Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([C:18]([OH:20])=O)[N:15]([CH3:17])[N:16]=2)=[C:8]([CH2:21][OH:22])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[F:55][C:56]([F:60])([F:59])[CH2:57][NH2:58]>CN(C=O)C>[F:55][C:56]([F:60])([F:59])[CH2:57][NH:58][C:18]([C:14]1[N:15]([CH3:17])[N:16]=[C:12]([O:11][CH2:10][C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH2:21][OH:22])[CH:13]=1)=[O:20]
Reactant: NCC(F)(F)F
Reactant: CCCCc1noc(CO)c1COc1cc(C(=O)O)n(C)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1noc(CO)c1COc1cc(C(=O)NCC(F)(F)F)n(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
To a solution of 5-(3-butyl-5-hydroxymethyl-isoxazol-4-ylmethoxy)-2-methyl-2H-pyrazole-3-carboxylic acid (50 mg, 0.16 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (57 mg, 0.18 mmol), N,N-diisopropyl ethyl amine (138 μL, 0.8 mmol) and 2,2,2-trifluoroethylamine HCl (24 mg, 0.18 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (silica, dichloromethane:methanol=100:0 to 95:5) afforded the title compound (47 mg, 75%) as a colorless oil. MS: m/e=391.2 [M+H]+.\
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][C:6]1[NH:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[S:8](=[O:17])(=[O:16])[N:7]=1)C.[OH-].[Na+:20]>CO.O>[Na+:20].[O:17]=[S:8]1(=[O:16])[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][N:10]=2)[NH:15][C:6]([CH2:5][C:4]([O-:18])=[O:3])=[N:7]1
Reactant: CCOC(=O)CC1=NS(=O)(=O)c2ncccc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C([O-])CC1=NS(=O)(=O)c2ncccc2N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
(1,1-Dioxo-1,4-dihydro-1λ6-thia-2,4,8-triaza-naphthalen-3-yl)-acetic acid ethyl ester (0.25 g, 0.928 mmol) was dissolved in methanol (5 mL) at approximately 60° C. Sodium hydroxide (0.111 g, 2.79 mmol) was dissolved in water (2.5 mL). Upon cooling to 25° C., the solutions were combined. The mixture was stirred at 25° C. for 3 h. The mixture was stored at −40° C. for 16 h. The mixture was concentrated in vacuo to afford the crude product, (1,1-dioxo-1,4-dihydro-1λ6-thia-2,4,8-triaza-naphthalen-3-yl)-acetic acid sodium salt (˜0.928 mmol), as a yellow film, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][NH:11][C:10](=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.[N+:14]([O-])([OH:16])=[O:15].NC(N)=N>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:12][NH:11][C:10](=[O:13])[CH2:9]2)=[CH:6][C:7]=1[N+:14]([O-:16])=[O:15]
Reactant: O=C1C[C@H](c2ccc(Cl)cc2)CN1
Reactant: O=[N+]([O-])O
Agent: N=C(N)N
Agent: O=S(=O)(O)O
Product: O=C1C[C@H](c2ccc(Cl)c([N+](=O)[O-])c2)CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
(4R)-4-(4-Chlorophenyl)pyrrolidin-2-one (44 g, 225.6 mmol) was treated with conc. sulfuric acid (220 mL). This solution was cooled in ice. Guanidine nitrate (27.5 g, 225.6 mmol) was added in portions. The reaction mixture was warmed to room temperature and stirred for 1 h. The mixture was then poured into ice. The product crashed out as a pale yellow solid and was filtered, washed with hexane, and dried to give the title compound (51 g, 95% yield). 1H-NMR (400 MHz, CD3OD): δ7.12 d, J=8.4 Hz, 1H), 6.73-6.74 (d, J=4.0 Hz, 1H), 6.52-6.55 (m, 1H), 3.70-3.74 (m, 1H), 3.54-3.62 (m, 1H), 3.32-3.46 (m, 1H), 2.63-2.69 (dd, J=16.4, 8.8 Hz, 1H), 2.37-2.43 (dd, J=16.8, 8.8 Hz, 1H); MS (ESI) m/z 241.05 (M+H)+.
Reaction SMILES: N1C=CN=C1.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=CC=CC=1.[C:21]([Si:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)Cl)([CH3:24])([CH3:23])[CH3:22].[OH2:39]>ClCCl>[C:21]([Si:25]([O:20][C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:6][CH:7]2[CH2:12][O:39]2)=[CH:19][CH:18]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: O
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of imidazole (12.97 g, 190 mmol) and 4-benzyloxy phenol (34.7 g, 173 mmol) in anhydrous dichloromethane (500 mL) was added drop-wise a solution of tert-butyidiphenylchlorosilane (50.0 g, 181 mmol) in dichloromethane (100 mL). The solution was stirred overnight at ambient temperature. The mixture was poured into water (500 mL) and the organic layer washed with saturated sodium hydrogen carbonate, water, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent evaporated to dryness. The solid was crystallized from diethyl ether to provide the title compound (68.9 g, 142 mmol).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([N:7]([CH3:10])[O:8][CH3:9])=[O:6].C([O-])([O-])=O.[K+].[K+].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CC#N>[CH3:10][N:7]([O:8][CH3:9])[C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: CON(C)C(=O)CCCCl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CON(C)C(=O)CCCN1CCOCC1
Temperature: 105 °C
Yield: 44.2 %

Procedure:
To a solution of the product from Step 1 (3.01 g, 18.1 mmol) in MeCN (40 mL), was added K2CO3 (10 g, 72.4 mmol) and morpholine (1.58 mL, 18.1 mmol). This mixture was then heated to 105° C. in a sealed tube for overnight. The reaction mixture then diluted with MeCN (50 mL), then filtered and concentrated. Residue was taken up in Et2O (100 mL), washed with brine, dried over Na2SO4, filtered and concentrated to afford the title compound as a colorless oil (1.73 g, 44%), which was used directly to next step without further purification. MS (ES+) m/e 217 [M+H]+.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([O:15]C(=O)CCC)(=O)[CH2:11][CH2:12][CH3:13].[N:21]1C=CC=C[CH:22]=1>>[C:1]([C:2]1[CH:7]=[CH:6][C:5]([CH2:22][NH:21][C:10](=[O:15])[CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1)([OH:9])=[O:8]
Reactant: CCCC(=O)OC(=O)CCC
Reactant: c1ccncc1
Reactant: O=C(O)c1ccccc1
Product: CCCC(=O)NCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Aminomethyl)benzoic acid (3.0 g) is suspended in pyridine (15 mL) and the mixture cooled in an ice water bath. Butyric anhydride (9.2 mL) is added dropwise to the stirred suspension over a 20 min period. The ice bath is removed and the mixture stirred at room temperature overnight. The mixture is poured into 150 mL ice water and made acidic (pH 1.5) by addition of concentrated HCl. The precipitate is recovered by suction filtration and recrystallized from ethyl acetate to produce N-(4-carboxybenzyl)butyramide, m.p. 186.5°-187.5° C.
Reaction SMILES: [I:1]I.[CH3:3][CH:4]([C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11])[CH2:5][CH:6]([CH3:8])[CH3:7].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CO>[I:1][C:14]1[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([CH:4]([CH3:3])[CH2:5][CH:6]([CH3:7])[CH3:8])[CH:15]=1
Reactant: CC(C)CC(C)c1ccccc1N
Reactant: II
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Product: CC(C)CC(C)c1cc(I)ccc1N
Temperature: 0 °C
Reaction time: 4 h
Yield: 89.4 %

Procedure:
In methanol was dissolved 2.53 g (10 mmol) of iodine, and 2-(1,3-dimethylbutyl)aniline (1.77 g, 10 mmol) was added thereto under ice-cooling, after which an aqueous solution of sodium hydrogencarbonate (1.26 g, 15 mmol) was added thereto and the resulting mixture was stirred at 0° C. for 4 hours. Sodium thiosulfate was added to the reaction mixture, and the resulting mixture was concentrated under reduced pressure, diluted with ethyl acetate and then washed with water. The organic layer was dried over magnesium sulfate and the residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 2.71 g of the desired compound.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=1)=[O:9])([CH3:6])[CH3:5].O.O[Li].O>CO>[CH:28]([C:25]1[CH:24]=[CH:23][C:22](/[CH:21]=[CH:20]/[C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:18]=[CH:19][C:10]=2[C:8]([NH:7][C:4]([CH3:6])([CH3:5])[C:3]([OH:31])=[O:2])=[O:9])=[CH:27][CH:26]=1)([CH3:30])[CH3:29]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1/C=C/c1ccc(C(C)C)cc1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CC(C)c1ccc(/C=C/c2c(C(=O)NC(C)(C)C(=O)O)ccc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 52 %

Procedure:
207 mg 2-({1-[(E)-2-(4-isopropyl-phenyl)-vinyl]-naphthalene-2-carbonyl}-amino)-2-methyl-propionic acid methyl ester were dissolved in 6 ml of MeOH and 2 ml of water was added. After addition of 114 mg of LiOH.H2O the reaction was stirred at room temperature for 14 h. Filtration of the crude mixture, RP-HPLC and freeze-drying gave 104 mg of 2-({1-[(E)-2-(4-isopropyl-phenyl)-vinyl]-naphthalene-2-carbonyl}-amino)-2-methyl-propionic acid (42%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[NH2:11].C(O[C:15]([CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=N)C>C(O)C>[F:8][C:7]1[C:2]2[N:1]=[C:15]([CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:11][C:3]=2[C:4]([F:10])=[C:5]([F:9])[CH:6]=1
Reactant: CCOC(=N)C(C)C(=O)OCC
Reactant: Nc1c(F)cc(F)c(F)c1N
Solvent: CCO
Product: CCOC(=O)C(C)c1nc2c(F)cc(F)c(F)c2[nH]1
Yield: 42.6 %

Procedure:
A mixture of 1,2-diamino-3,4,6-trifluorobenzene (1.92 g, 11.8 mmol), ethyl 2-ethoxycarbonimidoylpropionate (3.1 g, 14.7 mmol) and absolute ethanol (6 ml) was heated at reflux until no further progression of the reaction was indicated by TLC indicated the reaction was not progressing further, filtered from NH4Cl and concentrated. The residue was purified by chromatography on silica (hexane: methylene chloride: ethyl acetate, 5:5:1) to give ethyl 2-(4,6,7-trifluoro-1H-benzoimidazol-2-yl)propionate (1.37 g, 42%) as a tan crystalline solid; NMR (CDCl3): δ 10.35 (s, ½H), δ 7.05 (s, ½H), 6.7 (m, 1H), δ 4.25 (dd, 2H), δ 4.15 (dd, 1H), δ 1.73 (d, 3H), δ 1.31 (t, 3H); M+ 272.9 (calcd for C12H11F3N2O2: 272.23).
Reaction SMILES: [CH2:1]([N:5]([CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=1)[C:8]#[N:9])[CH3:6])[CH:2]([CH3:4])[CH3:3].[S:23]([O:28]C)([O:26][CH3:27])(=[O:25])=[O:24]>>[CH3:27][O:26][S:23]([O-:28])(=[O:25])=[O:24].[C:8]([CH:7]([N+:5]([CH2:1][CH:2]([CH3:4])[CH3:3])([CH3:27])[CH3:6])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:11]=1)#[N:9]
Reactant: CC(C)CN(C)C(C#N)c1cccc(Oc2ccccc2)c1
Reactant: COS(=O)(=O)OC
Product: CC(C)C[N+](C)(C)C(C#N)c1cccc(Oc2ccccc2)c1
Product: COS(=O)(=O)[O-]
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of α-(N-isobutyl-N-methylamino)-3-phenoxybenzeneacetonitrile (7.35 g) and dimethyl sulfate (3.15 g) was stirred at a temperature of 100° C. for a period of 4 hours to give N-(α-cyano-3-phenoxybenzyl)-N-isobutyl-N,N-dimethylammonium methyl sulfate. Proton nuclear magnetic resonance spectrum (d6 -acetone; δ in ppm): 1.18 (6H, d of d); 3.45 (3H, s); 3.53 (3H, s); 6.84 (1H, s); 7.0-7.7 (9H, m).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.C([Li])CCC.[CH2:35]([C@H:42]1[CH2:46][O:45][C:44](=[O:47])[NH:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O1CCNC1=O>C1COCC1.CCCCCC>[CH3:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][C:13]([N:43]2[C@@H:42]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:46][O:45][C:44]2=[O:47])=[O:15])=[CH:9][CH:10]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1ccc(CCC(=O)O)cc1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C1NCCO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CCC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
To a stirring solution at -78° C. of 4-(1,1-dimethylethyl)benzenepropanoic acid (1.29 g, 6.25 mmol) and triethylamine (1.05 mL, 7.51 mmol) in dry THF (26 mL) was added pivaloylchloride (0.77 mL, 6.25 mmol) dropwise. After the addition, the mixture was stirred at -78° C. for 10 minutes and at 0° C. for 30 minutes. During this time metalated oxozolidinone was prepared separately by dropwise addition of n-butyl lithium (4.29 mL of a 1.6M solution in hexane) to a solution of (S)-(-)-4-benzyl-2-oxazolidinone (1.23 g of 99% pure, 6.88 mmol) in dry THF (26 mL). The metalated oxazolidinone solution was then added, at -78° C., via a cannula to the previously prepared reaction mixture and stirred for 1 h at 0° C. The reaction was quenched at 0° C. by addition of saturated NH4Cl solution (16 mL) and was concentrated. Saturated NH4Cl solution (25 mL) was added to the residue and the mixture was extracted with CH2Cl2 (3×100 mL). The combined organic phases were washed with saturated NaHCO3 (100 mL) and dried (NaSO4). Filtration and concentration provided crude product (2.50 g) which was purified via flash chromatography, eluting with a mixture of EtOAc and hexane (1:3) to provide (S)-3-[3-[4-(1,1-dimethylethyl)phenyl]-1-oxopropyl]-4-(phenylmethyl)-2-oxazolidinone (1.82 g, 4.98 mmol) in 80% yield, mp 123°-126° C.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[OH-].[K+].S(Cl)([Cl:12])=O.[CH:14]1[CH:19]=CC=CC=1>>[ClH:12].[CH:1]([N:4]([CH:5]([CH3:7])[CH3:6])[CH2:19][CH2:14][Cl:12])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: c1ccccc1
Reactant: CC(C)NC(C)C
Agent: [K+]
Agent: [OH-]
Product: CC(C)N(CCCl)C(C)C
Product: Cl
Temperature: 25 °C
Yield: 38 %

Procedure:
3.6 ml (53.6 mmol) of 2-chlorohydrin was added dropwise into 5 ml (35.7 mmol) of diisopropylamine. The mixture was heated to the reflux temperature and reacted for 5 h. After cooling to room temperature, 8% KOH and 10 ml benzene were added. The mixture was stirred and the benzene layer separated was washed with a saturated saline solution, then dried over anhydrous sodium sulfate and filtrated. Into the filtrate, 5.2 ml (71.3 mmol) of thionyl chloride was added dropwise. The mixture was reacted for 12 h at room temperature, then concentrated to dry in a reduced pressure to obtain 2.73 g white solid with the yield of 38%. m.p. 129-131° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[OH:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.CO>CN(C=O)C>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][NH:1][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[OH:8])=[CH:19][CH:20]=1
Reactant: NC1CCCCC1O
Reactant: COc1ccc(CCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(CCNC2CCCCC2O)cc1
Temperature: 100 °C

Procedure:
Mix (±)-2-aminocyclohexanol (1.5227 g, 13.2 mmol), K2CO3 (4.56 g, 33.0 mmol), and 1-(2-chloroethyl)-4-methoxybenzene (2.0 mL, 13.2 mmol) in DMF (30 mL). Heat at 100° C. for 24 hours. Cool down to room temperature and filtrate with MeOH wash. Concentrate and remove DMF azeotropically with xylenes. Take up the residue in CH2C2 and H2O (100 mL each). Separate the layers and extract the aqueous layer with CH2Cl2 (2×100 mL). Wash the organic layers with H2O and brine (100 mL each). Dry the combined organic layers over MgSO4, concentrate and purify by flash chromatography, eluting with 50:45:5 EtOAc/CH2Cl/2.0 M NH3 in MeOH to afford 2-(4-methoxyphenethylamino)cyclohexanol. (1.38 g, 42%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][C:9]#[CH:10].[CH:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:13])[CH3:12]>CC(C)=O>[CH:11]([N:14]1[CH2:19][CH2:18][N:17]([CH2:10][C:9]#[CH:8])[CH2:16][CH2:15]1)([CH3:13])[CH3:12]
Reactant: CC(C)N1CCNCC1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C#CCN1CCN(C(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of cesium carbonate (1 eq, 0.78 mmol, 0.254 g) in acetone (3 ml) is added 3-bromoprop-1-yne (80% in toluene) (1 eq, 0.78 mmol, 0.1 g) followed by 1-isopropylpiperazine (1 eq, 0.78 mmol, 0.073 ml). The reaction mixture is stirred for 4 hours at room temperature. The resulting suspension is filtered and the filtrate evaporated to afford the title compound; [M+H]+ 167.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[C:13]2[C:8](=[C:9]([O:14][CH3:15])[CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:16]([N:18]2[CH2:23][CH2:22][C:21]3([CH2:32][C:31](=[O:33])[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:34]5[NH:38][N:37]=[N:36][N:35]=5)[CH:29]=4)[O:24]3)[CH2:20][CH2:19]2)=[O:17])[CH:5]=1.[CH3:39]I>CN(C=O)C>[CH3:2][O:3][C:4]1[C:13]2[C:8](=[C:9]([O:14][CH3:15])[CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:16]([N:18]2[CH2:23][CH2:22][C:21]3([CH2:32][C:31](=[O:33])[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:34]5[N:38]([CH3:39])[N:37]=[N:36][N:35]=5)[CH:29]=4)[O:24]3)[CH2:20][CH2:19]2)=[O:17])[CH:5]=1
Reactant: CI
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn[nH]4)ccc2O3)nc2c(OC)cccc12
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnnn4C)ccc2O3)nc2c(OC)cccc12
Temperature: 25 °C
Reaction time: 13 h

Procedure:
The sodium salt (15.7 mg) obtained in Example 18 was dissolved in 0.3 mL of DMF, 0.009 mL of methyl iodide was added to it, and the mixture was stirred at room temperature for 13 hours. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate, washed with water and saturated brine in order, then dried over sodium sulfate, and concentrated. The residue was purified through silica gel chromatography (chloroform/methanol=10/1) to obtain 1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-(1-methyltetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one (this is referred to as 1-isomer) and 1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-(2-methyltetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one (this is referred to as 2-isomer) both as colorless powders. 1-Isomer: 1H-NMR (CDCl3) δ: 8.20 (1H, d, J=2.3 Hz), 8.05 (1H, dd, J=8.5, 2.3 Hz), 7.78 (1H, d, J=8.4 Hz), 7.48 (1H, dd, J=8.4, 7.9 Hz), 7.25 (1H, d, J=8.5 Hz), 7.20 (1H, s), 7.09 (1H, d, J=7.9 Hz), 4.67-4.57 (1H, m), 4.29-4.18 (1H, m), 4.22 (3H, s), 4.09 (3H, s), 4.04 (3H, s), 3.69-3.58 (1H, m), 3.46-3.33 (1H, m), 2.91 (1H, d, J=16.8 Hz), 2.84 (1H, d, J=16.8 Hz), 2.30-2.20 (1H, m), 2.16-1.88 (3H, m). MS [M+H]+=515. 2-Isomer: 1H-NMR (CDCl3) δ: 8.65 (1H, d, J=2.3 Hz), 8.29 (1H, dd, J=8.7, 2.3 Hz), 7.77 (1H, d, J=8.5 Hz), 7.47 (1H, dd, J=8.5, 7.6 Hz), 7.19 (1H, s), 7.15 (1H, d, J=8.7 Hz), 7.08 (1H, d, J=7.6 Hz), 4.65-4.54 (1H, m), 4.39 (3H, s), 4.23-4.13 (1H, m), 4.08 (3H, s), 4.03 (3H, s), 3.69-3.57 (1H, m), 3.46-3.33 (1H, m), 2.88 (1H, d, J=16.7 Hz), 2.80 (1H, d, J=16.7 Hz), 2.28-2.19 (1H, m), 2.15-2.05 (1H, m), 2.01-1.85 (2H, m). MS [M+H]+=515.
Reaction SMILES: Br[C:2]1[C:3]([NH2:18])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[N:7]=1.[C:19]1([S:25]([NH2:28])(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C@@H]1(N)CCCC[C@H]1N.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[NH2:18][C:3]1[C:2]([NH:28][S:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:27])=[O:26])=[N:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:5][N:4]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnc(N)c(Br)n2)cc1
Reactant: NS(=O)(=O)c1ccccc1
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2cnc(N)c(NS(=O)(=O)c3ccccc3)n2)cc1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 6.3 %

Procedure:
3-bromo-5-(4-methylsulfonylphenyl)pyrazin-2-amine (0.05 g, 0.152 mmol), benzene sulfonamide (0.12 g, 0.762 mmol), (1R,2R)-cyclohexane-1,2-diamine (0.017 g, 0.152 mmol), cuprous iodide (0.058 g, 0.305 mmol) and K2CO3 (0.042 g, 0.305 mmol) were combined together in dioxane (4 mL) and heated for 15 minutes under microwave conditions at 120° C. and then 140° C. for a further 20 minutes. The reaction mixture was concentrated in vacuo, and the residue was partitioned between DCM and water. The layers were separated and the aqueous further extracted with DCM. The combined organic extract was dried (MgSO4), filtered and concentrated in vacuo. This material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, and freeze-dried to give the title compound (3.9 mg, 3.65% Yield). H1 NMR (400.0 MHz, DMSO) δ 8.34 (s, 1H), 8.04-8.01 (m, 2H), 7.88 (d, J=8.6 Hz, 2H), 7.81 (d, J=8.7 Hz, 2H), 7.67-7.64 (m, 3H) and 3.23 (s, 3H). MS (ES+) 405.0
Reaction SMILES: Br[C:2](Br)=[CH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)[CH2:6][CH2:5]1.C([Li])CCC.O>O1CCCC1.CCCCCC>[C:3]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C@H:12]2[CH2:13][CH2:14][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:16][CH2:17]2)[CH2:6][CH2:5]1)#[CH:2]
Reactant: CCCCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](C=C(Br)Br)CC2)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: C#C[C@H]1CC[C@H](CC[C@H]2CC[C@H](CCCCC)CC2)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 2.66 g of trans-1-(2,2-dibromovinyl)-4-[2-(trans-4-pentylcyclohexyl)ethyl]cyclohexane in 120 ml of absolute tetrahydrofuran was placed at -78° C. in a sulphonation flask under argon gasification and treated within 10 minutes with 15.2 ml of a 0.1N solution of butyl lithium in hexane. After completion of the addition, the mixture was stirred at -78° C. for a further 2 hours, then poured into 100 ml of water and extracted three times with 100 ml of petroleum ether each time. The organic phases were washed twice with 50 ml of water each time and once with 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (1.90 g) on silica gel with hexane gave 1.48 g (88%) of trans-1-ethynyl-4-[2-(trans-4-pentylcyclohexyl)ethyl]cyclohexane as a trans/cis epimer mixture (about 9:1). Fractional crystallization from 50 ml of methanol yielded 883 mg of pure trans-1-ethynyl-4-[2-(trans-4-pentylcyclohexyl)ethyl]cyclohexane as colourless crystals; m.p. (C-N) 51.3° C., cl.p. (N-I) 68.0° C.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[NH2:2].CO[CH:14](OC)[CH2:15][CH:16](OC)OC.Cl.[CH3:24]O>>[N:1]1([C:3]2[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=2)[C:6]([O:8][CH3:24])=[O:7])[CH:16]=[CH:15][CH:14]=[N:2]1
Reactant: CO
Reactant: COC(CC(OC)OC)OC
Reactant: NNc1cccc(C(=O)O)c1
Agent: Cl
Product: COC(=O)c1cccc(-n2cccn2)c1

Procedure:
The mixture of 3-hydrazinobenzoic acid (2.0 g), 1,1,3,3-tetramethoxypropane (2.2 ml) and conc. hydrochloric acid (2.4 ml) in methanol (10.0 ml) was heated under reflux for 2 hours, and the mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution and brine. The residue was obtained by evaporating solvent, and purified by column chromatography on silica gel eluting with dichloromethane. The fractions containing the desired product were collected and evaporated in vacuo to give methyl 3-(pyrazol-1-yl)benzoate (1.33 g).