Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:10](OC)(OC)([O:12][CH3:13])[CH3:11].C(OC(=O)C)(=O)C>>[C:3]([C:2](=[C:10]([O:12][CH3:13])[CH3:11])[C:1]([O:8][CH3:9])=[O:7])([O:5][CH3:6])=[O:4]
Reactant: COC(C)(OC)OC
Reactant: COC(=O)CC(=O)OC
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C(C(=O)OC)=C(C)OC
Temperature: 130 °C
Yield: 77.5 %

Procedure:
264 g (2 mol) of dimethyl malonate, 961 g (8 mol) of trimethyl orthoacetate and 1 g of catalyst from Example 1 were put into the pressure apparatus described in Example 2. The mixture was heated to 130° C., whereupon an internal pressure of 1.5 bar developed. 100 g of acetic anhydride were then metered in over the course of 12 hours, the low-boiling component was distilled off at a head temperature of 82° to 87° C. and the reaction temperature was gradually increased to 160° C. After complete distillation of the low-boiling component, the mixture was cooled, the excess trimethyl orthoacetate distilled off at reduced pressure and the crude product was fractionated through a short column at a head temperature of 110° C. under a high vacuum of 0.3 mbar. In this way methyl 2-carbomethoxy-3-methoxy-2-butenoate was obtained in a yield of 77.5% and methyl 2-carbomethoxy-3,3-dimethoxy-butanoate was obtained in a yield of 11% of the theoretical yield.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:8]=2)[N:4]=[CH:3]1.[Li]CCCC.[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][N:36]=1)[CH:32]=[O:33]>C1COCC1>[Cl:28][C:29]1[CH:30]=[C:31]([CH:32]([C:3]2[N:2]([CH3:1])[CH:6]=[C:5]([C:7]3[O:11][N:10]=[C:9]([C:12]4[CH:13]=[CH:14][C:15]([O:18][C:19]([F:20])([F:22])[F:21])=[CH:16][CH:17]=4)[N:8]=3)[N:4]=2)[OH:33])[CH:34]=[CH:35][N:36]=1
Reactant: Cn1cnc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)c1
Reactant: O=Cc1ccnc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nc1C(O)c1ccnc(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
To a solution of 5-(1-methyl-1H-imidazol-4-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (500 mg, 1.61 mmol) in THF (10 mL) at −78° C., n-BuLi (2.0 mL, 3.2 mmol, 1.6 M) was added slowly. After stirred at −78° C. for 30 min, 2-chloroisonicotinaldehyde (454 mg, 3.22 mmol) in THF (5 mL) was dropwise added. The mixture was gradually warmed to 0° C., and stirred for 1 h. After quenched by water (20 mL), the mixture was extracted by EA (2×20 mL). The combined organic phases were washed by water (2×30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to afford the crude product, which was purified by prep-TLC (EtOAc:Petroleum ether=1:1) to give (2-chloropyridin-4-yl)(1-methyl-4-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-imidazol-2-yl)methanol as a yellow solid (230 mg, 31.7%). MS (ES+) C19H13ClF3N5O3 requires: 451, found: 452 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:14])[CH2:11][O:12][CH3:13])[N:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[CH:21]=1.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:14][C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[NH:25][CH:26]=[N:27]4)[CH2:11][O:12][CH3:13])[N:7]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:6]=2[CH:21]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: COC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COCC(Nc1ncnc2nc[nH]c12)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 90 °C
Yield: 32.4 %

Procedure:
A mixture of (R)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)-2-methoxyethylamine (110 mg, 0.39 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (93 mg, 0.39 mmol) and DIPEA (340 mL, 1.9 mmol) in n-butanol (2.5 mL) was heated at 90° C. in a sealed vial for 18 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford 171 as a white solid (51 mg, 32%). LCMS (Method B): RT 3.52 min [M+H]+ 404.0. 1H NMR (DMSO-d6, 400 MHz): δ 8.25-8.01 (2H, m), 7.87 (1H, s), 7.77-7.47 (6H, m), 7.15-7.05 (1H, m), 6.87 (1H, dd, J=8.93, 2.37 Hz), 5.64 (1H, s), 3.84 (2H, d, J=6.60 Hz), 3.14 (3H, s). Signals split due to presence of rotamers/tautomers
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:18])[CH3:2].[Cl:19][C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[CH2:22]Cl.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[Cl:19][C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[CH2:22][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:14]([O:16][CH3:17])=[O:15])[CH:7]=2)[C:12](=[O:13])[N:3]([CH2:1][CH3:2])[C:4]1=[O:18]
Reactant: CCn1c(=O)[nH]c2cc(C(=O)OC)ccc2c1=O
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCn1c(=O)c2ccc(C(=O)OC)cc2n(Cc2ccc(Cl)cc2Cl)c1=O
Yield: 73 %

Procedure:
A mixture of 3-ethyl-7-(methoxycarbonyl)-2,4(1H,3H)-quinazolinedione (2.17 g), 2,4-dichlorobenzyl chloride (2.05 g), potassium iodide (1.45 g) and potassium carbonate (5.0 g) in acetone (80 ml) was heated under reflux for 1.5 hr. After cooling, water (50 ml) was added to the reaction mixture and the precipitate was collected by filtration. The precipitate was washed with water (30 ml) and methyl t-butyl ether (30 ml) and dried to give the object compound (2.60 g).
Reaction SMILES: N=C=N.[F:4][C:5]([F:43])([F:42])[C:6]1[CH:7]=[C:8]([C:16]2([C:38]([F:41])([F:40])[F:39])[O:20][N:19]=[C:18]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]([C:31]([NH:33][CH2:34][C:35]([OH:37])=O)=[O:32])=[CH:23][CH:22]=3)[CH2:17]2)[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1.[F:44][C:45]([F:49])([F:48])[CH2:46][NH2:47]>ClCCl>[F:4][C:5]([F:42])([F:43])[C:6]1[CH:7]=[C:8]([C:16]2([C:38]([F:40])([F:41])[F:39])[O:20][N:19]=[C:18]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]([C:31]([NH:33][CH2:34][C:35](=[O:37])[NH:47][CH2:46][C:45]([F:49])([F:48])[F:44])=[O:32])=[CH:23][CH:22]=3)[CH2:17]2)[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1
Reactant: NCC(F)(F)F
Reactant: O=C(O)CNC(=O)c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)c2ccccc12
Agent: N=C=N
Solvent: ClCCl
Product: O=C(CNC(=O)c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)c2ccccc12)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
PS-Carbodiimide (400 mg, 123 mmol/g, Argonaut Technologies, Inc.) was added to a stirred mixture of N-[[4-[5-[3,5-bis(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-1-naphthalenyl]carbonyl]glycine (i.e. the product of Step C, 140 mg) and 2,2,2-trifluoroethylamine (0.038 mL) in dichloromethane (3 mL) at room temperature. The mixture was stirred at room temperature overnight, then filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with ethyl acetate/hexanes to provide the title compound (115 mg), a compound of this invention, as a white solid. 1H NMR (CDCl3): δ 8.77 (d, 1H), 8.16 (d, 1H), 8.13 (s, 2H), 8.01 (s, 1H), 7.51-7.60 (m, 3H), 7.46 (t, 1H), 7.42 (d, 1H), 7.33 (d, 1H), 4.31 (d, 1H), 4.23 (d, 2H), 3.83-3.92 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([P:8]([O-:12])[O:9][CH2:10][CH3:11])[O:5][CH2:6][CH3:7])[CH3:2].[C:13](#[N:17])/[CH:14]=[CH:15]/[CH3:16].[H-].[Na+].C(O)(=O)C>C(O)C>[C:13]([CH2:14][CH:15]([P:8]([CH:4]([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])(=[O:12])[O:9][CH2:10][CH3:11])[CH3:16])#[N:17]
Reactant: C/C=C/C#N
Reactant: CCOC(OCC)P([O-])OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(OCC)P(=O)(OCC)C(C)CC#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The starting material may be prepared as follows: A solution of 23.5 g of ethyl (diethoxymethyl)phosphonite and 6.7 g of crotononitrile in 30 ml of dry ethanol is added to a stirred mixture of 1.2 g of sodium hydride (50% dispersion in oil) in 30 ml of ethanol at 0° C. under an atmosphere of nitrogen. The reaction mixture is allowed to warm to room temperature and stirred for 4 hours. 1 ml of glacial acetic acid is added and the mixture concentrated under reduced pressure. The resulting crude product is dissolved in 50 ml of ethyl acetate, washed twice with 25 ml of water, and the organic extract is dried over magnesium sulphate, and then concentrated under reduced pressure. The crude product is distilled under reduced pressure to give ethyl 2-cyano-1-methylethyl(diethoxymethyl)phosphinate, b.p. 116° C./0.01 mbar, 31P=+42.2 and +42.0 ppm (CDCl3).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:6]([O:8][C:9](=[O:33])[N:10]([C:22]1[CH:27]=[C:26](Br)[N:25]=[C:24]([NH2:29])[C:23]=1[N+:30]([O-:32])=[O:31])[CH2:11][C:12]1[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=1)[CH3:7]>[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd+2]>[CH2:6]([O:8][C:9](=[O:33])[N:10]([C:22]1[CH:27]=[C:26]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[N:25]=[C:24]([NH2:29])[C:23]=1[N+:30]([O-:32])=[O:31])[CH2:11][C:12]1[CH:13]=[N:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=1)[CH3:7]
Reactant: CCOC(=O)N(Cc1ccc(C(F)(F)F)nc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Reactant: c1cocn1
Agent: [Pd+2]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)N(Cc1ccc(C(F)(F)F)nc1)c1cc(-c2ncco2)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 70, using oxazole (30 mg), (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (100 mg) and palladium bis(triphenylphosphine)dichloride (30 mg), giving the product (61 mg) as a yellow solid
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[CH:6]=[CH:5]2.[CH:22]([Sn](CCCC)(CCCC)CCCC)=[CH2:23]>C1(C)C=CC=CC=1>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:22]=[CH2:23])[CH:3]=2)[N:8]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccccc1CNc1ccc2cc(Br)ccc2n1
Solvent: Cc1ccccc1
Product: C=Cc1ccc2nc(NCc3ccccc3OC)ccc2c1

Procedure:
(6-Bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (example 2, step A, 500 mg, 1.46 mmol) was dissolved in 20 mL toluene. The reaction mixture was evacuated and backfilled with argon for three times to remove oxygen. Vinyltributyltin (462 mg, 1.46 mmol) and tetrakis(triphenylphosphin)palladium(0) (34 mg, 0.029 mmol) were added. The reaction mixture was refluxed overnight and evaporated. The residue was poured into 50 mL acetonitrile and extracted three times with heptane (50 mL each) to remove the tin products. The acetonitrile phase was dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->80:20 gradient). (2-Methoxy-benzyl)-(6-vinyl-quinolin-2-yl)-amine was obtained as a yellow oil (478 mg), MS: m/e=291.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C@H:13]([CH:17]([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[CH2:26]([O:15][C:14](=[O:16])[C@H:13]([NH:12][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH:17]([CH3:19])[CH3:18])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(S(=O)(=O)N[C@@H](C(=O)O)C(C)C)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N[C@@H](C(=O)OCc2ccccc2)C(C)C)cc1
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of 2(R)-(4-methoxybenzenesulfonylamino)-3-methylbutyric acid (40 g, 139.2 mmol) and cesium carbonate (85.7 g, 444 mmol) in dimethylformamide was added benzyl bromide (16.1 g, 135 mmol). The reaction mixture was stirred overnight. The dimethylformamide was removed on the rotoevaporator and the residue was dissolved in ethyl acetate (200 ml) and partitioned with an equal volume of water. The organic phase was collected and washed with an equal volume of brine. The aqueous phases were back extracted with ethyl acetate (2×150 ml), combined and dried over magnesium sulfate and condensed to provide 2(R)-(4-methoxybenzenesulfonylamino)-3-methylbutyric acid benzyl ester (42.6 g) as a white crystalline solid.
Reaction SMILES: Br[C:2]1[C:3]([C@@H:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.O1CCOCC1.[CH2:33]([Sn](CCCC)(CCCC)C#CC)[CH2:34][CH2:35]C>CCOC(C)=O>[C:33]([C:2]1[C:3]([C@@H:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1)#[C:34][CH3:35]
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1Br
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC#Cc1cccnc1[C@@H](NC(=O)OC(C)(C)C)c1ccc(C(F)(F)F)cc1

Procedure:
To a microwave vial containing (S)-tert-butyl ((3-bromopyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamate (500 mg, 1.159 mmol) and a stir bar was added 1,4-dioxane (6 mL). To this solution was added tetrakis(triphenyl-phosphine)palladium(0) (67.0 mg, 0.058 mmol, 0.05 eq) and tributyl(prop-1-yn-1-yl)stannane (458 mg, 1.391 mmol, 1.2 eq). The vial was capped and irradiated in a microwave at 120° C. for 20 min. The vial was allowed to cool, diluted with hexanes (5 mL) and loaded directly to a normal phase silica gel column (80 g ISCO, 0 to 40% EtOAc in hexanes) to provide (S)-tert-butyl ((3-(prop-1-yn-1-yl)-pyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].Br[C:12]1[S:13][CH:14]=[CH:15][N:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][C:12]1[S:13][CH:14]=[CH:15][N:16]=1
Reactant: Brc1nccs1
Reactant: COc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(Oc2nccs2)c(Cl)c1
Temperature: 160 °C
Yield: 87.9 %

Procedure:
A mixture of 2-chloro-4-methoxy-phenol (7.93 g, 0.05 mol), 2-bromothiazole (9.0 g, 0.055 mol) and potassium carbonate (7.6 g, 0.055 mol) in dimethyl sulfoxide was heated at 160° C. under nitrogen for 4 hours. The solution was cooled and treated with water, and the aqueous phase was extracted with dichloromethane. The organic layer was washed with brine, dried and concentrated to give 30 g of the crude material, which was purified on a silica gel (ethyl acetate/hexane 5-35%) to afford 10.62 g of the product as a light yellow oil (88% yield), 1H NMR (300 MHz, CDCl3) δ ppm 3.81 (s, 3H) 6.80 (d, J=4.04 Hz, 1H) 6.85 (dd, J=9.19, 2.94 Hz, 1H) 7.01 (d, J=2.94 Hz, 1H) 7.19 (d, J=3.68 Hz, 1H) 7.27 (d, J=8.82 Hz, 1H). MS (ESI), m/z 241.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][S:11][C:10]1=[S:15].C([O-])(=O)C.[Na+].[N+:21]([C:24]1[CH:25]=[C:26]([C:30]2[O:34][C:33]([CH:35]=O)=[CH:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22]>C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12](=[CH:35][C:33]2[O:34][C:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=3)=[CH:31][CH:32]=2)[S:11][C:10]1=[S:15]
Reactant: Cc1ccc(N2C(=O)CSC2=S)c(C)c1
Reactant: O=Cc1ccc(-c2cccc([N+](=O)[O-])c2)o1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(N2C(=O)C(=Cc3ccc(-c4cccc([N+](=O)[O-])c4)o3)SC2=S)c(C)c1

Procedure:
In 4.7 mL of 0.2 M ethanol was dissolved 0.1 g of 3-(2,4-dimethyl-phenyl)-2-thioxo-thiazolidin-4-one (0.42 mmol) synthesized in 1. The solution was mixed with 0.11 g of sodium acetate (1.34 mmol) and 0.15 g of 5-(3-nitro-phenyl)-furan-2-carboaldehyde (0.69 mmol), synthesized in 2, with stirring, and then heated for 4 hrs. The resulting reaction mixture was washed with ethanol to afford the title compound as a solid. When a solid was not formed, purification by silica gel column chromatography afforded 0.54 g of the title compound (yield: 28.6%).
Reaction SMILES: C([C:5]1([C:18]([NH2:20])=[O:19])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][NH:6]1)=[CH:16][CH:15]=[CH:14][CH:13]=3)(C)(C)C.[CH2:21]([O:28][C:29]([NH:31][C@@H:32]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@@H:33]1[O:35][CH2:34]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[CH2:21]([O:28][C:29]([NH:31][C@@H:32]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:33]([OH:35])[CH2:34][N:6]1[CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:5]1[C:18]([NH:20][C:9]([CH3:17])([CH3:10])[CH3:8])=[O:19])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H]1CO1)OCc1ccccc1
Reactant: CC(C)(C)C1(C(N)=O)NCCc2c1[nH]c1ccccc21
Solvent: CO
Product: CC(C)(C)NC(=O)C1c2[nH]c3ccccc3c2CCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1

Procedure:
A solution of 0.60 g of tert.butyl 1,2,3,4-tetrahydropyrido[3,4-b]indole-1-carboxamide and 0.66 g of 3(S)-(benzyloxyformamido)-1,2(S)-epoxy-4-phenylbutane in 20 ml of methanol was heated at reflux under argon for 16 hours and then evaporated to give a clear oil. The two diastereomeric products were separated by flash chromatography on silica gel using n-hexane/ethyl acetate (3:1) for the elution. There were obtained 268 mg of isomer A of 2-[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-1,2,3,4-tetrahydropyrido[3,4-b]indole-1-carboxamide, MS: m/e 569 [M+H]+, and 65 mg of isomer B of the same compound; MS: m/e 569 [M+H]+.
Reaction SMILES: C[C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][C:8]=3[C:9](=[O:11])[CH2:10][C:4]=2[CH:3]=1.[CH2:20](O)C.[BH4-].[Na+].O>CO>[CH3:20][C:19]1[CH:2]=[CH:3][C:4]2[CH2:10][CH:9]([OH:11])[C:8]3[CH:12]=[C:13]([S:16][CH3:17])[CH:14]=[CH:15][C:7]=3[O:6][C:5]=2[CH:18]=1
Reactant: CCO
Reactant: CSc1ccc2c(c1)C(=O)Cc1cc(C)ccc1O2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CSc1ccc2c(c1)C(O)Cc1ccc(C)cc1O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8.9 G. of 10,11-dihydro-2-methyl-8-methylthio-dibenz[b,f]oxepin-10-one are suspended in 65 ml. of ethanol and treated with a solution of 1.25 g. of sodium borohydride in 4.3 ml. of water. The mixture is stirred for 2 hours at room temperature. Then, 20 ml. of methanol are added thereto and the resulting mixture is heated at reflux for 15 minutes. Thereafter, the methanol and ethanol are removed by evaporation in vacuo. The residue is extracted with chloroform, the chloroform extracts are washed with water, dried and evaporated in vacuo. The residue is crystallized from diisopropyl ether, and there is obtained 10,11-dihydro- 3-methyl-8-methylthio-dibenz[b,f]oxepin- 10-ol having a melting point of 67°-69° C.
Reaction SMILES: C(O[CH:5]1[CH2:9][CH2:8][CH:7]([CH2:10][O:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[O:6]1)(=O)C.[P:22]([O:29]CC)([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25].C([O-])(O)=O.[Na+]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:24]([O:23][P:22]([O:26][CH2:27][CH3:28])([CH:5]1[CH2:9][CH2:8][CH:7]([CH2:10][O:11][S:12]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:13])=[O:14])[O:6]1)=[O:29])[CH3:25]
Reactant: CCOP(OCC)OCC
Reactant: CC(=O)OC1CCC(COS(=O)(=O)c2ccc(C)cc2)O1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOP(=O)(OCC)C1CCC(COS(=O)(=O)c2ccc(C)cc2)O1
Temperature: -35 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of (±)-2-acetoxy-5-(p-toluenesulfonoxymethyl)-tetrahydrofuran (example 59) (1.63 g, 5.19 mmol) and triethyl phosphite (1.16 mL, 6.75 mmol) in methylene chloride (75 mL) at −35° C. was added titanium (IV) chloride (0.57 mL, 5.19 mmol) dropwise. The yellow solution was then stirred at −35° C. for 30 min and then at 0° C. for 30 min. Saturated NaHCO3 (75 mL) was then added to the reaction mixture and the suspension was then filtered through a CELITE diatomaceous earth. The mixture was then partitioned followed by extraction of the aqueous phase with methylene chloride (2×50 mL). The combined extracts were then washed with brine (100 mL), dried (MgSO4) and concentrated. The residue was then purified by chromatography eluting with 75% EtAc/hexanes-EtAc giving the title compound as 1:1 mixture of cis and trans isomers (1.42 g, 78%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[Cl:9]N1C(=O)CCC1=O.N1C=CC=CC=1>C1C=CC=CC=1>[Cl:9][CH2:1][S:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: CSc1ccncc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: ClCSc1ccncc1
Temperature: 25 °C
Yield: 46.5 %

Procedure:
A solution of 4-methylthiopyridine (2.28 g, 18.2 mmol), N-chlorosuccinimide (3.0 g, 23 mmol) and pyridine (2.9 mL, 3.0 mmol) in benzene (40 mL) was heated at 50°-60° C. for 3 h. The mixture was allowed to cool to room temperature. The solvent was decanted and the residue was rinsed with benzene (2×10 mL). The organic phases were combined and evaporated. The residue was passed through a pad of silica gel (40 g) to give the title material (1.35 g) contaminated with the starting material. The impure product was repurified on silica gel preparative plates (eluted with CH2Cl2 /CH3CN: 1/1) to give the pure title material (926 mg, 32%) as a yellow oil.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:10])[CH2:8][NH2:9])=[CH:3][CH:2]=1.CS[C:13](SC)=[CH:14][N+:15]([O-:17])=[O:16]>C(O)C.C1(C)C(C)=CC=CC=1>[N+:15]([CH:14]=[C:13]1[NH:9][CH2:8][CH:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[O:10]1)([O-:17])=[O:16]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCC(O)c1ccccc1
Solvent: Cc1ccccc1C
Solvent: CCO
Product: O=[N+]([O-])C=C1NCC(c2ccccc2)O1
Yield: 56.5 %

Procedure:
In a mixture of 60 ml of ethanol and 200 ml of xylene was dissolved 40 g of DL-β-hydroxyphenethylamine, and the resulting solution was added dropwise to a solution of 57.8 g of 1,1-bis(methylthio)-2-nitroethene in 600 ml of xyelene under reflux over a period of 1.5 hours to effect reaction. During the reaction, the low-boiling fractions were gradually removed by distillation and the reaction temperature was maintained at 130° C. to 140° C. After completion of the reaction, crystals were deposited with stirring under ice-cooling. The crystals deposited were collected by filtration, dried, and then mixed with 200 ml of a 5% (by weight) aqueous sodium hydroxide solution. After a slight amount of insolubles were removed by filtration, the filtrate was adjusted to pH 6 with a 10% (by weight) aqueous acetic acid solution, and the crystals deposited were collected by filtration and dried to obtain 34 g of 2-nitromethylene-5-phenyloxazolidine having a melting point of 139°-141° C.