Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[CH:25]=[C:24]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:27])[NH:23][C:22]=1[CH:35]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:35][C:22]4[NH:23][C:24]([C:26]([N:28]5[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]5)=[O:27])=[CH:25][C:21]=4[CH3:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(C(=O)N2CCN(C)CC2)[nH]c1C=O
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)N2CCN(C)CC2)[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 96 h
Yield: 100 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol) and 3-methyl-5-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (70.6 mg, 0.30 mmol) and piperidine (3 drops) in ethanol was stirred at room temperature for 4 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 124 mg (100%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.41 (s, 1H, NH), 11.77 (br s, 1H, NH), 9.22 (br s, 1H), 8.32 (s, 1H), 7.72 (dd, J=2.7 & 6.6 Hz, 1H), 7.42 (m, 1H), 7.32-7.37 (m, 2H), 6.58 (d, J=1.8 Hz, 1H), 3.68 (m, 4H, 2×CH2), 2.36 (m, 4H, 2×CH2), 2.22 (s, 3H, CH3), 2.20 (s, 3H, CH3). MS 496 [M++1].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[CH2:12]([Sn](CCCC)(CCCC)C=C)[CH2:13]CC>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.C1(C)C=CC=CC=1>[CH:12]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2)=[CH2:13]
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(c1)CCC2=O
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
To a mixture of 5-bromo-2,3-dihydro-1H-inden-1-one (2 g, 9.48 mmol), tributyl(vinyl)stannane (3.32 mL, 11.37 mmol) and toluene (30 mL) in a sealed tube was added Pd(Ph3P)4 (0.548 g, 0.474 mmol). Nitrogen was bubbled through the reaction for 5 min., the vessel was sealed and heated at 100° C. for 20 hr. After cooling the reaction mixture to room temperature, ethyl acetate (20 mL), water (30 mL) and celite were added. The mixture was stirred at room temperature for 30 min. and filtered. The EtOAc layer was separated and the aqueous layer was re-extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried (sodium sulfate) and concentrated under reduced pressure. Flash chromatography purification (40 g silica gel column, 5→50% ethyl acetate in hexanes) afforded 5-vinyl-2,3-dihydro-1H-inden-1-one (1.2 g, 7.59 mmol, 80% yield) as a yellow solid. The product had an HPLC ret. time=2.50 min. (condition C); LC/MS M+1=159.2.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:21]1[S:25][C:24]([NH2:26])=[N:23][N:22]=1>>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:21]2[S:25][C:24]([NH2:26])=[N:23][N:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCCOc1cccc(CN2CCCCC2)c1
Reactant: Nc1nnc(Br)s1
Product: Nc1nnc(NCCCCOc2cccc(CN3CCCCC3)c2)s1

Procedure:
The compound is prepared by a method analogous to that of Example 51 from 4-[3-(1-piperidinylmethyl)phenoxy]1-butanamine and 5-bromo-1,3,4-thiadiazole-2-amine.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH:15]([F:17])[F:16])[CH:9]=O)[C:2]#[C:3][CH3:4].C(O)(=O)[CH2:19][C:20]([OH:22])=[O:21].Cl>N1CCCCC1.N1C=CC=CC=1>[CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:9]=[CH:19]/[C:20]([OH:22])=[O:21])[CH:11]=[CH:12][C:13]=1[O:14][CH:15]([F:17])[F:16])[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1cc(C=O)ccc1OC(F)F
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CC#CCOc1cc(/C=C/C(=O)O)ccc1OC(F)F
Temperature: 120 °C
Reaction time: 16 h
Yield: 61.2 %

Procedure:
A solution of 3-(but-2-ynyloxy)-4-difluoromethoxybenzaldehyde (0.53 g, 2.2 mmol) and malonic acid (0.34 g, 3.3 mmol) in a mixture of piperidine (0.2 mL) and pyridine (5.0 mL) was heated to 120° C. and stirred for 16 h. The mixture was cooled to rt and acidified with 1 M HCl. The crude product was collected by filtration and recrystallised from acetonitrile to give (E)-3-(3-(but-2-ynyloxy)-4-difluoromethoxyphenyl)-2-propenoic acid (0.38 g, 61%) as a colourless crystalline solid; mp 206-208° C.; δH (500 MHz, DMSO-d6) 1.84 (t, J=2.2 Hz, 3H, C≡CH3), 4.87 (q, J=2.2 Hz, 2H, OCH2), 6.55 (d, J=16.0 Hz, 1H, CH═CHCO2H), 7.13 (t, J=72.0 Hz, 1H, CHF2), 7.19 (d, J5,6=8.0 Hz, 1H, H5), 7.30 (dd, J5,6=8.0, J2,6=2.0 Hz, 1H, H6), 7.52 (d, J2,6=2.0 Hz, 1H, H2), 7.54 (d, J=16.0 Hz, 1H, CH═CHCO2H), 12.41 (br s, 1H, CO2H); δC (125 MHz, DMSO-d6) 3.1, 56.8, 74.1, 84.1, 113.6, 116.4 (t, J=256 Hz), 119.7, 120.6, 122.0, 132.4, 141.2, 142.9, 148.6, 167.4; νmax 1011, 1113, 1267, 1516, 1629, 1686, 2578, 2924 cm−1.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[CH:13]=[CH:14]/[CH:15]=O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[S:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23]>>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:21]2[S:17][C:18](=[O:23])[NH:19][C:20]2=[O:22])=[CH:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(/C=C/C=C/C=O)cc1
Reactant: O=C1CSC(=O)N1
Product: CC(C)Oc1ccc(CCCCCC2SC(=O)NC2=O)cc1
Yield: 26 %

Procedure:
According to the same manner as that described in Example 23, (E,E)-5-(4-isopropoxyphenyl)-2,4-pentadienal was condensed with 2,4-thiazolidinedione, and the resulting compound was subjected to catalytic hydrogenation to give 5-[5-(4-isopropoxyphenyl)pentyl]-2,4-thiazolidinedione as an oil (yield: 26%).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].C(N(CC)CC)C.[CH2:14]([O:16][CH2:17]Cl)[CH3:15]>ClCCl>[C:1]([O:6][CH2:17][O:16][CH2:14][CH3:15])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: CCOCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCOCC
Yield: 90.5 %

Procedure:
To a 500-mL, 3-necked round bottomed flask equipped with a thermocouple temperature monitor, 250-mL addition funnel, nitrogen inlet and a magnetic stirrer was added 150 mL of dichloromethane, and 18.9 g (0.22 mol) of methacrylic acid. The addition funnel was charged with a mixture of 22.3 g (0.23 mol) of triethylamine and 25 mL of dichloromethane which was then added in a thin stream to the flask with stirring in an ice-bath. Upon completion of the addition, the addition funnel was recharged with a mixture of 18.9 g (0.2 mol) of chloromethyl ethyl ether and 25 mL of dichloromethane which was subsequently added dropwise to the reaction mixture with cooling over about 15 minutes. The ice bath was removed and the mixture stirred at room temperature overnight. The resulting suspension was filtered and the filtrate washed several times with saturated bicarbonate, water and brine and dried over anhydrous magnesium sulfate. Filtration and removal of the solvent by evaporation on a rotary evaporator provided 26.1 g of a yellowish oil which was distilled at reduced pressure to provide 20.3 g (70%) of the title compound as a clear, colorless oil.
Reaction SMILES: C([O:8][C:9](=[O:24])[CH2:10][C@@H:11]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:12][C:13]([NH2:15])=[O:14])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[Si:17]([O:16][C@H:11]([CH2:10][C:9]([OH:24])=[O:8])[CH2:12][C:13]([NH2:15])=[O:14])([C:20]([CH3:22])([CH3:23])[CH3:21])([CH3:19])[CH3:18]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CC(N)=O)CC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CC(N)=O)CC(=O)O

Procedure:
(S)-benzyl-3-(tert-butyl dimethylsilyloxy)glutaramate (70 g) was dissolved in ethyl acetate (350 ml) and placed in a 500 ml glass pressure vessel. To this dry 5% Pd/C (1.4 g) was added under vacuum and pressurized with hydrogen gas at 2.7 bar overpressure. The mixture was stirred magnetically while remaining connected to the hydrogen source. The catalyst was removed by filtration and washed with a small volume of ethyl acetate (25 ml). The clear filtrate was mixed with water and dilute ammonia. The aqueous phase was isolated and the organic phase extracted with water. The combined aqueous phase was washed with MTBE and degassed under vacuum to remove traces of organic solvent. The mixture was placed in an ice-bath. The cooled aqueous solution was acidified using dilute phosphoric acid to obtain thick suspension. This was filtered, washed with cold water and dried to yield (S)-3-(tert-butyl dimethylsilyloxy)glutaric acid monoamide.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][S:31]([C:34]2[CH:35]=[C:36]3[C:40](=[CH:41][CH:42]=2)[NH:39][C:38](=[O:43])[CH2:37]3)(=[O:33])=[O:32])=[CH:26][CH:25]=1.N1CCCCC1>C(O)C>[F:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][S:31]([C:34]2[CH:35]=[C:36]3[C:40](=[CH:41][CH:42]=2)[NH:39][C:38](=[O:43])/[C:37]/3=[CH:21]\[C:3]2[NH:4][C:5]3[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[C:7](=[O:20])[C:6]=3[C:2]=2[CH3:1])(=[O:33])=[O:32])=[CH:28][CH:29]=1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccc(F)cc3)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccc(F)cc4)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Temperature: 25 °C
Yield: 74.8 %

Procedure:
3-Methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d (57.6 mg, 0.21 mmol) and 5-(4-fluoro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one 65a (57.6 mg, 0.19 mmol) were dissolved in 2 ml of ethanol, and added with 42 μl of piperidine to the solution at room temperature. Upon completion of the addition, the reaction mixture was heated to reflux for 3 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (3 ml×2) and dried to obtain the title compound (Z)-2-((5-(4-fluorobenzyl sulfonyl)-2-oxoindolin-3-ylidene)methyl)-3-methyl-5-(2-(piperidin-1-yl)ethyl)-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one 67 (84 mg, yield 76%) as an orange solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6]([C:12]([N:14]1[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]1)=[O:13])=[CH:5]2.C(N(CC)CC)C.[C:29]([O:32][CH2:33]C)(=[O:31])C>C(O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:33][O:32][C:29]([C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6]([C:12]([N:14]1[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]1)=[O:13])=[CH:5]2)=[O:31]
Reactant: O=C(c1cc2cc(Br)cc(Cl)c2[nH]1)N1CCC(F)(F)CC1
Reactant: CCOC(C)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)c1cc(Cl)c2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1
Temperature: 25 °C
Yield: 69 %

Procedure:
The mixture consistent of 100 mg (0.265 mmol) (5-bromo-7-chloro-1H-indol-2-yl)-(4,4-difluoro-piperidin-1-yl)-methanone, 15 mg (0.0184 mmol) 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride and 55.6 μL (0.398 mmol) triethylamine in 1 mL ethanol and 1 mL ethyl acetate was stirred overnight at 100° C. under an atmosphere of carbon monoxide (120 bar). After cooling to room temperature the reaction mixture is filtered, evaporated and chromatographed on silica gel with ethyl acetate:n-heptane (1:2 v/v) as eluant to give the desired compound as a colorless solid (69%).
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)[CH3:19].[C:22](=O)([O-])[O-].[K+].[K+]>[Cl-].C[N+](C)(C)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:19][N:18]1[C@@H:15]2[CH2:16][C:17]3[CH:1]=[CH:2][C:3]([O:4][CH3:22])=[C:5]4[O:9][C@H:8]5[C@@H:10]([OH:11])[CH:12]=[CH:13][C@@H:14]2[C@:7]5([C:6]=34)[CH2:21][CH2:20]1
Reactant: O=C([O-])[O-]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: C[N+](C)(C)c1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Yield: 99 %

Procedure:
Morphine of 70% purity 407 parts (1 mole part), potassium carbonate 552 parts (4 moles part) and trimethylphenyl-ammonium chloride 188 parts (1.1 moles part) are heated under stirring in toluene (4000 parts) at 45° to 120° C. for 2-5 hrs. to yield 296 parts codeine (99% yield), after workup as in Example 1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[C:28]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)([OH:30])=[O:29]>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:34]3[CH:35]=[CH:36][C:31]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[CH:3][CH:4]=2)[CH2:9]/[C:10](=[N:11]\[OH:12])/[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)=[C:21]([CH3:27])[CH:22]=1
Reactant: Cc1cc(/C(CC(c2ccc(Br)cc2)c2ccc(Cl)cc2C)=N/O)ccn1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: Cc1cc(/C(CC(c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccc(Cl)cc2C)=N/O)ccn1

Procedure:
In analogy to example 74, step 6, from 3-(4-bromophenyl)-3-(4-chloro-2-methylphenyl)-1-(2-methylpyridin-4-yl)propan-1-one oxime (example 138) and 4-carboxyphenylboronic acid was prepared the title compound as a light brown foam, MS (ESI+): m/z=485.162 [M+H]+.
Reaction SMILES: Cl.[NH2:2]O.[CH3:4][C:5]([CH3:14])([CH3:13])[C:6](=O)[CH2:7][C:8]([O:10]C)=[O:9].O>C(O)C>[C:5]([C:6]1[NH:2][O:10][C:8](=[O:9])[CH:7]=1)([CH3:14])([CH3:13])[CH3:4]
Reactant: NO
Reactant: COC(=O)CC(=O)C(C)(C)C
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(=O)o[nH]1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
A mixture of 8.8 grams (126 mmol, 1 eq) of hydroxylamine hydrochloride and 10 grams (126 mmol, 1 eq) in 40 mL of ethanol was heated to reflux and 20 grams (126 mmol, 1 eq) of methyl 4,4-dimethyl-3-oxopentanoate was added. The reaction mixture was heated for 2 hours and then allowed to cool to room temperature overnight. The mixture formed a precipitate. To this mixture was added 50 mL of water with stirring and more precipitate formed. The solid was collected by filtration and dried. This gave 13.1 grams (48% yield) of the desired product. mp 110°-15° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:19]=[CH:20][C:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[BH4-].[Na+]>C(O)C>[OH:27][CH:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:20][CH2:19][NH:1][CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CCCCCCC(N)C(=O)OCC
Reactant: C=CC(=O)CCCCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCC(O)CCNC(CCCCCCC(=O)OCC)C(=O)OCC
Reaction time: 3 h

Procedure:
Diethyl 2-aminononanedioate (10.40 g) and oct-1-en-3-one (5.04 g) were mixed slowly at 0° C., with stirring, and set aside at room temperature for 3 h., giving diethyl 2-(3-oxoctylamino) nonanedioate as a colourless oil, 2.3(4H, multiplet, --CH2 --CO2Et and NCH2CH2CO--), 3.16(1H, triplet, EtO2C--CHR--N), 4.11(2H, quartet, --O--CH2 --CH3), 4.17(2H, quartet, --O--CH2 --CH3). A stirred solution of this ketone (13.5 g) in absolute ethanol (140 ml) was treated dropwise at 0° C. with sodium borohydride (665 ml) in absolute ethanol (70 ml), then kept for 31/2 h. at room temperature, and concentrated at 40° C. in vacuo. The residue dissolved in water, was brought to pH 5 with N hydrochloric acid and extracted throughly with chloroform, the extract was washed with water, dried, and evaporated, giving diethyl 2-(3-hydroxyoctylamino)nonanedioate as a colourless oil.
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[CH2:7]([C:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2OC=1C(O)=O)[CH2:8][CH2:9][CH3:10].CN(C=O)C>C(Cl)Cl>[CH2:7]([C:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:3][C:2]=1[C:1]([Cl:6])=[O:5])[CH2:8][CH2:9][CH3:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCc1c(C(=O)O)oc2ccccc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCc1c(C(=O)Cl)oc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl Chloride (3.86 mL, 44.2 mmol) was added under nitrogen at room temperature to a solution of 3-butyl-benzofuran-2-carboxylic acid (1.93 g, 8.84 mmol) in 60 mL of methylene chloride. After the addition a catalytic amount of DMF (10 μL) was added and the reaction was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. To remove the excess oxalyl chloride the residue was dissolved in benzene and the solvent removed under reduced pressure to give 3-butyl-benzofuran-2-carbonyl chloride, which was immediately used in step 2 without additional purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH:16]([OH:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:26]I>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH:16]([O:18][CH3:26])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:19][CH2:20][CH:21]3[CH2:22][CH2:23]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(OCC3CC3)cc2C(O)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CN(C(=O)OC(C)(C)C)Cc2ccc(OCC3CC3)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 200 mg (0.626 mmol) 6-cyclopropylmethoxy-4-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (example XLIII.1) in 3 mL THF are added 30 mg (0.69 mmol) NaH (55%) and stirred at r.t. for 30 min. Then 35 μL (0.56 mmol) methyl iodide are added and the reaction mixture is stirred at 80° C. over night. The reaction mixture is quenched by the addition of water and extracted three times with EtOAc. The organic layers are combined, dried over MgSO4, filtered and the solvent is removed in vacuo.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH2:5]([NH2:16])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:5]([NH:16][C:1]([NH:16][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[S:2])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCN
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCCCCCCCCCNC(=S)NCCCCCCCCCCC
Reaction time: 0.75 h
Yield: 60.7 %

Procedure:
Thiophosgene (10.9 mls, 0.14 moles) is added dropwise to a well stirred mixture of undecylamine (49.9 g, 0.29 moles) and water (400 mls). The mixture is heated to reflux following the addition. After 45 minutes the mixture is allowed to cool while potassium carbonate (20.0 g, 0.14 moles) is added in portions, and is then reheated to reflux. After three hours the mixture is cooled and the product is filtered off, triturated in 2N HCl, refiltered, rinsed with water, and dried. Recrystallization from ethylacetate gave the product (32.7 g) mp 70°-72° C.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[NH:17][CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[C:1]1([NH:7][C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[NH:17][C@H:18]2[CH2:23][CH2:22][CH2:21][N:20]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=3)[CH2:19]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: O=C(Nc1ccccc1)N[C@@H]1CCCC[C@H]1NC1CCCNC1
Product: O=C(Nc1ccccc1)N[C@@H]1CCCC[C@H]1N[C@H]1CCCN(c2ccc(C(F)(F)F)cn2)C1

Procedure:
1-Phenyl-3-((1R,2R)-2-((S)-1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-3-ylamino)cyclohexyl)urea was synthesized using 1-phenyl-3-((1R,2R)-2-(piperidin-3-ylamino)cyclohexyl)urea (from intermediate C, Example 1) (100 mg, 0.32 mmol) and 2-fluoro-5-(trifluoromethyl)pyridine (57.4 mg, 0.35 mmol) according to General Procedure A to give 15 mg (10.3%) of white solid. Anal. Calcd. for C24H30F3N5O m/z 461.2, found: 462.2 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 8.18 (m, 1H), 7.30 (m, 1H), 7.21 (m, 4H), 7.00 (m, 1H), 6.67 (d, J=8.9 Hz, 1H), 6.18 (d, J=5.4 Hz, 1H), 4.47 (m, 1H), 3.79 (m, 1H), 3.59 (m, 3H), 3.23 (m, 1H), 2.33 (m, 1H), 2.07 (m, 4H), 1.87 (m, 3H), 1.67 (d, J=7 Hz, 2H), 1.49 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: ClCCCOc1ccccc1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Fc1ccc2c(C3CCN(CCCOc4ccccc4)CC3)noc2c1
Yield: 47 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.0 g, 18.2 mmol), K2CO3 (3.0 g, 21.8 mmol), KI (100 mg), 3chloropropoxybenzene (3.4 g, 20.0 mmol), and acetonitrile was stirred at reflux under nitrogen for 30 hours. The reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried with MgSO4 and concentrated to afford 6.2 g of a damp, beige solid. The compound was recrystallized twice from ethanol to yield (47%) of 6-fluoro-3-[1-(3-phenoxypropyl)-4-piperidinyl]-1,2-benzisoxazole as a light beige solid, m.p.=78-80° C.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:36]([NH:39][NH2:40])(=[O:38])[CH3:37]>O1CCCC1>[C:36]([NH:39][NH:40][C:18]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20])(=[O:38])[CH3:37]
Reactant: CC(=O)NN
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 91.6 %

Procedure:
To a solution of the carboxylic acid (6b, 2.37 g, 8.57 mmol) of Example 9 or 16 in tetrahydrofuran (50 mL) were added triethylamine (1.39 mL) and isobutyl chloroformate (1.32 mL) under ice-cooling, followed by agitating at 0° C. for 20 minutes. To the reaction solution was added acetohydrazide (807 mg) at 0° C., stirred at room temperature for 40 minutes and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to afford 2.61 g of the title compound (yield 92%).