Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.CCOCC.[Br-].[CH3:10][N:11]([CH3:49])[C:12]1[CH:48]=[CH:47][C:15]([CH:16]=[N:17][N:18]2[CH:22]=[CH:21][N+:20](CC(C3C=CC(N(C)C)=CC=3)=O)=[C:19]2[C:35]2[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[C:37]([O:45][CH3:46])[CH:36]=2)=[CH:14][CH:13]=1.C(#N)C>>[CH3:49][N:11]([CH3:10])[C:12]1[CH:48]=[CH:47][C:15]([CH:16]=[N:17][N:18]2[CH:22]=[CH:21][N:20]=[C:19]2[C:35]2[CH:36]=[C:37]([O:45][CH3:46])[C:38]([O:43][CH3:44])=[C:39]([O:41][CH3:42])[CH:40]=2)=[CH:14][CH:13]=1
Reactant: COc1cc(-c2n(N=Cc3ccc(N(C)C)cc3)cc[n+]2CC(=O)c2ccc(N(C)C)cc2)cc(OC)c1OC
Agent: [Br-]
Solvent: CC#N
Solvent: CCO
Solvent: CCOCC
Product: COc1cc(-c2nccn2N=Cc2ccc(N(C)C)cc2)cc(OC)c1OC

Procedure:
In an analogous manner, from 1-[[p-(dimethylamino)benzylidene]amino]-2-(3,4,5-trimethoxyphenyl)imidazole, there is obtained after 2 days at 50° in acetonitrile 3-[[p-(dimethylamino)benzylidene]amino]-1-[p-(dimethylamino)phenacyl]-2-(3,4,5-trimethoxyphenyl)imidazolium bromide of melting point 232° (ethanol/ether).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:12])[C:7]=1CC(O)=O.C(N1C=CN=C1)(N1C=CN=C1)=[O:14].[CH:25]1([CH2:30][CH:31]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=2)[CH2:32][NH2:33])[CH2:29][CH2:28][CH2:27]C1>C1COCC1>[CH2:29]1[CH2:28][CH2:27][CH:30]([C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=2)([C:7]2[C:6]([Cl:12])=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])[C:32]([NH2:33])=[O:14])[CH2:25]1
Reactant: O=C(O)Cc1c(Cl)cncc1Cl
Reactant: COc1cccc(C(CN)CC2CCCC2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1cccc(C(C(N)=O)(c2c(Cl)cncc2Cl)C2CCCC2)c1
Yield: 93.7 %

Procedure:
By working in a way similar to that described in example 4 but using (3,5-dichloro-pyridin-4-yl)-acetic acid (1.94 g, 9.43 mmoles), carbonyldiimidazole (1.68 g, 10.373 mmoles), THF (30 ml) and 3-cyclopentyl-2-(3-methoxy-phenyl)-propylamine (2.2 g, 9.43 mmoles), obtained as described in example 8, 3.35 g of the title compound were obtained (yield: 98.3%), m.p.: 106-107° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:22])[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1.[F:23][C:24]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].C(N(CC)CC)C>C1COCC1>[F:23][C:24]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:25]=1[C:26]([NH:22][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)=[O:27]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCOCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1nccc1-c1cc(NC(=O)c2ccc(F)cc2F)ccc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.9 %

Procedure:
A mixture of 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine (200 mg, 0.66 mmole), 2,4-difluoro-benzoyl chloride (140 mg, 1.2 eq), and triethylamine (0.2 mL, 2 eq) in 3 mL THF was stirred at room temperature for 10 minutes. The mixture was purified by HPLC to give title compound as a white solid (99 mg, 34%). 1H NMR (Acetone-d6, 400 MHz) δ 2.92-3.06 (m, 2H), 3.13-3.17 (m, 2H), 3.50-3.58 (m, 4H), 3.68 (s, 3H), 3.82-3.85 (m, 2H), 4.36 (t, 2H), 6.29 (s, 1H), 7.24 (d, J=9.09 Hz, 2H), 7.44 (dt, J=10.1, 2.78 Hz, 1H), 7.49 (s, 1H), 7.67 (s, 1H), 7.72-7.79 (m, 1H), 7.81 (dd, J=9.09, 2.78 Hz, 1H). Exact mass calculated for C23H24F2N4O3 442.2, found 443.5 (MH+).
Reaction SMILES: CC(C)=[O:3].[CH2:5]([C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][CH2:17][CH:18]2[C:21]([NH2:23])=[O:22])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O>O>[C:5]([C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][CH2:17][CH:18]2[C:21]([NH2:23])=[O:22])=[CH:14][CH:13]=1)(=[O:3])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)=O
Reactant: NC(=O)C1CCc2ccc(Cc3ccccc3)cc21
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)C1CCc2ccc(C(=O)c3ccccc3)cc21
Reaction time: 8 h

Procedure:
To 150 ml. of acetone is added 12.5 g. of 6-benzylindan-1-carboxamide, followed by the dropwise addition of a solution of 5 g. of sodium dichromate in 24 ml. of 6N sulfuric acid. After the addition has been completed, the mixture is stirred overnight. Then, 200 ml. of water is added and the acetone is distilled off under reduced pressure. The residue is extracted with ethyl acetate. The extract is washed with water and dried, followed by removal of the solvent by distillation under reduced pressure. The residue is purified by column chromatography (500 g. of silica gel; eluted with a 7:3 solvent mixture of chloroform and acetone) and the resultant crude crystals are recrystallized from benzene. The procedure gives 6-benzoylindan-1-carboxamide as crystals melting at 195°-197° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[N+:13]([CH3:16])([O-:15])=[O:14]>>[N+:13]([CH:16]=[CH:7][C:6]1[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=1)([O-:15])=[O:14]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Product: O=[N+]([O-])C=Cc1ccc(C(F)(F)F)cc1
Yield: 98 %

Procedure:
In close analogy to the procedure described above, 4-Trifluoromethyl-benzaldehyde is reacted with nitromethane to provide the title compound.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9])C=O)(=[O:3])[CH3:2].[C:16](Cl)(=[O:18])[CH3:17].[CH:20]([Cl:23])(Cl)Cl>O>[C:1]([NH:4][C@@H:5]1[C@@H:8]([O:9][C:16](=[O:18])[CH3:17])[C@H:10]([O:11][C:1](=[O:3])[CH3:2])[C@@H:12]([CH2:14][O:15][C:8](=[O:9])[CH3:5])[O:13][C@@H:20]1[Cl:23])(=[O:3])[CH3:2]
Reactant: ClC(Cl)Cl
Reactant: CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(=O)Cl
Solvent: O
Product: CC(=O)N[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@@H]1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-D-glucopyranosyl chloride was prepared as follows. 2-Acetamido-2-deoxy-D-glucose (50 g, 0.226 mol) was added to chilled acetyl chloride (125 ml). The mixture was then stirred at room temperature for 16 hr. Chloroform (300 ml) was added to the reaction mixture through the condenser and the resulting homogeneous solution was added to a vigorously stirred solution of 400 grams of ice and 100 ml of water. The organic layer was separated, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and filtered. This filtrate was concentrated to about 75 ml under reduced pressure. Ether (400 ml) was added to the concentrated solution and left at room temperature for 2 hr to give the product as a white solid. This white solid was filtered and dried in a vacuum desiccator over sodium hydroxide and phosphorous pentoxide to give 52.5 grams of the title cmp. M.p. 123°-125° C.
Reaction SMILES: [H-].[Na+].C1COCC1.C(OP([CH2:16][C:17]#[N:18])(=O)OCC)C.[C:19]1([CH:25]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:26]2[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O.C(OC(=O)C)C>[C:19]1([CH:25]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:26]2[CH2:31][CH2:30][C:29](=[CH:16][C:17]#[N:18])[CH2:28][CH2:27]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CC=C1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
2.9 g (97 mmol) 80% sodium hydride are suspended in abs. THF and a solution of 21.5 g (121 mmol) diethyl-(cyanomethyl)-phosphonate in 150 ml abs. THF is added dropwise under light cooling. The mixture is subsequently stirred 30 minutes at RT and then a solution of 26.5 g (100 mmol) N-(diphenylmethyl)4-piperidone in 80 ml abs. THF is added dropwise. The suspension is left to stand overnight and subsequently added to 200 ml acetic acid ethyl ester and 100 ml water. The organic phase is separated and washed with 100 ml water, dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with dichloromethane. Yield: 22.7 g (78%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][Cl:10])[CH:4]=1.[CH3:11][CH:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH3:13].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O>[CH3:13][CH:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][CH:24]([CH2:2][C:3]2[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=2)[CH2:9][Cl:10])[CH2:23][CH2:22]1)[CH3:11]
Reactant: CC(C)Oc1ccccc1N1CCCCC1
Reactant: ClCc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)Oc1ccccc1N1CCC(Cc2cccc(CCl)c2)CC1
Yield: 25.5 %

Procedure:
A biphasic solution of α,α'-dichloro-m-xylene (2.40 g, 0.0137 mol), N-[2-(1-methylethoxy)phenyl]piperidine (3.00 g, 0.0137 mol), sodium carbonate (2.19 g, 0.020 mol), ethyl acetate (20 mL), and H2O (20 mL) was refluxed for 3 h. The organic layer was separated, dried (MgSO4), filtered, and evaporated to an oil. The residue was chromatographed on silica gel using chloroform as eluant to give 3-[[1-[2-(1-methylethoxy)phenyl]-4-piperidinyl]methyl]benzyl chloride (1.25 g, 25%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]23[O:16][CH2:15][C:12]([CH2:17][CH2:18][CH3:19])([CH2:13][O:14]2)[CH2:11][O:10]3)=[CH:5][CH:4]=1)#[CH:2].CN(C)C(Cl)=O.[CH3:26][N:27]([CH3:31])[C:28](Cl)=[S:29]>>[CH3:26][N:27]([CH3:31])[C:28](=[S:29])[C:2]#[C:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]23[O:10][CH2:11][C:12]([CH2:17][CH2:18][CH3:19])([CH2:13][O:14]2)[CH2:15][O:16]3)=[CH:7][CH:8]=1
Reactant: C#Cc1ccc(C23OCC(CCC)(CO2)CO3)cc1
Reactant: CN(C)C(=S)Cl
Agent: CN(C)C(=O)Cl
Product: CCCC12COC(c3ccc(C#CC(=S)N(C)C)cc3)(OC1)OC2

Procedure:
N,N-Dimethyl-3-[4-(4-(4-n-propyl-2,6,7-trioxabicyclo[2,2,2]oct-1-yl)phenyl]-prop-2-ynamide and N,N-dimethyl-3-[4-(4-n-propyl-2,6,7-trioxabicyclo[2,2,2]-oct-1-yl) phenyl]-prop-2-ynthioamide were prepared using similar methodology from 1-(4-ethynylphenyl)-4-n-propyl-2,6,7-trioxabicyclo[2,2,2]octane and dimethylcarbamoyl chloride and dimethylthiocarbamoyl chloride respectively.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH:9][CH3:10])=[CH:4][CH:3]=1.[CH3:11]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:44][C:45]1([F:51])[CH2:47][CH:46]1C(O)=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:10]([CH:46]3[CH2:47][C:45]3([F:51])[F:44])[N:8]([CH3:11])[C:6]=2[CH:7]=1
Reactant: CNc1ccc(Br)cc1N
Reactant: O=C(O)C1CC1(F)F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(C2CC2(F)F)nc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
A mixture of 5-bromo-N′-methylbenzene-1,2-diamine (300 mg), HATU (567 mg), N,N-diisopropylethylamine (0.255 ml), 2,2-difluorocyclopropanecarboxylic acid (182 mg) and DMF (10 ml) was stirred at room temperature for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4, passed through NH silica gel pad and concentrated in vacuo. The precipitate was washed with IPE/hexane, collected by filtration and dried in vacuo to give the title compound (255 mg) as a yellow solid.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]=1[OH:17])([CH3:6])([CH3:5])[CH3:4].[C:18]1([N:24]2[C:28](=[O:29])[CH:27]=[CH:26][C:25]2=[O:30])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[C:13]([C:9]1[CH:10]=[C:11]([CH:27]2[CH2:26][C:25](=[O:30])[N:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:28]2=[O:29])[CH:12]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[C:8]=1[OH:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: O=C1C=CC(=O)N1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C2CC(=O)N(c3ccccc3)C2=O)cc(C(C)(C)C)c1O
Yield: 2.1 %

Procedure:
This compound is prepared by the procedure of Example 1 from 2.40 g (0.1 mol) of sodium hydride, 20.63 g (0.1 mol) of 2,6-di-tert-butylphenol, and 17.32 g (0.1 mol) of N-phenylmaleimide in tetrahydrofuran. The reaction mixture is concentrated in vacuo and the residue is dissolved in 150 ml of toluene. The toluene solution is extracted sequentially with 1M sodium hydroxide (2×100 ml) and water (2×50 ml). The organic phase is dried over anhydrous sodium sulfate and then the solvent is removed in vacuo. The residue is triturated with petroleum ether to give 0.78 g (2%) of white crystals: mp 204° C.
Reaction SMILES: [CH2:1]([CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Cs+].CN(C=[O:25])C>>[CH2:1]([C:8]([OH:25])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Reactant: CN(C)C=O
Agent: [Cs+]
Agent: [F-]
Product: CCOC(=O)C(O)(Cc1ccccc1)C(=O)OCC
Temperature: 40 °C

Procedure:
A mixture of diethyl benzylpropanedioate (41 g) and CsF (49.8 g) in 90 mL of DMF was heated at 40° C. with vigorous air bubbling for 3 days. The resulting mixture was diluted with ethyl acetate (800 mL) and washed with water (3×1 L). The organic layer was concentrated and then purified by Biotage silica gel column chromatography (5-20% ethyl acetate in hexanes) to give the title product as a colorless oil. 1H NMR (300 MHz, CDCl3) δ: 7.22-7.26 (m, 5H), 4.23 (q, J=7.2 Hz, 4H), 3.80 (br, 1H), 3.35 (s, 2H), 1.26 (t, J=7.2 Hz, 6H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]#[N:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[NH2:13][C:12]1[C:3]2[CH:4]=[C:5]3[C:10]([CH:9]=[CH:8][CH:7]=[CH:6]3)=[CH:11][C:2]=2[O:1][C:15]=1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=[O:17]
Reactant: N#Cc1cc2ccccc2cc1O
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc3ccccc3cc12
Temperature: 80 °C
Reaction time: 16 h
Yield: 57.8 %

Procedure:
To a stirred solution of 3-hydroxy-naphthalene-2-carbonitrile from step 2 (200 mg, 1.18 mmol) and 2,2′,4′-trichloroacetophenone (317 mg, 1.42 mmol, 1.2 eq) in anhydrous N,N-dimethylformamide (4.7 mL) was added potassium carbonate (326.7 mg, 2.36 mmol, 2.0 eq), and the orange reaction mixture was stirred at 80° C. for 16 h. The resulting dark wine colored reaction was diluted with ethyl acetate and water. The organic layer was washed with saturated aqueous ammonium chloride, water, brine, and dried over magnesium sulfate. The solvent was removed at reduced pressure and the crude product was purified on the MPLC (biotage) eluted with 15% ethyl acetate-hexane. Crystallization from ether-hexane afforded 243 mg (57.7%) of the desired benzofuran. 1H-NMR (DMSO-d6) δ 8.66 (s, 1H), 7.99 (d, J=8.1 Hz, 1H), 7.93 (d, J=8.1 Hz, 1H), 7.88 (s, 1H), 7.76 (d, J=1.5 Hz, 1H), 7.72 (broad s, 2H), 7.63 to 7.42 (m, 4H); LC-MS (ES MH+=356).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([OH:10])(=O)=[O:8])[CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12].[ClH:17]>P(Cl)(Cl)(Cl)=O>[ClH:12].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([Cl:17])(=[O:10])=[O:8])[CH:2]=1
Reactant: O=S(=O)(O)c1cccnc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1cccnc1
Temperature: 120 °C

Procedure:
A mixture of pyridine-3-sulfonic acid (15.0 g), phosphorous pentachloride (24.0 g) and phosphorous oxychloride (30 mL) was heated to 120° C. for 16 h. The reaction was cooled to room temperature, and the resulting suspension was saturated with HCl (g). A white precipitate was collected, washed with CHCl3, and dried in vacuo to afford the title compound (15.6 g). 1H NMR (400 MHz, DMSO) δ 8.98 (s, 1H), 8.85 (d, 1H), 8.66 (d, 1H), 8.02 (t, 1H).
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[C:6]1([CH3:16])[CH:11]=[CH:10][C:9](S(Cl)(=O)=O)=[CH:8][CH:7]=1.[CH2:17]1[CH2:21][O:20][CH2:19]C1>>[CH2:16]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH:21]2[CH2:17][CH2:19][O:20]2)[CH2:8][CH2:7]1)[CH2:1][CH3:2]
Reactant: [Li]CCCC
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: CCC[C@H]1CC[C@H](C2CCO2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
THF (1,000 ml) was added to 1-(trans-4-propyl-cyclohexyl)-propane-1,3-diol(4) (229.3 g) prepared in the third step in a reaction vessel under an atmosphere of nitrogen. n-Butyllithium (1.63 M in n-hexane; 702 ml) was added dropwise to the mixture at around −5° C. After 30 minutes of stirring, p-toluenesulfonyl chloride (218.2 g) in a THF (1,000 ml) solution was added dropwise. After the reaction mixture had been stirred for 30 minutes, n-butyllithium (1.63 M in n-hexane; 702 ml) was added dropwise at around −5° C., and then the reaction mixture was heated slowly up to the reflux temperature. After the evolution of gas had ceased, the reaction mixture was cooled to room temperature, and quenched with a saturated aqueous solution of ammonium chloride, and then water (1,000 ml) was added to give two layers. The water layer was extracted with toluene (500 ml) three times, and the combined organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was treated with silica gel chromatography (silica gel: 200 g, eluent: heptane/ethyl acetate=90/10 by volume) and distilled under reduced pressure (71 to 74° C., 3 mmHg) to give 2-(trans-4-propyl-cyclohexyl)-oxetane (5) (145 g) in 70% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.[CH2:34]([O:36][C:37](=[O:42])[C@H:38]([CH2:40][OH:41])[NH2:39])[CH3:35].C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH:15]1([CH2:14][CH2:13][CH2:12][C@@H:8]([C:9]([NH:39][C@@H:38]([CH2:40][OH:41])[C:37]([O:36][CH2:34][CH3:35])=[O:42])=[O:11])[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Reactant: CCOC(=O)[C@@H](N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)[C@H](CO)NC(=O)[C@H](CCCC1CCCCC1)CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.1 %

Procedure:
A solution of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 1) (5.00 g, 16.76 mmol) in dichloromethane (75 ml) was treated sequentially with 1-hydroxybenzotriazole hydrate (2.49 g, 18.43 mmol), serine ethyl ester hydrochloride (3.13 g, 18.43 mmol) and N,N-diisopropylethylamine (6.13 ml, 35.19 mmol) and the resulting mixture was stirred at 0° C. under a nitrogen atmosphere for 15 minutes. 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.53 g, 18.43 mmol) was then added and the mixture was stirred for 48 hours being allowed to warm to room temperature over this time. The mixture was diluted with dichloromethane (200 ml), washed sequentially with water, aqueous citric acid solution (10% w/v), a saturated aqueous solution of sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was then purified by column chromatography on silica gel eluting a gradient system of ethyl acetate:pentane (10:90) to (50:50) to afford the title compound as a colourless oil (5.41 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=O)=[C:17]([O:23][CH3:24])[CH:16]=2)([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][S:26]([CH2:28][S:29]([CH3:31])=O)=[O:27].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCCC1.CO>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[C:28]([S:29][CH3:31])[S:26]([CH3:25])=[O:27])=[C:17]([O:23][CH3:24])[CH:16]=2)([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C2(O)CCN(Cc3ccccc3)CC2)ccc1C=O
Reactant: CS(=O)CS(C)=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C2(O)CCN(Cc3ccccc3)CC2)ccc1C=C(SC)S(C)=O

Procedure:
3.43 g of 4-(1-benzyl-4-hydroxypiperidin-4-yl)-2-methoxybenzaldehyde was dissolved in 30 ml of tetrahydrofuran. To the resulting solution were added 2.42 ml of methyl methylsulfinylmethyl sulfoxide and 2 ml of a 40% solution of benzyltrimethylammonium hydroxide in methanol and the resulting mixture was heated under reflux for 3 hours. After concentrating the reaction mixture, water was added thereto followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 4.58 g of the title compound as a pale yellow oily substance.
Reaction SMILES: [ClH:1].Cl.[N:3]1([CH2:8][CH2:9][O:10][C:11]2[CH:40]=[CH:39][C:14]([CH2:15][C:16]3[C:17]4[CH:38]=[CH:37][CH:36]=[CH:35][C:18]=4[S:19][C:20]=3[C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]4[N:31]=CN[CH:34]=4)=[O:29])=[CH:23][CH:22]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.[NH:41]1[CH:45]=CC(C(O)=O)=N1.[NH4+].[OH-].Cl>C(Cl)(Cl)Cl.CO>[ClH:1].[ClH:1].[N:3]1([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:15][C:16]3[C:17]4[CH:38]=[CH:37][CH:36]=[CH:35][C:18]=4[S:19][C:20]=3[C:21]3[CH:22]=[CH:23][C:24]([NH:27][C:28]([C:30]4[CH:34]=[CH:45][NH:41][N:31]=4)=[O:29])=[CH:25][CH:26]=3)=[CH:39][CH:40]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(Nc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1)c1c[nH]cn1
Reactant: O=C(O)c1cc[nH]n1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1)c1cc[nH]n1
Yield: 48 %

Procedure:
By essentially following the conditions described in Example 16, Part E, the free base of the title compound was prepared as a solid from 2-(4-aminophenyl)-3-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzo[b]thiophene (Example 16; Part D) and 3-pyrazole carboxylic acid in 48% yield following radial chromatography (SiO2; 1% then 3% then 5% MeOH in CHCl3 sat'd with NH4OH). The solid was taken up in 5 mL MeOH, and the solution was treated with 1 mL of 1 N HCl. The solution was concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:19]=1.[C:20](=O)([O-])[O-].[Cs+].[Cs+].IC.CN(C)C=O>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:20])[C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:19]=1
Reactant: O=C1CCN(C2CCCCC2)c2nc(Cl)ncc2N1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)CCN(C2CCCCC2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.12 g (0.00042 mole) of 2-chloro-9-cyclohexyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-20), 0.469 g (0.00144 mole) of cesium carbonate, 0.135 g (0.00096 mole) of iodomethane and 1 mL of dimethylformamide was stirred overnight at ambient temperature and then diluted with 5 mL of water. The mixture was stirred for 15 minutes and the solid was collected by filtration to give 2-chloro-9-cyclohexyl-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20) which was used without further purification.