Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N+:2]([CH2:5][C@H:6]([NH2:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[N:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:26][CH:25]=1)=[C:22]=[O:23]>CO>[CH2:30]([C:27]1[CH:26]=[CH:25][C:24]([NH:21][C:22](=[O:23])[NH:11][C@@H:6]([CH2:5][N+:2]([CH3:3])([CH3:4])[CH3:1])[CH2:7][C:8]([O-:10])=[O:9])=[CH:29][CH:28]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCc1ccc(N=C=O)cc1
Reactant: C[N+](C)(C)C[C@H](N)CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCCCCCCCc1ccc(NC(=O)N[C@H](CC(=O)[O-])C[N+](C)(C)C)cc1
Reaction time: 18 h

Procedure:
To a solution of (R)-aminocarnitine (22 mg, 0.14 mmol) and diisopropylethylamine (71 uL, 0.41 mmol) in MeOH (2 mL) was added 1-isocyanato-4-octylbenzene (63 uL, 0.27 mmol) and the reaction stirred for 18 h. The MeOH was removed in vacuo and the residue stirred with 1:1 ether/EtOAc. Impurities dissolved into the ether/EtOAc which were discarded and the remaining material taken up into 90:10 CH2Cl2/MeOH and then loaded onto a short SiOH plug. The title compound was eluted by increasing MeOH content in 10% steps to 60%. The compound was then taken up into 90:10 CH2Cl2/MeOH and filtered through a plug of celite which gave after drying the title compound as a white powder (9 mg, 17%). 1H NMR (400 MHz, CD3OD) δ 7.27 (d, 2H, J=8.4 Hz), 7.09 (d, 2H, J=8.4 Hz), 4.73-4.71 (m, 1H), 3.78-3.53 (m, 2H), 3.25 (s, 9H), 2.75-2.72 (m, 2H), 2.55 (t, 2H, J=8.0 Hz), 1.60-1.29 (m, 12H), 0.90 (t, 3H, J=6.8 Hz); MS ESI 392.3 [M+H]+, calcd for [C22H37N3O3+H]+ 392.55.
Reaction SMILES: C(C1C=C(C(C)C)C=C(C(C)C)C=1S(NN=[C:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])(=O)=O)(C)C.Br[C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH:37]=[O:38]>>[CH:36]1([CH:37]([OH:38])[C:21]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:22][CH2:23][N:24]([CH3:25])[CH3:26])[CH2:39][CH2:40][CH2:41][CH2:34][CH2:35]1
Reactant: O=Cc1cccc(Br)c1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)NN=C(CCN(C)C)c2ccccc2)c(C(C)C)c1
Product: CN(C)CC=C(c1ccccc1)C(O)C1CCCCC1

Procedure:
By using a method similar to that described in Example 22, but starting from β-dimethylaminopropiophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (20 g) and 3-bromobenzaldehyde (5.6 cc), 1-(3-bromophenyl)-4-dimethylamino-2-phenyl-2-buten-1-ol (Z) hydrochloride (11.3 g) is obtained in the form of a white solid melting at 188° C. after recrystallisation from isopropanol (200 cc).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[N:39]1([CH2:45][CH2:46][NH2:47])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.NN>CCO.O>[NH2:3][CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:47][CH2:46][CH2:45][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:34])[C:15]1=[O:38]
Reactant: NCCN1CCOCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCn1c(=O)c(C(=O)NCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.252 g, 0.49 mmol) in EtOH (15 mL) under nitrogen was treated with 2-(4-morpholinyl)ethanamine (0.321 mL, 2.44 mmol) for 30 min. (150° C. in a microwave vessel. The reaction was further microwaved for an additional 30 min.@150° C. after the addition of another equivalent (0.064 mL) of the amine. The reaction was transferred to a test tube, diluted with EtOH (30 mL), and treated with hydrazine (0.4 mL, 13 mmol)@50° C. overnight. After the reaction was cooled to ambient temperature the resulting suspension was diluted with water (120 mL) and refrigerated overnight. The resulting suspension was filtered, washed with 2:1 water:EtOH and thoroughly dried under high vacuum to provide the title compound as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 2.27 (s, 1 H), 2.39-2.46 (m, 5 H), 2.70-2.81 (m, 2 H), 3.40-3.53 (m, 1 H), 3.57-3.61 (m, 6 H), 4.16 (s, 2 H), 4.18-4.26 (m, 2 H), 7.10-7.17 (m, 2 H), 7.35-7.41 (m, 2 H), 8.13-8.15 (m, 1 H), 8.50-8.51 (m, 1 H), 10.36-10.43 (m, 1 H); ES+ MS: 470 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](B(OC(C)C)OC(C)C)[CH:7]=[N:8][CH:9]=1)#[C:2][CH3:3].FC(F)(F)S(O[C:25]1[CH:38]=[C:37]2[C:28]([O:29][C:30]3[C:31]([F:58])=[CH:32][C:33]([C:52]4[CH2:53][O:54][CH2:55][CH2:56][CH:57]=4)=[CH:34][C:35]=3[C@:36]32[N:43]=[C:42]([NH:44]C(OC(C)(C)C)=O)[CH2:41][O:40][CH2:39]3)=[CH:27][CH:26]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].C(O)(C(F)(F)F)=O>CN(C=O)C.C(Cl)Cl.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>[O:54]1[CH2:55][CH2:56][CH:57]=[C:52]([C:33]2[CH:32]=[C:31]([F:58])[C:30]3[O:29][C:28]4[C:37](=[CH:38][C:25]([C:6]5[CH:7]=[N:8][CH:9]=[C:4]([C:1]#[C:2][CH3:3])[CH:5]=5)=[CH:26][CH:27]=4)[C@:36]4([N:43]=[C:42]([NH2:44])[CH2:41][O:40][CH2:39]4)[C:35]=3[CH:34]=2)[CH2:53]1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(COC1)c1cc(OS(=O)(=O)C(F)(F)F)ccc1Oc1c(F)cc(C3=CCCOC3)cc12
Reactant: CC#Cc1cncc(B(OC(C)C)OC(C)C)c1
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: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC#Cc1cncc(-c2ccc3c(c2)[C@@]2(COCC(N)=N2)c2cc(C4=CCCOC4)cc(F)c2O3)c1
Temperature: 85 °C
Yield: 57.2 %

Procedure:
In a microwave vial, diisopropyl 5-(prop-1-ynyl)pyridin-3-ylboronate (0.109 g, 0.443 mmol), (S)-5-(tert-butoxycarbonylamino)-2′-(5,6-dihydro-2H-pyran-3-yl)-4′-fluoro-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthene]-7′-yl trifluoromethanesulfonate (0.218 g, 0.355 mmol), and Pd(PPh3)4 (0.041 g, 0.035 mmol) were taken up in DMF (3.7 mL). Aqueous sodium carbonate (1.0 M, 1.064 mL, 1.064 mmol) was added. Argon gas was blown through the vessel, which was sealed and heated in an 85° C. oil bath for 1.5 h. The reaction was concentrated. The residue was taken up in water (10 mL) and the aqueous phase was extracted with 5% MeOH/DCM (3×20 mL). The organics were combined, washed with dilute brine (5 mL), dried over sodium sulfate and concentrated. The residue was transferred to a microwave vial in DCM (2 mL), and TFA (0.683 mL, 8.87 mmol) was added. The vessel was sealed and heated in a 50° C. oil bath for 1.5 h. The reaction was concentrated, and the residue was neutralized with 0.5 M aqueous Na2CO3 (15 mL). The aqueous phase was extracted with 5% MeOH/DCM (3×20 mL). The organics were combined, washed with dilute brine (6 mL), dried over sodium sulfate and concentrated. The residue was purified by chromatography (7% MeOH/DCM) to afford (S)-2′-(5,6-dihydro-2H-pyran-3-yl)-4′-fluoro-7′-(5-(prop-1-ynyl)pyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (98 mg, 0.203 mmol).
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:9]=[CH:10][C:11]([O:14]C)=[N:12][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CI.[C:18](=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:1][C:2]1([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[N:12]([CH3:18])[CH:13]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C2(O)CCCCC2)cn1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: Cn1cc(C2(O)CCCCC2)ccc1=O
Yield: 81.9 %

Procedure:
A mixture of 5-(1-hydroxycyclohexyl)-2-methoxypyridine (17.1 g), methyl iodide (11.7 g) and potassium carbonate (22.8 g) was heated in 330 mL of refluxing acetonitrile for 18 hours. The mixture was cooled and filtered, and the solids were washed with methanol. The filtrate was concentrated to yield 14.0 g of powder, which was used in subsequent reactions without further purification.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:13]2[C:14](=[O:19])[O:15][C:16](=[O:18])[NH:17][C:12]=2[CH:11]=[CH:10][CH:9]=1.S(OC)(OC)(=O)=O>CS(C)=O>[CH3:1][N:17]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([Cl:7])[C:13]=2[C:14](=[O:19])[O:15][C:16]1=[O:18]
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CS(C)=O
Product: Cn1c(=O)oc(=O)c2c(Cl)cccc21
Reaction time: 0.2 h

Procedure:
Anhydrous potassium carbonate (16.8 g.) was added gradually to a suspension of the known compound 1,2-dihydro-5-chloro-2,4-dioxo-3,1-(4H)-benzoxazine (11.7 g.) in dry dimethyl sulphoxide (110 ml.) and the mixture stirred at room temperature for 20 minutes Dimethyl sulphate (7 ml.) was added dropwise with vigorous stirring at 30°-35° for 12 minutes and the mixture allowed to settle. The supernatant liquid was decanted into an ice/dilute hydrochloric acid mixture (600 ml.; 0.05 M.HCl). The resulting precipitate was collected, washed with water and dried in vacuo to give 1,2-dihydro-1-methyl-5-chloro-2,4-dioxo-3,1-(4H)-benzoxazine m.p. 199°-201° (dec.).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.CO>O>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Clc1cccc(N2CCN(CCCNC(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)c1
Agent: Cl
Solvent: CO
Solvent: O
Product: NCCCN1CCN(c2cccc(Cl)c2)CC1
Yield: 68 %

Procedure:
Gaseous hydrochloric acid is introduced for 10 min into a round bottom flask containing 11.2 g (22.6 mmol) of 3-[4-(3-chlorophenyl]piperazin-1-yl]-N-(triphenylmethyl)propanamine and 300 ml of methanol, while the mixture is cooled in a bath of iced water. The mixture is allowed to return to room temperature and is then heated under reflux for 5.5 h. The solution is reduced to half its volume and is allowed to cool. The solid which precipitates is filtered off, is treated with water and aqueous ammonia, the mixture is extracted with ethyl acetate, the organic phase is washed with water and is dried and the solvent is evaporated off. 3.9 g of light yellow oil are obtained.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[N:30]1([CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])[CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCCC1>[F:25][C:18]1[CH:19]=[C:20]([CH3:24])[C:21]([F:23])=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:39][CH2:38][CH2:37][CH2:36][CH2:35][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:29])[S:14][N:13]=1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)cc1F
Reactant: NCCCCN1CCCC1
Solvent: C1CCOC1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN3CCCC3)c2C(N)=O)cc1F
Temperature: 47.5 °C
Reaction time: 24 h
Yield: 81.9 %

Procedure:
A mixture of [4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester (0.34 g, 0.81 mmol), 4-pyrrolidinobutylamine (0.12 g, 0.81 mmol) and tetrahydrofuran (2.8 mL) was shaken at 45-50° C. for 24 hours. The mixture was concentrated and purified by radial chromatography (4 mm plate, CH3OH—CHCl3—NH4OH (10:89:1) to (15:84:1)), affording 0.31 g of the title compound as a colorless solid. The material was dissolved in ca. 10 mL of 4:1 methanol-chloroform at −10° C. and was treated with a solution of methanesulfonic acid (0.043 mL in 0.5 mL of CH3OH). After stirring for 5 minutes, the mixture was concentrated in vacuo, and the residue was triturated with methanol-ether, affording 0.35 g of the title compound (82%) as a colorless solid. HPLC ret. time: 3.3 minutes. 1H NMR (400 MHz, D2O) δ 6.74 (dd, 1H, J=6.0, 9.6 Hz), 6.63 (dd, 1H, J 6.4, 10.4 Hz), 4.61 (s, 2H), 3.44 (m, 2H), 3.05-2.98 (m, 4H), 2.98-2.81 (m, 2H), 2.62 (s, 3H), 1.95-1.93 (m, 4H), 1.83-1.80 (m, 2H), 1.6-1.5 (m, 2H), 1.4-1.3 (m, 2H) ppm; MS (APCl, m/z): 468 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[CH:4][C:3]=1[CH3:13].[Li]C(C)(C)C.C1C[O:22][CH2:21]C1>>[CH:21]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[CH:4][C:3]=1[CH3:13])=[O:22]
Reactant: Cc1cc(C(C)(C)C#N)ccc1Br
Reactant: C1CCOC1
Agent: [Li]C(C)(C)C
Product: Cc1cc(C(C)(C)C#N)ccc1C=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
2-(4-bromo-3-methylphenyl)-2-methylpropanenitrile (3.31 g, 13.9 mmol) is dissolved in dry THF (80 mL). The mixture is cooled to −78° C. and tert-BuLi (1.7 M in pentane, 18 mL, 30.6 mmol) is added. After 30 minutes, the reaction is quenched with DMF (10 mL), volatiles are evaporated and the residue purified by normal phase MPLC (SiO2, heptane to heptane/EtOAc 3:1), giving 2-(4-formyl-3-methylphenyl)-2-methylpropanenitrile (1.89 g, 10.2 mmol, 73%) as a colorless liquid. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.70 (s, 6H) 2.64 (s, 3H) 7.49 (s, 1H) 7.55 (dd, J=8.01, 2.15 Hz, 1H) 7.86 (d, J=7.81 Hz, 1H) 10.22 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1C(O)=O.C([O-])([O-])=O.[Cs+].[Cs+].[C:28]([O:36][CH2:37][CH3:38])(=[O:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCOCC1.O.C(OCC)(=O)C>[CH3:12][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([CH:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:28]([O:36][CH2:37][CH3:38])=[O:35])=[CH:3][CH:4]=2)[N:9]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc2ccc(Br)cc2n1
Agent: O=C(O)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc2ccc(C)nc2c1
Temperature: 100 °C
Yield: 25.7 %

Procedure:
A mixture of 7-bromo-2-methylquinoline (2.00 g, 9.01 mmol), Cu(I)I (0.172 g, 0.90 mmol), picolinic acid (0.222 g, 1.80 mmol), Cs2CO3 (8.80 g, 27.0 mmol) and diethyl malonate (2.73 mL, 18.0 mmol) in dioxane (25 mL) was stirred at 100° C. for hours. After cooling to ambient temperature, ethyl acetate (30 mL) and water (15 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography on silica gel (3:2 hexane/ethyl acetate) to give diethyl 2-(2-methylquinolin-7-yl)malonate (0.7 g, 2.32 mmol, 26% yield) as oil.
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:20])[N:8]([CH2:18][CH3:19])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])C.[CH3:21][O:22][CH2:23][CH2:24][NH2:25]>C(O)C>[CH2:18]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)[C:15]([OH:16])=[C:6]([C:4]([NH:25][CH2:24][CH2:23][O:22][CH3:21])=[O:5])[C:7]1=[O:20])[CH3:19]
Reactant: CCOC(=O)c1c(O)c2ccc(C)nc2n(CC)c1=O
Reactant: COCCN
Solvent: CCO
Product: CCn1c(=O)c(C(=O)NCCOC)c(O)c2ccc(C)nc21
Reaction time: 8 h

Procedure:
A stirred mixture of 1.38 g. (0.005 mole) of 1-ethyl-1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (prepared as in Example 1) and 0.75 g. (0.01 mole) of 2-methoxyethylamine in 20 ml. of ethanol was heated under reflux for 5 hours. The solution was left at room temperature overnight. The precipitate which formed was collected and was stirred in 100 ml. of a 20% aqueous acetic acid solution for 30 minutes. The insoluble material was collected, air dried and was recrystallized from heptane to give 0.9 g. of the title compound, m.p. 118°-20° C.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH2:5]([N:7]([CH2:14][CH2:15][CH2:16][NH2:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:6].C(N(CC)CC)C>C(Cl)Cl>[CH2:5]([N:7]([CH2:14][CH2:15][CH2:16][N:17]=[C:1]=[S:2])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:6]
Reactant: CCN(CCCN)c1ccccc1
Reactant: S=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CCCN=C=S)c1ccccc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A solution of thiophosgene (7.43 ml) in CH2Cl2 (300 ml) was added dropwise over 11/2 hours at 20° C. under a nitrogen atmosphere to a stirred solution of N-ethyl-N-(3-aminopropyl)aniline (17.8 g) and triethylamine (27.8 ml) in CH2Cl2 (500 ml). The mixture was stirred at 20° C. for a further 1/2 hours then heated under reflux for 11/2 hours. The mixture was allowed to cool, washed with water, dried over MgSO4, filtered and solvent removed from the filtrate in vacuo. The product was purified by chromatography on silica gel eluting with CH2Cl2 to give N-ethyl-N-(3-isothiocyanatopropyl)aniline (7.2 g) as a red oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC(N)=[S:14].[OH-].[K+].O>C(O)C>[CH2:1]([O:8][CH2:9][CH2:10][SH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(N)=S
Reactant: ClCCOCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: SCCOCc1ccccc1
Yield: 58.1 %

Procedure:
A solution of 2-benzyloxy-1-chloroethane (Synthesis, 1990, 495.) (7.2 g, 0.043 mol) and thiourea (3.2 g; 0.043 mol) in 95% ethanol (50 ml) was refluxed for 24 hours. To the reaction mixture, potassium hydroxide (4 g, 0.061 mol) and water (40 ml) were added and they were refluxed for 5 hours. The solvent was then distilled off under reduced pressure. The residue was neutralized with a 10% aqueous solution of sulfuric acid, followed by extraction with ethyl ether. The ether solution was washed with water, dried over sodium sulfate and then distilled off under reduced pressure, whereby 2-benzyloxyethanethiol (4.2 g, yield: 59.0%) was obtained as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([CH3:11])[N:10]=2)[N:7]=1.[C:12]1([CH:18]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][NH2:29])[CH2:22][CH2:21]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)C(C)C)C.C(=O)([O-])O.[Na+]>C(O)CCC.C(OCC)(=O)C>[C:30]1([CH:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][NH:29][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([N:8]=[C:9]([CH3:11])[N:10]=4)[N:7]=3)[CH2:22][CH2:21]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: Cc1nc2ccc(Cl)nn2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2n1
Temperature: 0 °C
Yield: 30.9 %

Procedure:
6-Chloro-2-methyl[1,2,4]triazolo[1,5-b]pyridazine (655 mg) and 4-(diphenylmethoxy)-1-piperidinepropanamine (1.26 g) was suspended in n-butanol (20 ml), followed by addition of N-ethyldiisopropylamine (1.94 ml). The mixture was refluxed under heating for 22 hours, followed by addition of ice-water and sodium hydrogen carbonate and extraction with ethyl acetate. The extract was washed with an aqueous sodium chloride saturated solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica-gel column chromatography and eluted with a mixture of ethyl acetate, methanol and triethylamine (50:5:1). Fractions containing the objective compound were collected and concentrated. The resulting crystals were washed with hexane and dried to yield the title compound (547 mg).
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][N:9]=[CH:10]2.[OH-].[Na+]>C(O)(=O)C>[CH:10]1[C:11]2[C:6](=[C:5]([CH2:4][C:3]([OH:15])=[O:2])[CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][N:9]=1
Reactant: COC(=O)Cc1cccc2cnccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C(O)Cc1cccc2cnccc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
Isoquinolin-5-yl-acetic acid methyl ester (Preparation 6, Step 3; 90 mg, 0.448 mmol) was treated with aqueous sodium hydroxide (4N, 3 mL) and the solution was heated at 50° C. for 4 h. The solution was cooled to 0° C. and acetic acid (2 mL) was added dropwise, which resulted in the formation of a precipitate. The mixture was kept at 0° C. overnight (ca. 15 h) and the precipitate was removed via filtration and was washed with water. The solid was dried in air to afford 35 mg (47% yield) of isoquinolin-5-yl-acetic acid; 1H NMR (400 MHz, CD3OD) δ 9.24 (s, 1H), 8.47 (d, J=6.2 Hz, 1H), 8.04 (d, J=7.9 Hz, 1H), 7.96 (d, J=6.2 Hz, 1H), 7.74 (d, J=6.6 Hz, 1H), 7.66 (t, J=7.6 Hz, 1H), 4.11 (s, 2H); MS (AP/CI): 188.3 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([B:10]([OH:12])[OH:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(B(O)O)cc1
Reaction time: 1 h

Procedure:
A solution of 4-carboxyphenylboronic acid (25 g) and concentrated sulphuric acid (1 ml) in methanol (250 ml) was heated under reflux for 36 hours. Volatile material was removed by evaporation and the residue was dissolved in ethyl acetate (200 ml). Water (100 ml) was added and the mixture was stirred for 1 hour. The organic phase was separated and washed with saturated sodium bicarbonate solution (50 ml), water (100 ml) and saturated sodium chloride solution (50 ml). The solution was dried (MgSO4) and the solvent was removed by evaporation to give 4-methoxycarbonylphenylboronic acid (27.7 g), m.p. 227-229° C.
Reaction SMILES: [ClH:1].Cl[C:3]1[CH:4]=[CH:5][C:6]([CH3:11])=[C:7]([NH:9][NH2:10])[CH:8]=1.N[C:13]([CH3:17])=[CH:14][C:15]#[N:16]>>[NH2:16][C:15]1[N:9]([C:7]2[CH:8]=[CH:3][C:4]([Cl:1])=[CH:5][C:6]=2[CH3:11])[N:10]=[C:13]([CH3:17])[CH:14]=1
Reactant: CC(N)=CC#N
Reactant: Cl
Reactant: Cc1ccc(Cl)cc1NN
Product: Cc1cc(N)n(-c2ccc(Cl)cc2C)n1

Procedure:
5-chloro-2-methylphenylhydrazine HCl (80.32 g.) was reacted with 3-amino-2-butene nitrile (32.5 g.) as described in Example XLIII to give 60.5 g. product, mp 86°-87°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH3:15])[CH2:9][C:10]([O:12]C)=[O:11])=[CH:4][C:3]=1[NH:16][C:17](=[O:32])[C@H:18]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C@@H:19]([CH3:24])[C:20]([F:23])([F:22])[F:21].S(=O)(=O)(O)O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH3:15])[CH2:9][C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[NH:16][C:17](=[O:32])[C@H:18]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C@@H:19]([CH3:24])[C:20]([F:23])([F:22])[F:21]
Reactant: CCC(CC(=O)OC)c1ccc(Cl)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CCC(CC(=O)O)c1ccc(Cl)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1
Temperature: 140 °C
Reaction time: 1.5 h

Procedure:
650 mg (1.33 mmol) of methyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)pentanoate (diastereomer mixture) were dissolved in 2 ml of acetic acid, 1 ml of 30% strength sulphuric acid was added and the mixture was heated at reflux (bath temperature about 140° C.). After 1.5 h, the reaction mixture was cooled and added to water. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with sat. sodium bicarbonate solution and sat. sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. After drying under high vacuum, the residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1). This gave 600 mg of the target product (95% of theory).