNc1cccc(Cl)c1)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of 3-chloroaniline (10.3 mL, 97.4 mmol), the product from Step G (23.9 g, 97.4 mmol), and acetic acid (27.8 mL, 487 mmol) in dichloroethane (250 mL) under nitrogen was added sodium triacetoxyborohydride (41.3 g, 195 mmol). The reaction was stirred overnight, then quenched with saturated sodium bicarbonate solution. The solution was diluted with CHCl3, and the organic phase was washed with water, 10% citric acid and brine. The solution was dried over sodium sulfate and concentrated in vacuo to provide the crude product (34.8 g) which was chromatographed on silica gel with 20% ethyl acetate in hexane to obtain the title compound.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:9][CH2:8][CH:7]([N:18]3C(=O)C4C(=CC=CC=4)C3=O)[C:6]2=[O:29])[CH2:3][CH2:2]1.O.NN>CO.CCOCC>[NH2:18][CH:7]1[CH2:8][CH:9]=[CH:10][C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[C:6]1=[O:29].[NH2:18][CH:7]1[CH2:8][CH:9]=[CH:10][C@@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[C:6]1=[O:29]
Reactant: O=C1C(N2C(=O)c3ccccc3C2=O)CC=CC(c2ccccc2)N1CC1CC1
Agent: NN
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: NC1CC=C[C@@H](c2ccccc2)N(CC2CC2)C1=O
Product: NC1CC=C[C@H](c2ccccc2)N(CC2CC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To 2-[1-(cyclopropylmethyl)-2-oxo-7-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-yl]-1H-isoindole-1,3(2H)-dione (4d) (126 mg) dissolved in MeOH (4 mL) was added hydrazine hydrate (0.033 mL) and the mixture was stirred overnight at RT. A white precipitate formed in solution. The reaction mixture was diluted with ether and the precipitate was filtered and washed with ether. The etheral filtrate was concentrated and the resulting residue dissolved in DCM. The DCM solution was washed with H2O and brine, dried (Na2SO4) and concentrated to an oil. The diastereomeric mixture was separated via preparative plate chromatography (eluent 10% MeOH/DCM) to give (7R)-3-amino-1-(cyclopropylmethyl)-7-phenyl-1,3,4,7-tetrahydro-2H-azepin-2-one (4f) (28 mg) and (7S)-3-amino-1-(cyclopropylmethyl)-7-phenyl-1,3,4,7-tetrahydro-2H-azepin-2-one (4e) (40 mg) (combined yield of 82%).
Reaction SMILES: [C:1]([CH2:11][N:12]1[CH2:16][CH2:15][N:14]=[CH:13]1)([O:3]CC1C=CC=CC=1)=[O:2].C(O)C.[H][H].[ClH:22]>C(OCC)(=O)C.[Pd]>[ClH:22].[C:1]([CH2:11][N:12]1[CH2:16][CH2:15][N:14]=[CH:13]1)([OH:3])=[O:2]
Reactant: [H][H]
Reactant: O=C(CN1C=NCC1)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)CN1C=NCC1

Procedure:
A suspension of 10.9 g. (0.05 mole) of N-carbobenzyloxymethylimidazoline and 50 mg. of 5% palladium-on-charcoal in 100 ml. of ethanol is shaken in an atmosphere of hydrogen at atmospheric pressure. When the theoretical amount of hydrogen has been absorbed, the spent catalyst is filtered and the filtrate treated with one equivalent of hydrogen chloride dissolved in ethyl acetate. The resulting solution is then concentrated to dryness in vacuo and the residual product triturated with ether and filtered.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[C:13]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:4][N:3]=1.Cl.[CH3:26][N:27]1[CH:31]=[C:30]([NH2:32])[CH:29]=[N:28]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:26][N:27]1[CH:31]=[C:30]([NH:32][C:2]2[N:7]=[C:6]([NH:8][CH:9]3[C:13]4([CH2:14][CH2:15][CH2:16][CH2:17]4)[CH2:12][N:11]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:10]3)[CH:5]=[CH:4][N:3]=2)[CH:29]=[N:28]1
Reactant: Cn1cc(N)cn1
Reactant: CC(C)(C)OC(=O)N1CC(Nc2ccnc(Cl)n2)C2(CCCC2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cn1cc(Nc2nccc(NC3CN(C(=O)OC(C)(C)C)CC34CCCC4)n2)cn1
Temperature: 150 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
To a solution of tert-butyl 4-((2-chloropyrimidin-4-yl)amino)-2-azaspiro[4.4]nonane-2-carboxylate (528 mg, 1.50 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (240.52 mg, 1.8 mmol) in n-BuOH (8 mL) was added DIPEA (581.60 mg, 4.5 mmol). After addition, the reaction mixture was stirred at 150° C. overnight. The resulting mixture was concentrated in vacuo and purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1 to 20/1) to give the product as a yellow oil (550 mg, 88.9%).
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:2]([OH:8])=[CH:3][C:4]([OH:7])=[CH:5][CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH2:20][C:21](Cl)=[O:22].O>[N+](C1C=CC=CC=1)([O-])=O>[OH:8][C:2]1[C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:5]2[C:21](=[O:22])[CH2:20][O:7][C:4]=2[CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: Oc1ccc(-c2ccccc2)c(O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: O=C1COc2cc(O)c(-c3ccccc3)cc21
Temperature: 40 °C
Reaction time: 3 h
Yield: 40.8 %

Procedure:
A solution of biphenyl-2,4-diol (0.24 g, 1.3 mmol) in nitrobenzene (1.0 mL) was added with aluminum chloride (0.60 g, 4.5 mmol) at room temperature. Then, the reaction mixture was added with chloroacetyl chloride (0.60 g, 1.7 mmol) under ice cooling. The mixture was stirred at 40° C. for 3 hours, and then added with water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (100:0→90:10)) to obtain 6-hydroxy-5-phenylbenzofuran-3(2H)-one (0.12 g, 42%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:14]2[CH:15]=[N:16][N:17]([CH2:19][CH3:20])[CH:18]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]1[NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41]>CN(C=O)C>[C:40]([O:39][C:38]([NH:37][C@H:32]1[CH2:33][CH2:34][CH2:35][CH2:36][C@H:31]1[NH:30][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:14]2[CH:15]=[N:16][N:17]([CH2:19][CH3:20])[CH:18]=2)[N:3]=1)=[O:44])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: CCn1cc(-c2nc(Cl)cc(C#N)c2C(=O)OC)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc(C#N)c2C(=O)OC)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 19.1 %

Procedure:
To a solution of methyl 6-chloro-4-cyano-2-(1-ethyl-1H-pyrazol-4-yl)nicotinate (201 mg, 0.691 mmol) in DMF (1 mL) was added DIPEA (0.242 mL, 1.383 mmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (237 mg, 1.106 mmol). The reaction mixture was stirred at 100° C. overnight, after which the solvent was removed, and the resulting crude material was diluted in MeOH (5.0 mL) and purified via reverse phase preparative HPLC. The collected fractions were collected and ACN was removed via rotary evaporation. The resulting aq solution was neutralized with saturated aq NaHCO3 and washed with EtOAc (2×200 mL), dried over Na2SO4, and filtered. The organic phase was stripped to dryness via rotary evaporation to yield the title compound (62 mg, 19%). [M+H] calc'd for C24H32N6O4, 469; found, 469.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5].[CH2:17]([CH:19]1[O:21][CH2:20]1)Br>>[O:21]1[CH2:20][CH:19]1[CH2:17][O:1][C:2]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5]
Reactant: BrCC1CO1
Reactant: COC(=O)CCC(=O)c1ccc(C)cc1O
Product: COC(=O)CCC(=O)c1ccc(C)cc1OCC1CO1

Procedure:
Methyl 3-(2-hydroxy-4-methylbenzoyl)propionate was reacted with epibromohydrin in a similar manner to the procedure described in Example 1(ii) to give methyl 3-[2-(2,3-epoxypropoxy)-4-methylbenzoyl]propionate, m.p. 61.5°-63°.
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1.[C-:15]#[N:16].[Na+]>CS(C)=O>[C:15]([CH2:2][C:3]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1)#[N:16]
Reactant: CC(C)c1cc2c(cc1CCl)OCO2
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)c1cc2c(cc1CC#N)OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
6.9 g of 5-chloromethyl-6-isopropyl-1,3-benzodioxole was dissolved in 100 ml of dimethyl sulfoxide, followed by the addition of 3.12 g of sodium cyanide. The obtained mixture was stirred at a room temperature for 3 hours and distilled to remove the solvent. Ethyl acetate was added to the residue and the obtained mixture was washed with water and a saturated aqueous solution of common salt successively, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to obtain 6.26 g of the title compound as a crude oil.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3[NH:18][CH:19]=[CH:20][C:12]2=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=P(Cl)(Cl)Cl.CN([CH:29]=[O:30])C>>[N:1]1([CH2:7][CH2:8][C:9]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3[NH:18][C:19]([CH:29]=[O:30])=[CH:20][C:12]2=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: O=C(CCN1CCCCC1)N1CCCCc2[nH]ccc21
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cc2c([nH]1)CCCCN2C(=O)CCN1CCCCC1

Procedure:
3-Piperidin-1-yl-1-(5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]azepin-4-yl)-propan-1-one (225 mg, 0.8 mmol) was formylated with POCl3 (91 μL, 1.2 eq.) and DMF(1 mL) using standard Vilsmierer condition to give 96 mg of 4-(3-piperidin-1-yl-propioyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine-2-carbaldehyde as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([C:15]([F:18])([F:17])[F:16])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:12][C:11]1[C:2]([CH3:1])=[C:3]([CH:8]=[C:9]([C:15]([F:16])([F:17])[F:18])[CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(C(F)(F)F)cc(N)c1C
Temperature: 80 °C

Procedure:
To a stirred solution of methyl 2-methyl-3-nitro-5-(trifluoromethyl)benzoate (5.6 g, 20.97 mmol) in ethanol (40 mL) was added ammonium chloride (5.6 g, 104.6 mmol) dissolved in water (30 mL) and iron powder (4.67 g, 85.16 mmol). The resulting mixture was heated at 80° C. for 1 h. On completion, water was added to the reaction then the mixture was filtered through celite. The filtrate was extracted with ethyl acetate. The combined organic layers were dried then concentrated under reduced pressure to give methyl 3-amino-2-methyl-5-(trifluoromethyl)benzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:22]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: Cc1ccccc1C(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 94.2 %

Procedure:
Beginning with 10 mg (0.0437 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 6.0 μL (0.0458 mMol) 2-methylbenzoyl chloride, 14.3 mg (95%) of the title compound were recovered.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.S(Cl)(Cl)=O.[CH3:15][Si](C=[N+]=[N-])(C)C.[BrH:22]>ClCCl.C(O)(=O)C>[BrH:22].[Br:22][CH2:15][C:8]([CH:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)=[O:10]
Reactant: CN1CCC(C(=O)O)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: Br
Solvent: O=S(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCC(C(=O)CBr)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
A mixture of 1-methyl-piperidine-4-carboxylic acid (0.40 g, 2.79 mmol) and thionyl chloride (0.32 mL, 4.44 mmol) in dichloromethane (10 mL) was heated to reflux for 6 h. The reaction mixture was distilled under reduced pressure and the residue dissolved in dry acetonitrile (4 mL). Trimethylsilyl diazomethane (4 mL, 8.08 mmol) was added and the mixture stirred for 2 h at ambient temperature. The reaction was cooled to 0° C. and 30% HBr in acetic acid (2 mL) added dropwise. The reaction mixture was warmed to room temperature and stirred for 1 h. The precipitate was filtered and washed with ether to afford 2-bromo-1-(1-methyl-piperidin-4-yl)-ethanone hydrobromide (200 mg, 33%).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>CN(C=O)C>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][O:10][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:4]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COCc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.4 g) in DMF (8 ml) was added dropwise a solution of 3-pyridinemethanol (1.09 g) in DMF (5 ml), and the mixture was stirred at room temperature for 30 minutes. Then a solution of tert-butyl bromoacetate (1.62 ml) in DMF (5 ml) was added to the mixture. After stirring for one hour, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in AcOEt (20 ml), washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified with SiO2 column chromatography (eluted with 1% MeOH in CHCl3) to give tert-butyl (3-pyridylmethoxy)acetate (435 mg) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([C:12]1[CH:13]=[C:14]([C:16]([Cl:21])=[CH:17][C:18]=1[O:19][CH3:20])[NH2:15])=[O:11].C(N(CC)[C:25](Cl)=[S:26])C.ClC1C=CC=CC=1.O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([C:12]1[CH:13]=[C:14]([N:15]=[C:25]=[S:26])[C:16]([Cl:21])=[CH:17][C:18]=1[O:19][CH3:20])=[O:11]
Reactant: COc1cc(Cl)c(N)cc1C(=O)Nc1c(C)cccc1C
Reactant: CCN(CC)C(=S)Cl
Solvent: Clc1ccccc1
Solvent: ClCCl
Solvent: O
Product: COc1cc(Cl)c(N=C=S)cc1C(=O)Nc1c(C)cccc1C
Yield: 46 %

Procedure:
A mixture of 3-[N-(2,6-dimethylphenyl)carbamoyl]-4-methoxy-6-chloroaniline (650 mg), diethylthiocarbamoyl chloride (360 mg) and chlorobenzene (6 ml) is refluxed for 30 minutes. The reaction mixture is mixed with water and shaken with methylene chloride. The organic layer is washed with water, dried over Glauber's salt and concentrated to remove the solvent. The residue is chromatographed on a column of silica gel, which is eluted with methylene chloride. The eluted fractions are collected and the solvent is evaporated. The residue is recrystallized from ethyl acetate to give 3-[N-(2,6-dimethylphenyl)carbamoyl]-4-methoxy-6-chlorophenyl isothiocyanate (340 mg) as crystals melting at 191°-192.5° C.
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>C(O)(=O)C>[C:1]([C:5]1[C:13]2[O:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([N+:16]([O-:18])=[O:17])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc2c1OCC2(C)C
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc([N+](=O)[O-])cc2c1OCC2(C)C
Temperature: 22 °C
Reaction time: 4 h
Yield: 18.5 %

Procedure:
To a solution of 7-tert-butyl-2,3-dihydro-3,3-dimethylbenzofuran (10.0 g 49.0 mmol) in glacial acetic acid (80 mL) is added dropwise 70% HNO3 (4.0 mL, 5.7 g, 63.7 mmol). The reaction mixture darkens to a deep green color over the course of the addition. The reaction is monitored by TLC (2% EtOAc/hexanes), and is allowed to stir at 22° C. for 4 h. Then the reaction mixture is partitioned between Et2O (100 mL) and H2O (2×100 mL). The ethereal layer was washed with saturated aqueous Na2CO3 (50 mL), dried (MgSO4), filtered and evaporated to a red solid (9.12 g). Crystallization from hexane provides the title compound as orange prisms (2.26 g, 18.5%). A second crop yields slightly less pure material (4.93 g, 40.3%) which was used without further purification, mp=93°-94° C.
Reaction SMILES: [Br:1][CH2:2][CH:3]=[CH:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[C:15]1([P:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1C=CC=CC=1>[Br-:1].[CH2:8]([O:7][C:5]([CH2:4][CH:3]=[CH:2][PH:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(C=CCBr)OCc1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: O=C(CC=C[PH](c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Product: [Br-]
Yield: 58.6 %

Procedure:
A solution of benzyl 4-bromo-but-2-enate (430 mg, 1.68 mmol) and triphenylphosphine (661 mg, 2.52 mmol) in benzene (3 ml) was stirred at room temperature under nitrogen for 20 hours. The resulting white solid was collected through filtration and washed with benzene (3×2 ml), and dried at 100° C. under vacuum to give the title compound (510 mg, 59% yield). 1H NMR (CD3OD): δppm 4.60 (2H, m, slowly disappeared due to deuterium exchange), 5.13 (2H, s), 6.16 (1H, dd, J1=15.3 Hz, J2=1.1 Hz), 6.81 (1H, m), 7.33 (5H, m), 7.78 (12 H, m), 7.90 (3H, m). 13C NMR (CD3OD): δppm 67.6 (t), 68.1 (t), 118.3 (s), 118.8 (s), 119.4 (s), 120.0 (s), 129.3 (d), 129.4 (d), 129.5 (d), 129.6 (d), 129.7 (d), 131.4 (d), 131.5 (d), 131.7 (d), 134.7 (d), 134.85 (d), 134.94 (d), 135.1 (d), 135.2 (d), 135.3 (d), 136.5 (d), 136.6 (d), 136.69 (d), 136.73 (d), 155.7 (s); 165.8 (s).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]([F:11])([F:10])[C:7]([OH:9])=[O:8].[F:12][C:13]1[CH:14]=[CH:15][C:16]([N+:25]([O-:27])=[O:26])=[C:17]([CH:24]=1)[O:18][C@H:19]1[CH2:22][C@H:21]([NH2:23])[CH2:20]1.C(N(CC)CC)C>C(Cl)Cl>[F:5][C:6]([F:11])([F:10])[C:7]([OH:9])=[O:8].[F:12][C:13]1[CH:14]=[CH:15][C:16]([N+:25]([O-:27])=[O:26])=[C:17]([CH:24]=1)[O:18][C@H:19]1[CH2:20][C@H:21]([NH:23][C:1](=[O:3])[CH3:2])[CH2:22]1
Reactant: CC(=O)Cl
Reactant: N[C@H]1C[C@H](Oc2cc(F)ccc2[N+](=O)[O-])C1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@H]1C[C@H](Oc2cc(F)ccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
450 μl Acetylchloride were added to a mixture of 1.8 g trans-3-(5-fluoro-2-nitrophenoxy)-cyclobutylamine trifluoroacetate and 3.7 ml triethylamine in 30 ml methylene chloride and stirred for 2 hours at rt. The mixture was extracted two times with water. The organic phase was dried and concentrated. The residue was stirred with diethylether and filtrated. The residue was dried in a drying cabinet.