Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][C:7]([C:9]2[N:10]=[C:11]([S:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[S:12][CH:13]=2)=[CH:6][CH2:5][N:4]1[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25].ClS([N:34]=[C:35]=[O:36])(=O)=O.O.C(OCC)(=O)C>C(Cl)(Cl)Cl>[NH2:34][C:35]([O:1][CH2:2][C@@H:3]1[CH2:8][C:7]([C:9]2[N:10]=[C:11]([S:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[S:12][CH:13]=2)=[CH:6][CH2:5][N:4]1[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])=[O:36]
Reactant: C=CCOC(=O)N1CC=C(c2csc(SCc3ccc(OC)cc3)n2)C[C@H]1CO
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: C=CCOC(=O)N1CC=C(c2csc(SCc3ccc(OC)cc3)n2)C[C@H]1COC(N)=O
Reaction time: 0.17 h
Yield: 92.1 %

Procedure:
To a solution of allyl (2S)-2-(hydroxymethyl)-4-{2-[(4-methoxybenzyl)sulfanyl]-1,3-thiazol-4-yl}-3,6-dihydro-1(2 H)-pyridinecarboxylate (75 mg, 0.17 mmol) in chloroform (1 ml) was added at 0–5° C. chlorosulfonylisocyanate (17 ml, 0.20 mmol). Three hours later, chlorosulfonylisocyanate (10 ml, 0.11 mmol) was further added thereto. Three hours later, to the mixture was added water and the mixture was stirred for 10 minutes. To the solution was added ethyl acetate and the solution was separated with a separating funnel. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and the organic layer was removed in vacuo. The residue was purified with preparative TLC to give allyl (2S)-2-{[(aminocarbonyl)oxy]methyl}-4-{2-[(4-methoxybenzyl)sulfanyl]-1,3-thiazol-4-yl}-3,6-dihydro-1(2 H)-pyridinecarboxylate (74.5 mg, 90%).
Reaction SMILES: B(F)(F)F.CCOCC.C(O[C:14]1([O:31][C@@H:30]([C@@H:32]([C@@H:37]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[O:38][C:39](=[O:41])[CH3:40])[O:33][C:34](=[O:36])[CH3:35])[C@H:25]([NH:26][C:27](=[O:29])[CH3:28])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[CH2:19]1)[C:15](=[O:18])[O:16][CH3:17])(=O)C.[CH3:47][CH:48]([CH2:50][CH2:51][CH2:52][C@H:53]([C@@H:55]1[C@:72]2([CH3:73])[C@H:58]([C@H:59]3[C@H:69]([CH2:70][CH2:71]2)[C@:67]2([CH3:68])[C:62]([CH2:63][C@@H:64]([O:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][SH:81])[CH2:65][CH2:66]2)=[CH:61][CH2:60]3)[CH2:57][CH2:56]1)[CH3:54])[CH3:49]>C(Cl)(Cl)Cl>[C:22]([O:21][C@@H:20]1[C@@H:25]([NH:26][C:27](=[O:29])[CH3:28])[C@H:30]([C@@H:32]([C@@H:37]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[O:38][C:39](=[O:41])[CH3:40])[O:33][C:34](=[O:36])[CH3:35])[O:31][C:14]([S:81][CH2:80][CH2:79][CH2:78][CH2:77][CH2:76][CH2:75][O:74][C@H:64]2[CH2:65][CH2:66][C@@:67]3([CH3:68])[C:62](=[CH:61][CH2:60][C@@H:59]4[C@@H:69]3[CH2:70][CH2:71][C@@:72]3([CH3:73])[C@H:58]4[CH2:57][CH2:56][C@@H:55]3[C@H:53]([CH3:54])[CH2:52][CH2:51][CH2:50][CH:48]([CH3:47])[CH3:49])[CH2:63]2)([C:15](=[O:18])[O:16][CH3:17])[CH2:19]1)(=[O:24])[CH3:23]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCS)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: COC(=O)C1(OC(C)=O)C[C@H](OC(C)=O)[C@@H](NC(C)=O)[C@H]([C@H](OC(C)=O)[C@@H](COC(C)=O)OC(C)=O)O1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COC(=O)C1(SCCCCCCO[C@H]2CC[C@@]3(C)C(=CC[C@H]4[C@@H]5CC[C@H]([C@H](C)CCCC(C)C)[C@@]5(C)CC[C@@H]43)C2)C[C@H](OC(C)=O)[C@@H](NC(C)=O)[C@H]([C@H](OC(C)=O)[C@@H](COC(C)=O)OC(C)=O)O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 20.9 %

Procedure:
Boron trifluoride etherate (700 μl, 5.5 mmol) is added to a solution of methyl 2,4,7,8,9-penta-O-acetyl-N-acetyl-D-neuraminate (1.01 g, 1.96 mmol) and 6-(5-cholesten-3β-yloxy)-hexane-1-thiol (0.98 g, 1.96 mmol) in dry chloroform (5 ml). The mixture is stirred under nitrogen for 5 hours at room temperature, and washed with aqueous sodium bicarbonate and water. The dried solution is concentrated to a residue which is put on a silica gel column and eluted with chloroform-ethyl ether-methanol (31:10:1). The β-anomer is isolated as a glass (400 mg), [α]D -38.5° (c 1.5, chloroform).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][NH:4]1.C(N(CC)CC)C.[CH2:23]([O:30][C:31](Cl)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CO>[CH2:23]([O:30][C:31]([N:4]1[C@H:3]([CH2:2][OH:1])[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC[C@@H]1Cc2c([nH]c3ccccc23)CN1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1Cc2[nH]c3ccccc3c2C[C@H]1CO
Reaction time: 3 h
Yield: 86 %

Procedure:
2.02 g of (3S)-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline are dissolved in 24 ml of methanol, and 1.5 ml of triethylamine and 1.8 ml of benzyloxycarbonyl chloride are added dropwise to the mixture. The mixture is stirred at 5°-10° C. for 3 hours, and the mixture is evaporated to remove the solvent. The residue is dissolved in ethyl acetate. The solution is washed with water, a 0.5M citric acid solution and water, dried and then evaporated to remove the solvent. 2.90 g of (3S)-2-benzyloxycarbonyl-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline are obtained as colorless oil. Yield: 86%
Reaction SMILES: [Br:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:11])[CH:8]=2)[C:3]1=[O:12].[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[C:16]([NH2:18])=[S:17]>>[BrH:1].[Cl:11][C:7]1[CH:6]=[CH:5][C:4]2[C:3]3([OH:12])[N:18]=[C:16]([C:15]4[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:14]=4[Cl:13])[S:17][CH:2]3[CH2:10][C:9]=2[CH:8]=1
Reactant: NC(=S)c1ccc(Cl)cc1Cl
Reactant: O=C1c2ccc(Cl)cc2CC1Br
Product: Br
Product: OC12N=C(c3ccc(Cl)cc3Cl)SC1Cc1cc(Cl)ccc12

Procedure:
This compound is prepared analogously to the process described in Example 1c using 2-bromo-5-chloroindan-1-one and 2,4-dichlorothiobenzamide; melting point: 220-230° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:30][C@@H:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=1)[OH:32])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[C:19]([S:26][CH:27]([CH3:29])[CH3:28])[CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:40]([O:43][CH2:44][CH2:45][CH2:46][S:47]([NH2:50])(=[O:49])=[O:48])(=[O:42])[CH3:41].C1CCN2C(=NCCC2)CC1.Cl>O1CCCC1.C(OCC)(=O)C>[C:40]([O:43][CH2:44][CH2:45][CH2:46][S:47]([NH:50][C:23]([C:20]1[CH:21]=[CH:22][C:17]([C:14]2[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:30][C@@H:31]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[OH:32])=[CH:16][CH:15]=2)=[CH:18][C:19]=1[S:26][CH:27]([CH3:29])[CH3:28])=[O:24])(=[O:48])=[O:49])(=[O:42])[CH3:41]
Reactant: CC(=O)OCCCS(N)(=O)=O
Reactant: CC(C)Sc1cc(-c2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CC(=O)OCCCS(=O)(=O)NC(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)cc1SC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
To a solution of 4′-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-3-(isopropylthio)-4-biphenylcarboxylic acid (150 mg) in tetrahydrofuran (1.5 ml) was added N,N′-carbonyldiimidazole (64 mg) and stirred at room temperature for 30 minutes. To the mixture were added 3-(aminosulfonyl)propyl acetate (67 mg) and 1,8-diazabicyclo[5.4.0]-7-undecene (55 μl) and stirred at room temperature, and then stirred at 50° C. for 3 hours. The reaction mixture was poured into 0.1N hydrochloric acid and ethyl acetate and the organic layer was separated. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to give 3-[[[[4′-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-3-(isopropylthio)-4-biphenylyl]carbonyl]amino]sulfonyl]propyl acetate (72 mg). To a solution of the product (72 mg) in methanol (2.0 ml) and tetrahydrofuran (2.0 ml) was added sodium hydroxide aqueous solution (1N, 532 μl) and stirred at room temperature for 10 minutes. To the mixture was added hydrochloric acid aqueous solution (1N, 532 μl) and diluted with ethyl acetate. The solution was poured into water and ethyl acetate and the organic layer was separated. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified with silica gel column chromatography to give tert-butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-[4′-[[[(3-hydroxypropyl)sulfonyl]amino]carbonyl]-3′-(isopropylthio)-4-biphenylyl]-ethyl]carbamate (49 mg).
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[C:15]([N:17]2[CH2:21][CH2:20][O:19][C:18]2=[O:22])[CH:14]=[CH:13][C:8]=1[C:9]([O:11]C)=O.[CH3:24][C:25]1[C:26]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:27][C:28]([CH3:32])=[C:29]([CH3:31])[CH:30]=1>>[O:23]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[C:15]([N:17]2[CH2:21][CH2:20][O:19][C:18]2=[O:22])[CH:14]=[CH:13][C:8]=1[C:9]([N:36]1[CH2:37][CH2:38][N:33]([C:26]2[C:25]([CH3:24])=[CH:30][C:29]([CH3:31])=[C:28]([CH3:32])[N:27]=2)[CH2:34][CH2:35]1)=[O:11]
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Reactant: COC(=O)c1ccc(N2CCOC2=O)cc1N1CCCS1(=O)=O
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3N3CCCS3(=O)=O)CC2)nc1C
Yield: 25 %

Procedure:
By reaction and treatment in the same manner as in Example 63 and using methyl 2-(1,1-dioxoisothiazolidin-2-yl)-4-(2-oxooxazolidin-3-yl)benzoate (170 mg) described in Preparation Example 117 and 1-(3,5,6-trimethylpyridin-2-yl)piperazine (103 mg) described in Preparation Example 175, the title compound (64.2 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1.[C:16]([NH2:19])(=[S:18])[CH3:17]>>[CH3:1][O:2][C:3]([C:4]1[N:19]=[C:16]([CH3:17])[S:18][C:5]=1[C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1)=[O:15]
Reactant: CC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1cccc(C)c1
Product: COC(=O)c1nc(C)sc1-c1cccc(C)c1

Procedure:
prepared by reaction of 3-Chloro-2-oxo-3-m-tolyl-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.98 min; [M+H]+=248.5.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:13].Cl[C:15]1[C:16]2[N:23]=[CH:22][S:21][C:17]=2[N:18]=[CH:19][N:20]=1.CCN(CC)CC.Cl>CN(C=O)C.O>[CH3:13][C:7]1[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][CH2:3][NH:2][C:15]1[C:16]2[N:23]=[CH:22][S:21][C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: Cc1cc(O)ccc1OCCN
Reactant: Clc1ncnc2scnc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(O)ccc1OCCNc1ncnc2scnc12
Reaction time: 24 h
Yield: 28.7 %

Procedure:
4-(2-Aminoethoxy)-3-methylphenol hydrochloride (0.30 g, 1.5 mmol), 7-chlorothiazolo[5,4-d]pyrimidine (0.25 g, 1.5 mmol), and Et3N (300 mg, 3 mmol) were dissolved with magnetic stirring in DMF (6 mL) in a 25 mL round bottom flask equipped with a dry nitrogen line at 25° C. After 24 h, the reaction mixture was diluted with H2O (120 mL), and treated with 2 N HCl to adjust the pH to 5. After 24 h, a dark yellow solid precipitated and was removed by filtration. The filtrate was extracted with EtOAc (2×50 mL), and the pooled organic fractions were filtered and concentrated in vacuo to afford 3-methyl-4-[2-(thiazolo[5,4-d]pyrimidin-7-ylamino)-ethoxy]-phenol (Compound 22; 0.13 g) as a yellow powder, which was used without further purification in the next step: ESIMS m/z 303.0 ([M+H]+).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([SH:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28]>CN(C=O)C>[CH:1]1[C:10]2[C:5](=[C:6]([S:11][C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=3[N+:27]([O-:29])=[O:28])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Sc1cccc2cnccc12
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Sc2cccc3cnccc23)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
According to the method in Example 10, 5-isoquinolinethiol 1.00 g (6.2 mmol) was dissolved in DMF 14 ml, potassium carbonate 1.60 g (11.6 mmol) and 4-chloro-3-nitrobenzonitrile 1.00 g (5.5 mmol) were added and stirred at room temperature for 15 minutes, and 4-(5-isoquinolylsulfanyl)-3-nitrobenzonitrile 1.69 g (quantitative) was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH3:14][Si:15]([CH2:18][CH2:19][O:20][CH2:21]Cl)([CH3:17])[CH3:16]>CN(C=O)C>[CH3:14][Si:15]([CH3:17])([CH3:16])[CH2:18][CH2:19][O:20][CH2:21][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: N#Cc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2ccc(C#N)cc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
1H-Indole-6-carbonitrile (CAS #:15861-36-6) (1.47 g, 10.34 mmol) was dissolved in DMF (103 mL) and cooled to 0° C. NaH (60% in mineral oil, 0.620 g, 15.51 mmol) was added in one batch. The reaction was allowed to stir at room temperature for 15 minutes. SEMCl (2.38 mL, 13.44 mmol) was added at 0° C. and stirred for 20 minutes. The reaction was quenched with saturated ammonium chloride and then EtOAc was added. The organic layer was removed and the water layer was extracted again with EtOAc. The combined organics were washed with water, dried over MgSO4 filtered and concentrated. The resulting residue was purified via flash chromatography (0-50% EtOAc:heptanes) to obtain title compound. MS (ESI+) m/z 273.23 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[N:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=O)[O:5][CH3:6].[CH3:16][O:17][N:18]=[C:19]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[C:20](=[N:22][NH2:23])[CH3:21]>CO>[CH3:1][O:2][C:3](=[O:15])[N:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=[N:23][N:22]=[C:20]([CH3:21])[C:19](=[N:18][O:17][CH3:16])[C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)[O:5][CH3:6]
Reactant: CON=C(C(C)=NN)c1ccc(F)cc1
Reactant: COC(=O)N(OC)c1ccccc1C=O
Solvent: CO
Product: CON=C(C(C)=NN=Cc1ccccc1N(OC)C(=O)OC)c1ccc(F)cc1
Yield: 23.9 %

Procedure:
A solution of 1.05 g of (2-formyl-phenyl)-N-methoxycarbamic acid methyl ester and 1.05 g of 1-(4-fluorophenyl)-2-hydrazono-propan-1-on-O-methyl-oxime in 5 ml of methanol is stirred at room temperature for 4 hours. The resulting by-product (symmetric azine of 1-(4-fluorophenyl)-2-hydrazono-propan-1-on-O-methyl-oxime) is removed by filtration and the filtrate is placed in a refrigerator over night. The product which has crystallised is filtered off (1.0 g). By concentrating the mother liquor and by means of fractional crystallisation of the residue, a further 0.48 g of the title compound are obtained in the form of yellow crystals having a melting point of 88-90° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=[N:14][CH:15]=2)=[CH:6][CH:5]=1.[H][H]>C(O)C.[Pd]>[F:22][C:2]([F:1])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1cncc(-c2ccc(OC(F)(F)F)cc2)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CNCC(c2ccc(OC(F)(F)F)cc2)C1

Procedure:
2.5 g (7.6 mmol) of ethyl 5-[4-(trifluoromethoxy)phenyl]pyridine-3-carboxylate were dissolved in 60 ml of ethanol, 1.14 g of Pd/C (10%) were added and the mixture was hydrogenated in an autoclave at 60° C. at a hydrogen pressure of 50 bar overnight. The reaction mixture was filtered through silica gel. The resulting solution was concentrated under reduced pressure. Water was added to the residue, and the solution was adjusted to pH 8 using aqueous 1 N sodium hydroxide solution. The mixture was then extracted with dichloromethane. The organic phase was dried over sodium sulphate and concentrated. Yield: 1.76 g (66% of theory)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH2:9])[C:5]([O:10][CH3:11])=[CH:4][N:3]=1.C(O)(C)C.[N:16]#[C:17]Br.C([O-])([O-])=O.[Na+].[Na+]>O>[NH2:16][C:17]1[N:7]2[C:2]([Cl:1])=[N:3][CH:4]=[C:5]([O:10][CH3:11])[C:6]2=[N:8][N:9]=1
Reactant: COc1cnc(Cl)nc1NN
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COc1cnc(Cl)n2c(N)nnc12
Temperature: 42 °C
Reaction time: 3.5 h
Yield: 173.2 %

Procedure:
A 5 liter (L) 3-neck round bottom flask with thermowell was fitted with a condenser/N2 inlet, mechanical stirrer and an addition funnel. The pot was charged with 2-chloro-4-hydrazino-5-methoxypyrimidine (136 g of 70.7 wt. %, 96 g active, 0.55 mol) and isopropyl alcohol (IPA; 1100 mL). Cyanogen bromide (185 g of 34.6 wt. % in CH3CN, 64 g active, 0.6 mol) was added rapidly causing a slow endotherm from 22 to 15° C. and then a slow exotherm to 27° C. During the exotherm the mixture goes through a very thick stage which lasts several minutes. The slurry was then warmed to 42° C. and held there for 3.5 h at which time high pressure liquid chromatography (HPLC) analysis indicated the reaction was complete. The slurry was cooled to room temperature and treated with a solution of Na2CO3 (64 g, 0.6 mol) in water (1100 mL) over a 30 minute (min) period causing the temperature to exotherm 4° C. The mixture was stirred at ambient temperature for 2 h and then the solid was collected by filtration. The filter cake was washed with water (400 mL) and then pressed as dry as possible under aspirator pressure. This provided the title compound (190.1 g of wet cake, 51 wt % by HPLC, 97 g active, 88%) as a brown solid. Drying a sample to a constant weight resulted in the following data: MS(GC, 70eV) 201(15%), 200 (30%), 199 (70%), 198 (100%); 1 H NMR (300 MHz, DMSO-d6) 3.92 (s, 3H), 6.51 (br s, 2H), 7.11 (s, 1H).
Reaction SMILES: CO[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=O)C1C=CC(OC)=CC=1.[CH2:21]([NH2:24])[CH2:22][NH2:23]>>[NH:23]1[CH:10]2[C:5]3[C:4]([C:3](=[O:20])[N:24]2[CH2:21][CH2:22]1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: NCCN
Reactant: COC(=O)c1ccccc1C(=O)c1ccc(OC)cc1
Product: O=C1c2ccccc2C2NCCN12

Procedure:
Condense methyl-o-(p-methoxybenzoyl)benzoate (7 g.) and ethylenediamine (8 ml.) by procedure of Example 1 to obtain 9b-p-methoxyphenyl)-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one, m.p. 159° C. (elemental analysis confirms the empirical formula C17H16N2O2), reduce with lithium aluminum hydride, and treat with hydrogen chloride as described in Example 1 to obtain 1,2,3,4,5,6-hexahydro-1-(p-methoxyphenyl)-2,5-benzodiazocine dihydrochloride, m.p. 260° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34])[C:5]([NH:7][C@H:8]([CH2:26][CH2:27][OH:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([C:22](=NO)[CH3:23])[N:19]([CH3:21])[CH:20]=2)=[CH:12][CH:11]=1)=[O:6].[C:36]([O-:39])([O-])=O.[K+].[K+].BrC[C:44](OCC)=[O:45]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:34])[CH3:35])[C:5]([NH:7][C@H:8]([CH2:26][CH2:27][OH:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([C:22]3([CH3:23])[O:39][CH2:36][CH2:44][O:45]3)[N:19]([CH3:21])[CH:20]=2)=[CH:12][CH:11]=1)=[O:6]
Reactant: CCOC(=O)CBr
Reactant: O=C([O-])[O-]
Reactant: CC(=NO)c1nc(-c2ccc(C[C@@H](CCO)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C(=O)N[C@H](CCO)Cc2ccc(-c3cn(C)c(C4(C)OCCO4)n3)cc2)cc1Cl
Temperature: 60 °C
Reaction time: 3 h
Yield: 78.7 %

Procedure:
To a solution of compound 3 (2.66 g, 7.27 mmol) in DMF (15 mL) was added K2CO3 (2.00 g, 15 mmol) and ethyl bromoacetate (1.61 mL, 14.5 mmol). The resulting mixture was stirred at 60° C. for three hours. The mixture was diluted with water and extracted with EtOAc (3×50 mL). The organic layers were combined, dried over Na2SO4, and concentrated. Purification with column chromatography (Hexanes/EtOAc 50:50) gave the product 4 (3.02 g, 91%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH2:19])[CH2:17][CH3:18].[BH4-].[Na+]>C(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:16]([NH:19][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1)[CH2:17][CH3:18]
Reactant: CCCN
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCNCc1cccc(Oc2ccccc2)c1
Temperature: 80 °C
Yield: 57.3 %

Procedure:
3-Phenoxybenzaldehyde (2.00 mL, 2.29 g, 11.6 mmol), n-propylamine (0.95 mL, 0.68 g, 11.5 mmol), and p-toluenesulfonic acid monohydrate (15 mg, 0.08 mmol) were dissolved in absolute ethanol (15 mL), then heated to 80° C. in a sealed tube for 2.5 hours. The reaction was cooled to room temperature, transfered to a round-bottom flask, then sodium borohydride (440 mg, 11.6 mmol) was added, followed by heating under reflux for 2.5 hours. The reaction was concentrated, the residue partitioned between water and EtOAc, the EtOAc layer washed with water and brine. After drying with Na2SO4, filtration, and concentration, the residue was purified by chromatography on silica gel eluting with 4:6 followed by 3:7 hexane-EtOAc to give 1.59 g (57%) of the title compound as a light yellow oil. 1H NMR (CDCl3) δ 7.30 (m, 3H), 7.08 (m, 2H), 7.00 (m, 3H), 6.88 (dd, 1H), 3.77 (s, 2H), 2.60 (t, 2H), 1.53 (m, 2H), 0.92 (t, 3H). MS (DCl/NH3) m/e 242 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].CN1C=CN=C1.Cl.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[N:30][O:31][C:32]=2[C:33]2[CH:38]=[C:37]([O:39][CH3:40])[C:36]([O:41][CH3:42])=[C:35]([O:43][CH3:44])[CH:34]=2)=[CH:24][C:23]=1[NH2:45]>C1COCC1>[C:2]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10](=[O:12])[NH:45][C:23]1[CH:24]=[C:25]([C:28]2[CH:29]=[N:30][O:31][C:32]=2[C:33]2[CH:34]=[C:35]([O:43][CH3:44])[C:36]([O:41][CH3:42])=[C:37]([O:39][CH3:40])[CH:38]=2)[CH:26]=[CH:27][C:22]=1[O:21][CH3:20])([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COc1ccc(-c2cnoc2-c2cc(OC)c(OC)c(OC)c2)cc1N
Agent: Cl
Agent: Cn1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(-c2cnoc2-c2cc(OC)c(OC)c(OC)c2)cc1NC(=O)CNC(=O)OC(C)(C)C
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of N-t-Boc-glycine (357 mg, 2 mmol) and N-methyl-imidazole (0.162 mL, 2 mmol) in THF (16 mL) cooled with ice methanesulfonyl chloride (0.158 mL, 2 mmol) was added. Ice batch was removed, compound 5 (0.4 g, 1 mmol) was added as a solid, followed by thriethylamine (0.144 mL, 2.02 mmol), and the reaction mixture was stirred at 40-50° C. overnight. A resulted solution was decanted from a solid, a flask rinsed with EtOAc, and a combined organic solution was washed with saturated ammonium chloride solution, then twice with water, brine and dried over anhydrous sodium sulfate. The solution was filtered out through a celite pad, concentrated and the residue was dissolved in 2-propanol (3 mL) with heating, and hexane (1-2 mL) was added drop-wise to start precipitation. In 1 hour a solid was filtered out, washed with 1:1 Hexane:ether mixture (10 ml×2) and vacuum-dried to give compound 6, 0.49 g (93.7%), LC purity 99%. 1H NMR (DMSO-d6): δ 9.11 (s, 1H), 8.81 (s, 1H), 8.22 (s, 1H), 7.24 (m, 1H), 7.20-7.15 (m, 2H), 6.91 (s, 2H), 3.87 (s, 3H), 3.73 (m, 2H), 3.70 (s, 3H), 3.66 (s, 6H). 1.40 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[OH:12][CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:17]1[CH:18]=[C:14]([CH2:13][OH:12])[N:15]=[CH:16]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: OCc1c[nH]cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(-n2cnc(CO)c2)c(F)c1
Yield: 75.4 %

Procedure:
3,4-Difluoro-nitrobenzene (23.85 g) was dissolved in acetonitrile (180 ml), followed by 4-hydroxymethylimidazole (14.7 g) and ethyldiisopropylamine (65.2 ml). The mixture was stirred and heated to reflux for 2 days. After cooling, acetonitrile was evaporated and the residue was shaken with a mixture of methyl t-butyl ether (200 ml) and water (100 ml), and the solid filtered. After washing with a mixture of methyl t-butyl ether (50 ml) and water (25 ml), the solid was dried in vacuo at 60° C. overnight, to give product (26.8 g) mp 157-159° C.