Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:5]2[CH:10]=[N:9][C:8]([C:11]#[N:12])=[N:7][C:6]=2[N:13]=1.[CH:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:20]([C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:3]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:4][C:5]3[CH:10]=[N:9][C:8]([C:11]#[N:12])=[N:7][C:6]=3[N:13]=2)=[CH:24][CH:23]=1)=[O:21]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ncc2cc(-c3ccccc3)c(Cl)nc2n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cc1ncc2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Temperature: 95 °C

Procedure:
A mixture of 7-chloro-6-phenylpyrido[2,3-d]pyrimidine-2-carbonitrile (2-4) (0.350 g, 1.31 mmol), 4-formylphenyl boronic acid (0.492 g, 3.28 mmol), cesium carbonate (1.28 g, 3.94 mmol), and Pd(PtBu3)2 (0.067 g, 0.131 mmol) in anhydrous dioxane (8 mL) was degassed (3× vacuum pump/refilled with N2) and heated to 95° C. for 18 hr. The mixture was cooled, diluted with water, and extracted 3× with CH2Cl2. The combined organics were dried (anhd. Na2SO4), filtered, concentrated and purified by silica gel chromatography (10-30% EtOAc in Hexanes). 1H-NMR (500 MHz, CDCl3) δ 10.05 (s, 1H), 9.61 (s, 1H), 8.44 (s, 1H), 7.84 (d, 2H, J=8.3 Hz), 7.72 (d, 2H, J=8.3 Hz), 7.46-7.36 (m, 3H), 7.29-7.25 (m, 2H); LRMS, calc'd: 337.0, found: 337.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[NH:8][C:7](=[O:13])[CH2:6][CH2:5]2.[Cl:14]N1C(=O)CCC1=O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:14])[CH:11]=1)[NH:8][C:7](=[O:13])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)c(F)cc2N1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: O=C1CCc2cc(Br)cc(Cl)c2N1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 6-bromo-7-fluoro-3,4-dihydroquinolin-2(1H)-one (122-3; 3 g, 0.0012 mol) in N,N-dimethylformamide (30 mL) was added N-chlorosuccinimide in N,N-dimethylformamide (3 mL) (1.4 g, 0.0105 mol) at 70° C. drop wise over a period of 2 h. Reaction mass was allowed to stir at 70° C. for 14 h. The reaction mixture was cooled and diluted with ice cold water. The precipitated solid was filtered and dried to obtain title compound. MS (M−1): 278.12.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=O.[K+].[Br-]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]1[NH:11][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=2[N:10]=1
Reactant: O=C(O)c1ccccc1F
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2nc(-c3ccccc3F)[nH]c2c1
Yield: 15 %

Procedure:
Prepared from 4-nitrophenylenediamine and 2-fluorobenzoic acid, in a manner similar to that of Example 31b. Yield: 15%; Rf (7/3 toluene/ethyl acetate): 0.55; IR (KBr): 2996, 1625, 1520, 1479, 1340 cm−1; 1H-NMR (d6-DMSO) 8.5-8.0 (m, 3H); 7.2-7.9 (m, 4H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[CH:7][N:8]([CH3:10])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:19]([O:21][CH3:22])=[O:20].CCOC(C)=O>C(#N)C>[CH3:22][O:21][C:19]([C:7]1[N:8]([CH3:10])[CH:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:6]=1)=[O:20]
Reactant: COC(=O)Cl
Reactant: Cn1cnc(C(C)(C)C)c1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1nc(C(C)(C)C)cn1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 4-tert-butyl-1-methyl-1H-imidazole (800 mg, 5.79 mmol, prepared as described in the previous step) and triethylamine (2.00 mL, 14.4 mmol) in acetonitrile (10 mL) at −30° C. was added methyl chloroformate (0.890 mL, 11.6 mmol) slowly under Ar. The resulting mixture was warmed to room temperature and continued to stir for 16 h. The resulting mixture was then treated with EtOAc (50 mL) and washed with H2O (2×20 mL), brine (20 mL) and then dried with Na2SO4. The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel (0:100-10:90 MeOH/DCM) to yield 4-tert-butyl-1-methyl-1H-imidazole-2-carboxylic acid methyl ester as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ: 6.78 (s, 1H), 3.95 (s, 3H), 3.92 (s, 3H), 1.30 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calculated For C10H16N2O2: 197.1 (M+H). Measured: 197.1.
Reaction SMILES: Cl[C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8].[CH3:10][NH:11][CH3:12]>>[CH3:10][N:11]([CH3:12])[C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1cc[nH]c1Cl
Reactant: CNC
Product: CN(C)c1[nH]ccc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
This compound was prepared in a manner analogous to that set forth in Step C of Example 2, using 0.65 gram (0.0045 mole) of 2-chloro-3-nitropyrrole (prepared in Steps D-F of Example 1) and 5.0 mL (excess) of dimethylamine. The microwave chemical reactor was maintained at 100° C. during a 45-minute period, after which time the reaction was considered to be complete. The crude product was purified with column chromatography on silica gel. Elution was accomplished using 25% hexane in diethyl ether, then 100% diethyl ether as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.2 gram of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1)=[O:5].[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[SH:27].C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([S:27][C:19]2[S:18][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=2)=[CH:8][CH:7]=1)=[O:5]
Reactant: Sc1nc2ccccc2s1
Reactant: O=C(c1ccc(F)cc1)c1cc(Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(c1ccc(Sc2nc3ccccc3s2)cc1)c1cc(Cl)ccc1Cl
Temperature: 110 °C
Yield: 78.2 %

Procedure:
A charge of 269.1 g (1.00 mol) of 2,5-dichloro-4′-fluorobenzophenone, 175.6 g (1.05 mol) of 2-benzothiazolethiol, 152.0 g (1.10 mol) of potassium carbonate and 1.5 L of dehydrated N,N′-dimethylacetamide was weighed into a 3 L three-neck flask equipped with a stirrer, a thermometer, a cooling tube and a nitrogen gas introducing tube. The reaction solution was heated under nitrogen atmosphere to 110° C. for 2 hours using an oil bath. After the disappearance of raw materials was confirmed by thin layer chromatography, the reaction solution was left to cool to room temperature. The reaction solution was then gradually added to 3 L of water to coagulate a product, which was filtered. The product obtained by filtration was dissolved in 4 L of toluene. The organic layer was washed with brine until an aqueous layer became neutral. After the organic layer was dried over magnesium sulfate, the solvent was removed by an evaporator. A crude yield was 350.3 g. A 1.5 L aliquot of toluene heated to 80° C. was used for recrystallization to yield 325.4 g (0.782 mol) of a purified product in 78.2% yield.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:6]=1.[C:18]([C:20]1([NH:23][C:24]([C@H:26]2[N:30]([C:31]([C:33]3([CH3:36])[CH2:35][CH2:34]3)=[O:32])[CH2:29][C@@H:28](OS(C3C=CC=CC=3)(=O)=O)[CH2:27]2)=[O:25])[CH2:22][CH2:21]1)#[N:19].CC(C)([O-])C.[Li+].O>C1COCC1.C1(C)C=CC=CC=1>[C:18]([C:20]1([NH:23][C:24]([C@@H:26]2[CH2:27][C@@H:28]([S:11][C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([F:1])([F:16])[F:17])=[CH:6][C:7]=3[C:12]([F:13])([F:14])[F:15])[CH2:29][N:30]2[C:31]([C:33]2([CH3:36])[CH2:35][CH2:34]2)=[O:32])=[O:25])[CH2:21][CH2:22]1)#[N:19]
Reactant: FC(F)(F)COc1ccc(S)c(C(F)(F)F)c1
Reactant: CC1(C(=O)N2C[C@@H](OS(=O)(=O)c3ccccc3)C[C@H]2C(=O)NC2(C#N)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C(=O)N2C[C@H](Sc3ccc(OCC(F)(F)F)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.6 %

Procedure:
To a stirred suspension of 4-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-benzenethiol (30.4 g, 110 mmol) and benzenesulfonate (3S,5S)-5-(1-cyano-cyclopropylcarbamoyl)-1-(1-methyl-cyclopropanecarbonyl)-pyrrolidin-3-yl ester (41.7 g, 100 mmol) in THF (50 mL) was added at room temperature 20% lithium tert-butoxide in THF (44.0 g≅49.5 mL, 110 mmol) over 40 min. After stirring at room temperature for 18 h, the reaction mixture was hydrolyzed with deionized water (400 mL) and extracted twice with ethyl acetate (400 mL & 200 mL). Both organic layers were washed with 10% brine (200 mL), combined, dried over Na2SO4, and filtered. Evaporation of the solvent and careful drying (45° C./≧10 mbar) gave 56.3 g crude product as voluminous, off-white foam, which was dissolved in 250 mL toluene at 50° C. The crystallization, which started during cooling, was completed after stirring at room temperature for 1 h by the dropwise addition of 200 mL heptane (note 11), followed by stirring at room temperature for 20 h. Filtration and drying (50° C./10 mbar/3 days for removal of toluene to ˜1%) yielded 51.2 g (95.7%) title product as an off-white crystalline powder, mp. 66-76° C. [α]D20=−67.5 (c 1.0; CHCl3). 1H NMR (CDCl3, 400 MHz) δ0.55-0.70 (m, 2H), 0.87-0.95 (m, 1H), 1.02-1.10 (m, 1H), 1.13-1.23 (m, 2H), 1.31 (s, 3H), 1.42-1.55 (m, 2H), 1.85-1.97 (m, 1H), 2.74-2.85 (m, 1H), 3.80-4.00 (m, 3H), 4.40 (q, J=7.8 Hz, 2H), 4.60 (dd, J1=8.1 Hz, J2=4.6 Hz, 1H), 7.11 (dd, J1=8.6 Hz, J2=2.7 Hz, 1H), 7.30 (d, J=3.0 Hz, 1H), 7.61 (d, J=8.6 Hz, 1H), 8.05 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=O)[C@H:3]1[C@H:7]2[CH2:8][CH2:9][C@@H:4]1[C@H:5]([O:10][C:11](=[O:24])[C:12]([OH:23])([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:6]2.[NH2:35][CH2:36][C@@H:37]([C:46]1[CH:55]=[CH:54][C:53]([OH:56])=[C:52]2[C:47]=1[CH:48]=[CH:49][C:50](=[O:57])[NH:51]2)[O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl>[C:42]([Si:39]([CH3:41])([CH3:40])[O:38][C@H:37]([C:46]1[CH:55]=[CH:54][C:53]([OH:56])=[C:52]2[C:47]=1[CH:48]=[CH:49][C:50](=[O:57])[NH:51]2)[CH2:36][NH:35][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][N:2]([CH3:1])[C@H:3]1[C@H:7]2[CH2:8][CH2:9][C@@H:4]1[C@H:5]([O:10][C:11](=[O:24])[C:12]([OH:23])([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:6]2)([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: CN(CCCCCCCCC=O)[C@H]1[C@H]2CC[C@@H]1[C@H](OC(=O)C(O)(c1cccs1)c1cccs1)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(CCCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12)[C@H]1[C@H]2CC[C@@H]1[C@H](OC(=O)C(O)(c1cccs1)c1cccs1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of hydroxy-di-thiophen-2-yl-acetic acid (1S,2R,4S,7S)-7-[methyl-(9-oxo-nonyl)amino]bicyclo[2.2.1]hept-2-yl ester (max 0.73 mmol), 5-[(R)-2-amino-1-(tert-butyldimethylsilanyloxy)ethyl]-8-hydroxy-1H-quinolin-2-one (245 mg, 0.73 mmol), sodium triacetoxyborohydride (186 mg, 0.88 mmol), and acetic acid (2 drops) in dry 1,2-dichloroethane was stirred at ambient temperature overnight. The reaction mixture was partitioned between DCM and satd NaHCO3 (aq). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo to afford a dark green/brown gum that solidified on standing, which was purified by preparative HPLC (system 2, 35% B+1% B/min). The fractions containing pure product were concentrated, neutralised with satd NaHCO3 (aq), and extracted with DCM. After concentration in vacuo a green/brown oil was obtained.
Reaction SMILES: Br[CH2:2]C(C1C=CC(OC)=C(OC)C=1)=O.ClC1C=NNC=1C(OC)=O.[Cl:25][C:26]1[CH:27]=[N:28][N:29]([CH2:35][C:36]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=2)=[O:37])[C:30]=1[C:31]([O:33][CH3:34])=[O:32]>>[Cl:25][C:26]1[CH:27]=[N:28][N:29]([CH2:35][C:36]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=2)=[O:37])[C:30]=1[C:31]([O:33][CH2:34][CH3:2])=[O:32]
Reactant: COC(=O)c1c(Cl)cnn1CC(=O)c1ccc(OC)c(OC)c1
Reactant: COc1ccc(C(=O)CBr)cc1OC
Agent: COC(=O)c1[nH]ncc1Cl
Product: CCOC(=O)c1c(Cl)cnn1CC(=O)c1ccc(OC)c(OC)c1

Procedure:
Following the procedure of Example 5.01, beginning with 2-bromo-1-(3,4-dimethoxyphenyl)ethanone (1.20 g, 4.63 mmol) and methyl 4-chloro-1H-pyrazole-5-carboxylate (855 mg, 5.33 mmol), methyl 4-chloro-1-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-1H-pyrazole-5-carboxylate 5.21 was synthesized.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7]O)[CH:6]=1.S(Cl)([Cl:11])=O>ClCCl>[ClH:11].[Cl:11][CH2:7][N:5]1[CH:6]=[C:2]([CH3:1])[CH:3]=[N:4]1
Reactant: Cc1cnn(CO)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cnn(CCl)c1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.12 g of 4-methyl-1H-pyrazole-1-ylmethanol was dissolved to 50 ml of dichloromethane. 3.4 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure to obtain 1.61 g of 1-(chloromethyl)-4-methyl-1H-pyrazole hydrochloride.
Reaction SMILES: [Br:1][C:2]1([Br:10])[CH2:4][C:3]1([CH3:9])[C:5]([O:7]C)=[O:6].[OH-].[Li+].Cl>O1CCCC1.O>[Br:1][C:2]1([Br:10])[CH2:4][C:3]1([CH3:9])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)C1(C)CC1(Br)Br
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C(=O)O)CC1(Br)Br
Reaction time: 8 h
Yield: 620.4 %

Procedure:
To 25 mL of a 50:50 mixture of tetrahydrofuran/water was added 2,2-dibromo-1-methylcyclopropanecarboxylic acid, methyl ester(2.72 g, 10 mmol)and lithium hydroxide (0.8 g, 20 mmol). The reaction mixture was stirred overnight. The reaction mixture was acidified with 1 M hydrochloric acid (24 mL). The reaction mixture was extracted with dichloromethane (2×25 mL) and the organic phases were collected, washed with brine, dried (MgSO4)and evaporated to give the title product (16 g) as white crystals mp 108-109° C.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH:6]1[CH:7]=[CH:8][C:9]2[S:14]C=[CH:12][C:10]=2[CH:11]=1.C(Br)C=C.[NH4+].[Cl-]>C1COCC1>[CH3:4][CH:3]=[CH:2][C:1]1[S:14][C:9]2[CH:8]=[CH:7][CH:6]=[CH:11][C:10]=2[CH:12]=1
Reactant: [Li]CCCC
Reactant: c1ccc2sccc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: CC=Cc1cc2ccccc2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
n-Butyl lithium (16.7 ml, 2.5 N in hexanes) was added dropwise to a stirred solution of thianaphthene (5.0 g, 37.3 mmol) in THF (80 mL) at -78° C. under a dry N2 atmosphere. After the addition wascompleted, the mixture was warmed up and stirred at 0° C. for 30 min. Allylbromide (16.1 mL, 186.5 mmol ) was added. After an additional 3.5 h., sat. aq. NH4Cl was added and the reaction mixture was partitioned between water and ether. The ether phase was washed with brine and dried. Silica gel (120 mL) was added. Solvents were removed and the silica adsorbate was flash chromatographed (eluent petroleum ether) to provide the title compound as an oil (3.74 g, 58%): NMR (CDCl3); δ 7.76 (d, J=9 Hz, 1H), 7.66 (d, J=9 Hz, 1H), 7.36-7.20 (m, 2H), 7.02 (s, 1H), 6.14-5.96 (m, 1H), 5.22 (dd, J=2, 17 Hz, 1H), 5.16 (dd, J=2, 17 Hz, 1H), 3.66 (d, J=8 Hz, 2H); MS (EI): [M+] 174 (100%); Anal. Calc. for C11H10S: C, 75.82, H, 5.78, N, 0.00. Found: C, 72.88, H, 5.56, N, 0.13.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([OH:18])=O)[C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[N:7]([CH2:13][CH3:14])[C:6]=2[CH:15]=1.C(Cl)(=O)OCC.[NH2:25][CH:26]1[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:25][CH:26]2[CH:31]3[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]3)[CH2:27]2)=[O:18])[C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[N:7]([CH2:13][CH3:14])[C:6]=2[CH:15]=1
Reactant: CCN1C(=O)C(C)Oc2c(C(=O)O)cc(Cl)cc21
Reactant: NC1CN2CCC1CC2
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCN1C(=O)C(C)Oc2c(C(=O)NC3CN4CCC3CC4)cc(Cl)cc21
Product: Cl

Procedure:
A solution of 4.2 g of 6-chloro-4-ethyl-3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid in 100 ml of tetrahydrofuran is cooled to below 0° C. and 5 ml of triethylamine is added under stirring thereto. Further, 2.0 g of ethyl chlorocarbonate is added and the mixture is stirred for 30 minutes. To the resultant mixture is added 3.0 g of 3-aminoquinuclidine and the mixture stirred for 5 hours. After completion of the reaction, aqueous sodium hydrogen carbonate and ethyl acetate are added. The organic layer is separated, washed with water and dried over magnesium sulfate. The solvent is distilled off and the residue is converted into the corresponding hydrochloride by treating with ethanolic hydrochloric acid followed by recrystallizing from ethanol-ethyl acetate to give 6-chloro-4-ethyl-3,4-dihydro-2-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide hydrochloride, melting at 249°-252° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][CH2:12][CH2:11][CH2:10][C:7]2([CH2:9][CH2:8]2)[CH:6]1[OH:14])=[O:4].C(N(CC)CC)C.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]([CH:5]1[CH2:13][CH2:12][CH2:11][CH2:10][C:7]2([CH2:9][CH2:8]2)[CH:6]1[O:14][C:22](=[O:24])[CH3:23])=[O:4]
Reactant: COC(=O)C1CCCCC2(CC2)C1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)C1CCCCC2(CC2)C1OC(C)=O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 4-hydroxy-spiro[2.6]nonane-5-carboxylic acid methyl ester (0.899 g) obtained in Step 2 in chloroform (18 mL) were added successively triethylamine (6.33 mL), 4-dimethylaminopyridine (0.11 g) and acetic anhydride (2.15 mL) under argon atmosphere and ice-cooling, followed by stirring the mixture at room temperature for 3.5 hours. After ice-cooling the reaction mixture and adding saturated aqueous sodium bicarbonate solution thereto, the reaction mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (diethyl ether:hexane (volume ratio)=1:9) to give 4-acetoxy-spiro[2.6]nonane-5-carboxylic acid methyl ester (1.06 g).
Reaction SMILES: [CH2:1]([N:8]([CH2:24][C@H:25]([OH:47])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:30]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:29]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[NH2:69][CH2:70][CH2:71][C:72]1[C:80]2[C:75](=[CH:76][CH:77]=[CH:78][CH:79]=2)[NH:74][CH:73]=1>ClCCl.C(#N)C.C(N(CC)CC)C>[CH2:1]([N:8]([CH2:24][C@H:25]([OH:47])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[C:30]([NH:42][S:43]([CH3:46])(=[O:44])=[O:45])[CH:29]=1)[C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:69][CH2:70][CH2:71][C:72]3[C:80]4[C:75](=[CH:76][CH:77]=[CH:78][CH:79]=4)[NH:74][CH:73]=3)=[O:20])=[CH:17][CH:16]=2)[CH2:13][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(C(=O)O)cc3)CC2)ccc1OCc1ccccc1
Reactant: NCCc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(C(=O)NCCc4c[nH]c5ccccc45)cc3)CC2)ccc1OCc1ccccc1
Reaction time: 24 h

Procedure:
A solution of 0.3 g (0.45 mmol) of trans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy]-2-hydroxypropyl}amino)cyclohexyl]benzoic acid (preparation 3), of 0.78 g (0.91 mmol) of 1-hydroxybenzotriazole, of 0.175 g (0.91 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, of 0.19 ml of triethylamine and of 0.138 g (0.86 mmol) of tryptamine in a mixture of 4 ml of dichloromethane and 0.8 ml of acetonitrile is stirred for 24 h. The solvents are evaporated under reduced pressure. Dichloromethane and water are added and the organic phase is washed three times with water. The organic phases are dried over magnesium sulfate and concentrated under reduced pressure. The title compound is obtained in the form of a white solid (0.246 g, 58%) after purification on silica gel (eluent: heptane/ethyl acetate 60/40 for 10 min, 60/40 to 40/60 in 10 min and then 40/60 for 20 min gradient). [M+H+]=801.6
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]1[C:14]2[NH:13][C:12](=[O:15])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)[CH:21]=[C:22]1[S:26][C:25](=[O:27])[NH:24][C:23]1=[O:28]>>[F:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][CH:35]([NH:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]2[C:14]3[NH:13][C:12](=[O:15])[NH:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:34][CH2:33]1)[CH:21]=[C:22]1[S:26][C:25](=[O:27])[NH:24][C:23]1=[O:28]
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: O=C1CCN(c2ccc(C=C3SC(=O)NC3=O)cc2F)CC1
Product: O=C1NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)c(F)c2)S1

Procedure:
The title compound was prepared from 4-((2S)-3-amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one (U.S. Pat. No. 5,786,356/1998) and 5-[3-fluoro-4-(4-oxo-piperidine-1-yl)-benzylidene]-thiazolidine-2,4-dione (which was obtained in Example 62) according to the procedure of Example 63 as an olive green solid; mp 162-164° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.66-1.74 (m, 2H), 2.07-2.17 (m, 2H), 2.74-2.83 (m, 2H), 3.12-3.15 (m, 2H), 3.43-3.48 (m, 1H), 3.52-3.56 (m, 2H), 3.98-4.11 (m, 1H), 5.63 (brs, 1H), 6.62 (m, 2H), 6.87 (t, J=8.1 Hz, 1H), 7.18 (t, J=9.1 Hz, 3H), 7.27-7.35 (m, 1H), 10.60 (s, 1H), 10.7 (s, 1H); MS (ES) m/z: 527.9 (MH+); HRMS Calcd. for C25H28FN5O5S(MH+): 528.1716. Found: 528.1702.
Reaction SMILES: O.[C:2]12([CH3:12])[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]2[OH:11].C[C@H]1C[C@@H:18]([OH:20])[C@H:17](C(C)C)CC1>C(O)C>[C:2]12([CH3:12])[C:8]([CH3:9])([CH3:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:3]2([CH2:17][CH2:18][OH:20])[OH:11]
Reactant: CC1(C)C2CCC1(C)C(O)C2
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Solvent: O
Solvent: CCO
Product: CC1(C)C2CCC1(C)C(O)(CCO)C2

Procedure:
5 l of distilled water is added to 233.3 g of the genus Gelatin and the aqueous mixture is heated to produce a Gelatin solution. And 137 g of Borneol, and 0.5 l of l-menthol are solved with 3.5 l of ethanol to produce a Borneol-ethanol solution.