Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](I)[CH:3]=1.[Cu](C#N)[C:14]#[N:15].[Cl-].[NH4+].N>C(OCC)(=O)C.O.CN1CCCC1=O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:14]#[N:15])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1I
Reactant: N#C[Cu]C#N
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Br)cc1C#N
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To methyl 4-bromo-2-iodobenzoate (3.52 g) described in Preparation Example 190 were added copper cyanide (1.16 g) and N-methylpyrrolidone (21 mL) and the mixture was stirred at 60° C. for 1 hr. Under cooling with water, ethyl acetate, saturated aqueous ammonium chloride solution and aqueous ammonia were added and the mixture was extracted with ethyl acetate. The organic layer was washed once with saturated aqueous ammonium chloride solution and aqueous ammonia, once with saturated aqueous ammonium chloride solution and once with saturated brine, and dried over sodium sulfate. The solvent was evaporated to give the title compound (2.39 g).
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:7]=1)=O.[OH-].[Na+]>>[F:19][C:16]([F:17])([F:18])[CH2:15][CH2:14][O:13][CH2:12][C:8]1[N:7]=[C:6]([NH2:5])[CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)C(=O)Nc1cccc(COCCC(F)(F)F)n1
Agent: [Na+]
Agent: [OH-]
Product: Nc1cccc(COCCC(F)(F)F)n1

Procedure:
This material was prepared in analogy to example 86 step B] from 2,2-dimethyl-N-[6-(3,3,3-trifluoro-propoxymethyl)-pyridin-2-yl]-propionamide (0.2 g) and 3M aqueous NaOH (1.31 mL) as a brown oil (0.159 g). MS (ESI): 221.2 (MH+).
Reaction SMILES: Br[C:2]1[N:6]([NH:7][C:8](=[O:18])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH3:17])[C:5]([CH2:19][CH2:20][CH3:21])=[N:4][C:3]=1[CH3:22].[Cu][C:24]#[N:25].N1C=CC=CC=1.[I-].[K+]>C(OCC)(=O)C>[C:24]([C:2]1[N:6]([NH:7][C:8](=[O:18])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH3:17])[C:5]([CH2:19][CH2:20][CH3:21])=[N:4][C:3]=1[CH3:22])#[N:25]
Reactant: N#C[Cu]
Reactant: CCCc1nc(C)c(Br)n1NC(=O)c1ccccc1OCC
Agent: [I-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCc1nc(C)c(C#N)n1NC(=O)c1ccccc1OCC
Temperature: 100 °C
Reaction time: 6 h

Procedure:
N-(5-Bromo-4-methyl-2-propylimidazol-1-yl)-2-ethoxybenzamide from Example 2a (0.5 g, 1.2 mmol) and copper(I) cyanide (0.3 g, 3.5 mmol) are introduced into 12.5 ml of pyridine and heated at 100° C. for 6 hours. Potassium iodide (23 mg, 0.56 mmol) is added to the mixture, which is then stirred for a further 6 hours at 100° C. The reaction mixture is cooled to room temperature and, after addition of 50 ml of ethyl acetate, washed with dilute alkaline H2O2 solution. The aqueous phase is re-extracted with ethyl acetate, and the combined ethyl acetate phase is concentrated, finally azeotroped with toluene and again concentrated.
Reaction SMILES: N[C@H](C(OC)=O)[C@H](CC)C.CC(C)(OC([NH:17][C@@H:18]([CH2:35][CH:36]([CH3:38])[CH3:37])[CH:19]([OH:34])[CH2:20][NH:21][C:22]([NH:24][C@H:25]([C:30]([O:32][CH3:33])=[O:31])[C@H:26]([CH2:28][CH3:29])[CH3:27])=[O:23])=O)C.[ClH:40]>O1CCOCC1>[ClH:40].[NH2:17][C@@H:18]([CH2:35][CH:36]([CH3:37])[CH3:38])[CH:19]([OH:34])[CH2:20][NH:21][C:22]([NH:24][C@H:25]([C:30]([O:32][CH3:33])=[O:31])[C@H:26]([CH2:28][CH3:29])[CH3:27])=[O:23]
Reactant: CC[C@H](C)[C@H](NC(=O)NCC(O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)OC
Agent: CC[C@H](C)[C@H](N)C(=O)OC
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@H](C)[C@H](NC(=O)NCC(O)[C@@H](N)CC(C)C)C(=O)OC
Reaction time: 2.5 h

Procedure:
The isoleucine, methyl ester product from part (d) (0.43 g., 1.03 mmole) is dissolved in a solution of hydrochloric acid in dioxane (2N, 3 ml.) and kept at room temperature for 2.5 hours. The mixture is then concentrated to dryness in vacuo to give N-[[[(3S)-3-amino-2-hydroxy-5-methylhexyl]amino]carbonyl]-L-isoleucine, methyl ester, monohydrochloride.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[NH:27]1[CH2:30][CH2:29][CH2:28]1>C(#N)C>[CH3:26][S:23]([C:17]1[CH:16]=[C:15]2[C:20]([CH2:21][CH2:22][CH:13]([CH2:12][N:27]3[CH2:30][CH2:29][CH2:28]3)[O:14]2)=[CH:19][CH:18]=1)(=[O:24])=[O:25]
Reactant: C1CNC1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc2c(c1)OC(CN1CCC1)CC2

Procedure:
Preparation according to Example 25: [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), azetidine (0.2 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 281 (M+, 3), 131 (6), 77 (5), 71 (5), 70 (bp).
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:16](=[O:17])[C:15]3[N:14]([CH2:18][C:19](=[O:21])[CH3:20])[CH:13]=[N:12][C:11]=3[N:10]([CH2:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:8]2=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[CH:1]1([CH2:6][N:7]2[C:16](=[O:17])[C:15]3[N:14]([CH2:18][CH:19]([OH:21])[CH3:20])[CH:13]=[N:12][C:11]=3[N:10]([CH2:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[C:8]2=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)Cn1cnc2c1c(=O)n(CC1CCCC1)c(=O)n2CC1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)Cn1cnc2c1c(=O)n(CC1CCCC1)c(=O)n2CC1CCCC1

Procedure:
1,3-Di-cyclopentylmethyl-7-(2-oxopropyl)-xanthine was dissolved in methanol and stirred for 2 hours at room temperature with 5 equivalents of sodium borohydride. Thereafter, the solvent was removed in vacuo and the residue partitioned between dichloromethane and water. The organic layer was then separated and dried over sodium sulphate. After removing the organic solvent the title compound was crystallised from absolute ethanol as a white crystalline solid, m.p. 139° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1C(OC(C)(C)C)=O)[OH:7].FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([CH:8]1[CH2:12][CH2:11][CH2:10][NH:9]1)[OH:7]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(O)c1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC(c1ccco1)C1CCCN1
Yield: 7.2 %

Procedure:
N-Boc-pyrrolidine (5.0 g) is dissolved in diethyl ether (60 mL) and the solution is cooled to −78° C. N,N,N′,N′-Tetramethylethylenediamine (TMEDA) (4.4 mL) is added to the mixture followed by sec-butyl lithium (27.0 mL, 1.3 M in cyclohexane) maintaining the temperature below −60° C. After 2 h, 2-furaldehyde (2.9 mL) is added and the mixture is stirred at −70° C. for an additional 30 min. The reaction mixture is allowed to warm to room temperature and is then quenched with water (25 mL) and poured into EtOAc (200 mL). The separated organic layer is washed with saturated aq. ammonium chloride (3×50 mL) followed by brine (50 mL), dried (MgSO4), and concentrated The crude product is purified by column chromatography (heptane/EtOAc, 8/1; 5/1) to afford 4.97 g of 2-furyl(N-Boc-pyrrolidin-2-yl)methanol as a mixture of diastereomers. The resulting 2-furyl(N-Boc-pyrrolidin-2-yl)methanol (4.43 g) is dissolved in dichloromethane (200 mL) and trifluoroacetic acid (30 mL) is added. The mixture is poured into a 1 M solution of sodium hydroxide. The organic layer is separated and washed with saturated aq. sodium bicarbonate (2×100 mL). The aqueous layers are extracted with dichloromethane (4×50 mL) and the combined organic layers are concentrated. The crude product is purified by column chromatography (CH2Cl2/methanol/NH4OH, 95/5/1; 90/10/1). The resulting oil is distilled in a Kugelrohr apparatus (0.175-200° C., 0.2 Torr) to afford 0.20 g of the title compound as a mixture of diastereomers. Physical characteristics. MS (ESI+) m/z 168 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9](Br)[CH2:10][Br:11].[OH-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10][Br:11]
Reactant: Oc1ccccc1Cl
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccccc1OCCBr
Temperature: 100 °C

Procedure:
22.4 ml (0.2 mole) of 2-chlorophenol and 34.6 ml (0.4 mole) of ethylene dibromide are mixed and heated at 100° C. The mixture is stirred vigourously with 125 ml 1.6N NaOH, continued heat and stirred till the pH value to 7. Upon cooling, after filtrating the extracted solids, the mixed solution's organic layer is extracted with chloroform and rinsing the extracted solids with NaCl and MgSO4. The generated product is filled into silica gel chromatography columns. The mixture solution of Hexane and Ethylacetate was used as the eluent solution. Upon purification, until white crystallization 2(2-chlorophenoxy)ethylbromide is obtained.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CN(C)C=O.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[N:19][CH:20]=1.[OH-].[Na+]>O>[Br:14][C:15]1[CH:16]=[C:17]([Cl:1])[C:18]([NH2:21])=[N:19][CH:20]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc(Br)cc1Cl
Reaction time: 4 h
Yield: 88 %

Procedure:
With cooling with ice, 1-chloropyrrolidine-2,5-dione (10 g, 76 mmol) was added to an N,N-dimethylformamide solution (30 ml) of 5-bromopyridine-2-amine (12 g, 69 mmol), and stirred for 4 hours. The reaction solution was diluted with water, neutralized with aqueous 5 N sodium hydroxide solution, and extracted with diethyl ether. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:chloroform:ethyl acetate=25:25:50) to obtain 5-bromo-3-chloropyridine-2-amine (12.6 g, yield: 88%) as a brown solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N+:19]([CH:22]([CH3:24])[CH3:23])([O-:21])=[O:20].[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[CH:35]=[O:36].C([Si](C)(C)Cl)(C)(C)C>O1CCCC1.C(N(CC)CC)C>[CH3:23][C:22]([N+:19]([O-:21])=[O:20])([CH3:24])[CH:35]([C:26]1[CH:27]=[CH:28][C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=1)[OH:36]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CC(C)[N+](=O)[O-]
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C(O)c1ccc2ccccc2c1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To tetrabutylammonium fluoride 3 hydrate (2.41 g) was added tetrahydrofuran (20 ml) and the mixture was ice-cooled. To the mixture were added 2-nitropropane (2.7 ml), 2-naphthaldehyde (3.12 g) and triethylamine (2.8 ml) under an argon atmosphere. To the mixture was added a solution of tert-butyldimethylchlorosilane (4.51 g) in tetrahydrofuran (20 ml). The resulting mixture was stirred for 40 min while allowing to warm to room temperature from ice-cooling. After removing insoluble matter by filtration, the filtrate was poured into a solution (500 ml) of diethyl ether-n-hexane=1:3 and the mixture was washed twice with water (40 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was subjected to crystallization from n-hexane to give the title compound (3.78 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][O:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>>[CH3:17][S:18]([N:14]1[CH2:13][CH2:12][CH:11]([O:10][CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH2:16][CH2:15]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: C1CCC(OCCOC2CCNCC2)OC1
Product: CS(=O)(=O)N1CCC(OCCOC2CCCCO2)CC1
Yield: 79.1 %

Procedure:
Using 4-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]piperidine (561 mg, 2.54 mmol) synthesized in (17b) and methanesulfonyl chloride (375 μL, 3.06 mmol), the desired title compound (618 mg, yield 83%) was obtained by the same method as in Reference Example 2 (2c).
Reaction SMILES: Cl.[CH3:2][C@H:3]1[O:8][C@@H:7]([CH3:9])[CH2:6][N:5]([C:10]2[CH:11]=[C:12]([C@@H:16]([NH2:18])[CH3:17])[CH:13]=[CH:14][CH:15]=2)[CH2:4]1.[F:19][C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[CH:22]=[CH:23][C:24](O)=[O:25].C(Cl)CCl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:9][C@H:7]1[O:8][C@@H:3]([CH3:2])[CH2:4][N:5]([C:10]2[CH:11]=[C:12]([C@@H:16]([NH:18][C:24](=[O:25])[CH:23]=[CH:22][C:21]3[CH:27]=[CH:28][CH:29]=[CH:30][C:20]=3[F:19])[CH3:17])[CH:13]=[CH:14][CH:15]=2)[CH2:6]1
Reactant: C[C@@H]1CN(c2cccc([C@H](C)N)c2)C[C@H](C)O1
Reactant: O=C(O)C=Cc1ccccc1F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: C[C@@H]1CN(c2cccc([C@H](C)NC(=O)C=Cc3ccccc3F)c2)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Mixture of (S)-1-[3-(cis-2,6-dimethyl-morpholin-4-yl)-phenyl]-ethylamine hydrochloric acid salt, Preparation 31 (50 mg, 0.16 mmol), 2-fluorocinnamic acid (30 mg, 0.18 mmol), EDC (65 mg, 0.33 mmol), DMAP (20 mg, 0.16 mmol), triethylamine (0.09 ml, 0.65 mmol) in dichloromethane (0.7 mL) was stirred at room temperature overnight. The reaction mixture was purified by filtering through 2 g silica-gel syringe with 70% ethyl acetate/hexanes. The filtrate was concentrated under vacuum to provide the title compound as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[C:10]2[C:21]3([CH2:26][CH2:25][O:24][C:23]([NH2:27])=[N:22]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18](I)[CH:19]=3)[O:14][C:11]2=[N:12][CH:13]=1.[F:29][C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1>O1CCOCC1.O>[Br:7][C:8]1[CH:9]=[C:10]2[C:21]3([CH2:26][CH2:25][O:24][C:23]([NH2:27])=[N:22]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:35]4[C:30]([F:29])=[N:31][CH:32]=[CH:33][CH:34]=4)[CH:19]=3)[O:14][C:11]2=[N:12][CH:13]=1
Reactant: OB(O)c1cccnc1F
Reactant: NC1=NC2(CCO1)c1cc(I)ccc1Oc1ncc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: NC1=NC2(CCO1)c1cc(-c3cccnc3F)ccc1Oc1ncc(Br)cc12
Temperature: 85 °C

Procedure:
In a 150-mL resealable flask, potassium carbonate (1.557 g, 11.27 mmol 3-bromo-7-iodo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine (intermediate 25 1.97 g, 4.17 mmol), 2-fluoropyridin-3-ylboronic acid (0.441 g, 3.13 mmol), and PdCl2-dppf-dcm (0.225 g, 0.275 mmol) were suspended in dioxane (18 mL) and water (6 mL). Argon was blown through the vessel, which was sealed and heated in an 85° C. oil bath for 2 h. The reaction was concentrated to remove most of the dioxane. The aqueous residue was diluted further with dilute brine (50 mL), and the aqueous phase was extracted with 10% MeOH-DCM (3×100 mL). The organics were combined, washed with dilute brine (30 mL), dried over sodium sulfate and concentrated. The residue was purified by chromatography (4% MeOH/DCM), to afford (3-bromo-7-(2-fluoropyridin-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine) (1.03 g). MS (m/z) 441/443 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].[O:12]=[S:13]1(=[O:30])[CH2:18][CH2:17][N:16]2[CH2:19][CH2:20][CH2:21][C@@H:22]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:15]2=[N:14]1.N1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N.C(O[Cu]OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[O:29][C:26]1[CH:25]=[CH:24][C:23]([C@H:22]2[CH:15]3[NH:14][S:13](=[O:30])(=[O:12])[CH2:18][CH2:17][N:16]3[CH2:19][CH2:20][CH2:21]2)=[CH:28][CH:27]=1
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: CC(=O)O[Cu]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: c1ccncc1
Product: O=S1(=O)CCN2CCC[C@@H](c3ccc(Oc4ccc(F)c(Cl)c4)cc3)C2N1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.7 %

Procedure:
A mixture of (3-chloro-4-fluorophenyl)boronic acid (933 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (500 mg), pyridine (3.60 mL), cesium carbonate (581 mg), diacetoxycopper (648 mg) and powdered 4A MS (4 g) in MeCN (18 mL) was stirred at room temperature for 3 days. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) then recrystallized from EtOAc-THF/IPE to give (9S)-9-[4-(3-chloro-4-fluorophenoxy)phenyl]-3,4,6,1,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (290.6 mg) as a white solid.
Reaction SMILES: N[C@H](C([NH:11][C:12]([NH2:14])=[O:13])=O)CC1SC=CC=1.[N:15]1[CH:16]=[N:17][N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=12.[OH-].[Na+].OO.Cl>>[NH:11]([C:16]1[N:15]=[C:19]2[C:20]3[C:25]([CH2:26][CH2:27][N:18]2[N:17]=1)=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]([NH2:14])=[O:13]
Reactant: NC(=O)NC(=O)[C@@H](N)Cc1cccs1
Reactant: c1ccc2c(c1)CCn1ncnc1-2
Agent: Cl
Agent: OO
Agent: [Na+]
Product: NC(=O)Nc1nc2n(n1)CCc1ccccc1-2
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
2-Thiureido-5,6-dihydro-s-triazolo[5,1-a]isoquinoline (1.2 g.) is suspended in 20 ml. of 2% aqueous sodium hydroxide and 1.9 ml. of 30% H2O2 is added at 40°-45° C. After 15 minutes, the mixture is heated for 5 minutes at 80° C and, after cooling and neutralizing with dilute hydrochloric acid, the solid precipitate is recovered by filtration and purified by crystallization from 70% ethanol. Yield 0.8 g.; m.p. 210°-2° C.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][N:4]=1)#N>C(O)=O>[N:4]1[CH:3]=[CH:8][CH:7]=[C:6]([CH2:9][CH2:10][OH:11])[CH:5]=1
Reactant: N#Cc1ccc(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: O=CO
Product: OCCc1cccnc1
Yield: 54.8 %

Procedure:
2-(2-Cyanopyridin-5-yl)-1-triphenylmethyloxyethane (2.631 g) and formic acid (38.0 ml) were treated as reported in Tetrahedron Lett., 579 (1986). to give the title compound (0.455 g) as colorless crystals (yield: 45.7%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH2:9])=[CH:3][CH:2]=1.[CH:10](=O)[CH2:11][CH2:12][CH3:13].[BH4-].[Na+]>C(Cl)Cl>[CH2:10]([NH:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[CH2:11][CH2:12][CH3:13]
Reactant: NCCc1ccccc1
Reactant: CCCC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCNCCc1ccccc1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
2-Phenethylamine (12.5 mL, 12.1 g, 99.5 mmol), butyraldehyde (13.2 mL, 10.8 g, 150 mmol), and 3 Å molecular sieves were stirred at 50 ° C. for 1 h, then at RT for 5.5 h. The reaction was then diluted with CH2Cl2, filtered through celite, then concentrated to an oil. That oil was dissolved in absolute EtOH (150 mL-previously cooled to 0 ° C.), and NaBH4 (5.7 g, 150 mmol) was added. The reaction was stirred at RT overnight, concentrated, partitioned between water and Et2O, then the organic layer was washed with water and brine. After drying over Na2SO4, filtration, and concentration, the compound was purified by vacuum distillation using a 6″ Vigeraux column (98-100° C./9 mm). Recovered 8.2 g (46%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:18]([N:20]1[CH2:24][CH2:23][C@H:22]([F:25])[CH2:21]1)=[O:19])[C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH3:10])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Rh]>[C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:18]([N:20]1[CH2:24][CH2:23][C@H:22]([F:25])[CH2:21]1)=[O:19])[C@H:9]([CH:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](c1ccc(O)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Reactant: [H][H]
Agent: [Rh]
Solvent: CO
Product: C[C@@H](C1CCC(O)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Reaction time: 24 h

Procedure:
The material from Step B (0.022 g, 0.060 mmol) was hydrogenated at 50 psi hydrogen in the presence of 5% rhodium on alumina (22 mg) in methanol (5 mL) using a Parr shaker. After 24 h, the reaction mixture was filtered by passage through a syringe filter. Concentration of the filtrate in vacuo afforded the title compound as a mixture of cis and trans isomers containing a small amount of the fully reduced cyclohexane. LC/MS 395.3 (M+Na)
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[Cl:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:42]=[C:43]([CH2:56][CH3:57])[C:44]([NH:49][C@H:50]2[CH2:54][O:53][CH2:52][C@H:51]2[OH:55])=[N:45][C:46]=1[CH2:47][CH3:48].Br[CH2:59][CH2:60][CH2:61][F:62]>>[Cl:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:42]=[C:43]([CH2:56][CH3:57])[C:44]([NH:49][C@H:50]2[C@@H:51]([O:55][CH2:59][CH2:60][CH2:61][F:62])[CH2:52][O:53][CH2:54]2)=[N:45][C:46]=1[CH2:47][CH3:48]
Reactant: FCCCBr
Reactant: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@H]1COC[C@H]1O
Agent: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1COC[C@@H]1OCCCF

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting of cis-(+/−)-4-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}tetrahydrofuran-3-ol and 1-bromo-3-fluoropropane and making non-critical variations provided the title compound as a colorless semi-solid. IR (liq.) 2969, 2936, 2875, 1606, 1565, 1481, 1441, 1397, 1287, 1230, 1203, 1127, 1075, 1059, 1046 cm−1; OAMS supporting ions at: ESI+ 438.2; MS (EI) m/z 437 (M+); HRMS (FAB) calcd for C22H29CLFN3O3+H1 438.1960, found 438.1965. Anal. Calcd for C22H29ClFN3O3: C, 60.34; H, 6.67; N, 9.59. Found: C, 60.31; H. 6.78; N, 9.65.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[N:20]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22][CH:21]=1>[OH-].[K+].O>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[C:14](=[CH:26][C:23]2[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=Cc1ccncc1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C1C(=Cc2ccncc2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 21.7 %

Procedure:
6-(2-Imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.50 g, 1.95 mmol) was reacted with 4-pyridinecarboxaldehyde (0.248 g, 2.3 mmol) in 2.5 mL of 4% KOH for 8 hours at room temperature. The reaction was diluted with water, the resulting mixture was filtered, and the filtrate was extracted into EtOAc. The combined extracts were evaporated to dryness, and the resulting yellow solid was purified twice by flash chromatography (silica gel, 120 g, 9% MeOH in DCM) to afford 0.146 g of a yellow oil which crystallized on standing. Recrystallization from minimal iPrOH afforded the title compound as a light yellow powder (0.041 g, 6%), mp 128.5-129° C.; CI-MS mi/e 345 (M+), 346 (M+ +1);
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[C:8]1(O)[CH:13]=CC=[CH:10][CH:9]=1>C(O)(=O)C>[C:5]([O:4][C:1]1[CH:10]=[CH:9][CH:8]=[CH:13][CH:2]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccccc1
Solvent: CC(=O)O
Product: CC(=O)Oc1ccccc1

Procedure:
reacting acetic anhydride with a phenol to produce a phenyl acetate and acetic acid;
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[NH:10][C:9](=S)[CH2:8][O:7][C:6]=2[N:12]=1.O.[NH2:20][NH2:21]>O1CCCC1>[Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[NH:10]/[C:9](=[N:20]/[NH2:21])/[CH2:8][O:7][C:6]=2[N:12]=1
Reactant: S=C1COc2nc(Br)c(-c3ccccc3)cc2N1
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: N/N=C1\COc2nc(Br)c(-c3ccccc3)cc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
In a 15 ml vial was 6-bromo-7-phenyl-1H-pyrido[2,3-b][1,4]oxazine-2(3H)-thione (100 mg, 0.311 mmol) and hydrazine monohydrate (0.049 ml, 1.557 mmol) in tetrahydrofuran (5 ml) to give a brown solution. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and the crude residue was slurred in diethyl ether. The supernatant solvent was removed and the brown solid vas dried until constant weigh to afford the title compound (90 mg, 90%). It was used for the next step without further purification. LCMS (Method D): RT 0.770 min, M+1=321.