Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26](OCC)=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[NH2:34][CH:35]([CH2:38][OH:39])[CH2:36][OH:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26]([NH:34][CH:35]([CH2:38][OH:39])[CH2:36][OH:37])=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O
Reactant: NC(CO)CO
Product: O=C(NC(CO)CO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-(4-fluorobenzyl)-4-hydroxy-2-oxo-1-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-amino-1,3-propanediol using conditions similar to those employed in Example 563 to provide a white solid: ES+ MS: 499 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].Cl.Cl.[CH2:14]([NH:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:30][CH2:29][C:28]2[C:31]3[CH:21]1[CH2:22][CH2:23][C:24]=3[C:25]([O:34][CH3:35])=[C:26]([O:32][CH3:33])[CH:27]=2)[CH3:15].CCN(C(C)C)C(C)C>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:16]([CH2:17][CH2:18][CH2:19][N:20]1[CH2:30][CH2:29][C:28]2[C:31]3[CH:21]1[CH2:22][CH2:23][C:24]=3[C:25]([O:34][CH3:35])=[C:26]([O:32][CH3:33])[CH:27]=2)[CH2:14][CH3:15])(=[O:10])=[O:9]
Reactant: CCNCCCN1CCc2cc(OC)c(OC)c3c2C1CC3
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCCN1CCc2cc(OC)c(OC)c3c2C1CC3)S(=O)(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
2-Chlorobenzenesulfonyl chloride (246.1 mg, 1.17 mmol) was added to a solution of Ethyl-[3-(7,8-Dimethoxy-2,2a,4,5-tetrahydro-1H-3-aza-acenaphthylen-3-yl)-propyl]-amine dihydro-chloride (400 mg, 1.06 mmol) and N,N′-diisopropylethylamine (1.01 ml, 6.4 mmol) in CH2Cl2 (20 mL) and the mixture was stirred overnight at room temperature. The resulting solution was washed with water (3×20 mL), dried over Na2SO4 and evaporated to dryness. The free base was dissolved in ethyl acetate and A 2.8 M solution of hydrogen chloride in ethanol (0.50 mL) was then added. The product was crystallized and collected by filtration, and vacuum dried to give a white solid (233 mg, 43%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[CH2:18][CH:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:16][C:15](=O)[C:14]=3[CH:13]=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:27]([NH:30][NH2:31])([NH2:29])=[NH:28].[ClH:32].Cl.O>C(O)C>[ClH:32].[NH:30]([N:31]=[C:15]1[CH2:16][CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][C:19]2[N:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH:12]=[CH:13][C:14]1=2)[C:27]([NH2:29])=[NH:28]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2CC(c2ccccc2)CC3=O)cc1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2CC(c2ccccc2)CC3=NNC(=N)N)cc1
Yield: 87.8 %

Procedure:
A mixture of 1-(4-methylphenyl)sulfonyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (1.0 g), aminoguanidine hydrochloride (0.32 g), concentrated hydrochloric acid (0.14 ml), water (0.14 ml) and ethanol (50 ml) was refluxed for 20 minutes. Under reduced pressure, the solvent was evaporated, and the residue was washed with water, dried and recrystallized from ethanol to give 4-guanidinoimino-1-(4-methylphenyl)sulfonyl-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 19) (1.1 g) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=1)=[O:14].CC1(C)C(C)(C)OB([C:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(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>[F:23][C:22]([F:25])([F:24])[C:18]1[N:17]=[C:16]([NH:15][C:13](=[O:14])[NH:12][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH:35]=4)[CH:3]=3)[N:8]=[CH:7][CH:6]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=C(Nc1cccc(C(F)(F)F)n1)Nc1ccnc2ccc(Br)cc12
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: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3nccc(NC(=O)Nc4cccc(C(F)(F)F)n4)c3c2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 106.7 %

Procedure:
1.500 g of 1-(6-bromo-quinolin-4-yl)-3-(6-trifluoromethyl-pyridin-2-yl)-urea (3.65 mmol), 1.692 g of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (5.47 mmol), 0.422 g of tetrakis(triphenylphosphine)palladium(0) (0.365 mmol) and 8.21 ml of a 2M sodium carbonate solution (16.42 mmol) were dissolved/suspended in 32 ml DMF in a microwave vessel, flushed with vacuum/argon, and subsequently heated in the microwave for 1 h at 80° C. HPLC/MSD indicated almost complete formation of the desired product. The reaction mixture was poured on ice, stirred for 1 h, and the precipitation formed was filtered off and dried in vacuum for 24 h. 2 g of the desired product were obtained as an off white powder (yield: quant.). The quite pure raw material was used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([OH:11])[CH3:10])=[CH:4][CH:3]=1.Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([CH3:22])[CH:16]=[C:15]([CH3:23])[N:14]=1>>[CH3:22][C:17]1[CH:16]=[C:15]([CH3:23])[N:14]=[C:13]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([OH:11])[CH3:10])=[CH:6][CH:7]=2)[C:18]=1[N+:19]([O-:21])=[O:20]
Reactant: CC(O)Cc1ccc(N)cc1
Reactant: Cc1cc(C)c([N+](=O)[O-])c(Cl)n1
Product: Cc1cc(C)c([N+](=O)[O-])c(Nc2ccc(CC(C)O)cc2)n1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 1-(4-aminophenyl)-2-propanol (step 1) and 2-chloro-4,6-dimethyl-3-nitropyridine (step 2 of Example 1).
Reaction SMILES: [CH3:1][CH:2]([C:10]#[N:11])[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH2:18]=[O:19].[OH-].C([N+](CC)(CC)CC)C1C=CC=CC=1>O>[C:10]([C:2]([C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[CH:7][CH:8]=1)([CH3:1])[CH2:18][OH:19])#[N:11]
Reactant: C=O
Reactant: CC(C#N)c1ccc(Cl)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CC(C#N)(CO)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To an ice cold stirred solution of α-methyl-4-chlorobenzyl cyanide* (50 g., 0.3 mole) in 500 ml. of pyridine containing a suspension of paraformaldehyde (36 g., 1.2 mole) is added 1 ml. of benzyl triethylammonium hydroxide. The mixture is stirred under nitrogen at room temperature for 72 hours. The reaction mixture is poured into water and extracted with ether. The combined ether extracts are washed with water, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give a thick oil, 58.4 g, which is identified by nmr.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20]O)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS(Cl)(=O)=O.[CH3:39][NH:40][CH2:41][CH:42]([OH:50])[C:43]1[CH:44]=[CH:45][C:46]([OH:49])=[CH:47][CH:48]=1>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20][N:40]([CH2:41][CH:42]([OH:50])[C:43]4[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=4)[CH3:39])[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:23][CH:24]=1
Reactant: CNCC(O)c1ccc(O)cc1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)sc21
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Product: CN(Cc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2s1)CC(O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a solution of N-(4-chlorobenzyl)-2-(hydroxymethyl)-7-methyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (0.300 g) from Example No. 35 in DMF (17 mL) are added DMAP (16 mg), 2,4,6-collidine (0.27 mL), and methanesulfonyl chloride (0.16 mL). The reaction mixture is stirred at room temperature for 1 h and then synephrine (1.39 g) is added. The mixture is stirred at room temperature for 18 h and is then poured into water (50 mL). The resulting off-white solid is filtered off. Additional material precipitates out of the filtrate. The two lots of material are combined and purified by column chromatography (CH2Cl2, CH2Cl2/methanol, 99/1; 98/2; 96/4) to yield 0.253 g (60%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20](O)(=[O:23])[CH:21]=[CH2:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C=CC(O)=CC=1)O>O.C1(C)C(C)=CC=CC=1>[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:23])[CH:21]=[CH2:22]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Reactant: C=CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: C=CC(=O)OCCCCCCCC/C=C\CCCCCCCC
Yield: 80 %

Procedure:
To a 500 ml round bottom flask equipped with a stirrer, condenser, water trap and thermometer, was added oleyl alcohol (100 g, 0.373 moles), acrylic acid (27 g, 0.373) moles), p-toluenesulfonic acid monohydrate (1g, 1 wt%, hydroquinone (0.2 g, 0.2 wt%) and xylene (I00 ml). The reaction mixture was heated to reflux and maintained until no more water was collected (~4 hrs). The xylene solution was then concentrated to about half of its original volume. The crude product was then washed successively with water, saturated sodium bicarbonate solution, and then again with water. The organic solution was dried over sodium sulfate, filtered and the solvent evaporated under reduced pressure. The product was stabilized by 0.01 wt% of MEHQ. The yield was 80%.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[NH2:30][CH:31]([C:33]1[C:34](=[O:47])[NH:35][C:36]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)=[N:37][N:38]=1)[CH3:32].[C:48]([CH:51]([CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C:52](O)=[O:53])(=[O:50])[CH3:49]>>[C:48]([CH:51]([CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C:52]([NH:30][CH:31]([C:33]1[C:34](=[O:47])[NH:35][C:36]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)=[N:37][N:38]=1)[CH3:32])=[O:53])(=[O:50])[CH3:49]
Reactant: CCCCCC(C(C)=O)C(=O)O
Reactant: Cc1ccc(Cc2nnc(C(C)N)c(=O)[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCCCCC(C(C)=O)C(=O)NC(C)c1nnc(Cc2ccc(C)cc2)[nH]c1=O

Procedure:
The amount of 2-acetylheptanoic acid in dichloromethane from Example 17A is reacted analogously to Example 23A with 680 mg (5.0 mmol) of 1-hydroxy-1H-benzotriazole, 1.52 g (15.0 mmol) of 4-methylmorpholine, 960 mg (5.0 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 1.22 g (5.00 mmol) of 6-(1-aminoethyl)-3-(4-methylbenzyl)-1,2,4-triazin-5(4H)-one (Example 8A) to give 2-acetyl-N-{1-[3-(4-methylbenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}heptanamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24][NH:25][C:26]([O:28][CH3:29])=[O:27])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.C(=O)(O)[O-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[O:22][CH2:23][CH2:24][NH:25][C:26](=[O:27])[O:28][CH3:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 137.1 %

Procedure:
(R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-(methoxycarbonylamino)-ethoxy)methyl)piperidine-1-carboxylate (10.7 g, 25 mmol) was dissolved in a solution of 20% (V/V) TFA/CH2Cl2 (150 mL). The reaction mixture was stirred at room temperature for 1 h. TLC showed the reaction was completed. A solution of saturated sodium bicarbonate was added drop wise to adjust pH 8-9. The resulting mixture was extracted with CH2Cl2 (3×200 mL), washed with brine, dried over Na2SO4, concentrated in vacuo to afford methyl 2-((R)-(3-chlorophenyl)((R)-piperidin-3-yl)methoxy)ethylcarbamate (11.2 g, 100%), which was used for next step directly without purification.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:9]([C:11]2[S:15][CH:14]=[N:13][C:12]=2[CH3:16])[OH:10])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.N>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([CH:9]([C:11]2[S:15][CH:14]=[N:13][C:12]=2[CH3:16])[OH:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(O)c2scnc2C)c1
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Product: Cc1ncsc1C(O)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1-(3-Methoxyphenyl)-1-(4-methyl-5-thiazolyl)methanol (1 g) in dry dichloromethane (10 ml) was added dropwise to boron tribromide (1M solution in dichloromethane, 25 ml) at 0° C. The mixture was allowed to warm to room temperature and was stirred for 15 minutes. The mixture was poured onto ice (40 g) and 0.88 ammonia (10 ml). The precipitate was filtered off and purified by chromatography to give the title compound. M.p. 181°-184° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:17][C:18]1[S:26][C:25]2[C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[N:23][C:22]([Cl:33])=[N:21][C:20]=2[CH:19]=1>O1CCCC1>[Cl:33][C:22]1[N:23]=[C:24]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[C:25]2[S:26][C:18]([CH2:17][N:9]([CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[S:10]([CH3:13])(=[O:12])=[O:11])=[CH:19][C:20]=2[N:21]=1
Reactant: CS(=O)(=O)NCCN1CCOCC1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)N(CCN1CCOCC1)Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of N-(2-Morpholin-4-yl-ethyl)-methanesulfonamide in tetrahydrofuran under nitrogen was added sodium hydride, 60% dispersion in mineral (16 mg). The mixture was stirred at room temperature for 40 minutes. A solution of 6-Bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (125 mg) in tetrahydrofuran (5 ml) was added. The reaction mixture was stirred at room temperature for 3.5 hours, then 50° C. for 3.5 hours. The solvents were removed in vacuo to give a crude product which was purified by flash chromatography to yield N-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-(2-morpholin-4-yl-ethyl)-methanesulfonamide (138 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH:4]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)[CH2:5][NH:6][C:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)=O.[ClH:31].[CH2:32]([O:34][C:35]([CH:37]1[C:46]2[C:41](=[CH:42][C:43]([O:49][CH3:50])=[C:44]([O:47][CH3:48])[CH:45]=2)[C:40]([CH2:51][C:52]2[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[C:54]([O:60][CH3:61])[CH:53]=2)=[N:39][CH2:38]1)=[O:36])C>>[CH3:1][O:2][C:3]([CH:4]1[C:20]2[C:25](=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)=[N:6][CH2:5]1)=[O:30].[ClH:31].[CH3:32][O:34][C:35]([CH:37]1[C:46]2[C:41](=[CH:42][C:43]([O:49][CH3:50])=[C:44]([O:47][CH3:48])[CH:45]=2)[C:40]([CH2:51][C:52]2[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[C:54]([O:60][CH3:61])[CH:53]=2)=[N:39][CH2:38]1)=[O:36]
Reactant: CCOC(=O)C1CN=C(Cc2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc21
Reactant: COC(=O)C(CNC(=O)Cc1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: Cl
Product: COC(=O)C1CN=C(Cc2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc21

Procedure:
The hydrochloride of 3,4-dihydro-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]-4-isoquinoline carboxylic acid methyl ester was prepared by treating 2-(3,4-dimethoxyphenyl)-3-{{[(3,4-dimethoxyphenyl)methyl]carbonyl}amino}propanoic acid methyl ester via the method described for the preparation of 3,4-dihydro-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]-4-isoquinolinecarboxylic acid ethyl ester hydrochloride. Crystallization from methanol provided analytically pure 3,4-dihydro-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]-4-isoquinolinecarboxylic acid methyl ester, hydrochloride, mp 199°-200°.
Reaction SMILES: [I-].[CH3:2][O:3]/[N:4]=[C:5](\[C:10]1[CH:11]=[N+:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1)/[C:6]([F:9])([F:8])[F:7].CO.[BH4-].[Na+].O.CO>O>[CH3:2][O:3][N:4]=[C:5]([C:10]1[CH:15]=[CH:14][CH2:13][N:12]([CH3:16])[CH:11]=1)[C:6]([F:9])([F:7])[F:8]
Reactant: CO/N=C(\c1ccc[n+](C)c1)C(F)(F)F
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CON=C(C1=CN(C)CC=C1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
1-Methyl-3-(α,α,α-trifluoroacetyl)pyridinium-O-methyl oxime iodide (D10) (10.4 g, 0.030 mol) in a 1:1 mixture of water and methanol (20 ml) was added dropwise to a suspension of sodium borohydride (2.17 g, 0.057 mol) in 1:1 water/methanol (40 ml) at 0° C. The reaction mixture was maintained at 0° C. for 0.5 h then warmed to room temperature and stirred at this temperature for 1 h. The mixture was diluted with water (40 ml) and extracted with chloroform (3×100 ml). The combined organic extracts were dried (Na2SO4) and evaporated to give a gum which was chromatographed on silica using ethyl acetate as eluant to afford in order of elution 1-methyl-3-(α,α,α-trifluoroacetyl)-1,6-dihydropyridine-O-methyl oxime (3.65 g, 55%) as a mobile oil which rapidly became highly coloured and 1-methyl-3-(α,α,α-trifluoroacetyl)-1,2,5,6-tetrahydropyridine-O-methyl oxime (1.52 g, 23%) as a pale yellow mobile oil which consisted of a 14:1 mixture of E and Z isomers. A portion of this material (0.5 g, 0.0023 mol) was taken-up in benzene and irradiated (254 A) for 4 days. The benzene was removed in vacuo and the residue was filtered through silica using ethyl acetate as eluant to give a 3:1 mixture of E and Z isomers (0.25 g). Addition of oxalic acid gave a solid which was recrystallised twice from methanol/acetone to give the E isomer (0.12 g) m.p. 140°-143° C. The combined mother liquors were evaporated to give a solid which was a 1:1 mixture of E and Z isomers (E4) m.p. 103°-110° C.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:24]=[C:23]2[O:25][CH2:26][CH2:27][O:28][C:22]2=[CH:21][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)=O.[Cl:29][CH2:30][C:31](=O)[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>C(O)(=O)C>[Cl:29][CH2:30][C:31]1[C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[C:8]2[C:7](=[CH:24][C:23]3[O:25][CH2:26][CH2:27][O:28][C:22]=3[CH:21]=2)[N:6]=1
Reactant: COc1ccc(C(=O)c2cc3c(cc2N)OCCO3)cc1OC
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(CCl)nc2cc3c(cc2c1-c1ccc(OC)c(OC)c1)OCCO3
Temperature: 100 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
Conc. sulfuric acid (0.3 ml) was added to a mixture of 2-amino-3',4'-dimethoxy-4,5-ethylenedioxybenzophenone (6.5 g), ethyl 4-chloroacetoacetate (3.7 g) and acetic acid (60 ml), and the resulting mixture was stirred at 100° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was poured into water. The mixture was made alkaline with 2N NaOH and extracted with chloroform. The chloroform layer was washed with water and dried (MgSO4), and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel. From the fraction eluted with chloroform/ethyl acetate (7:3, v/v), ethyl 2-chloromethyl-4- (3,4-dimethoxyphenyl)-6,7-ethylenedioxyquinoline-3-carboxylate (5.5 g, 60%) was obtained and recrystallized from acetone.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>C(Cl)Cl>[F:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][N:11]([C:21](=[O:23])[CH3:22])[CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: Fc1nccnc1C1CCNCC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(c2nccnc2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-fluoro-3-(piperidin-4-yl)pyrazine (0.311 g, 1.716 mmol) dissolved in DCM (5 mL) was added triethylamine (0.286 mL, 2.06 mmol), then acetyl chloride, reagent grade (0.134 mL, 1.89 mmol). The reaction mixture was stirred at RT for 1 h then partitioned between DCM and water. The aqueous layer was extracted with DCM (3×) and the combined organic layer was washed with brine, dried (Na2SO4) and concentrated to give 1-(4-(3-fluoropyrazin-2-yl)piperidin-1-yl)ethanone as a yellow oil. MS (ESI, pos. ion) m/z: 224.0 (M-56).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][N:3]=1.C([Li])CCC.CN(C)[CH:32]=[O:33].O>C1(C)C=CC=CC=1>[F:24][C:18]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=1[CH:9]([S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[C:6]([CH3:8])=[CH:7][C:2]([CH:32]=[O:33])=[N:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)ncc1C(Sc1ccccc1)c1cc(F)ccc1F
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C=O)ncc1C(Sc1ccccc1)c1cc(F)ccc1F
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-bromo-5-[(2,5-difluorophenyl)(phenylthio)methyl]-4-methyl pyridine (1.2 g, 3.0 mmol) in toluene (30 ml) was cooled to −78° C., and n-butyllithium (1.54 M hexane solution, 2.5 ml, 3.9 mmol) was added in an argon atmosphere. After stirring for 10 minutes at the same temperature, the mixture was allowed to warm to −40° C., stirred for 30 minutes, and cooled again to −78° C., and N,N-dimethylformamide (302 μl, 3.9 mmol) was added thereto. After stirring for 30 minutes at the same temperature, water was added to the mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, subsequently dried over anhydrous sodium sulfate, and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel column chromatography. The fraction obtained from an elution with hexane:ethyl acetate=93:7 was concentrated under reduced pressure to obtain the title compound mg, 0.70 mmol, 25%) as a colorless oily substance.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]([CH3:13])[CH2:3]1.[Cl:14][C:15]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:16]=1[C:17](Cl)=[O:18]>C1COCC1>[Cl:14][C:15]1[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][C:16]=1[C:17]([NH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]([CH3:13])[CH2:3]1)=[O:18]
Reactant: CCOC(=O)C1CCC(N)CC1C
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1Cl
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Ethyl 4-amino-2-methylcyclohexanecarboxylate (780 mg, 4.21 mmol) in THF (10 ml) is treated with TEA (1.174 ml, 8.42 mmol) and the reaction mixture is cooled to 0° C. 2-Chloro-5-(trifluoromethyl)benzoyl chloride (921 mg, 3.79 mmol) is added dropwise and the reaction mixture is stirred and allowed to warm to RT. After 3 hours, the reaction is quenched with water and partitioned between EtOAc and sat. sodium bicarbonate. The organic portion is separated and dried over MgSO4 and concentrated in vacuo to afford the title compound which is used without further purification. [MH]+392.26.