Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3=[CH:8][CH:9]=[C:10]([OH:22])[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=43)[CH2:4][CH2:3]1)=O.Cl.C[O:25][NH2:26].[OH-].[Na+].[CH3:29]O>O>[CH3:29][CH:14]1[C:16](=[N:26][OH:25])[CH2:17][C@:18]2([OH:21])[C@:5]34[CH2:4][CH2:3][N:2]([CH3:1])[C@@H:19]2[CH2:20][C:7]2[CH:8]=[CH:9][C:10]([OH:22])=[C:11]([O:12][C@@H:13]13)[C:6]4=2
Reactant: CO
Reactant: CON
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1C(=NO)C[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3C)[C@H]1O5

Procedure:
A solution of oxymorphone (0.9 g, 3 mmol) and O-methyl hydroxylamine hydrochloride (0.33 g, 3.9 mmol) in 15 mL MeOH containing 1.6 mL of 10% aqueous NaOH was refluxed for 5 h, cooled, diluted with water (approximately 100 mL) and extracted with 150 mL CHCl3 (3×50 mL). The combined extracts were dried (MgSO4), and evaporated. The residue obtained was recrystallized from CH2Cl2 -hexane to yield 0.84 g on the product. It was further purified by flash column chromatography on silica gel, eluting with EtOAc-EtOH-NH40H (100:1:1) (approx. size 40 microns). The combined fractions were evaporated in vacuo and the residue obtained was recrystallized from hexane-petroleum ether. Yield: 0.4 g (40%). mp 115-116 C. IR: (KBr): No C=O absorption at 1730 cm-1. 1H NMR (CDCl3) δ 4.92 (s,C5H), 3.85 (s, OCH3) Rf: silica gel 60 in EtOAc-EtOH-NH40H (100:1:1) 0.30. Anal. Calcd for: C18H22N2O4C, 65.44; H, 6.71; N, 8.48. Found: C, 65.51; H, 6.74; N, 8.46.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:11](=O)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[C:7]([OH:10])[C:8]=1[OH:9])#[N:2].[NH2:17][C:18]1C(O)=[CH:22][CH:21]=[C:20]([CH3:25])[CH:19]=1>CN(C)C=O.O>[OH:9][C:8]1[C:7]([OH:10])=[CH:6][C:5]([C:11]2[C:12](=[O:13])[O:14][C:15]3[CH:22]=[CH:21][C:20]([CH3:25])=[CH:19][C:18]=3[N:17]=2)=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: COC(=O)C(=O)c1cc(O)c(O)c(C#N)c1
Reactant: Cc1ccc(O)c(N)c1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2oc(=O)c(-c3cc(O)c(O)c(C#N)c3)nc2c1
Temperature: 25 °C

Procedure:
1.075 g of methyl (3-cyano-4,5-dihydroxyphenyl)glyoxylate and 0.60 g of 2-amino-p-cresol are stirred at 120° for 70 minutes in 2 ml of dimethylformamide. The mixture is subsequently cooled to room temperature and diluted with 15 ml of water. The precipitate is filtered and dried in a water-jet vacuum at 80° for 6 hours. After recrystallization from acetonitrile there is obtained 2,3-dihydroxy-5-(6-methyl-2-oxo-2H-1,4-benzoxazin-3-yl)benzonitrile of m.p. 278°-280°.
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[O:27][N:26]=[C:25]([O:28][CH2:29][C:30]4[N:31]=[C:32]([C:36]5[CH:41]=[CH:40][C:39]([CH2:42][C:43]([O:45]CC)=[O:44])=[CH:38][CH:37]=5)[O:33][C:34]=4[CH3:35])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[O:27][N:26]=[C:25]([O:28][CH2:29][C:30]4[N:31]=[C:32]([C:36]5[CH:41]=[CH:40][C:39]([CH2:42][C:43]([OH:45])=[O:44])=[CH:38][CH:37]=5)[O:33][C:34]=4[CH3:35])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=2)[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3cc(COc4nn(-c5ccccc5)cc4/C=C/c4csc(CC)n4)on3)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2cc(OCc3nc(-c4ccc(CC(=O)O)cc4)oc3C)no2)cs1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a mixture of ethyl (4-{4-[({5-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]isoxazol-3-yl}oxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (193 mg), tetrahydrofuran (3 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (0.9 mL), and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture were added 1N hydrochloric acid (0.9 mL) and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from ethyl acetate-diethyl ether gave (4-{4-[({5-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]isoxazol-3-yl}oxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetic acid as colorless prism crystals (112 mg, yield 61%). melting point: 156-158° C.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH:7]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH:8][C:9]([C:11]1[CH:20]=[C:19]2[C:14]([C:15]([Cl:25])=[CH:16][N:17]=[C:18]2[NH:21][C:22]([NH2:24])=[NH:23])=[CH:13][CH:12]=1)=[O:10])(C)(C)C.[C:34]([C:38]([OH:40])=[O:39])([F:37])([F:36])[F:35]>C1(C)C=CC=CC=1>[F:35][C:34]([F:37])([F:36])[C:38]([OH:40])=[O:39].[Cl:25][C:15]1[C:14]2[C:19](=[CH:20][C:11]([C:9]([NH:8][CH:7]([C:6]([OH:33])=[O:5])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:10])=[CH:12][CH:13]=2)[C:18]([NH:21][C:22]([NH2:24])=[NH:23])=[N:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)C(Cc1ccccc1)NC(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: N=C(N)Nc1ncc(Cl)c2ccc(C(=O)NC(Cc3ccccc3)C(=O)O)cc12

Procedure:
A solution of N-[(4-Chloro-1-guanidino-7-isoquinolinyl)carbonyl]-DL-phenylalanine t-butyl ester (210 mg, 0.48 mmol) in CF3CO2H (1 mL) was stirred at room temperature for 1 h. The solution was diluted with PhMe, evaporated in vacuo, and the residue was triturated with Et2O to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]-DL-phenylalanine trifluoroacetate (196 mg, 0.37 mmol).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)[CH3:2].[OH2:17]>CC(C)=O>[CH2:1]([C:3]1[O:4][C:5]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)[CH3:2]
Reactant: CCc1cc(=O)c2cc(CCO)ccc2o1
Reactant: O
Solvent: CC(C)=O
Product: CCc1cc(=O)c2cc(CC(=O)O)ccc2o1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
This red solution was added dropwise to a stirred solution of 2-(2-ethyl-4-oxo-4H-1-benzopyran-6-yl)ethan-1-ol (3.5 g) in acetone (30 mls) maintained at 20° C. until a permanent red colouration was obtained. The reaction was stirred at room temperature for a further 11/2 hours. Water was added and the product was extracted with ether (3x). The separated ethereal solution was extracted with sodium bicarbonate which was washed with water, acidified with dilute hydrochloric acid and extracted with chloroform. The chloroform solution was washed with a small volume of saturated brine solution and dried over anhydrous magnesium sulphate. Evaporation of the solvent yielded the product as an off-white solid (2.2 g). Recrystallisation from benzene yielded pale yellow needle crystals mp 171°-172° C. (1.1 g). The mother liquors were concentrated and a second crop was obtained as a pale yellow solid (0.6 g).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]1[CH:8]2[CH2:9][CH:10]([C@H:11]([OH:23])[C:12]3[CH:21]=[CH:20][N:19]=[C:18]4[C:13]=3[CH:14]=[C:15]([OH:22])[CH:16]=[CH:17]4)[N:5]([CH2:6][CH2:7]2)[CH2:4]1.Br[CH2:25][CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].C(=O)([O-])[O-].[K+].[K+].CO>CC(C)=O.C1OCCOCCOCCOCCOCCOC1>[OH:23][C@@H:11]([C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([O:22][CH2:25][CH2:26][CH2:27][N:28]3[C:32](=[O:33])[C:31]4[C:30](=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:29]3=[O:38])[CH:14]=2)[N:19]=[CH:20][CH:21]=1)[C@@H:10]1[N:5]2[CH2:6][CH2:7][C@H:8]([C@@H:3]([CH:2]=[CH2:1])[CH2:4]2)[CH2:9]1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: C=CC1CN2CCC1CC2[C@H](O)c1ccnc2ccc(O)cc12
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Product: C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](O)c1ccnc2ccc(OCCCN3C(=O)c4ccccc4C3=O)cc12
Temperature: 25 °C
Yield: 26.9 %

Procedure:
A mixture of 6-hydroxycinchonine (1) (2.5 g, 8.06 mmol), N-(3-bromopropyl)phthalimide (2.16 g, 8.06 mmol), anhydrous potassium carbonate (1.3 g, 9.4 mmol) and 18-crown-6 (5 mg) in 75 ml of dry acetone was allowed to reflux for 16 h under argon atmosphere. The reaction was cooled to room temperature and 30 ml of methanol was added to make a homogeneous solution. The resulting solution was concentrated and the residue was partially purified on silica gel column chromatography using 5% methanol in chloroform as the eluent. This product was repurified on silica gel column chromatography using 10% methanol in chloroform and yielded 1.08 g (2.17 mmol, 27%) of (11) as off-white solids. MS, IR and NMR data confirmed compound identity.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:12]([BH3-])#N.[Na+].[C:16](=[O:19])(O)[O-].[Na+]>C(O)(=O)C>[C:16]([N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[C:9]([CH3:11])[CH:8]=2)[CH2:4][CH2:5]1)(=[O:19])[CH3:12]
Reactant: O=C([O-])O
Reactant: [BH3-]C#N
Reactant: Cc1cc(C)c2cc[nH]c2c1
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)N1CCc2c(C)cc(C)cc21
Temperature: 0 °C

Procedure:
4,6-Dimethylindole (1.08 g) was dissolved in acetic acid (20 ml), and sodium cyanoborohydride (2.3 g) was added portionwise at 15° C. The mixture was stirred at said temperature for one hour and poured into ice water. Saturated aqueous sodium bicarbonate was added to neutralize the mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in benzene, and acetic anhydride (840 mg) was added, which was followed by stirring at room temperature for one hour. The reaction mixture was washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was chromatographed (ISCO, hexane/EtOAc, 0-40%, 40 min) to give 1.3 g of 1-acetyl-4,6-dimethylindoline.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]=O)[C:5]#[N:6].[CH3:12][C:13](=[O:18])[CH2:14][C:15](=[O:17])[CH3:16].C(O)(=O)C.N1CCCCC1>ClCCl>[C:15]([C:14]([C:13](=[O:18])[CH3:12])=[CH:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[CH3:1])(=[O:17])[CH3:16]
Reactant: CC(=O)CC(C)=O
Reactant: Cc1cc(C#N)ccc1C=O
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC(=O)C(=Cc1ccc(C#N)cc1C)C(C)=O

Procedure:
950 mg (6.54 mmol) of 3-methyl-4-formylbenzonitrile [S. Levesque et al., Bioorg. Med. Chem. Lett. 11, 3161-3164 (2000], 655.2 mg (6.544 mmol) of 2,4-pentanedione, 589.5 mg (9.82 mmol) of acetic acid and 111.5 mg (1.31 mmol) of piperidine are dissolved in 35 ml of dichloromethane and heated under reflux with an inverse water trap overnight. Cooling is followed by washing twice with water, and the organic phase is dried with magnesium sulfate. The solvent is removed in a rotary evaporator and the residue is purified by column chromatography (silica gel, mobile phase: initially dichloromethane, then isohexane/ethyl acetate 3:1). After concentration of the product fractions, the residue is crystallized from diethyl ether and dried under high vacuum. 1.12 g (75.3% of theory) of the title compound are obtained.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH2:13][C:12](=[O:15])[NH:11][C:10]=2[CH:16]=1>C(O)(=O)C>[OH:5][C:6]1[C:7]([N+:1]([O-:4])=[O:2])=[CH:8][C:9]2[O:14][CH2:13][C:12](=[O:15])[NH:11][C:10]=2[CH:16]=1
Reactant: O=[N+]([O-])O
Reactant: O=C1COc2ccc(O)cc2N1
Solvent: CC(=O)O
Product: O=C1COc2cc([N+](=O)[O-])c(O)cc2N1

Procedure:
Fumic nitric acid (δ1.52, 2.6 ml, 0.062 mole) in acetic acid (5 ml) was added dropwise under stirring to 6-hydroxy-2H-1,4-benzoxazin-3-(4H)-one (Coupler (1), 10.3 g, 0.062 mole) in acetic acid (100 ml) at room temperature. The 6-hydroxy-7-nitro-1,4-benzoxazin-3-one (6.7 g, 51%) separated as yellow prisms.
Reaction SMILES: [CH3:1][C:2]([CH3:56])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:53])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:52])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42]([NH:44][C:45]4[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=4)=[O:43])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:55])[CH3:54])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].[C:57]([OH:63])([C:59]([F:62])([F:61])[F:60])=[O:58].CC#N>ClCCl>[C:57]([OH:63])([C:59]([F:62])([F:61])[F:60])=[O:58].[OH2:4].[Cl:51][C:48]1[CH:49]=[CH:50][C:45]([NH:44][C:42](=[O:43])/[CH:41]=[CH:40]/[C@:23]23[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:38])[CH3:39])=[C:24]2[C@@H:25]2[C@@:20]([CH3:52])([CH2:21][CH2:22]3)[C@@:19]3([CH3:53])[C@@H:28]([C@:29]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:54])([CH3:55])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:56])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]4)[CH2:27][CH2:26]2)=[CH:46][CH:47]=1
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)Nc2ccc(Cl)cc2)CC1=O
Solvent: ClCCl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)Nc2ccc(Cl)cc2)CC1=O
Product: O
Yield: 93.5 %

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-((4-chlorophenyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (230 mg, 0.291 mmol) in Dichloromethane (DCM) (4 mL) was added TFA (2 mL, 0.291 mmol). The reaction mixture was stirred at r.t for 2 hs and evaporated in vacuo to afford crude product, which was purified by preparative-HPLC (Mobile Phase: A=0.05% TFA/H2O, B=MeCN) to give the product 4-(((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-((4-chlorophenyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (100 mg, 0.136 mmol, 46.8%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.60-7.53 (m, 3H), 7.28 (d, J=8.4 Hz, 2H), 7.12 (d, J=15.6 Hz, 1H), 5.84 (d, J=15.6 Hz, 1H), 4.50 (dd, J=11.2, 5.2 Hz, 1H), 3.22 (m, 1H), 2.77 (d, J=11.6 Hz, 1H), 2.68 (d, J=16.0 Hz, 1H), 2.57 (d, J=15.6 Hz, 1H), 2.32 (d, J=18.8 Hz, 1H), 2.20 (d, J=19.2 Hz, 1H), 2.11 (d, J=12.0 Hz, 1H), 1.93-0.77 (m, 44H); LC/MS: m/z calculated 733.4. Found 734.3 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH2:10][CH:9]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[O:8][C:5]2=[CH:6][N:7]=1.Cl[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19]>>[CH:21]([O:20][C:18]([N:14]1[CH2:15][CH2:16][CH:11]([CH:9]2[O:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH2:10]2)[CH2:12][CH2:13]1)=[O:19])([CH3:23])[CH3:22]
Reactant: CC(C)OC(=O)Cl
Reactant: Clc1cc2c(cn1)OC(C1CCNCC1)C2
Product: CC(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1

Procedure:
The title compound is prepared from 5-chloro-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and isopropyl chloroformate following a procedure analogous to that described in Example 4. LC (method 7): tR=1.37 min; Mass spectrum (ESI+): m/z=325 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[C-:9]#[N:10].[Na+]>C(OCC)C.CN(C)C>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:9]#[N:10])[N:7]=1
Reactant: [C-]#N
Reactant: Cc1ccnc(Cl)n1
Agent: CN(C)C
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccnc(C#N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To a solution of 2-chloro-4-methylpyrimidine (3.00 g, 23.3 mmol; 3B Pharmachem International, China) in ethyl ether (24 mL) was added a solution of sodium cyanide (2.86 g, 58.3 mmol) in trimethylamine solution (1:3, trimethylamine:water, 24.0 mL). The reaction mixture was stirred at room temperature overnight. The aqueous layer was extracted with ethyl ether (3×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to yield the title compound, 4-methyl-pyrimidine-2-carbonitrile (1.80 g; 64.8%), which was used in the next step without further purification. 1H NMR (400 MHz, D2O) δ8.64 (d, J=5.4 Hz, 1H), 7.59 (d, J=5.5 Hz, 1H).
Reaction SMILES: Cl[C:2]1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[CH2:15]([O:22][C:23](=[O:35])[NH:24][C@@H:25]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:26]=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:36]1([NH2:43])[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH2:42]>CC#N>[CH2:15]([O:22][C:23](=[O:35])[NH:24][C@@H:25]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)/[CH:26]=[N:42]/[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[NH:43][CH3:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: Nc1ccccc1N
Reactant: O=C[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Solvent: CC#N
Product: CNc1ccccc1/N=C/[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.3 %

Procedure:
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 0.20 g, 0.86 mmoles) was added to a room temperature solution of ((S)-1-Benzyl-2-oxo-ethyl)-carbamic acid benzyl ester (0.24 g, 0.86 mmoles) and 1,2-phenylenediamine (0.093 g, 0.86 mmoles) in CH3CN (10 mL). The reaction mixture was stirred at room temperature for 16 h, and then concentrated in vacuo. The residue was re-dissolved in EtOAc (150 mL), and washed with saturated aqueous NaHCO3 (3×125 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to give a brown oily solid. Purification of the residue by flash chromatography on silica gel eluting with 10-40% EtOAc/heptane afforded 0.091 g (28% yield) of {(S)-1-Benzyl-2-[(E)-2-methylamino-phenylimino]-ethyl}-carbamic acid benzyl ester as a colorless oil: ES+ LC/MS m/e 372 (M+H), RT=3.03 min; 1H NMR (CDCl3) D9.90 (bd s, 1), 7.68 (bd s, 1), 7.21-7.33 (m, 11), 7.16 (d, 2, J=6.7 Hz), 5.64 (d, 1, J=7.2 Hz), 5.15 (dd, 1, J=15.2, 7.5 Hz), 5.07 (s, 2), 3.45 (d, 2, J=7.5 Hz).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]3[O:12][CH2:13][CH2:14][O:15][C:5]=3[C:4]=2[N:3]1[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([NH:24]C(=O)OC(C)(C)C)[CH2:20][CH2:19]1.Cl>C(Cl)(Cl)Cl.O1CCOCC1.CO>[NH2:24][CH:21]1[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][N:3]2[C:4]3[C:5]4[O:15][CH2:14][CH2:13][O:12][C:6]=4[CH:7]=[CH:8][C:9]=3[CH:10]=[CH:11][C:2]2=[O:1])[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc4c(c32)OCCO4)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC1CCN(CCn2c(=O)ccc3ccc4c(c32)OCCO4)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
1,1-dimethylethyl {1-[2-(9-oxo-2,3-dihydro[1,4]dioxino[2,3-h]quinolin-10(9H)-yl)ethyl]-4-piperidinyl}carbamate (1 g; 2.34 mmol) was dissolved in chloroform (8 ml) and 4M HCl in 1,4-dioxane (10 ml) added. This was then stirred at rt for 1 h. The salts from the reaction were dissolved in MeOH and all solvents then removed. The residues were redissolved in MeOH and stirred with amberlyst ion exchange resin until a neutral pH was reached. The resin was filtered off and all solvents were removed. The crude residues were subjected to column chromatography on silica gel using a 0-20% 2M NH3: MeOH/DCM gradient to give the desired product (425 mg; 55%).
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:14]([O:16][CH3:17])=[O:15].[CH:18]1([NH:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>[OH-].[Na+].O>[CH:25]1([NH:24][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1.[CH3:17][O:16][C:14]([NH:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:15]
Reactant: COC(=O)Cl
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)N[C@H](Cc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5 g (30 mmol) of D-phenylalanine is dissolved in 15 ml of 2M NaOH solution, cooled to 0° C. and, simultaneously, 16.5 ml of 2M NaOH solution and 2.55 ml (33 mmol) of methyl chloroformate are added. The mixture is stirred at this temperature for 30 min, then at room temperature for 2 hours. Diluted with 40 ml of water, the mixture is washed with 10 ml of diethyl ether, acidified to pH3 with 3M HCl and extracted with 4×20 ml of ethyl acetate. The pooled organic extracts are washed with water (20 ml), dried over anhydrous sodium sulphate and evaporated at a pressure of 2.0-2.5 kPa. The residue is dissolved in 60 ml of diisopropyl ether and 6 ml (30 mmol) of dicyclohexylamine is added. The separated crystals are filtered off, washed with diisopropyl ether and dried in air.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:42]1([C@@H:46]([NH:53][CH3:54])[CH2:47][N:48]2[CH2:51][CH:50]([OH:52])[CH2:49]2)[CH2:45][CH2:44][CH2:43]1>C(Cl)Cl.CN1C(=O)CCC1>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([N:53]([C@H:46]([CH:42]2[CH2:45][CH2:44][CH2:43]2)[CH2:47][N:48]2[CH2:49][CH:50]([OH:52])[CH2:51]2)[CH3:54])=[O:17])=[CH:18][CH:19]=1
Reactant: CN[C@@H](CN1CC(O)C1)C1CCC1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ccc(Cl)cc1)[C@@H](CN1CC(O)C1)C1CCC1
Temperature: 25 °C
Yield: 52.4 %

Procedure:
DIPEA (0.275 mL, 1.57 mmol) was added to a suspension of 4-chlorobenzoic acid (82 mg, 0.52 mmol) and TBTU (168 mg, 0.52 mmol) in DCM (1 mL) at rt. The reaction mixture was stirred for 45 min before a solution of (R)-1-(2-cyclobutyl-2-(methylamino)ethyl)azetidin-3-ol (Compound G2.6) (184 mg, 0.52 mmol) in NMP (1.000 mL) was added. The reaction mixture was stirred at rt over the weekend. The reaction mixture was washed with NaHCO3 (8% aq.2 mL). The organic layer was passed through a phase separator and the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound (88 mg, 52%). 1H NMR (600 MHz, DMSO-d6) δ 1.38-1.52, 1.55-1.62, 1.64-1.95, 2.00-2.06, 2.21-2.25, 2.27-2.33, 2.36-2.43, 2.55-2.62, 2.64-2.68, 2.70-2.72, 2.73-2.79, 3.23-3.26, 3.40-3.44, 3.54-3.57, 4.11-4.18, 4.43-4.51, 5.20-5.27, 7.29-7.35, 7.47-7.54. HRMS (M+H)+: calculated 323.1526. found 323.1535
Reaction SMILES: C([Mg]Br)C.[CH:5](NC(C)C)(C)C.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C:21]1=[S:26].[CH3:27][O:28][C:29](=O)[O:30]C.Cl>CCOCC.O1CCCC1>[CH3:27][O:28][C:29]([C:22]1[CH2:23][CH2:24][CH2:25][N:20]([C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[Cl:12])[C:21]=1[S:26][CH3:5])=[O:30]
Reactant: CC(C)NC(C)C
Reactant: S=C1CCCCN1c1ccc(Cl)cc1Cl
Reactant: COC(=O)OC
Agent: CC[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C1=C(SC)N(c2ccc(Cl)cc2Cl)CCC1
Temperature: 80 °C

Procedure:
To 39.6 ml of a 3M solution ethylmagnesium bromide in ether was added 100 mL of dry tetrahydrofuran under an atmosphere of nitrogen. Then 16.7 mL of diisopropylamine was added dropwise. The reaction mixture was then heated to 80° C. for 1 h. After cooling to room temperature, the mixture was treated with a solution of 6.19 g of 1-(2,4-dichlorophenyl)piperidine-2-thione in 50 mL of dry tetrahydrofuran, heated to 80° C. for 30 min, and cooled again to room temperature. Then the mixture was treated dropwise with 10.0 mL of dimethylcarbonate and heated to 80° C. for 26 h. After cooling to room temperature, 100 g of ice was added along with 150 mL of 1.2M HCl. The mixture was extracted three times with 100 mL portions of dichloromethane. The combined organic extracts were washed with 100 mL of brine, dried over magnesium sulfate, concentrated, and then kept under high vacuum at 50° C. to remove the higher boiling volatile materials. The residue was purified by flash silica gel chromatography using 7% acetone/hexane as solvent yielding 5.25 g of 1-(2,4-dichlorophenyl)-2-methylsulfanyl-1,4,5,6-tetrahydropyridine-3-carboxylic acid methyl ester as a yellow solid, mp 83–86° C.