Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([NH2:23])=[O:22])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[C:35]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:11]([C@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([NH2:23])=[O:22])[S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])=[CH:14][CH:15]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: CC(C)C[C@H](C(N)=O)N(Cc1ccc(N)cc1)S(=O)(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(CN([C@H](CC(C)C)C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Reaction time: 18 h
Yield: 41 %

Procedure:
A solution of the compound of Example 48[(2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(4-aminobenzyl)amino]-4-methyl-pentanoic acid amide (250 mg, 0.60 mmol) and Et3N (120 mg, 1.2 mmol) in CH2Cl2 (20 mL) was treated with acetyl chloride (56 mg, 0.72 mmol). After stirring for 18 h, the reaction was concentrated, chromatographed using silica gel flash chromatography (1% methanol/CH2Cl2) to afford the titled compound (110 mg, 41%). MS (ESI), (M−H)− 422.9; 1H NMR (CDCl3) δ 7.67 (d, 2H, J=8.0), 7.28-7.46 (m, 6H), 7.12 (br s, 1H), 6.24 (br s, 1H), 5.19 (br s, 1H), 4.48 (dd, 2H, J=50, 15), 4.27 (t, 1H, J=7.0), 2.18 (s, 3H), 1.80-2.01 (m, 1H), 1.12-1.32 (m, 2H), 0.75 (d, 3H, J=7.0), 0.67 (d, 3H, J=7.0).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[CH:11]/[C:12](=O)[CH2:13][C:14](=O)/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:19][CH:18]=3)[CH:8]=2)[CH:3]=[CH:2]1.CC(O)=O.O.[NH2:39][NH2:40].C([O-])([O-])=O.[K+].[K+]>C1COCC1.CCOC(C)=O.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[CH:11]/[C:12]3[NH:40][N:39]=[C:14](/[CH:15]=[CH:16]/[C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[CH:19][CH:18]=4)[CH:13]=3)[CH:8]=2)[CH:3]=[CH:2]1
Reactant: NN
Reactant: O=C(/C=C/c1ccc(OCCN2CCOCC2)cc1)CC(=O)/C=C/c1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: C(=C/c1cc(/C=C/c2ccc3cc[nH]c3c2)[nH]n1)\c1ccc(OCCN2CCOCC2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
To 1.5 g of (1E,6E)-1-(1H-indol-6-yl)-7-[4-(2-morpholinoethoxy)phenyl]hepta-1,6-diene-3,5-dione were added 13.5 mL of AcOH and 1.31 mL of hydrazine monohydrate, and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was allowed to cool back to room temperature and poured into a stirring mixture of 18.7 g of K2CO3, 95 mL of cold water, 30 mL of AcOEt and 20 mL of THF. The organic layer was separated, washed with saturated brine, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography (CHCl3/acetone or CHCl3/methanol system) to give 0.62 g of the title compound (42% yield).
Reaction SMILES: [ClH:1].C(OCC)(=O)C.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:55])[C@@H:22]([NH:30][C:31]([CH2:33][N:34]2[C:39]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:38][N:37]([C:46](=[O:50])[CH2:47][O:48][CH3:49])[CH:36]([CH:51]([CH3:53])[CH3:52])[C:35]2=[O:54])=[O:32])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(OCC)(=O)C>[ClH:1].[CH:51]([CH:36]1[N:37]([C:46](=[O:50])[CH2:47][O:48][CH3:49])[CH:38]=[C:39]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:34]([CH2:33][C:31]([NH:30][C@@H:22]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21](=[O:55])[N:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)=[O:32])[C:35]1=[O:54])([CH3:53])[CH3:52]
Reactant: COCC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@@H](Cc2ccccc2)C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)C(=O)C1C(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COCC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@@H](Cc2ccccc2)C(=O)N2CCNCC2)C(=O)C1C(C)C
Reaction time: 1 h

Procedure:
A 4 N hydrogen chloride/ethyl acetate solution (0.24 ml) is added to a solution of (2S)-1-(4-tert-butoxycarbonylpiperazin-1-yl)-2-{(3RS)-3-isopropyl-4-methoxyacetyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-oxo-3-phenylpropane (190 mg, Compound No. 1-55) in ethyl acetate (3 ml), and the mixture is stirred for one hour. The reaction mixture is concentrated under reduced pressure to give the titled compound (146 mg).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[C:13]3[N:14]([N:23]=[CH:24][N:25]=3)[C:15]([C:18]3[CH:19]=[N:20][NH:21][CH:22]=3)=[CH:16][N:17]=2)[CH:6]=1)[CH3:2].[OH:27][C:28]1[CH:35]=[CH:34]C(CN)=[CH:30][CH:29]=1>>[OH:27][C:28]1[CH:35]=[CH:34][C:2]([CH2:1][NH:3][C:4](=[O:26])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]3[C:13]4[N:14]([N:23]=[CH:24][N:25]=4)[C:15]([C:18]4[CH:19]=[N:20][NH:21][CH:22]=4)=[CH:16][N:17]=3)[CH:6]=2)=[CH:30][CH:29]=1
Reactant: CCNC(=O)c1cccc(Nc2ncc(-c3cn[nH]c3)n3ncnc23)c1
Reactant: NCc1ccc(O)cc1
Product: O=C(NCc1ccc(O)cc1)c1cccc(Nc2ncc(-c3cn[nH]c3)n3ncnc23)c1

Procedure:
This compound may be prepared using methods as described for Compound 129, using 4-hydroxybenzylamine in step 5. LCMS: Rt=0.98 min (100%), m/z (ESI) 427 (M+H)+.
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:15]2[C:14]([Cl:16])=[N:13][CH:12]=[N:11][C:10]=2[N:9]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:8]=1.[I:22][C:23]1[CH:24]=[C:25]([CH:32]=[CH:33][CH:34]=1)[C:26](N(OC)C)=[O:27]>C1COCC1>[Cl:16][C:14]1[C:15]2[C:7]([C:26]([C:25]3[CH:32]=[CH:33][CH:34]=[C:23]([I:22])[CH:24]=3)=[O:27])=[CH:8][N:9]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: Clc1ncnc2c1c(Br)cn2C1CCCC1
Reactant: CON(C)C(=O)c1cccc(I)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1cccc(I)c1)c1cn(C2CCCC2)c2ncnc(Cl)c12
Temperature: 25 °C
Yield: 49.4 %

Procedure:
n-BuLi (3.65 mL, 2.5 M in hexanes, 9.14 mmol) was added dropwise to a solution of 5-Bromo-4-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 8.31 mmol) in THF (50 mL) at −78° C. After 30 min a solution of 3-Iodo-N-methoxy-N-methyl-benzamide (2.29 g, 7.8 mmol) in THF (10 mL) was added. After 30 min the reaction was quenched with water and allowed to warm to room temperature. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with water and dried over Na2SO4. Recrystallization from MeOH afforded the title compound as a white solid (1.74 g, 49%). MS: 451.9/453.9 (MH+); HPLC Rf: 7.44 min. (HPLC method 4).
Reaction SMILES: CC1C=CC(S(OCC2CC3C=CC=C(C(C)(C)C)C=3O2)(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].[N:30]([CH2:33][CH:34]1[CH2:38][C:37]2[CH:39]=[CH:40][CH:41]=[C:42]([C:43]([CH3:46])([CH3:45])[CH3:44])[C:36]=2[O:35]1)=[N+]=[N-].[N-]=[N+]=[N-]>[Pd]>[C:43]([C:42]1[C:36]2[O:35][CH:34]([CH2:33][NH2:30])[CH2:38][C:37]=2[CH:39]=[CH:40][CH:41]=1)([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)c1cccc2c1OC(CN=[N+]=[N-])C2
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(C(C)(C)C)c3O2)cc1
Agent: [N-]=[N+]=[N-]
Product: CC(C)(C)c1cccc2c1OC(CN)C2
Yield: 67 %

Procedure:
Treatment of (±)-(7-tert-butyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (12.43 g, 0.035 mol) with sodium azide (6.73 g, 0.103 mol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-7-tert-butyl-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.750 g, 10 wt. %) generally according to the procedure described for Example 1 gave 5.56 g (67%) of (±)-1-(7-tert-butyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp 177-180° C. (dec); Anal. Calcd. for C13H19NOHCl: C, 64.59; H, 8.34; N, 5.79. Found: C, 64.34; H, 9.19; N, 5.73.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@@H:9]([OH:15])[CH2:10][CH2:11][O:12]2)=[CH:7][CH:6]=1)=[O:4].N1C=CN=C1.[CH3:21][C:22]([Si:25](Cl)([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C=O)C>[Si:25]([O:15][C@@H:9]1[C:8]2[C:13](=[CH:14][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[O:12][CH2:11][CH2:10]1)([C:22]([CH3:24])([CH3:23])[CH3:21])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1ccc2c(c1)OCC[C@@H]2O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)OCC[C@@H]2O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (S)-methyl-4-hydroxyl-3,4-dihydro-2H-chromene-7-carboxylate (10.2 g, 49.0 mmol), imidazole (3.70 g, 53.9 mmol), and TBSCl (8.12 g, 53.9 mmol) in DMF (100 mL) was stirred for 24 h at RT. The reaction mixture was quenched with H2O and extracted with ether (3×). The organic extracts were dried over MgSO4, and concentrated to give a brown oil. 1H NMR (400 MHz, CDCl3): δ 0.74 (s, 15H), 1.81 (m, 1H), 1.91 (m, 1H), 3.87 (s, 3H), 4.02 (m, 1H), 4.11 (m, 1H), 4.67 (t, 5.2 Hz, 1H), 7.09 (s, 1H), 7.11 (d, 7.6 Hz, 1H), 7.23 (d, 7.6 Hz, 1H).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[O:7][C:8]3[C:9](=[C:11]([C:15]([OH:17])=O)[CH:12]=[CH:13][CH:14]=3)[N:10]=2)[N:3]=[CH:2]1.[ClH:18].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:42][C@H:43]1[CH:48]2[CH2:49][CH2:50][N:45]([CH2:46][CH2:47]2)[CH2:44]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[ClH:18].[N:45]12[CH2:50][CH2:49][CH:48]([CH2:47][CH2:46]1)[C@H:43]([NH:42][C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:8]3[O:7][C:6]([C:4]4[N:3]=[CH:2][S:1][CH:5]=4)=[N:10][C:9]=13)=[O:17])[CH2:44]2
Reactant: O=C(O)c1cccc2oc(-c3cscn3)nc12
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cccc2oc(-c3cscn3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32.8 %

Procedure:
A mixture of 2-(thiazol-4-yl)benzoxazole-4-carboxylic acid (80 mg, 0.32 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (122 mg, 0.64 mmol), 1-hydroxybenzotriazole (86 mg, 0.64 mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (81 mg, 0.41 mmol) in DMF (5 mL) was stirred at room temperature for 10 min, then triethylamine (0.13 mL, 1.0 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (100 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organics were washed with water (5×25 mL), brine (25 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) and recrystallization from acetonitrile to afford the desired product (41 mg, 37%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.52 (d, J=7.1 Hz, 1H), 9.03 (d, J=2.1 Hz, 1H), 8.35 (d, J=2.1 Hz, 1H), 8.22 (dd, J=7.8, 1.0 Hz, 1H), 7.78 (dd, J=8.1, 1.0 Hz, 1H), 7.53 (t, J=7.9 Hz, 1H), 4.42-4.35 (m, 1H), 3.60-3.53 (m, 1H), 3.25-3.05 (m, 2H), 3.02-2.90 (m, 3H), 2.28-2.10 (m, 2H), 1.87-1.80 (m, 2H), 1.75-1.67 (m, 1H); MS (ESI+) m/z 355 (M+H).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].NC(N)=N.[C:13]([CH:18]([C:33]#[N:34])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)(OCC)=[O:14].S(=O)(=O)(O)O>CN(C)C=O.CO>[NH2:4][C:3]1[N:5]=[C:33]([NH2:34])[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)=[C:13]([OH:14])[N:2]=1
Reactant: CCOC(=O)C(C#N)CCCCc1ccc(C(=O)OC)cc1
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCCCc2c(N)nc(N)nc2O)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 0.71 g (1.05 eq) of guanidine hydrochloride, 0.40 g (1.05 eq) of sodium methoxide, and 20 mL of anhydrous methanol is stirred under nitrogen for 30 minutes. The solid which forms is removed by filtration and the filtrate concentrated under reduced pressure. To the residue (guanidine free base) is added 2.15 g (1.0 eq) of methyl 4-(5-carbethoxy-5-cyanopentyl)benzoate in 20 mL of anhydrous dimethylformamide. This mixture is stirred under nitrogen with gentle heating for 12 hours, cooled, and then mixed with very dilute sulfuric acid. The solid is collected, washed with water and then diethyl ether, and dried to yield methyl 4-[4-(2,4-diamino-6-hydroxypyrimidin-5-yl)butyl]-benzoate, m.p. 203°-205° C.; IR (KBR) vmax 3495, 3380, 2925, 2850, 1685, 1600, 1490, 1430, 1359, 1282, 1174, 1111, 1015, and 754 cm-1 ; 1H NMR (d6DMSO) delta 9.74 (bs, 1H (3)--NH), 7.83 (d, J=8.1 Hz, 2H, Ar), 7.31 (d, J=8.1 Hz, 2H, Ar), 5.87 (bs, 2H (2)--NH2), 5.60 (bs, 2H, (6)--NH2), 3.80 (s, 3H, CH3), 2.62 (t, J=7.6 Hz, 2H, (5)--CH2), 2.15 (t, J=7.2 Hz, 2H, benzyl), 1.51-1.55 (m, 2H, 2° aliphatic), 1.26-1.28 (m, 2H 2° aliphatic).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[CH3:18][C:19]1[S:23][C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:21][C:20]=1[C:30]([F:33])([F:32])[F:31]>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:27]1[CH2:28][CH2:29][N:24]([C:22]2[S:23][C:19]([CH3:18])=[C:20]([C:30]([F:33])([F:31])[F:32])[N:21]=2)[CH2:25][CH2:26]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Cc1sc(N2CCNCC2)nc1C(F)(F)F
Product: Cc1sc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)nc1C(F)(F)F
Yield: 60 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(5-methyl-4-trifluoromethyl-thiazol-2-yl)-piperazine. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 60%). MS (m/e): 492.3 (M+H+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[C:18]([CH3:26])[CH:17]=1.O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[C:18]([CH3:26])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Cl
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(C)cc1Oc1ccc(Br)cc1
Temperature: 150 °C
Reaction time: 14 h
Yield: 68.8 %

Procedure:
37.5 g (216.7 mmol) of 4-bromophenol and 35.4 g (256.2 mmol) of potassium carbonate are suspended in 500 ml of N,N-dimethylformamide and the suspension is stirred at room temperature for 1 h, before 36.6 g (197.0 mmol) of 4-chloro-2,5-dimethylnitrobenzene are added. The mixture is subsequently stirred at 150° C. for 14 h, water is added, and repeated extraction is carried out with ethyl acetate. The extracts are dried over Na2SO4 and filtered and the solvent is removed under reduced pressure. This is followed by purification by column chromatography (48.0 g, purity 91.0%, yield 68.8%, log P (pH 2.3)=4.86).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.Cl.[OH-].[Na+]>>[O:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]1[O:5][CH:1]1[CH2:2][CH2:4][CH2:8][CH2:7][O:6]1.[C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C1=COCCC1
Agent: C=C(C)C(=O)OCCO
Agent: Cl
Agent: [Na+]
Product: C1CCC(OC2CCCCO2)OC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A screw mouth-type bottle containing 55.4 g (0.43 mol) of hydroxyethyl methacrylate (trade name: Acryester HO; manufactured by Mitsubishi Rayon Co., Ltd.) and 37.0 g (0.44 mol) of dihydropyran (trade name: 3,4-Dihydro-2H-pyran; manufactured by Wako Pure Chemical Industries, Ltd.) is tightly closed by a rubber plug (Biton plug) and immersed in an ice bath. 0.47 g of concentrated hydrochloric acid is further added to the mixture, and the mixture is stirred at room temperature for 6 hours. The obtained reaction solution is passed through a column filled with sodium hydroxide to obtain a tetrahydropyranyl ether in which the OH group of hydroxyethyl methacrylate is protected by a protecting group.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][C:12](=O)[CH2:13][CH2:14][C:15]2([CH3:22])[C:19](=[O:20])[CH2:18][CH2:17][C:16]2=O)[CH:6]=[CH:7][CH:8]=1.O>C1C=CC=CC=1>[CH3:22][C@:15]12[CH2:14][CH2:13][C:12]3[C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH2:9][CH2:10][C:11]=3[C:16]1=[CH:17][CH2:18][C:19]2=[O:20]
Reactant: COc1cccc(CCCC(=O)CCC2(C)C(=O)CCC2=O)c1
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc2c(c1)CCC1=C2CC[C@]2(C)C(=O)CC=C12
Yield: 75.2 %

Procedure:
To 2-(6-m-methoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione (3 g) in benzene (100 cc) add polyphosphoric acid (from orthophosphoric acid, 15 g. and phosphorus pentoxide, 6 g.) and heat the mixture at 90° for 4 minutes under such reduced pressure as the need to control frothing will allow. Cool, add water, and extract the mixture with ether and ethyl acetate; isolate the product from the resulting solution to obtain the colorless crystalline 13β-methyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one (2 g), b.p. 115°-116°; ultraviolet absorption peak at 313 mμ (ε35,100).
Reaction SMILES: [C:1]1([S:7]([CH:10]=[CH:11][C:12]2[CH:13]=[C:14]([CH:22]=[C:23]([CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:24]=2)[CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1C=CC(S(NN)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]1([S:7]([CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:22]=[C:23]([CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:24]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C=Cc1cc(C=CS(=O)(=O)c2ccccc2)cc(Cc2cccnc2)c1
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1cc(CCS(=O)(=O)c2ccccc2)cc(Cc2cccnc2)c1
Yield: 78.4 %

Procedure:
A mixture of ethyl 3-(2-phenylsulphonylethenyl)-5-(3-pyridylmethyl)cinnamate (Preparation 20; 0.485 g) and 4-methylphenylsulphonyl hydrazine (2.08 g) in toluene (25 ml) was heated under reflux for 3 hours and then evaporated under vacuum. The residue was chromatographed on silica gel using an ethyl acetate in hexane elution gradient (50 to 100% ethyl acetate) initially followed by an ethyl acetate:diethylamine (95:5) mixture as eluent. The product fractions were combined and evaporated under vacuum to give the title compound as a gum (0.384 g); Rf 0.50 (SS 4); δ (CDCl3): 1.23(3H,t), 2.57(2H,t), 2.86(2H,t), 2.99(2H,m), 3.33(2H,m), 3.91(2H,s), 4.13(2H,q), 6.82(1H,s), 6.87(1H,s), 6.91(1H,s), 7.22-7.25(1H,m), 7.43-7.47(1H,m), 7.57-7.72(3H,m), 7.94-7.98(2H,m), 8.48- 8.51(2H,m).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[C:4]([CH3:12])[C:3]=1[CH:13]=[CH:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16]1.[H][H]>C1(C)C=CC=CC=1.[Pd]>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[C:4]([CH3:12])[C:3]=1[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16]1
Reactant: [H][H]
Reactant: CCCCCC1CCC(C=Cc2c(C)cc(OCC)c(F)c2F)CC1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCCCC1CCC(CCc2c(C)cc(OCC)c(F)c2F)CC1
Yield: 27.4 %

Procedure:
0.27 g of Pd/C was added to 6.53 g of the compound 1-1-3-18 having been dissolved in 50 mL of toluene and 50 mL of Solmix, and under a hydrogen atmosphere, the mixture was stirred at room temperature until hydrogen was not absorbed. Pd/C was removed, and the solvent was distilled off. The residue was purified by silica gel column chromatography and recrystallization to obtain 1.8 g of 1-(2,3-difluoro-4-ethoxy-6-methylphenyl)-2-(4-pentylcyclohexyl)ethane (Compound 1-1-3-5) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH:13]([CH:16]3[CH2:21][O:20][C:19](=[O:22])[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[C:6]([F:25])[C:5]=1[F:26])[CH3:2].[CH2:27]([Li])[CH2:28][CH3:29].[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH:13]([CH:16]3[CH2:21][O:20][C:19]([CH2:27][CH2:28][CH3:29])([OH:22])[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[C:6]([F:25])[C:5]=1[F:26])[CH3:2]
Reactant: CCOc1ccc(OCC2CCC(C3CCC(=O)OC3)CC2)c(F)c1F
Reactant: [Li]CCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC1(O)CCC(C2CCC(COc3ccc(OCC)c(F)c3F)CC2)CO1
Temperature: -70 °C
Reaction time: 1 h
Yield: 872.7 %

Procedure:
In a reactor under nitrogen atmosphere, 100 mL of THF was added to 4.5 g of 5-[4-(4-ethoxy-2,3-difluorophenoxymethyl)cyclohexyl]tetrahydropyran-2-one obtained in the twelfth step, and the mixture was cooled to −70° C., to which 15 mL of n-propyllithium (about 1.0 mmol) was added dropwise. After stirring the mixture at −70° C. for 1 hour, the temperature of the reaction mixture was increased to room temperature, and 50 mL of a saturated ammonium chloride aqueous solution was added thereto, followed by separating. The aqueous layer was extracted three times with 30 mL of diethyl ether, and the mixture including the organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by silica gel column chromatography to provide 3.6 g of 5-[4-(4-ethoxy-2,3-difluorophenoxymethyl)cyclohexyl]2-propyltetrahydropyran-2-ol.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([F:24])([CH3:23])[CH:7]([O:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=1)[C:8]([O:10]C)=[O:9].[OH-].[Na+]>CO.O1CCCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([F:24])([CH3:23])[CH:7]([O:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=1)[C:8]([OH:10])=[O:9]
Reactant: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(F)c1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(OC)nc(OC(C(=O)O)C(C)(F)c2cccs2)n1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
0.9 g (3 mmol) of methyl 3-(2-thienyl)-3-fluoro-2-(4,6-dimethoxypyrimidin-2-yl)oxybutyrate (from Ex. 3) are dissolved in 20 ml of methanol and 20 ml of tetrahydrofuran, and 3.7 g of 10% strength NaOH solution are added. The mixture is stirred for 6 hours at 60° C. and for 12 hours at room temperature, the solvents are distilled off in vacuo, and the residue is taken up in 100 ml of water. The aqueous phase is now extracted using ethyl acetate and subsequently brought to pH 1-2 using dilute hydrochloric acid and extracted using ethyl acetate. After the mixture has been dried over magnesium sulfate and the solvent distilled off, a small amount of acetone is added to the residue and the precipitate which has formed is filtered off with suction. After drying, 0.8 g of a white powder remains.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[OH:14].O[CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1.O.[OH-].[Na+]>CS(O)(=O)=O.CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH:13]([O:14][CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: OC(c1ccccn1)c1cc(OC(F)(F)F)ccc1F
Reactant: CN1CCC(O)CC1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CN1CCC(OC(c2ccccn2)c2cc(OC(F)(F)F)ccc2F)CC1
Temperature: 145 °C
Reaction time: 7 h

Procedure:
A mixture of (2-fluoro-5-trifluoromethoxyphenyl)pyridin-2-ylmethanol (340 mg) and 4-hydroxy-1-methylpiperidine (273 mg) in methanesulfonic acid (1.5 mL) is heated in a sealed tube at 145° C. for 24 hours and then at 155° C. for 7 hours. The mixture is cooled back to room temperature, poured into water which is then made alkaline with concentrated sodium hydroxide solution. The aqueous phase is extracted with diethyl ether. Pooled extracts are dried over magnesium sulphate and concentrated under reduced pressure. The residue is purified by column chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 95/5/0.5 to 90/10/0.5) to afford the pure base that is then converted into its dioxalate salt in acetone to give 2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]pyridine, dioxalate melting at 45° C.