Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:5]2[N:6]=[C:7]([NH:16][NH2:17])[CH:8]=[C:9]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:4]2[N:3]=1.C(O)(=O)C.[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O>C(O)C>[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=[N:17][NH:16][C:7]1[CH:8]=[C:9]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[N:4]2[N:3]=[C:2]([CH3:1])[CH:18]=[C:5]2[N:6]=1
Reactant: Cc1cccc(C=O)c1
Reactant: Cc1cc2nc(NN)cc(N3CCOCC3)n2n1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cccc(C=NNc2cc(N3CCOCC3)n3nc(C)cc3n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
There was dissolved, in ethanol (2 mL), (2-methyl-7-morpholin-4-yl-pyrazolo-[1,5-a]pyrimidin-5-yl)-hydrazine (24.7 mg, 0.0995 mM), then acetic acid (5.0 μL, 0.087 mM) and 3-methyl-benzaldehyde (12.9 μL, 0.109 mM) were added to the solution and the resulting mixture was stirred at room temperature for 2 hours. This reaction liquid was filtered and the resulting solid was washed with methanol to thus give the title compound (29.6 mg, yield: 85%).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]2)OCC1.[Br:12]Br.[NH2:14][C:15]([NH2:17])=[S:16]>Br>[BrH:12].[BrH:12].[S:16]1[C:10]2[CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6][C:5]=2[N:14]=[C:15]1[NH2:17]
Reactant: BrBr
Reactant: NC(N)=S
Reactant: NC1CCC2(CC1)OCCO2
Agent: Br
Product: Nc1nc2c(s1)CC(N)CC2
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
A solution of 9.43 g (60 mmol) (1,4-dioxa-spiro[4.5]dec-8-yl)amine in 120 mL concentrated aqueous hydrobromic acid is stirred for 15 minutes at room temperature and then 3.12 mL (60 mmol) bromine are added. After further stirring for 15 minutes, 4.56 g (60 mmol) of thiourea is added. The resulting solution is stirred for another at room temperature until a white precipitation can be observed. Afterwards the mixture is heated for 2 hours at 90° C. The clear reaction mixture is then concentrated under vacuum. The solid residue is suspended in ethanol, heated to reflux and filtrated after cooling to room temperature. The resulting residue is dried under high vacuum.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]=[O:21].[OH-].[K+].Cl>CO.O.C(Cl)Cl>[OH:21][CH2:20][C:14]1[C:15]([OH:19])=[CH:16][CH:17]=[C:18]2[C:13]=1[CH:12]=[CH:11][N:10]2[S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9]
Reactant: C=O
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(O)ccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(c1ccccc1)n1ccc2c(CO)c(O)ccc21
Temperature: 40 °C
Yield: 48.9 %

Procedure:
1-(Phenylsulfonyl)-1H-indol-5-ol (Intermediate 8, 0.80 g, 2.9 mmol) was dissolved in MeOH (20 mL) and formaldehyde (37 wt. % in H2O, 4.0 mL, 49 mmol) was added followed by a solution of KOH (1.64 g, 29.3 mmol) in water (20 mL). The reaction mixture was heated at 40° C. overnight. The mixture was made acidic with 1 M HCl and diluted with DCM, transferred to a separation funnel and extracted with DCM (2×). The combined organics were washed with brine (1×), dried (MgSO4) and evaporated. The crude product was dissolved in diethylether (100 mL) and evaporated to approximately 20 mL (precipitation of white crystals). The white crystals were filtered and washed with diethylether (2×) to give 0.43 g of the title compound as a white solid. MS m/z 286 [M+H—H2O]+.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[CH:28]([NH2:31])([CH3:30])[CH3:29]>CO>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:31][CH:28]([CH3:30])[CH3:29])=[N:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Fc1cccc(F)c1COc1cccnc1NC(=S)Nc1ccc(Cl)cc1
Reactant: CC(C)N
Solvent: CO
Product: CC(C)NC(=Nc1ccc(Cl)cc1)Nc1ncccc1OCc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of N-[3-(2,6-difluorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea (1.0 g, 0.0025 mol), yellow mercuric oxide (0.64 g, 0.003 mol) and isopropylamine (0.43 g, 0.0074 mol) in methanol (20 ml) was stirred at room temperature for 96 hours, and then heated at 50 ° C. for 8 hours. After cooling, the solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent and recrystallisation from acetonitrile gave the desired product. Yield 0.24 g (23%), m.p. 112°-113 ° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:18][NH2:19])[NH:10][CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)=[O:4].Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl.CCN(C(C)C)C(C)C>[O:23]=[C:21]1[N:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]2([C:3]([O:2][CH3:1])=[O:4])[CH2:18][NH:19]1
Reactant: COC(=O)C1(CN)CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C12CNCCN1C(=O)NC2
Reaction time: 0.5 h

Procedure:
3-Aminomethyl-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (Compound AA) from Step 3 was dissolved in 4 mL of dichloromethane and 1 mL of DIPEA, then triphosgene (108 mg, 0.36 mmol) was added at room temperature. After the reaction mixture was stirred for 30 minutes, the solvent was removed in vacuo. The residue was dissolved in 3 mL of dichloromethane and 1 mL of TFA. The reaction mixture was stirred for 1 hour at room temperature, and the solvent was removed in vacuo to give the crude Compound X which was used directly without further purification.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].[CH2:21]([O:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)(=O)C>O1CCCC1.[OH-].[Na+]>[CH2:21]([O:28][C:29]([NH:4][C:2]([C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][CH:6]=1)=[NH:3])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)CCCCOc1ccc(C(=N)N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CCCCOc1ccc(C(=N)NC(=O)OCc2ccccc2)cc1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
To a mixture of ethyl 5-(4-amidinophenoxy)valerate hydrochloride (14.6 g) in a mixture of tetrahydrofuran (150 ml) and 1N sodium hydroxide solution was added benzyloxycarbonyl chloride (10.4 ml) under cooling with ice-water for 1 hour. The mixture was stirred for 2 hours at 10° C. maintaining pH≈10 with 1N sodium hydroxide solution. The reaction mixture was poured into ethyl acetate (300 ml), and separated organic layer was washed with aqueous solution of sodium chloride, and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the resulting precipitate was washed with diethyl ether to give ethyl 5-[4-(N-benzyloxycarbonylamidino)phenoxy]valerate (171.48 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]([CH3:13])[CH3:12].[C:14](=[O:17])([O-])[O-].[K+].[K+].[Cl:20][C:21]1[C:28](Cl)=[C:27]([Cl:30])[C:24](C=O)=[CH:23][CH:22]=1>CS(C)=O>[CH:11]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([O:1][C:28]3[C:21]([Cl:20])=[CH:22][C:23]([CH:14]=[O:17])=[CH:24][C:27]=3[Cl:30])[CH:3]=2)[NH:7][CH:6]=1)([CH3:13])[CH3:12]
Reactant: O=Cc1ccc(Cl)c(Cl)c1Cl
Reactant: CC(C)c1c[nH]c2ccc(O)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)c1c[nH]c2ccc(Oc3c(Cl)cc(C=O)cc3Cl)cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Analogously to the procedure of Example V, 10.0 g (57.07 mmol) of 5-hydroxy-3-isopropylindole are dissolved in 300 ml of DMSO, 8.68 g (62.77 mmol) of potassium carbonate are added, the mixture is stirred for 10 min at room temperature and 11.95 g (57.07 mmol) of 4,5,6-trichlorobenzaldehyde are introduced in portions, and the mixture is additionally stirred for 2 hours at room temperature and 2 hours at 50° C. After quenching with ethyl acetate/ammonium chloride solution and silica gel chromatography by means of toluene, 12,01 g (85,4%) of the desired product are obtained.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH:9](OCC)=[O:10].[H-].[Na+]>C1COCC1>[CH:9]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[I:1])=[O:10]
Reactant: Nc1ccccc1I
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=CNc1ccccc1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.1 %

Procedure:
A solution of 2-iodaniline (6.0 g, 27.4 mmol) and ethyl formate (11.1 mL, 137.4 mmol) in 200 mL of THF was added dropwise to a suspension of sodium hydride (1.4 g, 34.2 mmol) in 250 mL of THF. The mixture was stirred at room temperature for 24 hours, quenched with water and extracted into ethyl acetate. The organic extract was dried (MgSO4), filtered and concentrated to give 6.3 g of crude N-formyl-2-iodoaniline as a tan solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].Cl.CO[C:10](OC)([CH3:12])[CH3:11].CC1C=CC(S(O)(=O)=O)=CC=1>O>[CH3:11][C:10]1([CH3:12])[O:6][CH:3]([CH2:2][NH2:1])[CH2:4][O:5]1
Reactant: COC(C)(C)OC
Reactant: NCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Product: CC1(C)OCC(CN)O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-aminopropane-1,2-diol (5 g, 54.88 mmol, 1.00 equiv) in water (15 mL). The pH value of the solution was adjusted to 1 with 37% hydrochloric acid. The resulting solution was stirred for 15 min at room temperature. Then the mixture was concentrated to dryness under vacuum. This was followed by the addition of 2,2-dimethoxypropane (32 mL), and 4-methylbenzene-1-sulfonic acid (423 mg, 2.46 mmol, 0.04 equiv). The resulting solution was stirred for 30 min at 85° C. The solid was collected by filtration, washed with acetone and then dissolved in dichloromethane. The PH value of the solution was adjusted to 9 with 2N sodium hydroxide solution. Two phases were separated. The aqueous phase was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate. Filtration and concentration under reducing pressure gave the title compound (light yellow oil). 1H-NMR (300 MHz, CDCl3): δ ppm 1.24(s, 3H), 1.33(s, 3H), 2.77 (s, 1H), 2.91(s, 1H), 3.67-3.72(m, 1H), 3.96-4.01(m, 1H), 4.20-4.28(m, 1H), 8.15(brs, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@:19]([CH2:32][CH:33]=O)([C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.[CH3:35][NH2:36].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@:19]([CH2:32][CH2:33][NH:36][CH3:35])([C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1
Reactant: CN
Reactant: COC(=O)[C@]1(CC=O)CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCC[C@@]1(C(=O)OC)CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OC(C)(C)C

Procedure:
The reaction was performed on the two separated batches of 1-(1,1-dimethylethyl) 2-methyl (2R,5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-2-(2-oxoethyl)-1,2-pyrrolidinedicarboxylate obtained from the previous step (D37, Procedure 1). The first batch (109 g) was dissolved in MeOH (440 mL) and MeNH2 in MeOH 2M solution (347 mL) was added. AcOH (11 mL) was added. NaBH(OAc)3 (49 g) was added portion wise after 10 minutes. More NaBH(OAc)3 (14.7 g) was added portion wise at 25° C. The reaction mixture was quenched with 28% aqueous malic acid (200 mL) followed by AcOEt (1000 mL). K2CO3 was added up to pH˜9. Organic phase was concentrated to dryness, re-dissolved in EtOAc (500 mL) and extracted with 20% citric acid (4×300 mL). The combined aqueous phases were treated with EtOAc (500 mL) and solid K2CO3 was added until pH˜9. The phases were separated and the organic phase was dried under Na2SO4 and evaporated to dryness to afford the title compound (80 g). The second batch (180 g) was dissolved in MeOH (628 mL) and MeNH2 in MeOH 2M solution (300 mL) was added. AcOH (31 mL) was added. NaBH(OAc)3 (78.8 g) was added portionwise at 0° C. after 10 minutes. The reaction mixture was quenched with saturated NH4Cl (890 mL) and EtOAc (890 mL). The phases were separated and the aqueous was extracted with EtOAc (4×300 mL). The organic phase was dried over Na2SO4, concentrated to dryness, re-dissolved in EtOAc (500 mL) and extracted with 20% citric acid (6×150 mL). The combined aqueous phases were treated with EtOAc (600 mL) and solid K2CO3 was added until pH 8/9. The Phases were separated and the organic phase dried over Na2SO4 and evaporated to dryness to afford the title compound (78 g). 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.55 (m, 1H); 7.42 (m, 3H); 7.25 (m, 2H); 6.98 (m, 2H); 5.14 (m, 2H); 4.85-4.69 (2m, 1H); 3.75-3.73 (2s, 3H); 2.36 (bs, 3H) 2.80-2.25 (m, 2H); 2.20-2.00 (m, 3H); 1.70 (m, 1H); 1.32-1.00 (2s, 9H).
Reaction SMILES: O.[NH2:2][NH2:3].[O:4]=[C:5]1[CH:10]=[CH:9][N:8]([C:11]2[CH:24]=[CH:23][C:14]([C:15]([CH:17]([CH3:22])[CH2:18][C:19](O)=[O:20])=O)=[CH:13][CH:12]=2)[CH:7]=[CH:6]1>O>[CH3:22][CH:17]1[C:15]([C:14]2[CH:23]=[CH:24][C:11]([N:8]3[CH:9]=[CH:10][C:5](=[O:4])[CH:6]=[CH:7]3)=[CH:12][CH:13]=2)=[N:3][NH:2][C:19](=[O:20])[CH2:18]1
Reactant: CC(CC(=O)O)C(=O)c1ccc(-n2ccc(=O)cc2)cc1
Reactant: NN
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc(-n2ccc(=O)cc2)cc1

Procedure:
Hydrazine hydrate (1.8 g) was added to a suspension of 3-[4-(4-oxo-1,4-dihydropyridin-1-yl)benzoyl]butanoic acid (5 g) in water (60 ml). The resulting solution was stirred under reflux for 2 hours and cooled to afford the title compound as a pale yellow solid, 4.45 g, m.p. 255°-258° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([O:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:7]2.[CH:19]([C:21]1[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=1)=[CH2:20].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCCCCC.CCOC(C)=O>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:23]1([CH3:27])[CH:24]=[CH:25][CH:26]=[C:21]([CH:19]=[CH:20][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][N:6]([O:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:7]3)[CH:22]=1
Reactant: C=Cc1cccc(C)c1
Reactant: O=C(ON1CCc2c(Br)cccc2C1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: Cc1cccc(C=Cc2cccc3c2CCN(OC(=O)C(F)(F)F)C3)c1

Procedure:
A solution of 5-bromo-2-trifluoroacetoxy-1,2,3,4-tetrahydroisoquinoline (616 mg, 2 mmol), 3-vinyltoluene (330 mg, 2.5 mmol), tri-o-tolylphosphine (50 mg) and palladium acetate (20 mg) in triethylamine (1 mL) were heated in a pressure bomb at 100° C. for 8 h. Column chromatography of the dark mixture (silica gel; hexane/EtOAc 40:1 then 20:1) afforded the title compound. FAB ms (m+1) 346.18
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[CH2:27][CH2:26][C:25]4[C:20](=[CH:21][C:22]([C:28]5[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=5)=[CH:23][CH:24]=4)[CH:19]=3)=[O:17])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.C[I:36].[C:37](OCC)(=O)C>CN(C=O)C>[I-:36].[OH:1][CH:2]1[CH2:3][CH2:4][N+:5]([CH3:37])([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[CH2:27][CH2:26][C:25]4[C:20](=[CH:21][C:22]([C:28]5[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=5)=[CH:23][CH:24]=4)[CH:19]=3)=[O:17])=[CH:13][CH:14]=2)[CH2:6][CH2:7]1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCC(O)CC4)cc2)CC3)cc1
Reactant: CCOC(C)=O
Reactant: CI
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C[N+]4(C)CCC(O)CC4)cc2)CC3)cc1
Product: [I-]
Temperature: 25 °C
Reaction time: 17 h

Procedure:
In DMF (3ml) was dissolved 3,4-dihydro-N-[4-(4-hydroxypiperidinomethyl)phenyl]-7-(4-methylphenyl)-naphthalene-2-carboxamide (130mg), and to the mixture was added methyl iodide (54 μl). The mixture was stirred at room temperature for 17 hours, and to the mixture was added ethyl acetate (100ml). The resulting precipitate was filtered and recrystallized from ethyl acetate-methanol to give 4-hydroxy-1-methyl-1-[4-[7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamido]benzyl]-piperidinium iodide (Compound 54) (138mg, ratio of isomers=58:42) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([OH:17])=O)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:18]=1.CCN=C=NCCCN(C)C.[C:30]([NH:37][C:38](=[NH:41])[S:39][CH3:40])([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:41]=[C:38]([S:39][CH3:40])[NH:37][C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])=[O:17])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:18]=1
Reactant: O=C(O)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Reactant: CSC(=N)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CSC(=NC(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
A mixture 8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylic acid (10.0 g, 30.3 mmol), EDCI (7.5 g, 36.4 mmol) in DCM (200 mL) was stirred at room temperature for 10 min, then DMAP (7.39 g, 60.6 mmol) was added by one portion. 10 minutes later, N-Boc-2-Methyl-isothiourea (6.9 g, 36.4 mmol) was added. The reaction mixture was stirred at room temperature overnight. After removal of the solvent, the residue was treated with methanol/water (20 mL, 1:1) to afford 10.2 g of methyl N′-8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbonyl-N-Boc-carbamimidothioate. Yield: 67%. 1H NMR (CDCl3, 400 MHz): δ12.33 (s, 1H), 7.95-7.51 (m, 2H), 7.35-6.94 (m, 2H), 4.28-4.25 (m, 2H), 3.15-3.30 (m, 2H), 2.52 (s, 3H), 1.51-1.45 (s, 9H). LC-MS: m/z=497 [M+H+]
Reaction SMILES: S1C2C=CC=CC=2N=C1N(COCC[Si](C)(C)C)C(C1C=CC=C2C=1CN(C1SC(C3C=CC(CO)=CC=3)=C(C(OCC)=O)N=1)CC2)=O.OCC1C=CC(B(O)O)=CC=1.[Br:60][C:61]1[C:65]2[N:66]=[CH:67][N:68]=[C:69](Cl)[C:64]=2[S:63][CH:62]=1.CC1(C)C(C)(C)OB([C:79]2[CH:84]=[CH:83][C:82]([OH:85])=[CH:81][CH:80]=2)O1>>[Br:60][C:61]1[C:65]2[N:66]=[CH:67][N:68]=[C:69]([C:79]3[CH:84]=[CH:83][C:82]([OH:85])=[CH:81][CH:80]=3)[C:64]=2[S:63][CH:62]=1
Reactant: Clc1ncnc2c(Br)csc12
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(CO)cc1
Agent: OCc1ccc(B(O)O)cc1
Product: Oc1ccc(-c2ncnc3c(Br)csc23)cc1

Procedure:
The title compound was prepared using similar conditions as described for the synthesis of compound 34D by substituting compound 34C and 4-(hydroxymethyl)phenylboronic acid with compound 65A and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, respectively: 1H NMR (DMSO-d6): δ 9.27 (s, 1H), 8.73 (s, 1H), 8.08-8.10 (m, 2H), 7.01-7.03 (m, 2H); ESI (−)/MS: 308 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[C:11]([N:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:21]2[CH2:22][CH2:23][CH2:24][N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:19][CH2:20]2)=[S:10])=[CH:4][CH:3]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCN(C(=S)Nc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-chlorophenyl isothiocyanate (5.0 g, 29.95 mmol), and BOC-homopiperazine (6.0 g, 29.95 mmol) in ethanol (50 mL) was stirred at room temperature for 2 hours. The mixture was evaporated under reduced pressure, the residue was partitioned between ethyl acetate and water and the layers were separated. The organic phase was dried over MgSO4 and evaporated under reduced pressure to give the title compound as a white foam.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1.[CH3:18][O-:19].[Na+]>CO>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:19][CH3:18])[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1c(Cl)cc(N2CCOCC2)nc1Cl
Agent: [Na+]
Solvent: CO
Product: COc1nc(N2CCOCC2)cc(Cl)c1[N+](=O)[O-]
Temperature: 65 °C
Yield: 44.8 %

Procedure:
To a solution of 4-(4,6-dichloro-5-nitropyridin-2-yl)-morpholine (2.02 g) in methanol (15 ml) was added sodium methoxide (0.98 g) and the mixture was heated for 16 hours at 65° C. After cooling to ambient temperature the reaction mixture was concentrated in vacuo. The crude product was subjected to flash chromatography (SiO2, heptane/ethylacetate 3:1) to furnish 0.89 g (45% yield) of 4-(4-chloro-6-methoxy-5-nitropyridin-2-yl)-morpholine (fast eluting band) and 0.38 g (19%) of 4-(6-chloro-4-methoxy-5-nitropyridin-2-yl)-morpholine (late eluting band), both as yellow solids.
Reaction SMILES: Cl[P:2]([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4].[Li].Cl[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18]Cl)[N:13]=1>O1CCCC1>[CH:3]([P:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][P:2]([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4])[N:13]=1)[CH:6]([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(C)P(Cl)C(C)C
Reactant: ClCc1cccc(CCl)n1
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)P(Cc1cccc(CP(C(C)C)C(C)C)n1)C(C)C
Temperature: -80 °C
Reaction time: 72 h

Procedure:
Chloro diisopropylphosphine (10.0 g, 65.5 mmol) in 50 ml of tetrahydrofuran was added dropwise to a suspension of lithium (containing ca. 0.5% Na) granules (1.18 g, 170 mmol) in 50 ml of tetrahydrofuran and the mixture was stirred for 72 hours. The reaction mixture was then filtered, cooled to −80° C., and a solution of 2,6-bis(chloromethyl)pyridine (5.98 g, 34 mmol) in 20 ml of tetrahydrofuran was slowly added via a dropping funnel with vigorous stirring, resulting in the formation of a red solution. The mixture was allowed to warm to room temperature and was then refluxed for one hour. The reaction was followed by 31P NMR spectroscopy to ensure completion and then the solvent was removed in vacuo. Hexanes (50 ml) and water (25 ml) were then added and the water layer was then removed. The hexanes layer was then filtered sequentially through a layer of sodium sulfate (Na2SO4) and silica gel and then the hexane was removed in vacuo to afford a yellow oil. Excess unreacted diisopropylphosphine can be removed in vacuo at 70° C. for 2 hours. Yield: 8.2 g (37%). 1H NMR (400 MHz, C6D6): δ 7.28 (m, 2 H, 3- and 5-H), 7.13 (m, 1H, 4-H), 3.12 (s, 4H, CH2), 1.89 (m, 4H, CH(CH3)2), 1.23 (m, 24H, CH(CH3)2). 31P{1H} NMR (162 MHz, C6D6): δ 7.0.