Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH2:20][N:12]2[C:13](=[O:19])[N:14]=[C:15]([O:17][CH3:18])[CH:16]=[C:11]2[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:22][CH2:23][CH3:24]>>[C:1]([C:9]1[N:10]=[C:11]2[CH:16]=[C:15]([O:17][CH3:18])[N:14]([CH2:22][CH2:23][CH3:24])[C:13](=[O:19])[N:12]2[CH:20]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2n(c(=O)n1)CC(C(=O)c1ccccc1)=N2
Reactant: CCCI
Product: CCCn1c(OC)cc2nc(C(=O)c3ccccc3)cn2c1=O

Procedure:
Using the procedure of Example 2, 2-benzoyl-7-methoxyimidazo[1,2-c]pyrimidin-5-one and iodopropane were reacted to obtain 2-benzoyl-7-methoxy-6-propyl-imidazo[1,2-c]pyrimidin-5-one. Spectral, yield and melting point data are given in Table I.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][C:11](N2CCCC2)=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[CH:20]=[CH2:21].[O:26]1CCOCC1>>[CH2:24]([O:23][C:19](=[O:22])[CH2:20][CH2:21][CH:10]1[CH2:9][CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12][C:11]1=[O:26])[CH3:25]
Reactant: C1=C(N2CCCC2)CCC(Cc2ccccc2)C1
Reactant: C=CC(=O)OCC
Reactant: C1COCCO1
Product: CCOC(=O)CCC1CC(Cc2ccccc2)CCC1=O

Procedure:
A solution of 1 g of the crude 1-(4-benzyl-cyclohex-1-enyl)-pyrrolidine and 1 mL of ethyl acrylate in 20 mL of dioxane was heated at reflux for 3 h, cooled and concentrated under reduced pressure. The resulting residue was diluted with 10 mL of water and 10 mL of 10% sulfuric acid and extracted into 2×100 mL of ether. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. Drying under vacuum gave 0.74 g of crude 3-(5-benzyl-2-oxo-cyclohexyl)-propionic acid ethyl ester as an oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH2:4][C@H:3]1[O:18][CH3:19].[Cl:20][C:21]1[N:22]=[C:23]([C:28](O)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:20][C:21]1[N:22]=[C:23]([C:28]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=3)[C:11]([O:13][CH3:14])=[O:12])[CH2:4][C@H:3]2[O:18][CH3:19])=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: COC(=O)c1cccc(N2CC[C@H](N)[C@H](OC)C2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cccc(C(=O)OC)c3)C[C@H]2OC)nc1Cl

Procedure:
The same operation as in Example (1g) was performed using methyl cis(±)-3-(4-amino-3-methoxypiperidin-1-yl)benzoate obtained in Example (164a) (116.41 mg, 0.44 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (73 mg, 0.42 mmol), WSC hydrochloride (241.23 mg, 1.26 mmol) and HOBt (56.72 mg, 0.42 mmol), to obtain 148.3 mg of the title compound as a pale yellow oily substance (81%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4]C(C#N)=[N:6][CH:7]=1.[OH-].[Na+].N.[C:13]([OH:16])(=[O:15])[CH3:14]>C(O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:14]([C:13]([OH:16])=[O:15])=[N:6][CH:7]=1
Reactant: N#Cc1ccc(Br)cn1
Reactant: CC(=O)O
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-bromopyridine-2-carbonitrile (commercially available from Sigma-Aldrich, St. Louis, Mo.) in ethanol (1.4 M) was added 3 equivalents of sodium hydroxide as a 1.5 M aqueous solution and the resulting solution was allowed to reflux at a temperature of about 85° C. until no further evolution of ammonia gas was detected. The resulting solution was then concentrated under reduced pressure to provide a residue. The residue was dissolved in water, acidified with acetic acid, and allowed to stir for about 16 h at a temperature of about 25° C. to provide a solid precipitate. The solid was collected by vacuum filtration and washed with acetone to provide 5-bromopyridine-2-carboxylic acid (Compound B) as a solid. 5-bromopyridine-2-carboxylic acid (Compound B), 0.5 equivalents of HOBT, and 1 equivalent of EDCI were dissolved in DMF and combined with about 1.1 equivalents of 4-tert-butylaniline (Compound C; commercially available from Sigma-Aldrich) dissolved in DMF (0.8 M) and the resulting mixture was allowed to stir for about 2 h at about 25° C. The reaction mixture was then diluted with about 80 mL of 2N aqueous sodium hydroxide and extracted with ethyl acetate (3 extractions, 80 mL/extraction). The ethyl acetate layers were combined and the ethyl acetate was removed under reduced pressure to provide a solid. The resulting solid was suspended in water and filtered using vacuum filtration to provide Compound D as a solid. Compound D was dissolved in DMF (0.04M) and about 3 equivalents of the zinc bromide Compound F (commercially available from Sigma-Aldrich) and about 0.05 equivalents of Pd(PPh3)4 (commercially available from Sigma-Aldrich) were added to the solution under a nitrogen atmosphere, and the resulting reaction mixture was allowed to stir for about 2 h at a temperature of about 100° C. The solvent was then removed under reduced pressure to provide Pyridylene Compound E35(a). Pyridylene Compound E35(a) was purified using preparative thin-layer chromatography with a 1:1 ethyl acetate:hexane mobile phase to provide purified Pyridylene Compound E35(a) as an off-white solid (yield 47%).
Reaction SMILES: O/C=[C:3]1/[C:4](=[O:11])[CH2:5][CH2:6][C:7]([CH3:10])([CH3:9])[CH2:8]/1.F[B-](F)(F)F.[CH2:17]([O:19][CH+:20][O:21][CH2:22][CH3:23])[CH3:18]>>[CH2:17]([O:19][CH:20]([O:21][CH2:22][CH3:23])[CH:3]1[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][CH2:5][C:4]1=[O:11])[CH3:18]
Reactant: CC1(C)CCC(=O)/C(=C/O)C1
Reactant: CCO[CH+]OCC
Agent: F[B-](F)(F)F
Product: CCOC(OCC)C1CC(C)(C)CCC1=O

Procedure:
Another route involves reacting dimethylcyclohexanone (1A) with a prepared solution of diethoxycarbenium fluoroborate to provide 2-(diethoxymethyl)-4,4-dimethylcyclohexanone (8). The reaction is typically performed below room temperature in a solvent such as but not limited to methylene chloride. Chlorophenyl magnesium bromide is then added to a solution of 2-(diethoxymethyl)-4,4-dimethylcyclohexanone (8) to provide 1-(4-chlorophenyl)-2-(diethoxymethyl)-4,4-dimethylcyclohexanol (9). The reaction is typically performed below room temperature in a solvent such as but not limited to tetrahydrofuran. 1-(4-Chlorophenyl)-2-(diethoxymethyl)-4,4-dimethylcyclohexanol (9) can be treated with an acid such as but not limited to HCl, to provide the aldehyde intermediate (2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde) (4).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1.[CH:34]([N:37]([CH2:41][CH2:42]Cl)[CH:38]([CH3:40])[CH3:39])([CH3:36])[CH3:35]>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([O:15][CH2:42][CH2:41][N:37]([CH:38]([CH3:40])[CH3:39])[CH:34]([CH3:36])[CH3:35])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=1
Reactant: CC(C)N(CCCl)C(C)C
Reactant: COc1cc(-c2nc3ccc(O)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC
Product: COc1cc(-c2nc3ccc(OCCN(C(C)C)C(C)C)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC

Procedure:
The title compound was prepared by reacting the compound of Example 104 with 2-(N,N-diisopropylamino)ethyl chloride essentially as previously described. mp 184° C., MS 585, NMR, IR.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][N:3]=1.[C:12]([O:16][CH3:17])(=[O:15])[CH2:13][SH:14].CC([O-])(C)C.[K+].C1COCC1>CN(C=O)C>[NH2:9][C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][C:6]=2[O:10][CH3:11])[S:14][C:13]=1[C:12]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CS
Reactant: COc1ccnc(Cl)c1C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1sc2nccc(OC)c2c1N
Reaction time: 0.33 h

Procedure:
To 2-chloro-3-cyano-4methoxypyridine (2.02 g) and methyl thioglycolate (1.1 mL) in DMF (24 mL) at 5° C. was added a 1.0M solution of KOtBu/THF (14.6 mL). The reaction was stirred 20 min at 5°, then 1 h at RT, quenched in saturated NH4CI, the solid collected, washed with water and sucked dry. This was recrystallized from EtOAc to give 0.89 g of the tide compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:12]2[CH:18]=[CH:17][S:16][C:13]=2[NH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC([O-])(C)C.[K+]>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:12]2[CH:18]=[CH:17][S:16][C:13]=2[N:14]([S:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:27])=[O:26])[CH:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCc1c[nH]c2sccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCc1cn(S(=O)(=O)c2ccccc2)c2sccc12
Reaction time: 8 h

Procedure:
A mixture of N-(t-butoxycarbonyl)-2-(6H-thieno[2,3-b]pyrrol-4-yl)ethylamine (54 mg, 0.2 mmol), phenylsulfonyl chloride (70 mg, 0.22 mmol) and KOt-Bu (0.22 mL 1 M solution in THF, 0.22 mmol) in THF is shaken at ambient temperatures for 8 h and concentrated in vacuo. The resultant residue is dissolved in THF, treated with 4N HCl in dioxane (2 mL) shaken at room temperature for 16 h and concentrated in vacuo. This residue is dissolved in a mixture of DMSO, methanol and water and purified by preparative HPLC1, to afford the title product, [M+H]307, retention time (RT) 1.53 min. 1 Gilson Preparative HPLC conditions: Gilson Preparative HPLC system; YMC Pro-C18, 20 mm×50 mm ID, 5 uM column; 2 mL injection; Solvent A: 0.02% TFA/water; Solvent B:0.02% TFA/acetonitrile; Gradient: Time 0: 95% A; 2 min: 95% A; 14 min: 10% A, 15 min: 10% A, 16 min: 95% A; Flow rate 22.5 mL/min; Detection: 254 nm DAD.
Reaction SMILES: ClC1C=C2C(=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(Cl)(=O)=O.[I:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](S(C1C=CC=CC=1)(=O)=O)[C:34]([C:48]([O:50]CC)=O)=[C:33]2[S:53](Cl)(=[O:55])=[O:54].Cl.CN.[O:60]1[CH2:65][CH2:64][CH2:63][CH2:62][CH:61]1[CH2:66][NH2:67]>>[I:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:48]([NH2:7])=[O:50])=[C:33]2[S:53]([NH:67][CH2:66][CH:61]1[CH2:62][CH2:63][CH2:64][CH2:65][O:60]1)(=[O:54])=[O:55]
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(I)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: NCC1CCCCO1
Agent: CN
Agent: Cl
Product: NC(=O)c1[nH]c2ccc(I)cc2c1S(=O)(=O)NCC1CCCCO1

Procedure:
Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-iodo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and methylamine hydrochloride with (±)-1-tetrahydro-2H-pyran-2-ylmethanamine, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+ MS: 463.95 [M+H]+.
Reaction SMILES: BrNC(=[O:5])C.[OH:6][C@H:7]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:26]2[CH2:25][C@@H:24]([OH:31])[C@@:23]2([CH3:32])[C:13]3=[CH:14][CH2:15][C@@H:16]2[C:17]2([O:22][CH2:21][CH2:20][O:19]2)[CH3:18])[CH2:8]1.O.S([O-])([O-])=O.[Na+].[Na+]>CC(C)=O.C(O)(=O)C>[OH:6][C@H:7]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:9]3([O:5][CH:10]3[CH2:11][C@@H:12]3[C@@H:26]2[CH2:25][C@@H:24]([OH:31])[C@@:23]2([CH3:32])[C:13]3=[CH:14][CH2:15][C@@H:16]2[C:17]2([O:19][CH2:20][CH2:21][O:22]2)[CH3:18])[CH2:8]1
Reactant: CC1([C@H]2CC=C3[C@@H]4CC=C5C[C@@H](O)CC[C@]5(C)[C@H]4C[C@@H](O)[C@@]32C)OCCO1
Reactant: CC(=O)NBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: CC1([C@H]2CC=C3[C@@H]4CC5OC56C[C@@H](O)CC[C@]6(C)[C@H]4C[C@@H](O)[C@@]32C)OCCO1
Reaction time: 0.5 h

Procedure:
N-Bromoacetamide (211 mg, 1.5 mmol) is added to a stirred solution of the 5,14-diene (23) (500 mg, 1.34 mmol) in acetone (100 ml), acetic acid (2.5 ml), and water (5 ml) at 0° C. After 15 min sodium sulphite (5% soln, 50 ml) is added to the reaction mixture. The acetone is evaporated, and the aqueous layer extracted with dichloromethane (3×50 ml). The organic layer is dried (MgSO4), filtered and evaporated. Pyridine (1 ml) is added to the product, and stirred for 0.5 h. Dichloromethane (100 ml) is then added to the reaction mixture, and the dichloromethane is washed with citric acid (5% soln, 3×100 ml), saturated sodium bicarbonate (50 ml), and water (50 ml). The organic layer is dried (MgSO4), filtered and evaporated to give the mixture of 14,15- and 5,6-epoxides (360 mg, 69%) as a white foam. The mixture of epoxides could not be separated by silica gel column chromatography.
Reaction SMILES: [C:1]1([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:22][C:23](C)([O-:25])[CH3:24].[K+].C(C1OC1)Br>CC(N(C)C)=O>[C:1]1([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH:23]2[CH2:24][O:25]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1CCCCc1cccc2ccccc12
Reactant: CC(C)(C)[O-]
Agent: BrCC1CO1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: c1ccc(OCC2CO2)c(CCCCc2cccc3ccccc23)c1
Yield: 79.9 %

Procedure:
Following a procedure similar to that described in Example 1(a), 329 mg of 2-[4-(1-naphthyl)butyl]phenol (prepared as described in Preparation 16), 134 mg of potassium t-butoxide and 334 mg of epibromohydrin were reacted in 15 ml of dimethylacetamide. The crude product, extracted as described in Example 1(a), was purified as described in Example 1(a), to give 316 mg (yield 80%) of the title compound as a colorless oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[CH:4]1.Cl[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1>CN(C)C=O>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[N:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[CH:4]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: Clc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2nc(-n3ccc4cccnc43)ccc2c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
0.894 g of 60% sodium hydride (37.25 mmol) was added with stirring to 20 cm3 of dimethylformamide under an argon atmosphere at a temperature in the region of 20° C. and then a solution of 4 g (33.86 mmol) of 1H-pyrrolo[2,3-b]pyridine in 20 cm3 of dimethylformamide was gradually added. After stirring at a temperature in the region of 20° C. for 30 minutes, a solution of 5.816 g (35.55 mmol) of 2-chloroquinoline in 20 cm3 of dimethylformamide was added and then the reaction mixture was heated at a temperature in the region of 100° C. for 15 h. After concentrating to dryness under reduced pressure (2.7 kpa), the residue was taken up in 150 cm3 of water. The residual oil was taken up in 50 cm3 of diethyl ether. The light yellow crystals that formed were filtered off and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 20° C. 4.39 g of 1-(quinolin-2-yl)-1H-pyrrolo[2,3-b]pyridine were thus obtained in the form of an off-white solid melting at 129° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([NH:12][OH:13])=[NH:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH:14]1([CH2:19][CH2:20][C:21]([Cl:23])=O)[CH2:18][CH2:17][CH2:16][CH2:15]1>>[ClH:23].[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[N:11]=[C:21]([CH2:20][CH2:19][CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[O:13][N:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)CCC1CCCC1
Reactant: CC(C)N1CCC(C(=N)NO)CC1
Product: CC(C)N1CCC(c2noc(CCC3CCCC3)n2)CC1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 56, starting from 1-isopropyl-N-hydroxypiperidine-4-carboxamidine and 3-(cyclopentyl)propanoyl chloride.
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][CH2:4][CH2:5][C@H:6]([OH:8])[CH3:7].CCN(C(C)C)C(C)C.[S:19](Cl)([CH3:22])(=[O:21])=[O:20]>C(Cl)Cl>[CH3:7][C@@H:6]([O:8][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:9])[CH3:1]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)=CCC[C@@H](C)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)=CCC[C@@H](C)OS(C)(=O)=O
Temperature: 5 °C
Yield: 88.8 %

Procedure:
(R)-6-Methyl-hept-5-en-2-ol (1) (2.26 g, 17.6 mmol) and DIEA (5.52 mL, 31.7 mmol) were dissolved in anhydrous DCM (24 mL), the reaction mixture was cooled to 5° C., mesyl chloride (1.64 mL, 21.1 mmol) was added dropwise, and the reaction mixture was allowed to slowly warm to RT. After 18 h at RT the reaction mixture was diluted with DCM (60 mL), washed with water (3×35 mL), brine (35 mL), dried with MgSO4, solvent was concentrated to give a dark oil which was purified by SiO2 flash chromatography using Hexane-EtOAc to give the title compound as an oil (3.225 g, 86%). H1 NMR: see supporting information. TLC, Hexane-DCM-EtOAc, 40:40:20, 2 Rf 0.70 (developed with KMnO4 stain). 1H NNMR in CDCl3 (500 MHz): 5.08 ppm 1 Hm, 4.80 ppm 1 Hm, 2.99 ppm 3 Hs, 2.08 ppm 2 Hm, 1.75 ppm 1 Hm, 1.69 ppm 3 Hs, 1.624 1 Hm, 1.61 3 Hs, 1.43 ppm 3 Hd.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][C:10]2[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][C:3]=1[F:19].O1CCCC1.[Cl-].[NH4+]>O.[Zn]>[Cl:1][C:2]1[C:3]([F:19])=[CH:4][C:5]([NH:9][C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:6][C:7]=1[F:8]
Reactant: O=[N+]([O-])c1cccnc1Nc1cc(F)c(Cl)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cccnc1Nc1cc(F)c(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-(4-chloro-3,5-difluorophenyl)-3-nitropyridin-2-amine (C17) (100 mg, 0.35 mmol) in a 1:1 mixture of tetrahydrofuran and water (20 mL) was added ammonium chloride (148 mg, 2.77 mmol) followed by zinc (182 mg, 2.78 mmol), and the reaction mixture was stirred at room temperature for 2 hours. It was then diluted with water (10 mL) and extracted with ethyl acetate (3×20 mL); the combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford the product as a yellow solid. This material was used directly in the following step. Yield: 80 mg, 0.31 mmol, 89%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][C@H:8]([CH3:11])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].[Cl-].[NH4+]>ClCCl>[C:1]([O:5][C:6]([NH:7][C@H:8]([CH3:11])[CH2:9][O:10][S:23]([CH3:22])(=[O:25])=[O:24])=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 101.1 %

Procedure:
((R)-2-Hydroxy-1-methyl-ethyl)-carbamic acid tert-butyl ester (0.5 g, 2.85 mmol) was dissolved in dichloromethane (14 ml) and stirred in an ice bath. N,N-diisopropylethylamine (0.75 ml, 4.28 mmol) and then methanesulfonyl chloride (0.27 ml, 3.4 mmol) were slowly added and the reaction was warmed to room temperature over 16 h. Ammonium chloride solution was added to the reaction and it was extracted two times with ethyl acetate. The combined organics were washed with sodium chloride solution and dried over sodium sulfate. Evaporation gave 0.73 g of methanesulfonic acid (R)-2-tert-butoxycarbonylamino-propyl ester as a waxy white solid. 1H NMR (CDCl3) δ: 4.51-4.68 (m, 1H), 4.19-4.28 (m, 1H), 4.11-4.18 (m, 1H), 3.90-4.04 (m, 1H), 3.03 (s, 3H), 1.24 (d, J=6.8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:29])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[N+:25]([O-])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CO.[H][H]>[Ni].O1CCCC1>[ClH:1].[ClH:1].[NH2:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C:17]([NH:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([OH:29])[CH2:9][CH2:10]1)=[O:28]
Reactant: O=C(NCCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1ccc(F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: Cl
Product: Nc1cc(F)ccc1C(=O)NCCN1CCC(O)(c2ccc(Cl)cc2)CC1

Procedure:
A mixture of 4.5 parts of N--{2-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]ethyl}-4-fluoro-2-nitrobenzamide, 40 parts of methanol and 90 parts of tetrahydrofuran is hydrogenated at normal pressure and at room temperature with 2 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is converted into the hydrochloride salt in 2-propanol. The salt is filtered off and dried, yielding 2 parts of 2-amino-N-{2-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]ethyl}-4-fluorobenzamide dihydrochloride; mp. 210.7° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([S:12](Cl)(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH:22]1([NH2:25])[CH2:24][CH2:23]1>C1C=CC=CC=1>[Cl:1][C:2]1[C:11]([S:12]([NH:25][CH:22]2[CH2:24][CH2:23]2)(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: NC1CC1
Reactant: COC(=O)c1cccc(S(=O)(=O)Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: COC(=O)c1cccc(S(=O)(=O)NC2CC2)c1Cl
Yield: 54.2 %

Procedure:
To a solution of methyl 2-chloro-3-(chlorosulfonyl)benzoate (608 mg, 2.26 mmol) and K2CO3 (770 mg, 5.6 mmol) in 10 mL benzene was added cyclopropylamine (0.78 mL, 11.2 mmol). Purification of the product provided methyl 2-chloro-3-[(cyclopropylamino)sulfonyl]benzoate (355 mg, 54%) as a solid. 1H NMR (400 MHz, CDCl3), δ 8.28 (dd, 1H, J=7.9, 1.7 Hz), 7.90 (dd, 1H, J=7.8, 1.7 Hz), 7.48 (t, 1H, J=7.8 Hz), 5.63 (s, 1H), 3.93 (s, 3H), 2.17 (m, 1H), 0.65-0.58 (m, 2H), 0.57-0.50 (m, 2H); ESI-MS 290 (M+H), 312 (M+Na). Methyl 2-chloro-3-[(cyclopropylamino)sulfonyl]benzoate was hydrolyzed using aqueous NaOH to provide 2-chloro-3-[(cyclopropylamino)sulfonyl]benzoic acid as a solid, which was used without further purification. ESI-MS 276 (M+H), 298 (M+Na).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:11]=[C:12](NC=O)[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.Cl.[OH-:23].[Na+].O>CO>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][C:12]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[O:23]
Reactant: COc1cccc(C=C(NC=O)c2ccncc2)c1OC
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cccc(CC(=O)c2ccncc2)c1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of N-[2-(2,3-dimethoxyphenyl)-1-(4-pyridinyl)vinyl]formamide (45.2 g, 0.16 mol) in methanol (400 ml), cooled to 0° C., was added, dropwise, concentrated HCl (120 ml). After complete addition, the temperature was raised to between 35-40° C. for 2 h. The reaction was allowed to stand at ambient temperature for 1 h, and after cooling it in an ice bath, 50% aqueous NaOH was added dropwise until the mixture was basic. Water was added and the resulting white precipitate was collected to yield the desired ketone which was removed and recrystallized twice from isopropanol to afford the titled compound as a white solid, mp 99-101° C.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH2:11][C:12]1[CH:16]=[CH:15][NH:14][N:13]=1.O=[C:18]([CH2:25][CH2:26][CH3:27])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[F:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:5]2[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH2:25][CH2:26][CH3:27])[NH:11][C:12]3=[N:13][NH:14][CH:15]=[C:16]23)[CH:7]=[CH:8][CH:9]=1
Reactant: CCCC(=O)CC(=O)OCC
Reactant: Cc1c(F)cccc1C=O
Reactant: Nc1cc[nH]n1
Product: CCCC1=C(C(=O)OCC)C(c2cccc(F)c2C)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 3-fluoro-2-methylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.