Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[I:20]I.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[C:13]3[C:19]([I:20])=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cnc3[nH]ccc3c2)cc1OC
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2cnc3[nH]cc(I)c3c2)cc1OC
Temperature: -40 °C

Procedure:
5-(3,4-Dimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine, 82, (0.270 g, 0.00106 mol) was dissolved in Tetrahydrofuran (8.5 mL, 0.10 mol) under an atmosphere of Nitrogen. The solution was stirred at −40° C. and Iodine (0.269 g, 0.00106 mol) dissolved in 2.5 mL of Tetrahydrofuran was added. The chilled reaction mixture was stirred for 2 h and was then quenched with the addition of Sodium thiosulfate, pentahydrate (0.13 g, 0.00053 mol) in water (1M). The reaction mixture was partitioned between water (20 mL and ethyl acetate (30 mL). The two layers were seperated, and the aquous layer was extracted with ethyl acetate. The organic layers were washed with water and brine, dried with sodium sulfate, then concentrated under reduced pressure. The dark colored crude residue was carried onto the next reaction without further purification.
Reaction SMILES: CC([S@@]([NH:7][C@H:8]([C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=O)(C)C.[ClH:26].O1CCOCC1>CO>[ClH:26].[CH3:25][C:24]1[C:19]([C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][CH:10]=2)[NH2:7])=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cccnc1[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cccnc1[C@@H](N)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
A solution of (S)-2-methyl-N—((S)-(3-methylpyridin-2-yl)(4-(trifluoro-methyl)phenyl)methyl)propane-2-sulfinamide (0.355 g, 0.958 mmol) in MeOH (10 mL) was treated with hydrogen chloride, 4.0 M solution in 1,4-dioxane (0.6 mL, 2.400 mmol) and stirred at rt. The reaction was concentrated on the rotary evaporator resulting in a gummy residue. The residue (S)-(3-methylpyridin-2-yl)-(4-(trifluoromethyl)phenyl)methanamine hydrochloride was used in the next steps without further purification.
Reaction SMILES: [F:1][C:2]([F:29])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([O:21]C2CCCCO2)=[CH:13][C:12]=1[CH2:11][C@@H:10]3[CH3:28].C(O)(=O)C(O)=O>CO.O>[F:1][C:2]([F:29])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([OH:21])=[CH:13][C:12]=1[CH2:11][C@@H:10]3[CH3:28]
Reactant: C[C@H]1Cc2cc(OC3CCCCO3)ccc2[C@H]2CC[C@]3(C)C(=C(F)F)CC[C@H]3[C@@H]21
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: O
Product: C[C@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)C(=C(F)F)CC[C@H]3[C@@H]21
Yield: 94.8 %

Procedure:
A suspension of 1.2 g of 17-difluoromethylene-7β-methyl-3-tetrahydropyranyloxy-estra-1,3,5(10)-triene in 25 ml of methanol and 2.5 ml of water is refluxed with 1.2 g of oxalic acid for 1 hour at a bath temperature of 100° C. Then, it is concentrated by evaporation in a vacuum diluted with ethyl acetate, washed with water, sodium bicarbonate solution as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/acetone. After crystallization from hexane, 0.9 g of 17-difluoromethylene-7β-methyl-estra-1,3,5(10)-trien-3-ol is obtained as colorless crystals with a melting point of 119-120° C., [α]D22 =-10.6° (c=0.5% in pyridine).
Reaction SMILES: C([Li])(C)(C)C.[CH2:6]([O:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18]#[N:19])[CH:14]=[CH:15][CH:16]=1)[CH2:7][CH2:8][CH3:9].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:30])(=O)=O)=CC=1>C1COCC1>[CH2:6]([O:10][C:11]1[CH:12]=[C:13]([CH:17]([F:30])[C:18]#[N:19])[CH:14]=[CH:15][CH:16]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOc1cccc(CC#N)c1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCCOc1cccc(C(F)C#N)c1
Reaction time: 1 h
Yield: 53.4 %

Procedure:
Tert-butyllithium (1268 uL; 2.16 mmol) is added dropwise to a solution of 2-(3-butoxyphenyl)acetonitrile (371 mg; 1.96 mmol) in THF (16 mL) at −78° C., under nitrogen atmosphere. The light yellow solution turned into orange and stirring is continued for 1 hour. A solution of N-fluorobenzenesulfonimide (618 mg; 1.96 mmol) in THF (2 mL) is added dropwise and the reaction is stirred at −78° C. for 2 hours. TLC (petroleum ether/EtAc 9:1) reveals no presence of starting material and two more apolar spots. The reaction is then quenched by adding 0.01N HCl, then more water is added and extracted with DCM (three times). The combined organic layers are dried over Na2SO4, filtered and evaporated. The crude residue is purified by flash chromatography (petroleum ether/EtAc, 99/1) affording 217 mg (53%) of 2-(3-butoxyphenyl)-2-fluoroacetonitrile as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:22](=[NH:23])[N:21]([CH2:24][CH3:25])[C:14]3[N:15]=[C:16]([S:19][CH3:20])[N:17]=[N:18][C:13]=3[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:22](=[N:23][C:26](=[O:28])[CH3:27])[N:21]([CH2:24][CH3:25])[C:14]3[N:15]=[C:16]([S:19][CH3:20])[N:17]=[N:18][C:13]=3[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CCn1c(=N)c(-c2cc(OC)cc(OC)c2)cc2nnc(SC)nc21
Reactant: CC(=O)OC(C)=O
Product: CCn1c(=NC(C)=O)c(-c2cc(OC)cc(OC)c2)cc2nnc(SC)nc21
Temperature: 90 °C

Procedure:
To 4.7 g (13.2 mmol) of 7-(3,5-dimethoxy-phenyl)-5-ethyl-3-methylsulfanyl-5H-pyrido[2,3-e]-1,2,4-triazin-6-ylideneamine was added 55 mL of acetic anhydride. The reaction mixture was warmed at 90° C. overnight, and the very dark red solution was concentrated under house vacuum at 40° C. to give a dark brown residue, N-[7-(3,5-dimethoxy-phenyl)-5-ethyl-3-methylsulfanyl-5H-pyrido[2,3-e]-1,2,4-triazin-6-ylidene]-acetamide. MS (APCI) (m+1)/z 400.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[CH3:13])=[CH:5][CH:4]=1.[Cl-].[Cl-].[Cl-].[Al+3].[C:18](Cl)(=[O:20])[CH3:19].Cl>ClCCCl>[CH3:1][O:2][C:3]1[C:4]([C:18](=[O:20])[CH3:19])=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([CH3:13])[C:11]=2[CH:12]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)C(C)CCC2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1cc2c(cc1C(C)=O)CCCC2C
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.4 %

Procedure:
To a stirring solution of 7-methoxy-1-methyl-1,2,3,4-tetrahydro-naphthalene (6.3 g, 35.74 mmol) in 60 mL 1,2-dichloroethane at 0° C. under nitrogen as added aluminium trichloride (5.24 g, 39.32 mmol), followed by acetyl chloride (2.8 mL, 39.32 mmol). The resulting mixture was stirred for 18 hours at room temperature, then was poured into cold 5% aqueous HCl and extracted with methylene chloride. The organic layer was separated, washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to yield 5.1 g of 1-(3-methoxy-5-methyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanone, MP=48-50° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][C@@H:34]([OH:37])[CH2:33][C@@H:32]2[C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][C@@H:34]([OH:37])[CH2:33][C@@H:32]2[C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CC[C@@H](O)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1C[C@H](O)CC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 78.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S,2R,4R)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (153 mg, 0.242 mmol) prepared in Example 165c, triethylsilane (0.050 mL), trifluoroacetic acid (0.50 mL) and dichloromethane (1.0 mL), to yield the title compound (92.0 mg, 79%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH2:5].N1C=CC=CC=1.[Br:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:9])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH:5][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][Br:16]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C(Cl)CCCBr
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)CCCBr)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a solution of 1.08 g (8.4 mmole) of L-valine methyl ester in 30 ml of CH2Cl2 was added 1.36 ml (16.8 mmole) of pyridine, cooled to 0° C. and 1.55 g (8.4 mmole) of 4-bromobutanoyl chloride added. The solution was stirred at 0° C. for 40 minutes and at RT for 1 h. The solution was washed with satd. NaHCO3, brine and dried with anhy. Na2SO4; filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (5% EtOAc/CH2Cl2) to provide 1.82 g (77%) of desired product. 300 MHz 1H NMR (CDCl3) δ 0.92 (d, J=6 Hz, 3H), 0.96 (d, J=6 Hz, 3H) 2.20 (m, 3H), 2.46 (m, 2H), 3.50 (m, 2H), 3.76 (s, 3H), 4.58 (dd, J=4,7 Hz, 1H), 5.97 (br d, J=7 Hz, 1H). Mass spectrum: (M+H)+=297.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N+:15]([O-])=O.[H][H]>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[NH2:15]
Reactant: Nc1ccc(Oc2ccccc2)cc1[N+](=O)[O-]
Reactant: [H][H]
Solvent: CO
Product: Nc1ccc(Oc2ccccc2)cc1N

Procedure:
4.8 G. of 1-amino-2-nitro-4-phenoxybenzene is hydrogenated in 100 ml. methanol at 1 atmosphere pressure, in the presence of 1 g. of 5% palladized carbon, until the theoretical uptake of hydrogen has occurred. The catalyst is removed by filtration and the filtrate evaporated to give 1,2-diamino-4-phenoxybenzene.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5](=[O:18])[O:6][C:7]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([OH:17])=[CH:11][C:8]=2[C:9]=1[CH3:10].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(O)C.C(Cl)(Cl)Cl>[OH:17][C:12]1[C:13]([O:15][CH3:16])=[CH:14][C:7]2[O:6][C:5](=[O:18])[C:4]([CH2:3][CH2:2][N:30]3[CH2:29][CH2:28][N:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][CH3:19])[CH2:32][CH2:31]3)=[C:9]([CH3:10])[C:8]=2[CH:11]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1cc2oc(=O)c(CCCl)c(C)c2cc1O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1cc2oc(=O)c(CCN3CCN(c4ccccc4OC)CC3)c(C)c2cc1O
Yield: 14 %

Procedure:
Process A; starting materials: 3-(2-chloroethyl)-6-hydroxy-7-methoxy-4-methyl-2H-1-benzopyran-2-one (Example 27) and 1-(2-methoxyphenyl)piperazine; yield 14%; m.p. 235°-237° C. (from ethanol/chloroform).
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([CH2:16]Cl)[C:9]=2[CH3:18])[CH2:5][C:4](=[O:19])[C:3]=1[C:20](=[O:23])[CH2:21][CH3:22].[C-:24]#[N:25].[Na+]>>[OH:1][C:2]1[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([CH2:16][C:24]#[N:25])[C:9]=2[CH3:18])[CH2:5][C:4](=[O:19])[C:3]=1[C:20](=[O:23])[CH2:21][CH3:22]
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(CCl)c2C)CC1=O
Reactant: [C-]#N
Agent: [Na+]
Product: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(CC#N)c2C)CC1=O
Reaction time: 4 h
Yield: 81.8 %

Procedure:
A solution of 3-hydroxy 2-propionyl-5-(3-chloromethyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (3.32, 9.96 mmol) in dmf (15 ml) was added to a suspension of sodium cyanide (0.98, 19.9 mmol) in dmf (10 ml). The mixture was stirred at 70° for 4 h, then cooled and partitioned between methylene choride and water. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel (elution with an increasing gradient of ethyl acetate in methylene chloride) gave 3-hydroxy-2-propionyl-5-(3-cyanomethyl-2,4,6-trimethylphenyl) cyclohex-2-en-1-one (2.65 g, 81%) plus a further impure fraction. Proton magnetic resonance spectrum (CDCl3, δ in ppm): 1.18 (3H,t,J7 Hz); 2.33 (3H,s); 2.37 (3H,s); 2.42 (3H,s); 2.5-4.1(7H,m); 3.62 (2H,s); 7.90 (1H,s); 18.20 (1H,s). Infrared spectrum: ν (CHCl3) 2250 m cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Cl[S:13]([C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])(=[O:15])=[O:14]>CN(C1C=CN=CC=1)C>[CH3:22][O:21][C:19](=[O:20])[C:18]1[CH:23]=[CH:24][CH:25]=[C:16]([S:13](=[O:14])(=[O:15])[NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[CH:17]=1
Reactant: COC(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Product: COC(=O)c1cccc(S(=O)(=O)Nc2cccc3cccnc23)c1
Yield: 63.5 %

Procedure:
In the similar fashion using route 14 general procedure 27, 8-aminoquinoline (100 mg, 0.69 mmol), methyl 3-chlorosulfonylbenzoate (160 mg, 0.69 mmol) and DMAP (cat.) gave the title compound (150 mg, 64%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[N:16]1([C:22]2[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[N:16]1([C:22]2[N:27]=[CH:26][C:25]([NH:28][C:13]([C:3]3[C:2]([CH3:1])=[N:6][N:5]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[N:4]=3)=[O:15])=[CH:24][CH:23]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: Cc1nn(-c2ccccc2)nc1C(=O)O
Reactant: Nc1ccc(N2CCOCC2)nc1
Product: Cc1nn(-c2ccccc2)nc1C(=O)Nc1ccc(N2CCOCC2)nc1

Procedure:
With a procedure similar to example 1 above, 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid and 6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C19H20N6O2 (m/e) 364, obsd 365 (M+H).
Reaction SMILES: [OH:1][CH:2]([CH3:10])[CH2:3][NH:4][C:5](=[O:9])[C:6]([CH3:8])=[CH2:7].ClC(Cl)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>C(N(CC)CC)C>[Cl:15][CH2:16][C:17]([O:1][CH:2]([CH3:10])[CH2:3][NH:4][C:5](=[O:9])[C:6]([CH3:8])=[CH2:7])=[O:18]
Reactant: O=C(Cl)CCl
Reactant: C=C(C)C(=O)NCC(C)O
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: C=C(C)C(=O)NCC(C)OC(=O)CCl

Procedure:
The compound was prepared by the method described in Example 7, using N-(2-hydroxypropyl)methacrylamide (14.3 g), dichloroethane (200 ml), chloroacetyl chloride (11.3 g) and triethylamine (10.1 g). The product distilled at 112° C./0.1 mm (12 g) and was obtained as a viscous oil.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=[O:3])[CH3:2].[C:16]([NH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)(=[O:18])[CH3:17]>N1CCCCC1.C(Cl)(Cl)Cl>[C:16]([NH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[CH:2][C:1]([CH:4]2[C:9]([OH:10])=[C:8]([C:11](=[O:13])[CH3:12])[C:7](=[O:14])[O:6][C:5]2=[O:15])=[O:3])=[CH:22][CH:21]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Product: CC(=O)Nc1ccc(C=CC(=O)C2C(=O)OC(=O)C(C(C)=O)=C2O)cc1

Procedure:
To a mixture of 2.11 g. (0.01 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one and 1.63 g. (0.01 m.) of p-acetamidobenzaldehyde in 200 ml. of chloroform is added with stirring 25 drops of piperidine. The resulting solution is refluxed and azeotroped for 12 hours, filtered hot and the solid is washed with dilute hydrochloric acid, water and ether to give 3-(p-acetamidocinnamoyl)-5-acetyl-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 230°-231° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:22]=[CH:21][C:12]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1.[CH2:23]([N:26]=[C:27]=[O:28])[CH2:24][CH3:25]>C1(C)C=CC=CC=1>[C:13]([C:12]1[CH:21]=[CH:22][C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:27]([NH:26][CH2:23][CH2:24][CH3:25])=[O:28])=[CH:10][CH:11]=1)(=[O:14])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccccc1Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: CCCN=C=O
Solvent: Cc1ccccc1
Product: CCCNC(=O)Nc1ccccc1Nc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-(2-aminophenylamino)benzophenone (Compound 101, 0.58 g, 2 mmol) in toluene (10 ml) was added n-propylisocyanate (0.23 ml, 2.4 mmol). The reaction mixture was heated for 4 hours on a steam bath. After cooling the reaction mixture to room temperature the resulting precipitate was collected by filtration and washed with toluene. The crude product was dissolved in hot isopropanol and crystallized on cooling to afford the title compound.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[Cl:8][C:9]1[CH:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([C@@H:21]3[CH2:23][C@H:22]3[CH2:24][CH2:25][OH:26])[CH2:17][CH2:16]2)=[N:13][CH:14]=1.[Cl-].F[C:29]1[CH:34]=[CH:33][NH+:32]=[CH:31][CH:30]=1>C(OCC)(=O)C>[Cl:8][C:9]1[CH:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([C@@H:21]3[CH2:23][C@H:22]3[CH2:24][CH2:25][O:26][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)[CH2:17][CH2:16]2)=[N:13][CH:14]=1
Reactant: Fc1cc[nH+]cc1
Reactant: OCC[C@@H]1C[C@H]1C1CCN(c2ncc(Cl)cn2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1cnc(N2CCC([C@@H]3C[C@H]3CCOc3ccncc3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (100%, 20 mg, 0.85 mmol) was weighed into a vial, DMF (anhydrous, 2.1 mL) was added, followed by addition of rac-trans 2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (60 mg, 0.21 mmol) and the mixture stirred at room temperature for 5 min. The 4-fluoropyridinium chloride was then added and stirred at room temperature for 10 min. The mixture was heated to 50° C. for 1.5 hours, cooled to room temperature, and diluted with ethyl acetate (5 mL), quenched with saturated aq.NH4Cl (5 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (30% ethyl acetate/hexane) to yield the titled compound as a white solid. LC-MS (M+1): 359.54. Compounds Reported in Table 3 are Prepared by a General Procedure Analogous to that Described in Example 6, Steps 1 and 2, Described Above
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]2[C:9](=[O:18])[N:10]=[C:11]([NH:14][N+:15]([O-:17])=[O:16])[NH:12][CH:13]=2)[CH:4]=[N:3]1.[CH3:19]CN(C(C)C)C(C)C.CI>C(Cl)(Cl)Cl>[CH3:19][N:12]1[CH:13]=[C:8]([CH2:7][C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[C:9](=[O:18])[N:10]=[C:11]1[NH:14][N+:15]([O-:17])=[O:16]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cn1cc(Cc2c[nH]c(N[N+](=O)[O-])nc2=O)cn1
Solvent: ClC(Cl)Cl
Solvent: CI
Product: Cn1cc(Cc2cn(C)c(N[N+](=O)[O-])nc2=O)cn1
Temperature: 23 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
A solution of 5-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-(nitroamino)-4(1H)-pyrimidinone (500 mg, 1.998 mmol) and DIPEA (1.745 mL, 9.99 mmol) in chloroform (5 mL) was mixed with methyl iodide (0.150 mL, 2.398 mmol). The reaction mixture was stirred at 23° C. overnight. Purification via HPLC then afforded the title compound (103 mg, 19.51% yield). LCMS: rt=1.46 min, [M+H+]=265.1
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.N1C=CC=CC=1.[C:17](Cl)(=[O:20])[CH2:18][CH3:19]>ClCCl.Cl>[OH:20][C:17](=[C:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:9])[CH2:18][CH3:19]
Reactant: CCC(=O)Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(O)=C1C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (4.41 g, 30.0 mmol) and pyridine (4.85 mL, 60.0 mmol) in dichloromethane (24 mL) at 0° C. under argon is added propionyl chloride (2.95 mL, 33.0 mmol). The mixture is stirred at 0° C. for 1 h and at room temperature for 1 h before being diluted with 2 N HCl (40 mL) and extracted with dichloromethane (80 mL). The extract is washed (brine) and dried. Solvent is removed at reduced pressure to give 5.57 g (93%) of 2 as a yellow solid, mp 43-46° C. IR 3345, 2856, 1715, 1456 cm−1; 1H NMR (CDCl3) δ 1.29 (t, J=7.5 Hz, 3H, CH2CH3), 1.76 (s, 6H, CH3, CH3), 3.14 (q, J=7.5 Hz, 2H, CH2CH3), 15.42 (bs, 1H, OH).
Reaction SMILES: [O:1]=[C:2]1[N:9]2[C@H:5]([CH2:6][O:7][C@@H:8]2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.C([N-]C(C)C)(C)C.[Li+].[C:24]([O:28][C:29]([N:31]1[CH2:37][C@H:36]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:35][C@H:32]1[CH:33]=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].C(O)(=O)C>O1CCCC1>[C:24]([O:28][C:29]([N:31]1[CH2:37][C@H:36]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:35][C@H:32]1[CH:33]([OH:34])[CH:3]1[C:2](=[O:1])[N:9]2[C@H:5]([CH2:6][O:7][C@@H:8]2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C1CC[C@H]2CO[C@H](c3ccccc3)N12
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)C1C[C@H]2CO[C@H](c3ccccc3)N2C1=O
Reaction time: 0.5 h
Yield: 11.3 %

Procedure:
To a solution of (2R, 5S)-8-oxo-2-phenyl-3-oxa-1-azabicyclo[3.3.0]octane (50 g, 246 mmol, J. Org. Chem., 51, 3140 (1986)) in tetrahydrofuran (1500 ml), lithium diisopropylamide (2M tetrahydrofuran-heptane solution, 147.6 ml, 295.2 mmol) was dropwise added at -78° C., and the reaction solution was stirred at the same temperature for 30 minutes. A solution of (2S, 4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxyprolinal (61.0 g, 245.9 mmol) in tetrahydrofuran (400 ml) was dropwise added thereto, and the reaction solution was stirred at the same temperature for 30 minutes. Acetic acid (17.6 ml, 307.5 mmol) was dropwise added to the reaction solution. Then, the dry ice bath was removed and the reaction mixture solution was stirred for 30 minutes. To the reaction solution, ethyl acetate and 5% sodium hydrogen carbonate aqueous solution were added and the solution mixture was subjected to liquid separation and the aqueous layer was extracted with ethyl acetate. The organic layers were put together and washed with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. Ethyl acetate and n-hexane were added to the residue and the precipitated crystal was collected by filtration to obtain (2R, 5S)-7-[[(2S, 4R)-N-tert-butoxycarbonyl-4-(tert-butyldimethylsiloxy)pyrrolidin-2-yl](hydroxy)methyl]-8-oxo-2-phenyl-3-oxa-1azabicyclo[3.3.01octane diastereomer A (14.0 g, yield: 11.3%). The filtrate was concentrated to obtain an oily diastereomer mixture (114.7 g, yield: 87.5%).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[Br:30][C:31]1[CH:38]=[C:37]([F:39])[C:34]([CH:35]=O)=[C:33]([F:40])[CH:32]=1>O1CCCC1>[CH3:2][O:3][CH:4]=[CH:35][C:34]1[C:37]([F:39])=[CH:38][C:31]([Br:30])=[CH:32][C:33]=1[F:40]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1c(F)cc(Br)cc1F
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=Cc1c(F)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(Methoxymethyl)triphenylphosphonium chloride (1133 g, 3.7 mol) was suspended in tetrahydrofuran (7.0 L) under argon atmosphere, and stirred with ice-water cooling. t-BuOK (397 g, 3.54 mol) was added in portions. Then a solution of 4-bromo-2,6-difluorobenzaldehyde (340 g, 1.54 mol) in tetrahydrofuran (2.7 L) was added and the reaction was stirred at room temperature for 6 hours. The solution was then poured into ice-water and extracted with ethyl acetate (2×). The combined organic phases were dried and concentrated in vacuo. This material was purified by flash chromatography to afford the title compound.