Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH:6]([OH:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:3][CH2:4][CH3:5].[CH2:13](Br)[CH:14]=[CH2:15]>>[CH2:15]([O:12][CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:2]([CH3:1])=[CH:3][CH2:4][CH3:5])[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: CCC=C(C)C(O)CCCCC
Product: C=CCOC(CCCCC)C(C)=CCC
Yield: 55.9 %

Procedure:
10 g of 4-methyl-3-decen-5-ol are reacted with 12.1 g of allyl bromide analogously to Example 7. After the usual working-up, there are obtained 6.9 g of 5-allyloxy-4-methyl-3-decene, boiling point 51° C./0.03 Torr, nD20 =1.4447, odour: fatty, fruity, green, quince.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[NH:8][C:7](=[O:9])[CH2:6][CH2:5]1)[CH3:2].[CH3:10][CH:11](C)[CH2:12]CO>>[CH3:10][CH:11]([CH3:12])[CH2:2][CH2:1][O:3][CH:4]1[NH:8][C:7](=[O:9])[CH2:6][CH2:5]1
Reactant: CC(C)CCO
Reactant: CCOC1CCC(=O)N1
Product: CC(C)CCOC1CCC(=O)N1

Procedure:
5.5 g of 5-ethoxy-pyrrolidin-2-one, 30 cm3 of 3-methyl-butanol and 2.75 g of Amberlite-15 resin are agitated for 5 hours at ambient temperature. After leaving in the refrigerator for 18 hours, there is obtained, after filtering, 4.1 g of the expected product. m.p. 73°-75° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH2:11])[C:3]=1[C:12]#[C:13][Si](C)(C)C.[F-].[K+].C>CN(C=O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH2:11])[C:3]=1[C:12]#[CH:13]
Reactant: C[Si](C)(C)C#Cc1c(N)ncc([N+](=O)[O-])c1Cl
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#Cc1c(N)ncc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of 4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine (1.98 g, 7.34 mmol) in DMF (25 mL) was added potassium fluoride on alumina (40 wt %, 2.67 g, 18.35 mmol). The suspension was stirred at ambient temperature for about 1 h. Activated charcoal (0.3 g) was added and the suspension was filtered though Celite®, washing with DMF (150 mL). The solvent was removed under reduced pressure and the crude material was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM to afford 4-chloro-3-ethynyl-5-nitropyridin-2-amine (1.03 g, 71%) as a yellow solid: LC/MS (Table 1, Method n) Rt=0.59 min; MS m/z: 196 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.[Li]CCCC.CCCCCC.[B:26](OC(C)C)([O:31]C(C)C)[O:27]C(C)C>C1COCC1>[CH3:10][C:9]1([CH3:11])[C:4]2[CH:3]=[C:2]([B:26]([OH:31])[OH:27])[CH:14]=[CH:13][C:5]=2[NH:6][C:7](=[O:12])[O:8]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC1(C)OC(=O)Nc2ccc(Br)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
To a solution of 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (2 g, 7.8 mmol) in anhydrous THF (60 mL) was added a solution of n-BuLi in hexane (10 M, 2.4 mL, 24 mmol) at −78° C. under nitrogen. After stirring at −78° C. for 30 minutes, a slurry was obtained and treated with triisopropyl borate (6.5 mL, 28 mmol). The reaction medium was slowly warmed to ambient temperature and quenched with 1N aqueous hydrochloric acid solution (60 mL). Ethyl acetate (100 mL) was added and organic layer was separated, and aqueous layer was extracted with ethyl acetate (3×60 mL). The combined organic layer was washed with brine and dried with MgSO4. The solvent was removed in vacuo and the residue was purified by a silica gel flash chromatography (ethyl acetate:hexane/2:1) to afford (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid as a white solid (1.4 g, 81%): mp 249-250° C.; 1H-NMR (DMSO-d6) δ 10.21 (s, 1H, D2O exchangeable), 7.90-7.95 (br s, 2H, D2O exchangeable), 7.67 (m, 2H), 6.79 (d, 1H, J=7.8 Hz), 1.61 (s, 6H); MS (ESI) m/z 222 ([M+H]+, 87%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:13]([N:49]2[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]2)=[O:15])[CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1cc(C(=O)O)cc(Cl)c1F
Reactant: CN1CCNCC1
Agent: 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: CN1CCN(C(=O)c2cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c2)CC1

Procedure:
was prepared according to Scheme C3 (step A) from 3-(tert-butoxycarbonylamino-methyl)-5-chloro-4-fluoro-benzoic acid (150 mg, 0.49 mmol), HATU (282 mg, 0.74 mmol), 4-methylpiperazine (59 mg, 0.59 mmol) and DIPEA (0.26 mL, 1.5 mmol) in DMF (2 mL). MS (LC-MS): 386.0 [M]+; tR (HPLC conditions c): 3.77 min.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](O)[CH3:13].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:12][CH3:13])=[O:5]
Reactant: CCO
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(Cl)cnc1Cl
Temperature: 130 °C

Procedure:
To a solution of 2,5-dichloronicotinic acid (30 g, 0.16 mol) in toluene (100 ml) was added ethanol (50 ml) and conc. sulfuric acid (1 ml). The reaction mixture was heated at 130° C. for 3 days with stirring. Then the reaction mixture was cooled and poured into sat. sodium bicarbonate solution. The whole mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried (sodium sulfate), and concentrated to afford 34 g (quant.) of title compound:
Reaction SMILES: [CH3:1][NH:2][CH:3]([CH3:5])[CH3:4].[Br:6][CH2:7][C:8](Br)=[O:9]>CCOCC.O>[Br:6][CH2:7][C:8]([N:2]([CH3:1])[CH:3]([CH3:5])[CH3:4])=[O:9]
Reactant: CNC(C)C
Reactant: O=C(Br)CBr
Solvent: O
Solvent: CCOCC
Product: CC(C)N(C)C(=O)CBr
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution of 26 ml of methyl isopropylamine in 100 ml of ether was added to a solution of 10 ml of bromo acetyl bromide in 150 ml of ether cooled to −20° C. and the mixture was allowed to return to 20° C. The mixture was stirred for 30 minutes at 20° C. and diluted with water, decanted and extracted with ether. The extracts were dried and separated out by distillation to obtain 13 g of the expected product with a boiling point of 71° C. to 72° C. under 1 mmHg.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]([C:19]1[CH:20]=[C:21](OB(O)O)[CH:22]=[CH:23][CH:24]=1)=[O:18].C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:23]2[CH:24]=[C:19]([CH:20]=[CH:21][CH:22]=2)[C:17]([O:16][CH3:15])=[O:18])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc(OB(O)O)c1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(N2CCCC(NC(=O)OC(C)(C)C)C2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 46.1 %

Procedure:
3-(tert-Butoxycarbonylamino)piperidine (200 mg, 1.00 mmol), 3-(methoxycarbonyl)phenylboric acid (360 mg, 2.00 mmol) and molecular sieves 4 Å (100 mg) were suspended in dichloromethane (10 mL). To this suspension, copper (II) acetate (182 mg, 1.00 mmol) and triethylamine (0.280 mL, 2.00 mmol) were added and the mixture was stirred at room temperature for 15 hours. Subsequently, the reaction mixture was filtered through Celite and a saturated aqueous sodium bicarbonate solution was added to the filtrate. This mixture was extracted with ethyl acetate and the extract washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1->5:1) to give a colorless oil. This product was further purified by silica gel column chromatography (Chromatorex NH-DM2035 (Fuji Sylysia Chemical Co., Ltd.) hexane:ethyl acetate=10:1) to give 154 mg (46%) of the desired compound as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)=[CH:5][CH:4]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:20].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH2:20])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)CC(=O)CC2
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)CC(N)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-methoxy-2-tetralone (12.4 g; 70.7 mmol) dissolved in MeOH (350 mL) was added ammonium acetate (82 g; 1.06 mol) and the reaction was stirred for 30 min at room temperature. To the reaction was then added sodium cyanoborohydride (21.5 g; 353 mmol) and the reaction was refluxed for 1 h. Upon completion of the reaction, the reaction was cooled and the solvent removed under reduced pressure. The residue was diluted with EtOAc and 1N NaOH was added to quench the reaction. The aqueous phase was separated and the organic phase washed with H2O, brine, dried over Na2SO4, filtered, and the solvent removed under reduced pressure to yield 7-methoxy-1,2,3,4-tetrahydronapthalen-2-ylamine as a dark oil.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH3:22])=[C:18]([CH2:23][CH3:24])[NH:17][C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].S(OC)(O[CH3:30])(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH3:22])=[C:18]([CH2:23][CH3:24])[N:17]([CH3:30])[C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCc1[nH]c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)c1C
Reactant: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: CCc1c(C)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C

Procedure:
using isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4-ethyl-5-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate and dimethyl sulphate in dimethylformamide there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4-ethyl-3,5-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, 1H-NMR (CDCl3, 400 MHz) 7.82 ppm (d, 1H), 7.33 ppm (d, 1H), 5.23 ppm (m, 1H), 3.51 ppm (s, 3H), 2.71 ppm (m, 2H), 2.04 ppm (s, 3H), 1.35 ppm (d, 6H), 1.28 ppm (t, 3H),
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:12]O>O1CCOCC1>[OH:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:12])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)c1cccc(O)n1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1cccc(O)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 90 %

Procedure:
To a solution of 6-hydroxypicolinic acid (13.0 g, 93.5 mmol) in methanol (150 mL) at room temperature was added HCl in dioxane (4N, 10 mL). The resulting mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated to give methyl 6-hydroxypicolinate (13 g, 90%) as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]([NH2:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.Cl>C(Cl)(Cl)Cl>[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]([NH:19][C:3](=[O:4])[CH2:2][Cl:1])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Cl)CCl
Reactant: NC(Cc1ccccc1)c1cccs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(CCl)NC(Cc1ccccc1)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
A solution of chloroacetyl chloride (4 mL, 0.05 mol) in chloroform (40 mL) was added dropwise to a solution of α-(2-thienyl)benzeneethanamine (10 g, 0.049 mol) and triethylamine (14 mL, 0.098 mol) in chloroform (180 mL) at 0° C. The mixture was stirred to room temperature for 1 hour. Dilute HCl (300 mL of 0.75N) was added and the reaction mixture was partitioned. The chloroform layer was separated, dried (MgSO4) and concentrated to give the amide as a light brown solid (11 g).
Reaction SMILES: O[CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].P(CCCC)(CCCC)CCCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[C:51]1(=[O:61])[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:53](=[O:60])[NH:52]1>C1COCC1.CCOCC>[O:61]=[C:51]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:53](=[O:60])[N:52]1[CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: C[C@@H]1CCCN(C(=O)OCc2ccccc2)[C@@H]1CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@@H]1CCCN(C(=O)OCc2ccccc2)[C@@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a stirred solution of (2S,3R)-benzyl 2-(hydroxymethyl)-3-methylpiperidine-1-carboxylate (4.61 g, 17.5 mmol) and n-Bu3P (10.6 g, 52.4 mmol) in anhydrous THF (150 mL) was added 1,1′-(azodicarbonyl)dipiperidine (ADDP; 8.83 g, 35.0 mmol) at rt under nitrogen. The reaction mixture was stirred at rt for 30 min. To the reaction mixture was then added isoindoline-1,3-dione (3.09 g, 21.0 mmol), followed by heating at reflux for 20 h. After this time, the reaction mixture was cooled to rt, diluted with Et2O (100 mL), and further cooled with an ice/water bath. The resulting mixture was filtered and the filter cake was washed with Et2O (40 mL). The combined filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with hexanes/CH2Cl2/EtOAc (50:48:2) to hexanes/CH2Cl2/EtOAc (50:42:8). The material obtained from the chromatography was triturated with hexanes/CH2Cl2 (5:1) and solids removed by filtration. Concentration of the filtrate afforded the title compound as a colorless oil (6.12 g, 89%). ESI MS (M+H) 393.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O)(=[O:3])[CH3:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](I)=[C:16]([F:21])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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:13][C:14]1[CH:19]=[CH:18][C:17]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:1](=[O:3])[CH3:2])=[C:16]([F:21])[CH:15]=1
Reactant: Fc1cc(Cl)ccc1I
Reactant: CC(=O)c1ccccc1B(O)O
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)c1ccccc1-c1ccc(Cl)cc1F
Temperature: 85 °C
Yield: 53.7 %

Procedure:
2-Acetylphenylboronic acid (5 g, 30.5 mmol) and 4-chloro-2-fluoroiodobenzene (8.6 g, 33.5 mmol) were dissolved in a toluene/ethanol mixture (6:1, 175 mL). An aqueous solution of potassium carbonate (2 M, 60 mL) and tetrakis(triphenylphosphine)palladium (0) (1.06 g, 0.91 mmol) were added to the solution and the entire mixture was degassed using vacuum and stirring with intermittent nitrogen purge. The mixture was heated at 85° C. with stirring for 14 hours. The mixture was allowed to cool and then water was added. The organic phase was separated from the aqueous phase and the aqueous phase was extracted with ethyl acetate (3×100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to a crude oil. The crude oil was purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 5%-20% methyl tert-butyl ether in hexane, to afford the desired product (4.07 g, 54%) as a yellow oil;
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[NH2:8].[C:15]1([CH3:24])[C:16]([N:21]=[C:22]=S)=[CH:17][CH:18]=[CH:19][CH:20]=1.C(N=C=NC(C)C)(C)C>C(O)C>[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[NH:1][C:2]2[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: Cc1ccccc1N=C=S
Reactant: CCOC(=O)Cc1ccc(N)c(N)c1
Agent: CC(C)N=C=NC(C)C
Solvent: CCO
Product: CCOC(=O)Cc1ccc2nc(Nc3ccccc3C)[nH]c2c1

Procedure:
A mixture of ethyl 3,4-diaminophenylacetate (5.8 g, prepared according to the procedure of Mederski et al, Bioorg Med Chem Left, 1998, 8, pages 17-22) and o-tolylisothiocyanate (4.9 g) in ethanol (100 mL) was kept at room temperature overnight then treated with diisopropylcarbodiimide (7.6 g). The mixture was stirred at reflux for 5 hours then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of 10% methanol and ether (1:9, v/v) to give the title compound (5.2 g) as a yellow gum.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[CH:12][S:13][C:7]2=[N:6][C:5]=1[CH3:14].[F:15][C:16]1[CH:24]=[CH:23][C:22]2[NH:21][C@@H:20]3[CH2:25][CH2:26][NH:27][CH2:28][C@H:19]3[C:18]=2[CH:17]=1>>[F:15][C:16]1[CH:24]=[CH:23][C:22]2[NH:21][C@@H:20]3[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][C:4]4[C:9](=[O:10])[N:8]5[CH:11]=[CH:12][S:13][C:7]5=[N:6][C:5]=4[CH3:14])[CH2:28][C@H:19]3[C:18]=2[CH:17]=1
Reactant: Fc1ccc2c(c1)[C@@H]1CNCC[C@H]1N2
Reactant: Cc1nc2sccn2c(=O)c1CCCl
Product: Cc1nc2sccn2c(=O)c1CCN1CC[C@H]2Nc3ccc(F)cc3[C@@H]2C1

Procedure:
Using the same reaction procedure as described in example B.1, 6-(2-chloroethyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (3.4 g), prepared as described in EP-A-0,070,053, was reacted with (±)-trans-8-fluoro-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole, prepared as described in J. Med. Chem. 22:677--(1979), to form (±)-trans-6-[2-(8-fluoro-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indol-2-yl)ethyl]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (compound 15, mp. 140.9° C.).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[OH:28][C:29]1([C:33](O)=[O:34])[CH2:32][CH2:31][CH2:30]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33]([C:29]5([OH:28])[CH2:32][CH2:31][CH2:30]5)=[O:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)C1(O)CCC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)C1(O)CCC1

Procedure:
The title compound, white solid (81 mg, 76%), MS (ISP) m/z=429.4 [(M+H)+], mp 177.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 1-hydroxy-cyclobutane-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:29])=[C:16]([OH:30])[CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[C:32]([O-])([O-])=O.[K+].[K+].CI>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CN(C=O)C>[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:23]([Cl:29])=[CH:24][CH:25]=[CH:26][C:27]=2[Cl:28])=[C:16]([O:30][CH3:32])[CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(OCc2c(Cl)cccc2Cl)c(O)c1)NC(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H](Cc1ccc(OCc2c(Cl)cccc2Cl)c(OC)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a suspension of N-(tert-butoxycarbonyl)-4-(2,6-dichlorobenzyloxy)-3-hydroxy-L-phenylalanine methyl ester (0.45 g), K2CO3 (0.199 g), and n-Bu4NI (0.035 g) in DMF (4.0 mL) was added CH3I (0.072 mL) and the mixture was stirred overnight at room temperature. DMF was removed and the residue was partitioned between water and EtOAc. The organic layer was separated and the aqueous solution was extracted with EtOAc. The combined extract was dried (MgSO4) and evaporated. The residue was purified by preparative TLC (silica gel; eluent: hexanes/CH2Cl2/EtOAc, 3:3:1) to yield 0.396 g of N-(tert-butoxycarbonyl)-4-(2,6-dichlorobenzyloxy)-3-methoxy-L-phenylalanine methyl ester. ESMS: m/z 484 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([S:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])C>CO.[OH-].[Na+]>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([S:11][CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([OH:20])=[O:3])=[CH:17][CH:16]=1
Reactant: CCCCCC(Sc1ccc(OC)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC(Sc1ccc(OC)cc1)C(=O)O

Procedure:
2-(4-Methoxy-phenylsulfanyl)-heptanoic acid was prepared starting with 2-(4-methoxy-phenylsulfanyl)-heptanoic acid ethyl ester (4 g, 13.5 mmol) dissolved in methanol (300 ml) and 10N NaOH (25 ml). The resulting reaction mixture was worked up as outlined in example 1. Yield 3 g (83%). yellow oil. MS: 267.1 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18](I)[C:9]=2[C:8]1=[O:20].[Cl:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18]([C:34]3[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=3)[C:9]=2[C:8]1=[O:20]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C1c2c(I)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C1c2c(-c3ccc(Cl)cc3)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 100.2 %

Procedure:
In a similar manner to Reference Example 4, 5-[3,5-bis(trifluoromethyl)benzyl]-7-iodo-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (300 mg) was reacted with 4-chlorophenylboronic acid (160 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-chlorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (292 mg, 100%).
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]#[N:15])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][NH:17][C:18]([C:20]1[CH:21]=[N:22][N:23]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]=1[CH2:25][CH2:26][CH3:27])=[O:19])=[CH:7]2.[N-:34]=[N+:35]=[N-:36].[Na+].[Cl-].[NH4+].CN(C=O)C>O>[Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[NH:36][N:35]=[N:34][N:15]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][NH:17][C:18]([C:20]1[CH:21]=[N:22][N:23]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:24]=1[CH2:25][CH2:26][CH3:27])=[O:19])=[CH:7]2
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1c(C(=O)NCc2ccc3c(Br)c(OCC#N)ccc3c2)cnn1-c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(C(=O)NCc2ccc3c(Br)c(OCc4nnn[nH]4)ccc3c2)cnn1-c1ccccc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 65.3 %

Procedure:
A mixture of 1-phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-amide (0.15 g, 0.3 mmol), prepared in the previous step, sodium azide (0.059 g, 0.9 mmol), ammonium chloride (0.048 g, 0.9 mmol) and 10 mL of DMF was stirred at 100° C. for 1.5 h. By TLC starting material remained. Additional sodium azide (0.059 g, 0.9 mmol) and ammonium chloride (0.048 g, 0.9 mmol) were added and the reaction stirred at 100° C. for 2 h. Again by TLC starting material remained. Additional sodium azide (0.059 g, 0.9 mmol) and ammonium chloride (0.048 g, 0.9 mmol) were added and the reaction stirred at 100° C. for 5 h. The reaction was diluted with water and extracted four times with ethyl acetate. The organic layers were combined and acidified with ˜3 mL 1N HCl. The mixture was swirled for one minute and then the solution was dried (MgSO4) and filtered. The solvent was removed under reduced pressure and the resulting residue was taken up in 20 mL of water. The solid that formed was collected by filtration and dried under reduced pressure to give the title compound (0.107 g, 65%) as a tan solid, mp 219-220° C.