Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18](O)=[O:19])[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[F:1][C:2]1([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([CH2:18][OH:19])[N:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH2:7]1
Reactant: O=C(O)c1cc2ccccc2c(C2(F)C=CC=CC2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1cc2ccccc2c(C2(F)C=CC=CC2)n1

Procedure:
1-(1-Fluorophenyl)-3-isoquinolinecarboxylic acid was converted into its ethylester and then reduced using lithium aluminum hydride to obtain 1-(1-fluorophenyl)-3-isoquinolinemethanol. 1.26 g of the obtained 1-(1-fluorophenyl)-3-isoquinolinemethanol was reacted with 930 mg of methyl p-toluenesulfonate in the same manner as in Reference Example 10 to give 1.6 g of the desired compound as a pale orange-colored solid.
Reaction SMILES: BrC1C=CC(CCCNC)=CC=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([NH:23][CH3:24])=O)=[CH:16][CH:15]=1.B>C1COCC1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:23][CH3:24])=[CH:18][CH:19]=1
Reactant: CNC(=O)Cc1ccc(Br)cc1
Agent: B
Agent: CNCCCc1ccc(Br)cc1
Solvent: C1CCOC1
Product: CNCCc1ccc(Br)cc1
Yield: 96.7 %

Procedure:
Using a procedure analogous to that used to prepare 22B, 23A (1.6 g, 7.0 mmol) was reduced with borane in THF to yield 23B (1.45 g, 97%) as a clear oil. MS (ESI) m/z 214.22/216.22 (M+H)+.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:5][CH2:4]1)=O.S(=O)(=O)(O)O>C(O)C>[N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[CH:19][C:10]=1[CH2:9][N:6]1[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1
Reactant: O=CN1CCN(Cc2ccc3ccccc3n2)CC1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: c1ccc2nc(CN3CCNCC3)ccc2c1
Reaction time: 96 h
Yield: 97.6 %

Procedure:
1-Formyl-4-(2-quinolylmethyl)piperazine (86.00 g, 332 mmol) was dissolved in ethanol (800 ml), followed by the addition of concentrated sulfuric acid (49.04 g, 500 mmol). After the resulting mixture was heated under reflux and stirring for 4 days, the solvent was distilled off under reduced pressure. The thus-obtained residue was dissolved in water. After the resulting solution was washed twice with chloroform, the solution was rendered basic with a 10N aqueous solution of sodium hydroxide, followed by extraction with chloroform. The extract was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, whereby 73.65 g of the title compound were obtained as a pale amber oil (yield: 97.6%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=O)[CH2:8][C:9](=O)[C:10]([F:13])([F:12])[F:11])[CH:2]=1.C(C1C=NC=CC=1)(=O)C.[NH2:25][C:26]1[N:27]=[CH:28][NH:29][C:30]=1[C:31]#[N:32]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[N:27]3[CH:28]=[N:29][C:30]([C:31]#[N:32])=[C:26]3[N:25]=2)[CH:2]=1
Reactant: N#Cc1[nH]cnc1N
Reactant: O=C(CC(=O)C(F)(F)F)c1cccnc1
Agent: CC(=O)c1cccnc1
Product: N#Cc1ncn2c(C(F)(F)F)cc(-c3cccnc3)nc12
Yield: 12.8 %

Procedure:
Reaction of 1-pyridin-3-yl-4,4,4-trifluoro-butane-1,3-dione (217 mg, 1.0 mmol), prepared from commercially available 3-acetylpyridine according to general procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (37 mg, 13%). MS (ISP) 290.1 [(M+H)+]; mp 222° C.
Reaction SMILES: O=C1CCC(N2C3C=CC=CC=3NC2=O)CC1.N1(C(OC(C)(C)C)=O)CCNCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+].[C:51]([C:55]([N:57]1[CH2:62][CH2:61][N:60]([C@@H:63]2[CH2:68][CH2:67][C@H:66]([N:69]3[C:73]4[CH:74]=[CH:75][CH:76]=[CH:77][C:72]=4[NH:71][C:70]3=[O:78])[CH2:65][CH2:64]2)[CH2:59][CH2:58]1)=[O:56])([CH3:54])([CH3:53])[CH3:52]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCCl>[C:51]([C:55]([N:57]1[CH2:58][CH2:59][N:60]([C@H:63]2[CH2:64][CH2:65][C@H:66]([N:69]3[C:73]4[CH:74]=[CH:75][CH:76]=[CH:77][C:72]=4[NH:71][C:70]3=[O:78])[CH2:67][CH2:68]2)[CH2:61][CH2:62]1)=[O:56])([CH3:54])([CH3:52])[CH3:53]
Reactant: CC(C)(C)C(=O)N1CCN([C@H]2CC[C@@H](n3c(=O)[nH]c4ccccc43)CC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)C(=O)N1CCN([C@H]2CC[C@H](n3c(=O)[nH]c4ccccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1.5 g of 1,3-dihydro-1-(4-oxocyclohexyl)-2H-benzimidazol-2-one, 1.21 g of tert-butyl 1-piperazinecarboxylate, 20 mL of 1,2-dichloroethane, 0.40 mL of glacial acetic acid and 1.79 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was poured into 50 mL chloroform and 50 mL saturated aqueous Na2CO3 and the layers separated. The aqueous layer was extracted with 2'25 mL of chloroform and the combined organic layers dried over MgSO4 and concentrated under reduced pressure. Chromatography of the crude product on silica gel, eluting with 10% methanol in choroform gave, firstly, 0.63 g of 1,3-dihydro-1-{cis-4-[4-(tert-butylcarbonyl)piperazin-1-yl]-1-cyclohexyl}-2H-benzimidazol-2-one: 1H NMR (400 MHz, CDCl3) 7.47 (m, 1H), 7.25 (m, 1H), 7.05 (m, 2H), 4.55 (m, 1H), 3.54 (m, 4H), 2.49 (m, 6H), 2.27 (s, 0.8H), 2.15 (d, 2H), 1.97 (m, 0.2H), 1.57 (m, 4H), 1.49 (s, 9H). Later fractions gave 1,3-dihydro-1-{trans-4-[4-(tert-butylcarbonyl)piperazin-1-yl]-1-cyclohexyl}-2H-benzimidazol-2-one: 1H NMR (400 MHz, CDCl3) 7.15 (m, 2H), 7.06 (m, 2H), 4.28 (m, 1H), 3.46 (m, 4H), 2.56 (m, 4H), 2.5 (m, 1H), 2.26 (m, 2H), 2.03 (m, 6H), 1.47 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH:9]([CH3:11])[CH3:10])[C:3]=1[OH:12].[C:13](=S)(OCC)[S-:14].[K+]>C(O)C>[CH:9]([C:4]1[C:3]2[O:12][C:13]([SH:14])=[N:1][C:2]=2[C:7]([CH3:8])=[CH:6][CH:5]=1)([CH3:10])[CH3:11]
Reactant: Cc1ccc(C(C)C)c(O)c1N
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(C(C)C)c2oc(S)nc12
Yield: 60.3 %

Procedure:
To a solution of 4-chloro-6-isopropyl-3-methyl-2-nitrophenol (1.82 g, 7.92 mmol) obtained in Example 97 in ethanol (40 ml) was added 10% palladium carbon catalyst (1.8 g) and the mixture was stirred under hydrogen atmosphere at 60° C. for 3 hours. After the reaction was over, the reaction solution was filtered with celite and the filtrate was concentrated to provide 1.60 g of 2-amino-6-isopropyl-3-methylphenol (yield 99%) as pale brown solid. To a solution of this aminophenol (1.65 g, 7.92 mmol) in ethanol (25 ml) was added potassium O-ethyl dithiocarbonate (1.52 g, 9.50 mmol) and the mixture was heated to reflux for 8 hours and the solvent was evaporated. The resulting residue was dissolved in water, acidified to pH, 3-4 with 2 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, a saturated sodium chloride solution successively, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was crystallized from ethyl acetate-hexane to provide 0.99 g (yield 60%) of 7-isopropyl-2-mercapto-4-methylbenzoxazole as pale yellow needles.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:11][CH:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[F:20])[CH2:9]2)[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[NH2:30][C:31]1[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=1)[C:34]([NH:36][CH3:37])=[O:35]>C(O)(C)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH:10]2[CH2:11][N:8]([C:6]3[N:5]=[CH:4][N:3]=[C:2]([NH:30][C:31]4[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=4)[C:34]([NH:36][CH3:37])=[O:35])[N:7]=3)[CH2:9]2)=[C:14]([F:20])[CH:15]=1
Reactant: Fc1cc(Cl)ccc1OC1CN(c2ncnc(Cl)n2)C1
Reactant: CNC(=O)c1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CNC(=O)c1cccc(Nc2ncnc(N3CC(Oc4ccc(Cl)cc4F)C3)n2)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 48.4 %

Procedure:
To a solution of 2-chloro-4-(3-(4-chloro-2-fluorophenoxy)azetidin-1-yl)-1,3,5-triazine (0.800 g, 2.54 mmol) in Isopropanol (8 mL, 3 mL/mmol) was added DIPEA (0.7 mL, 3.81 mmol) and 3-amino-N-methylbenzamide (0.382 g, 2.54 mmol) and the reaction mixture was stirred at 80° C. for 24 h. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×40 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography to obtain 3-(4-(3-(4-chloro-2-fluorophenoxy)azetidin-1-yl)-1,3,5-triazin-2-ylamino)-N-methylbenzamide (0.527 g, 53%) as a solid. Observed mass (M+1): 428.9
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[NH:17])C1C=CC=CC=1.C.C(O)(=O)C>CO.[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][S:19]([C:22]1[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=1)(=[O:21])=[O:20])=[NH:17]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCCCCCOCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCCCCCO)cc1
Reaction time: 1 h
Yield: 100.2 %

Procedure:
3.20 g (7.9 mmol) of N—(N-(6-(benzyloxy)hexyl)carbamimidoyl)-4-methylbenzenesulfonamide were dissolved under nitrogen in MeOH. A few mg of 10% Palladium over activated charcoal were added. 1 mL of acetic acid was added. 3 vacuo hydrogen flush were done before stirring vigorously the reaction under a H2 atmosphere. The reaction was vigorously stirred at room temperature for 3 hours and checked by TLC. No conversion was found and 2 mL of acetic acid were added. After 1 hour, the TLC showed no conversion and more 10% Palladium over activated charcoal were added. After 3 days, the TLC showed a complete conversion and the solution was filtered over celite and the solvent evaporated to afford 2.480 g of N—(N-(6-hydroxyhexyl)carbamimidoyl)-4-methylbenzenesulfonamide as slightly yellow oil was obtained (yield=100%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:5]=[CH:6][C:7]2[C:16](=[O:17])[N:15]([CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:14][C@H:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8]=2[N:25]=1)[CH3:2].Br[C:27]1[CH:28]=[N:29][CH:30]=[N:31][CH:32]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(O)(C)(C)C>[CH2:1]([NH:3][C:4]1[N:5]=[CH:6][C:7]2[C:16](=[O:17])[N:15]([CH2:18][CH:19]3[CH2:20][CH2:21][N:22]([C:27]4[CH:28]=[N:29][CH:30]=[N:31][CH:32]=4)[CH2:23][CH2:24]3)[CH2:14][C@H:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8]=2[N:25]=1)[CH3:2]
Reactant: CCNc1ncc2c(n1)N1CCC[C@H]1CN(CC1CCNCC1)C2=O
Reactant: Brc1cncnc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(CC1CCN(c3cncnc3)CC1)C2=O
Yield: 39.2 %

Procedure:
(S)-9-Ethylamino-5-(piperidin-4-yl)methyl-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (83.6 mg, 0.243 mmol) obtained in Step 1, 5-bromopyrimidine (96.4 mg, 0.607 mmol), tris(dibenzylideneacetone)dipalladium (33.3 mg, 0.0364 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (57.4 mg, 0.146 mmol), and sodium tert-butoxide (46.6 mg, 0.485 mmol) were dissolved in 1,4-dioxane (2.8 ml) and tert-butyl alcohol (1.4 ml) under an atmosphere of nitrogen, and the mixture was stirred at 80° C. for 4 hours. The reaction mixture was filtered through sellite, and the residue obtained by concentrating the filtrate was purified by silica gel column chromatography, and crystallized from diisopropylether to give the title compound (Compound 32) (40.2 mg, 39%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:15]#[N:16].[K+].Cl>C(OCC)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:14])([C:15]#[N:16])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: N#CC1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
A solution of 1-benzylpiperidin-4-one (7.00 g) in 1:1 diethyl ether-water (30 mL) was cooled to 0° C. and treated with potassium cyanide (6.02 g), followed by hydrochloric acid (7.71 mL). The ice bath was removed and the mixture was stirred at room temperature for 18 hours. The phases were separated, and the aqueous layer was extracted with diethyl ether, dried and evaporated in vacuo to provide the title compound (4.08 g) having the following physical data.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]([OH:20])[CH2:18]Cl)=[N:5][N:6]=1.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22]>O1CCOCC1>[CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]([OH:20])[CH2:18][NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:5][N:6]=1
Reactant: Cc1nnc(C=Cc2ccccc2OCC(O)CCl)s1
Reactant: CC(C)(C)N
Solvent: C1COCCO1
Product: Cc1nnc(C=Cc2ccccc2OCC(O)CNC(C)(C)C)s1

Procedure:
1.6 g of 2-methyl-5-[2-(2-hydroxy-3-chloro-propoxy)-styryl]-1,3,4-thiadiazole and 10 ml of tert.-butylamine in 50 ml of dioxane are heated for 10 hours at 100° C. in an autoclave. After distilling off the volatile constitutents under reduced pressure the highly viscous crude product is chromatographed over a dry silica gel column, using chloroform. The residue obtained on evaporating the eluates containing the product gives 2-methyl-5-[2-(2-hydroxy-3-tert.-butylamino-propoxy)styryl]-1,3,4-thiadiazole. The compound, in its isolated form, is identical with the compound obtained as described in Example 3.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.[OH:13][C:14]1[CH:18]=[C:17]([N:19]2[C:23]3[CH:24]=[N:25][CH:26]=[CH:27][C:22]=3[N:21]=[CH:20]2)[S:16][C:15]=1[C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:21]1[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[N:19]([C:17]2[S:16][C:15]([C:28]([O:30][CH3:31])=[O:29])=[C:14]([O:13][CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=3)[CH:18]=2)[CH:20]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1cccc(C(F)(F)F)c1

Procedure:
In a similar manner as described for example B11, 102.8 mg of 3-(trifluoromethyl)benzyl bromide, 100 mg of methyl 3-hydroxy-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate, 59.7 mg of potassium carbonate in 3 ml anhydrous DMF yield the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.B(O[O-])=[O:12].[Na+].[B-]1(O)(O)OO[B-](O)(O)OO1>C(O)(=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N+:2]=1[O-:12]
Reactant: c1ccc2cnccc2c1
Reactant: O=BO[O-]
Agent: O[B-]1(O)OO[B-](O)(O)OO1
Agent: [Na+]
Solvent: CC(=O)O
Product: [O-][n+]1ccc2ccccc2c1
Reaction time: 8 h
Yield: 109 %

Procedure:
To a solution of isoquinoline (76.93 g, 595.6 mmol) in acetic acid (520 mL) was added portionwise every 10 min. 33.6 g of sodium perborate, NaBO3.4H2O. Over a 1 hour period a total of 201.6 g (1.31 mole) of perborate was added. The resulting mixture was stirred at 60° C. for 24 hours after which acetic acid was removed by passing a stream of air over the surface of the liquid contained in a large flat vessel overnight. The remaining solid was dissolved in 1 L of water and the solution neutralized with solid sodium bicarbonate. The solution was extracted with chloroform (3×300 mL) and the organic extracts dried over magnesium sulfate. Chloroform was evaporated and the residual white solid was redissolved in chloroform and precipitated by addition of hexane to give 65 g (75%) of the N-oxide: mp 138-140° C. (lit mp 141-142° C.)
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[CH:25]=[C:24]([S:26]([CH2:29][CH:30]([CH3:32])[CH3:31])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=1[CH3:33]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:22]2[CH:23]=[C:24]([S:26]([CH2:29][CH:30]([CH3:31])[CH3:32])(=[O:27])=[O:28])[CH:25]=[CH:20][C:21]=2[CH3:33])[CH:11]=1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)CC(C)C)cc1Br
Product: Cc1ccc(S(=O)(=O)CC(C)C)cc1C#Cc1cc(Cl)ccc1OCC(=O)O

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-chloro-2-ethynyl phenoxy)acetate (Intermediate 3) and 2-bromo-4-(isobutylsulfonyl)-1-methylbenzene (Intermediate 66), the title compound was obtained as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH2:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH:34][C:9]([CH2:8][NH:7][C:6](=[O:12])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:14][CH:13]=2)=[O:11])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=2)=[CH:19][CH:18]=1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Reactant: NC(c1ccc(Cl)cc1)c1cccc(C(F)(F)F)c1
Agent: Cl
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1ccc(Cl)cc1)c1cccc(C(F)(F)F)c1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(4-chloro-phenyl)-C-(3-trifluoromethyl-phenyl)-methylamine hydrochloride (CA [49703-70-0]).
Reaction SMILES: [CH2:1]([N:4]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[S:14][C:13]([CH2:15][NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[N:12][C:11]=2[CH:25]=1)=[O:6])[CH2:2][CH3:3].[ClH:33].C(O)C.C(=O)([O-])[O-].[NH4+:41].[NH4+]>C(O)(=O)C.C(Cl)Cl.C(O)C>[ClH:33].[CH2:1]([N:4]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[S:14][C:13]([CH2:15][NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23](=[NH:41])[NH2:24])=[CH:19][CH:18]=3)=[N:12][C:11]=2[CH:25]=1)=[O:6])[CH2:2][CH3:3]
Reactant: CCCN(CCC(=O)OCC)C(=O)c1ccc2sc(CNc3ccc(C#N)cc3)nc2c1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCO
Product: CCCN(CCC(=O)OCC)C(=O)c1ccc2sc(CNc3ccc(C(=N)N)cc3)nc2c1
Yield: 83 %

Procedure:
Prepared analogously to Example 9 from 2-[N-(4-cyanophenyl)aminomethyl]benzothiazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)amide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 83% of theory, C24H29N5O3 (467.59); Rf value: 0.31 (silica gel; methylene chloride/ethanol=4:1+a few drops of acetic acid); EKA mass spectrum: (M+H)+=468; (2M+H)+=935.
Reaction SMILES: Cl.Cl[C:3]1[CH:4]=[CH:5][C:6]2[CH2:15][C@H:14]3[C@@H:9]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:16][CH2:17][CH3:18])[CH2:8][C:7]=2[N:19]=1.Cl.[CH3:21][NH:22][CH3:23].[OH-].[Na+]>O>[CH3:21][N:22]([CH3:23])[C:3]1[CH:4]=[CH:5][C:6]2[CH2:15][C@H:14]3[C@@H:9]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:16][CH2:17][CH3:18])[CH2:8][C:7]=2[N:19]=1
Reactant: CCCN1CCC[C@H]2Cc3nc(Cl)ccc3C[C@@H]21
Reactant: CNC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCN1CCC[C@H]2Cc3nc(N(C)C)ccc3C[C@@H]21
Temperature: 200 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
A mixture of (±)-trans-2-chloro-6-propyl -5,5a,6,7,8,9,9a,10-octahydropyrido[2,3-g]quinoline hydrochloride (1.00 g, 3.32 mmol) and dimethylamine hydrochloride (15 g) was heated to 200° C. to form a homogeneous molten semi-solid. After 30 minutes, the molten semi-solid was poured into water, made basic with dilute NaOH solution, and extracted with methylene chloride. The extract was dried (Na2SO4) and concentrated to give the crude product as a brown solid. Purification by flash chromatography (10% methanol in methylene chloride, NH4OH) provided (±)-trans-2-dimethylamino-6-propyl-5,5a,6,7,8, 9,9a, 10-octahydropyrido [2,3-g]quinoline (Rf=0.54, 568 mg, 63% yield) as an orange oil.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:11][OH:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[ClH:27].[H][H]>[Pd]>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:11][OH:12])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6].[ClH:27]
Reactant: [H][H]
Reactant: COC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Product: COC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(C)C

Procedure:
4.20 Grams of Z-Leu-Ser-OCH3 was suspended in a mixture of 40 ml of methan-1 with 11.46 ml of 1N-hydrochloric acid, then a small amount of palladium black was added to the suspension, stirred for 18 hours under the condition of introducing hydrogen gas. After completion of the reaction the catalyst was removed by suction filtration, the filtrate was subjected to distillation under a reduced pressure, further to the residue obtained was added water and distillation under a reduced pressure were repeated 3 times. The residue thus obtained was dried under a reduced pressure in a desiccator containing phosphorus pentoxide as the desiccant to obtain the desired product.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].C(N(CC)CC)C.[C:13]1(=[O:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1>CN(C)C=O.CCCCC>[CH3:1][Si:2]([CH3:4])([CH3:3])[O:22][CH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1
Reactant: C[Si](C)(C)Cl
Reactant: O=C1CCc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCCCC
Product: C[Si](C)(C)OC1C=Cc2ccccc21

Procedure:
Trimethylsilyl chloride (5.7 g, 52.3 mmole), triethylamine (11.71 g, 116 mmole), and 1-indanone (6.22 g, 47.1 mmole) were dissolved in dimethyl formamide (25 mL) and refluxed for 17 hours. After cooling, the mixture was diluted with pentane (50 mL) and washed four times with saturated sodium bicarbonate. After backwashing the aqueous phase with pentane the organic layers were combined, washed with cold 2N HCl and cold saturated sodium bicarbonate, then dried over MgSO4. The solvent was evaporated and the residue distilled (bp 123°-125° C.).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[C:8]1([O:16][CH3:17])[C:9](=[CH:12][CH:13]=[CH:14][CH:15]=1)[O:10][CH3:11].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[CH3:11][O:10][C:9]1[CH:12]=[C:13]([CH:14]=[CH:15][C:8]=1[O:16][CH3:17])[C:4]([CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[O:5]
Reactant: O=C1CCC(=O)O1
Reactant: COc1ccccc1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)CCC(=O)O)cc1OC
Reaction time: 6 h
Yield: 64 %

Procedure:
70 g (0.7 mol) of succinic anhydride and 96.6 g (0.7 mol) of veratrol were dissolved in 2000 ml of methylene chloride, and 237 g (1.75 mol) of anhydrous aluminum chloride was added thereto at room temperature. The mixture was stirred at the same temperature for 6 hours. The reaction solution was allowed to stand for 15 hours, and then 1600 ml of 6N hydrochloric acid was dropwise added under stirring. The mixture was stirred for 1 hour, and the organic layer was separated. 300 ml of water was added to the organic layer and adjusted to pH7.5 with a saturated sodium hydrogencarbonate aqueous solution. The water layer was separated, adjusted to pH2.5 with 6N hydrochloric acid and allowed to stand in a refrigerator for 2 days. The precipitated crystals were collected by filtration, washed and dried to obtain 106.8 g (yield: 64%) of 3-(3,4-dimethoxybenzoyl)propionic acid.