Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[N:7]=[C:8]([C:12]([C:18]2[S:19][C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=2)([OH:17])[C:13]([F:16])([F:15])[F:14])[S:9][C:10]=1[CH3:11]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:17][C:12]([C:8]1[S:9][C:10]([CH3:11])=[C:6]([CH3:5])[N:7]=1)([C:18]1[S:19][C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=1)[C:13]([F:15])([F:16])[F:14])(=[O:3])[CH3:2]
Reactant: Cc1nc(C(O)(c2nc(C)c(C)s2)C(F)(F)F)sc1C
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC(c1nc(C)c(C)s1)(c1nc(C)c(C)s1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetyl chloride (0.68 ml) was added to a solution of 1,1-bis(4,5-dimethyl-2-thiazolyl)-2,2,2-trifluoroethanol (1.54 g) and 4-dimethylaminopyridine (2 g) in dry dichloromethane (70 ml). The mixture was stirred at room temperature overnight and was then washed with saturated aqueous sodium hydrogen carbonate solution. The organic phase was separated, dried and evaporated and the residue was purified by flash chromatography to give the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.O[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:27])[N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:12]=1.[SH:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>>[N:32]1[CH:33]=[CH:34][C:29]([S:28][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:27])[N:19]([CH3:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][CH:12]=2)=[CH:30][CH:31]=1
Reactant: CN(C(=O)Oc1ccc(CCO)cc1)c1ccccc1
Reactant: Sc1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)Oc1ccc(CCSc2ccncc2)cc1)c1ccccc1
Yield: 5 %

Procedure:
The title compound was prepared as its TFA salt in 5% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 4-mercaptopyridine. NMR (400 MHz; CDCl3): δ 3.07 (t, 2H), 3.36 (t, 2H), 3.44 (br s, 3H), 7.06 (br d, 2H), 7.20 (d, 2H), 7.25-7.43 (m, 7H), 8.51 (d, 2H); HPLC-MS: m/z=365.2 (M+1); Rt=2.53 min.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][CH:24]1[CH2:29][NH:28][CH2:27][CH2:26][NH:25]1>>[CH3:23][CH:24]1[NH:25][CH2:26][CH2:27][N:28]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:19])[CH2:29]1
Reactant: CC1CNCCN1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CC1CN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)CCN1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and 2-methylpiperazine to give 264. MS: (ESI+)=396.1
Reaction SMILES: [Cl:1][C:2]1[C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:21])[N:6]2[CH3:20].Br[C:23]1[CH:24]=[N:25][CH:26]=[C:27]([O:29][CH2:30][CH3:31])[CH:28]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:10]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([O:29][CH2:30][CH3:31])[CH:28]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:21])[N:6]2[CH3:20]
Reactant: CCOc1cncc(Br)c1
Reactant: CN1C(=O)Cc2c1ccc(B1OC(C)(C)C(C)(C)O1)c2Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CCOc1cncc(-c2ccc3c(c2Cl)CC(=O)N3C)c1
Temperature: 115 °C

Procedure:
To 4-chloro-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one (95 mg, 0.31 mmol) was added 3-bromo-5-ethoxy-pyridine (CAS#17117-17-8, 69 mg, 0.34 mmol), 1,2-dimethoxyethane (3.0 mL), and 2 M aqueous sodium carbonate (0.390 mL, 0.77 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (140 mg, 0.015 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 115° C. for 3 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 3%) to furnish 4-chloro-5-(5-ethoxy-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 303.0901 (M+H)1; 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (t, J=6.9 Hz, 3H), 3.26 (a, 3H), 3.61 (a, 2H), 4.15 (q, J=6.9 Hz, 2H), 6.84 (d, J=8.1 Hz, 1H), 7.28-7.33 (m, 2H), 8.26 (d, J=1.8 Hz, 1H), 8.32 (d, J=2.8 Hz, 1H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:9][CH2:8]1)#[N:2].Cl.[CH2:29]([OH:31])[CH3:30]>>[CH2:29]([O:31][C:1](=[NH:2])[CH2:3][CH2:4][CH2:5][O:6][C@H:7]1[CH2:8][CH2:9][C@H:10]([N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:11][CH2:12]1)[CH3:30]
Reactant: CCO
Reactant: CN([C@H]1CC[C@H](OCCCC#N)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Product: CCOC(=N)CCCO[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Reaction time: 48 h

Procedure:
0.35 g (0.87 mmol) trans-N-[4-(3-Cyano-propoxy)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide in 6 ml ethanol were treated with HCl gas at low temperature for 20 min. The mixture was kept at −20° C. for 48 h, was concentrated under reduced pressure to yield 400 mg (quant.) trans-4-{4-[Methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-butyrimidic acid ethyl ester as light brown oil, MS: 451 (MH+).
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:24])[NH:11][C:12]2[CH:13]=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]([C:28]1([C:31]2[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)([OH:27])=[O:26]>>[C:1]1([C@H:7]([O:9][C:10]([NH:11][C:12]2[CH:13]=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([C:34]3[CH:35]=[CH:36][C:31]([C:28]4([C:25]([OH:27])=[O:26])[CH2:30][CH2:29]4)=[CH:32][CH:33]=3)=[CH:19][CH:18]=2)=[O:24])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1(c2ccc(B(O)O)cc2)CC1
Reactant: C[C@@H](OC(=O)Nc1cnoc1-c1ccc(Br)cc1)c1ccccc1
Product: C[C@@H](OC(=O)Nc1cnoc1-c1ccc(-c2ccc(C3(C(=O)O)CC3)cc2)cc1)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6 using [5-(4-bromo-phenyl)-isoxazol-4-yl]-carbamic acid (R)-1-phenyl-ethyl ester and 4-(1-carboxycyclopropyl)phenylboronic acid.
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH2:7])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+].[F:25][C:26]([F:36])([F:35])[CH2:27][CH2:28][S:29][CH2:30][CH2:31][C:32](Cl)=[O:33]>O>[Cl:1][C:2]1[C:6]([NH:7][C:32](=[O:33])[CH2:31][CH2:30][S:29][CH2:28][CH2:27][C:26]([F:25])([F:35])[F:36])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1
Reactant: Nc1cn(-c2cccnc2)nc1Cl
Reactant: O=C(Cl)CCSCCC(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCSCCC(F)(F)F)Nc1cn(-c2cccnc2)nc1Cl
Yield: 71.9 %

Procedure:
A 100-mL, three-neck round bottom flask was charged with 3-chloro-(pyridin-3-yl)-1H-pyrazol-4-amine (1.00 g, 5.14 mmol) and ethyl acetate (10 mL). Sodium bicarbonate (1.08 g, 12.9 mmol) was added, followed by dropwise addition of 3-((3,3,3-trifluoropropyl)thio)-propanoyl chloride (1.36 g, 6.17 mmol) at <20° C. The reaction was stirred at 20° C. for 2 hours, at which point thin layer chromatography analysis [Eluent: ethyl acetate] indicated that the reaction was complete. The reaction was diluted with water (50 mL) and the layers separated. The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers were concentrated to dryness to afford a light brown oil. The residue was purified by flash column chromatography using 30-60% ethyl acetate/hexanes. The fractions containing pure product were concentrated to dryness to afford a white solid (1.40 g, 72%): mp 99-102° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.05 (d, J=2.7 Hz, 1H), 8.86 (s, 1H), 8.54 (dd, J=4.5, 1.4 Hz, 1H), 8.21 (ddd, J=8.4, 2.7, 1.4 Hz, 1H), 7.54 (dd, J=8.4, 4.7 Hz, 1H), 2.86 (t, J=7.3 Hz, 2H), 2.74 (td, J=6.5, 5.6, 4.2 Hz, 4H), 2.59 (ddd, J=11.7, 9.7, 7.4 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ 169.32, 147.49, 139.44, 135.47, 133.40, 126.60 (q, J=296 Hz), 125.49, 124.23, 122.30, 120.00, 35.18, 33.42 (q, J=27.2 Hz), 26.77, 23.05 (q, J=3.3 Hz); EIMS m/z 378 ([M]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C@H:7]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:8][C:9](=[O:24])[CH:10]([C:21](O)=[O:22])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:41]([O:48][NH2:49])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.CN1CCOCC1>CN(C=O)C>[C:1]([O:5][C:6](=[O:29])[C@H:7]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:8][C:9](=[O:24])[CH:10]([C:21](=[O:22])[NH:49][O:48][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: NOCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)C(Cc1ccc(C(C)C)cc1)C(=O)O)C(=O)OC(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)C(Cc1ccc(C(C)C)cc1)C(=O)NOCc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 48 h

Procedure:
The residue from stage (d) was stirred in DMF at -15° C. for 1 hour with HOBT (2 equiv) and DCCl (1 equiv). To the mixture was added a precooled solution of O-benzylhydroxylamine hydrochloride (1 equiv) and NMM (1 equiv) in DMF and stirring continued for 48 hour at +4° C. The product was filtered, the filtrate concentrated in vacuo, dissolved in ethyl acetate and acid/base washed in the normal manner. The solution was dried (MgSO4), evaporated in vacuo and the residue used the next stage without further purification.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1.[NH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH2:22]1.[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35]>C(O)(C)C.C(O)C>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:20][N:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24][CH2:23][CH2:22]4)[CH2:5][CH2:6]3)=[N:11][O:12][C:13]=2[CH:18]=1.[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:20][N:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24][CH2:23][CH2:22]4)[CH2:5][CH2:6]3)=[N:11][O:12][C:13]=2[CH:18]=1
Reactant: c1ccc2c(c1)CCCN2
Reactant: Fc1ccc2c(C3CCN(CC4CO4)CC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(C)O
Solvent: CCO
Product: OC(CN1CCC(c2noc3cc(F)ccc23)CC1)CN1CCCc2ccccc21

Procedure:
A stirred mixture of N-(2,3-epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3yl)piperidine (2.41 g, 8.73 mmol), 1,2,3,4-tetrahydroquinoline (1.33 g, 10 mmol, in isopropyl alcohol (50 ml) was heated at reflux for 6 hours. The solution was cooled and the solvent was removed on a rotary evaporator. The crude solid was purified by flash chromatography over a silica gel column (SiO2, 40 g, eluted with methylene chloride DCM, and 1-3% MeOH in DCM). The product thus purified weighed 2.0 g. This material was dissolved in ethanol and was treated with a solution of fumaric acid (567 mg, 1.0 eq) in ethanol. The solids collected were recrystallized again from ethanol (50 ml) to yield 1.0 g of white crystals, as a hemifumarate, m.p. 170°-171° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:4]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][SH:36])=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][S:36][C:2]2[N:7]=[N:6][C:5]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)=[C:4]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH:3]=2)=[CH:31][CH:30]=1
Reactant: COc1ccc(COc2cc(Cl)nnc2OCc2ccc(OC)cc2)cc1
Reactant: SCc1ccc(Cl)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(COc2cc(SCc3ccc(Cl)cc3)nnc2OCc2ccc(OC)cc2)cc1
Yield: 100 %

Procedure:
A mixture of 6-chloro-3,4-bis[(4-methoxybenzyl)oxy]pyridazine (Intermediate 7; 550 mg, 1.42 mmol), (4-chlorophenyl)methanethiol (248 mg, 1.56 mmol), Pd2(DBA)3 (52.1 mg, 0.057 mmol), XANTPHOS (65.8 mg, 0.114 mmol) and Hunig's base (ethyl diisopropylamine; 404 mg, 3.13 mmol) was subjected to microwave irradiation at 120° C. for 1 hour. The resulting mixture was poured into water and extracted into ethyl acetate before the combined organics were washed with brine and then dried (magnesium sulphate). The resulting solution was evaporated in vacuo and purified by silica chromatography (eluting with 0-40% dichlormethane in petrol) to yield 6-[(4-chlorobenzyl)sulfanyl]-3,4-bis[(4-methoxybenzyl)oxy]pyridazine (201 mg, 1.42 mmol, 28% yield).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12](=[O:23])OC1C=CC([N+]([O-])=O)=CC=1)[CH2:8]2.[NH:24]1[CH2:27][CH:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:25]1.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[CH:3]12[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]([CH2:10]3)[CH:2]1[NH:11][C:12]([N:24]1[CH2:27][CH:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:25]1)=[O:23])[CH2:9]2
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CN(C(=O)NC2C3CC4CC(C3)CC2C4)C1
Yield: 45.3 %

Procedure:
To a stirred solution of 4-nitrophenyl (2-adamantyl)carbamate (40 mg, 0.12 mmol) in CH2Cl2 (2 mL) was added tert-butyl azetidin-3-ylcarbamate (40 mg, 0.23 mmol), followed by i-Pr2NEt (0.05 mL, 0.28 mmol). The mixture was stirred over the weekend and applied to a 10-mL ChemElut cartridge prewetted with 5% aq HCl (6 mL). The cartridge was eluted with ether (20 mL). The eluate was evaporated to dryness and the residue was applied to 2-g silica SPE cartridge which was eluted sequentially with 0, 25, 50, 75, 100 and 100% EtOAc in hexanes (15 mL of each) to afford six fractions. Fraction 4 was concentrated to provide tert-butyl 1-(2-adamantylcarbamoyl)azetidin-3-ylcarbamate (19 mg, 43%). LC-MS Method 1, tR=1.74 min, m/z=350, 294; 1H NMR (CDCl3) 1.45 (s, 9H), 1.60-1.95 (14H), 3.75 (m, 2H), 3.89 (m, 1H), 4.22 (m, 2H), 4.39 (d, 1H), 4.46 (1H), 5.06 (1H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][C:16]([O:18]C)=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C:22]1([Mg]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>CCOCC>[OH:18][C:16]([C:2]1[CH:21]=[CH:20][CH:5]=[CH:4][CH:3]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:15][CH2:14][N:10]1[CH2:11][CH2:12][CH2:13][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:21][CH:20]=2)[CH2:8][CH2:9]1
Reactant: Br[Mg]c1ccccc1
Reactant: COC(=O)CCN1CCCN(Cc2ccc(Cl)cc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: OC(CCN1CCCN(Cc2ccc(Cl)cc2)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 54 mg of methyl 3-[4-(4-chlorobenzyl) homopiperazinyl]propionate in 10 mL of ether was mixed with under nitrogen, 4 mL of 1 M phenyl magnesium bromide. The mixture was stirred at room temperature for 30 minutes, mixed with aqueous saturated ammonium chloride and the mixture was extracted with 50 mL of ethyl acetate. The extract was washed with 50 mL of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, ethyl acetate/methanol 9:1) to give 65 mg of the titled compound. This was treated with a hydrogen chloride solution in ether and the solvent was removed under reduced pressure and the residue was dried to give the hydrochloride salt of the titled compound.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:28]([OH:30])=[O:29])[CH2:3][CH2:4][C:5](=[O:27])[NH:6][C:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]1[CH:14]=[CH:13][C:11]([CH3:12])=[CH:10][CH:9]=1.O>CO.Cl.[Pd]>[NH2:1][C@H:2]([C:28]([OH:30])=[O:29])[CH2:3][CH2:4][C:5](=[O:27])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:8]1[CH:14]=[CH:13][C:11]([CH3:12])=[CH:10][CH:9]=1
Reactant: Cc1ccc(C(NC(=O)CC[C@H](NC(=O)OCc2ccccc2)C(=O)O)(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1ccc(C(NC(=O)CC[C@H](N)C(=O)O)(c2ccccc2)c2ccccc2)cc1
Yield: 85 %

Procedure:
A suspension of 107.3 g Z-Gln(Mtt)OH (200 mM) in 800 ml methanol and 200 ml IN hydrochloric acid is hydrogenated at room temperature and normal pressure in the presence of 0.4 g palladium on carbon (10%) catalyst. On completion of the hydrogen uptake the catalyst is filtered off, washed with methanol and the filtrate, after addition of 27.9 ml triethylamine (200 mM) and 200 ml water, concentrated to a volume of about 600 ml. The formed crystalline precipitate is filtered off and washed with water until the washings are chloride-free. The obtained H-Gln(Mtt)OH contains 0.5-1 mole water and decomposes slowly above 231° C. Yield 85%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]4[CH2:29][O:28]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CN1CCCC1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:28])[CH2:29][NH:37][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C4CO4)cc3)cc2)CC1
Agent: CN1CCCC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CNCc4ccccc4)cc3)cc2)CC1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
1-[4′-(3-Methyl-4-oxiranyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.100 g, 0.26 mmol), benzylamine (0.034 mL, 0.31 mmol) and N-methylpyrrolidine (5 mL) were combined in a flask and stirred at 85° C. overnight. An additional portion of benzylamine (0.050 mL) was added and the reaction continued to stir at 85° C. for 48 hours. The reaction mixture was cooled and submitted to standard aqueous workup to give the title compound.
Reaction SMILES: [CH3:1][OH:2].[O:3]1[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:4]1>>[CH3:1][O:2][CH2:4][CH:5]([OH:3])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCC1CO1
Reactant: CO
Product: CCCCCCCCCCC(O)COC
Temperature: 60 °C
Reaction time: 3 h

Procedure:
The same reactor that was used in Production Example 5 was charged with 64 g (2 mol) of methanol and 2 g of boron trifluoride diethyl ether complex and then the mixture was raised to 60° C. Then, 184.3 g (1 mol) of 1,2-epoxydodecane was added dropwise to the mixture over one hour and the resulting mixture was kept as it was for 3 hours. The reaction was terminated just after confirming that 1,2-epoxydodecane left unreacted was less than 1% by gas chromatography and then the reaction mixture was cooled. Thereafter, methanol was removed in the same manner as in Production Example 5 to obtain 2-hydroxydodecyl methyl ether.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[O:3][CH2:2]1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C1CCCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:3]1[C:4]2([CH2:9][CH2:8][C:7]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:6][CH2:5]2)[O:11][CH2:1][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: O
Product: C1=C(N2CCCC2)CCC2(C1)OCCO2
Yield: 30.2 %

Procedure:
Reflux a solution of 1,4-cyclohexanedione mono-ethylene ketal (10.4 g, 66.5 mmol) and pyrrolidine (4.96 g, 69.8 mmol) and p-toluenesulfonic acid monohydrate (0.13 g, 0.66 mmol) in 50 mL cyclohexane overnight with a Dean-Stark trap and drying tube. Filter the mixture, wash with Et2O and concentrate the brown filtrate to afford 4.20 g of 1-(1,4-dioxa-spiro[4.5]dec-7-en-8-yl)-pyrrolidine as brown oil
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]2[O:22][C:21]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:20]=3[O:19][CH2:18]2)[CH2:12][CH2:11]1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>ClCCl>[Cl:27][C:24]1[CH:25]=[CH:26][C:20]2[O:19][CH2:18][C@H:17]([CH2:16][N:13]3[CH2:14][CH2:15][CH:10]([CH2:9][NH:8][S:35]([C:32]4[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=4)(=[O:37])=[O:36])[CH2:11][CH2:12]3)[O:22][C:21]=2[CH:23]=1
Reactant: NCC1CCN(C[C@H]2COc3ccc(Cl)cc3O2)CC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NCC1CCN(C[C@H]2COc3ccc(Cl)cc3O2)CC1)c1ccc(Cl)cc1
Reaction time: 20 h
Yield: 42.9 %

Procedure:
Triethylamine (0.62 ml) was added to a solution of (S)-4-(aminomethyl)-1-(7-chloro-1,4-benzodioxan-2-ylmethyl)piperidine (0.44 g) and 4-chlorobenzene-sulphonyl chloride (0.62 g) in dichloromethane (22 ml), under nitrogen, and stirred for 20 hours. The reaction was diluted with dichloromethane (100 ml), washed with water (100 ml) and brine (100 ml), dried over anhydrous magnesium sulphate and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with a 20:1 mixture of dichloromethane and methanol gave (S)-(-)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-chlorobenzene-sulphonamide as a white solid (0.30 g); m.p. 152-154° C., [α]D22.5 -23.8° (c=0.97, CH2Cl2).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:21]([N:23]([CH3:25])[CH3:24])=[O:22].[N:26]1([C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:24][N:23]([CH3:25])[C:21]([C:4]1[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:36](=[O:37])[C:35]1[CH:34]=[CH:33][C:32]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:40][CH:39]=1)=[CH:10][CH:9]=[C:8]([Cl:14])[CH:7]=2)=[O:22]
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Reactant: CN(C)C(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Product: CN(C)C(=O)c1c(CNC(=O)c2ccc(N3CCOCC3)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1

Procedure:
7-Chloro-3-[(4-morpholin-4-yl-benzoylamino)-methyl]-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid dimethylamide was prepared starting from intermediate C and 4-morpholin-4-yl-benzoic acid. MS calcd. for C30H29ClN4O4 [(M+H)+] 545.2, obsd. 545.2.