Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)=[O:19])=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30].C(N(CC)CC)C.C1COCC1>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.CO>[O:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH:22]1[O:21][NH:20][C:18](=[O:19])/[CH:17]=[CH:16]/[C:13]1[CH:14]=[CH:15][N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH:12]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C(/C=C/c1ccn(S(=O)(=O)c2ccc(I)cc2)c1)NOC1CCCCO1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NOC3CCCCO3)c2)cc1
Temperature: 100 °C
Yield: 45.8 %

Procedure:
Under nitrogen a microwave vial is charged with (E)-3-[1-(4-Iodo-benzenesulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (5.00 mmol), Trimethylsilylacetylene (6.00 mmol), CuI (0.50 mmol), bis(triphenylphosphine)palladium(II)chloride (0.25 mmol), triethylamine (10.0 mmol) and THF (8 ml). The reaction mixture is heated in a Personal Chemistry Microwave oven at 100° C. for 3600 seconds. Methanol is added to the reaction mixture and the solution is filtered over alumina (10 g, neutral, activity II-III) using MeOH as eluent. After evaporation of the solvent the crude product is purified by prep. HPLC yielding the title compound as yellow powder (2.29 mmol).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]#[N:5].[CH3:6][C@H:7]1[O:12][C@H:11]([CH3:13])[CH2:10][NH:9][CH2:8]1.C(N(CC)CC)C>C(O)C>[C:4]([CH2:3][CH2:2][N:9]1[CH2:10][C@@H:11]([CH3:13])[O:12][C@H:7]([CH3:6])[CH2:8]1)#[N:5]
Reactant: C[C@@H]1CNC[C@@H](C)O1
Reactant: N#CCCBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@@H]1CN(CCC#N)C[C@@H](C)O1
Temperature: 20 °C
Reaction time: 17 h
Yield: 79.3 %

Procedure:
3-Bromopropionitrile (4.06 g, 0.03 mole), cis/trans-2,6-dimethylmorpholine (4.0 g, 0.034 mole), triethylamine (5.0 ml ) and ethanol (50 ml ) were refluxed (78° C.) for 3 hours and left stirring at 20° C. for 17 hours. The solvent was evaporated and the residue purified by chromatography using silica gel/chloroform: 5% methanol to give els/trans N-(2-cyanoethyl)-2,6-dimethylmorpholine (4.0 g, 79%) as a colourless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH:12][C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[S:16]1[CH:20]=[CH:19][N:18]=[C:17]1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[S:16]1[CH:20]=[CH:19][N:18]=[C:17]1[N:21]1[CH2:22][CH2:23][N:24]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3([NH:12][C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]3)=[CH:5][CH:4]=2)[CH2:25][CH2:26]1
Reactant: CC(=O)NC1(c2ccc(CCl)cc2)CC1
Reactant: c1csc(N2CCNCC2)n1
Product: CC(=O)NC1(c2ccc(CN3CCN(c4nccs4)CC3)cc2)CC1

Procedure:
By similar reaction and treatment to that in Example 1(5) using N-(1-(4-chloromethylphenyl)cyclopropyl)acetamide obtained in Example 71(1) instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(thiazol-2-yl)piperazine obtained in Example 81(1) instead of phenylpiperazine, the title compound was obtained as pale-yellow crystals, m.p.=184-185° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[O:25]1[CH:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26]1>>[O:25]1[CH:29]=[CH:28][C:27]([C:30]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:31])=[CH:26]1
Reactant: O=C(Cl)c1ccoc1
Reactant: Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1
Product: O=C(Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1)c1ccoc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.008 mL (0.061 mMol) 3-furoyl chloride, the title compound was prepared essentially by the procedure described in Example 7. MS(m/e): 414(M+)
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]([N:10]1[CH2:14][C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:12][C:11]1=[O:23])[CH2:5][C:6]([F:9])([F:8])[CH3:7].O1CCCC1.O.[OH-].[Li+]>O>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C:13]1[CH2:14][N:10]([C@@H:4]([CH2:5][C:6]([F:9])([F:8])[CH3:7])[C:3]([OH:24])=[O:2])[C:11](=[O:23])[CH:12]=1
Reactant: COC(=O)[C@H](CC(C)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(F)(F)C[C@@H](C(=O)O)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.4 %

Procedure:
In a flask was placed (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4,4-difluoro-pentanoic acid methyl ester (139 mg, 0.39 mmol) in a 1:1 solution of tetrahydrofuran:water (8 mL) which was treated with lithium hydroxide monohydrate (35 mg, 0.78 mmol) and stirred for 1.5 h at 25° C. After such time, the mixture was concentrated in vacuo to remove the tetrahydrofuran and partioned between 1N aqueous hydrochloric acid (10 mL) and ethyl acetate (10 mL). The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to afford (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4,4-difluoro-pentanoic acid (130 mg, 96%) as a light amber foam: HR-ES-MS m/z calculated for C15H14NO4ClF2 [M+H]+ 346.0652, observed 346.0652.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[NH2:32][CH:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:29])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:32][CH:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[O:23])=[CH:17][C:9]1=2
Reactant: CN1CCC(N)CC1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: CN1CCC(NC(=O)c2cccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)c2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-amino-1-methylpiperidine as in General Procedure 10 to give the title compound. LCMS: m/z=543.99 (M+H+); retention time=0.53 minutes.
Reaction SMILES: CCCCC.[C:6]([Li])([CH3:9])([CH3:8])[CH3:7].C1COCC1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[C:31]([CH3:44])=[C:32]([CH3:43])[C:33]4[O:37][C:36]([CH3:39])([CH3:38])[C:35](=[O:40])[C:34]=4[C:41]=3[CH3:42])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>O>[C:6]([C:35]1([OH:40])[C:34]2[C:41]([CH3:42])=[C:30]([N:27]3[CH2:26][CH2:25][N:24]([C:21]4[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:23][CH:22]=4)[CH2:29][CH2:28]3)[C:31]([CH3:44])=[C:32]([CH3:43])[C:33]=2[O:37][C:36]1([CH3:39])[CH3:38])([CH3:9])([CH3:8])[CH3:7]
Reactant: [Li]C(C)(C)C
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Solvent: CCCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(C(C)(C)C)C(C)(C)O4)CC2)cc1
Temperature: 0 °C
Yield: 33 %

Procedure:
A pentane solution (2.00 mL, 3.08 mmol) containing 1.54 M t-butyllithium was added dropwise to a solution of THF (4 mL) containing 5-[4-(4-methoxyphenyl)piperazin-1-yl]-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one (800 mg, 2.03 mmol) synthesized in Reference Example 42 under argon atmosphere at −70° C. or lower, and then the mixture was warmed to 0° C. The reaction solution was stirred under ice-cooling condition for 30 minutes, and then water was added thereto and extraction was performed using ethyl acetate. The organic layer was washed with water and saturated saline, and then dried using anhydrous sodium sulfate. It was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane-ethyl acetate 100:0 to 8:1) and silica gel column chromatography (hexane-ethyl acetate 100:0 to 8:1), and after that, crystallization was performed using hexane to give 300 mg of the title compound (yield: 33%).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[Li].OC1C=CC=CN=1.[C:17](=O)([O-:34])[O:18][C:19]1([C:30](C)(C)C)[C:24](Cl)=C(Cl)C(Cl)=C(Cl)[CH:20]1Cl.Cl>[OH-].[Na+].O.C(Cl)(Cl)Cl.CN(C)C=O>[C:19]([O:18][C:17]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:34])([CH3:30])([CH3:24])[CH3:20]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(C)(C)C1(OC(=O)[O-])C(Cl)=C(Cl)C(Cl)=C(Cl)C1Cl
Agent: Cl
Agent: Oc1ccccn1
Agent: [Li]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
11.5 g. of L-proline is dissolved in 4N sodium hydroxide, and 100 ml. of dimethylformamide, 50 ml. of chloroform, 10.1 g. of the lithium salt of 2-hydroxypyridine and 36.6 g. of t-butylpentachlorophenyl carbonate are added thereto. The solution is stirred at room temperature for three hours, after which 100 ml. of chloroform and 200 ml. of water are added. After shaking, the water layer is acidified to a pH of 2 with 1N hydrochloric acid, and extracted with 200 ml. of ethyl acetate. The product is worked up as previously described to give t-butyloxycarbonyl-L-proline in 79 percent yield, m.p. 137° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[C:13](=[O:16])[CH2:14][Cl:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O>C(OCC)(=O)C.C1(C)C=CC(S(N[C@@H](C2C=CC=CC=2)[C@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.Cl[Rh+]C1(C)C(C)=C(C)C(C)=C1C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[C@H:13]([OH:16])[CH2:14][Cl:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](Cc1cccc2ccccc12)C(=O)CCl)OCc1ccccc1
Agent: CC1=C(C)C(C)([Rh+]Cl)C(C)=C1C
Agent: Cc1ccc(S(=O)(=O)N[C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O=CO
Product: O=C(N[C@@H](Cc1cccc2ccccc12)[C@H](O)CCl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
(3S)-3-Benzyloxycarbonylamino-1-chloro-4-naphthyl-2-butanone (190.1 mg, 0.5 mmol) and a formic acid/triethylamnine azeotropic mixture (0.1 ml) were added to a solution of chloro(pentamethylcyclopentadienyl)rhodium (III) (1S,2S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (0.34 mg, 0.0005 mmol, s/c=1000) in ethyl acetate (0.5 ml), followed by stirring at room temperature for 2 hours. After completion of the reaction, purification by silica gel column chromatography gave a desired compound, (2S,3S)-3-benzyloxycarbonylamino-1-chloro-2-hydroxy-4-naphthylbutane (179.0 mg; yield: 93.3%). As a result of HPLC analysis, the production ratio of the desired (2S,3S)-form to the isomeric (2R,3S)-form, (2S,3S):(2R,3S), was 10.9:1. The results of elementary analysis were as follows.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([CH3:14])([CH3:13])[O:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[C:4]([Cl:15])[C:3]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH:28]O>>[Cl:1][C:2]1[C:7]2[C:8]([CH3:13])([CH3:14])[O:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[C:4]([Cl:15])[C:3]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][S:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:28]
Reactant: CC1(C)OC(=O)Nc2cc(Cl)c(OCCCCSc3ccccc3)c(Cl)c21
Reactant: OO
Product: CC1(C)OC(=O)Nc2cc(Cl)c(OCCCCS(=O)c3ccccc3)c(Cl)c21

Procedure:
Prepared analogously to Example 2 from 5,7-dichloro-6-(4-phenylmercapto-butoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][S:24]([NH2:27])(=[O:26])=[O:25])=[CH:19][CH:18]=1>CN(C=O)C>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][S:24]([NH2:27])(=[O:25])=[O:26])=[CH:19][CH:18]=2)[N:7]=1
Reactant: COc1ccccc1-c1ccnc(Cl)n1
Reactant: Nc1ccc(CS(N)(=O)=O)cc1
Solvent: CN(C)C=O
Product: COc1ccccc1-c1ccnc(Nc2ccc(CS(N)(=O)=O)cc2)n1

Procedure:
A solution of 2-chloro-4-(2-methoxy-phenyl)-pyrimidine (0.883 g, 0.004 mol), and (4-amino-phenyl)-methanesulfonamide (0.745 g, 0.004 mol) (Bosch, J.; Roca, T. et al., Tetrahedron (2001), 57(6), 1041-1048. Owa, Takashi et al., Journal of Med. Chem. (1999), 42(19), 3789-3799) in DMF (12 ml) was stirred for 2 hours at 80° C. (TLC control). The solvent was removed under reduced pressure to afford {4-[4-(2-Methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-methanesulfonamide.
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:6]=2[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)#[N:2].B.Cl>O1CCCC1>[ClH:18].[NH2:2][CH2:1][C:3]1[O:4][C:5]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:6]=2[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#Cc1oc2ccc(Cl)cc2c1-c1ccccc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: NCc1oc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
Treat 2.0 g. 2-cyano-5-chloro-3-phenylbenzofuran (0.008 mole) in 30 ml of tetrahydrofuran with 18 ml of borane in tetrahydrofuran (1 m solution). Reflux for 2 hours. Cool, add 10 ml of 10% hydrochloric acid and reflux for 1/2 hour. Evaporate the solution to dryness. Dissolve the residue in 50 ml of ethanol. Add 30 ml of ethanol saturated with hydrogen chloride. Dry the precipitate obtained to yield the title compound; m.p. 254°-256°.
Reaction SMILES: O[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.S(Cl)([Cl:15])=O.Cl>>[Cl:15][CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1
Reactant: OCC1COc2ccccc2O1
Reactant: O=S(Cl)Cl
Agent: Cl
Product: ClCC1COc2ccccc2O1
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
202 g (1.21 mols) of 2-hydroxymethyl-1,4-benzodioxan are introduced into a 1 liter flask equipped with a stirrer, condenser and dropping funnel, and 288 g (2.42 mols) of thionyl chloride are run in dropwise. Violent evolution of HCl is observed. The mixture is heated under reflux until HCl ceases to be evolved, that is to say for 1 hour 30 minutes. The mixture is then distilled in vacuo after having driven off the excess thionyl chloride. 175.5 g (yield: 77.2%) of 2-chloromethyl-1,4-benzodioxan are obtained.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O>CS(O)(=O)=O>[CH2:11]1[C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]=2[C:14](=[O:16])[CH2:13][CH2:12]1
Reactant: O=C(O)CCCc1ccc2ccccc2c1
Agent: CS(=O)(=O)O
Product: O=C1CCCc2ccc3ccccc3c21
Yield: 73.8 %

Procedure:
To 300 ml of methane-sulfonic acid contained in a 1 liter, 3-neck flask equipped with thermometer, drying tube and magnetic stirring bar was added 82.0 g (0.38 mole) of γ-(2-naphthyl)butyric acid as prepared above and the reaction mixture was heated at 90°-95° C. for one hour with vigorous stirring. The yellow reaction mixture was cooled, poured on crushed ice and extracted with two 350 ml portions of ethyl acetate. The combined organic portions were washed with 5% aqueous sodium hydroxide, water, dried over anhydrous sodium sulfate and then treated with some silica gel powder and Norit A charcoal before filtering. Upon removing the solvent an off-white solid was obtained. Recrystallization from 375 ml of hexane containing 7-10 ml of chloroform gave an oil that solidified to yield 55.0 g (73.3% by weight) of 1,2,3,4-tetrahydro-4-phenanthrone as an off-white solid. M.P. 64°-66° C.; λmax 312 nm (7,510) ethanol; T.L.C. CH2Cl2. R f =.7.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:3]=1[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:31]=[CH:30][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]CCCC)=[O:22])=[CH:16][C:15]=2[C:28]#[N:29])=[CH:11][CH:10]=1)=[O:8].C(O)(C(F)(F)F)=O>ClCCl>[C:28]([C:15]1[CH:16]=[C:17]([CH2:20][C:21]([OH:23])=[O:22])[CH:18]=[CH:19][C:14]=1[O:13][C:12]1[CH:30]=[CH:31][C:9]([C:7](=[O:8])[NH:6][CH2:5][CH2:4][C:3]2[C:2]([Cl:1])=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:36])=[CH:10][CH:11]=1)#[N:29]
Reactant: CCCCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3c(Cl)cccc3Cl)cc2)c(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(CC(=O)O)ccc1Oc1ccc(C(=O)NCCc2c(Cl)cccc2Cl)cc1
Reaction time: 0.75 h
Yield: 111.5 %

Procedure:
tent-Butyl 2-(4-(4-((2,6-dichlorophenethyl)carbamoyl)phenoxy)-3-cyanophenyl)acetate (34 mg, 0.065 mmol) was dissolved in dichloromethane (1 ml) and TFA (1 ml) was added. After stirring for 45 minutes, the mixture was concentrated under reduced pressure to give 2-(3-cyano-4-(4-(2,6-dichlorophenethylcarbamoyl)phenoxy)phenyl)acetic acid (0.034 g).
Reaction SMILES: N(OCCC(C)C)=O.[CH3:9][N:10]1[C:14](N)=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:12]=[N:11]1.[CH3:21][S:22]SC>C(Cl)(Cl)Cl>[CH3:9][N:10]1[C:14]([S:22][CH3:21])=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:12]=[N:11]1
Reactant: CCOC(=O)c1cnn(C)c1N
Reactant: CSSC
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnn(C)c1SC
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 96.9 %

Procedure:
Add isopentyl nitrite (0.5 mL, 3.75 mmol) to a stirred 5° C. solution of ethyl 1-methyl-5-amino-1H-pyrazole-4-carboxylate (1.69 g, 10.0 mmol) and dimethyl disulfide (1.79 mL, 20.0 mmol) in CHCl3 under nitrogen in a 3-necked flask equipped with a thermometer and a condenser. Allow the reaction to warm to 20° C. in a H2O bath, and treat with additional isopentyl nitrite (1.5 mL, 11.3 mmol) dropwise. After 15 min, remove the reaction from the 20° C. H2O bath (exotherm raises temperature to 50° C. over approximately 1 min). Stir at ambient temperature under N2 overnight. Wash with H2O, and separate the layers. Extract the aqueous layer with CHCl3, combine the organic layers, dry over MgSO4, filter, and concentrate under reduced pressure. Purify the residue by flash silica gel chromatography (gradient of 0 to 35% EtOAc in hexanes) to afford the title compound (1.94 g, 97%). ES/MS m/z 201.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.[CH3:16][C:17]([CH3:20])([O-])[CH3:18].[Na+].BrCC1CC1>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:16][CH:17]3[CH2:20][CH2:18]3)[CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: Clc1ncc2c(n1)N1CCOCC1CN2
Reactant: CC(C)(C)[O-]
Agent: BrCC1CC1
Agent: [Na+]
Solvent: CS(C)=O
Product: Clc1ncc2c(n1)N1CCOCC1CN2CC1CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40.4 %

Procedure:
2-Chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 200 mg, 0.882 mmol) was dissolved in DMSO (4.4 mL). Sodium tert-butoxide (102 mg, 1.059 mmol) was then added to give a brown solution. After 5 minutes, (bromomethyl)cyclopropane (86 μL, 0.882 mmol) was added dropwise. The reaction mixture was stirred for 2 hours at room temperature then quenched with aqueous saturated NH4Cl. The reaction mixture was diluted with ethyl acetate and washed with aqueous saturated NH4Cl (3×25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was loaded onto an ISCO® silica gel cartridge (12 g) and eluted with an ethyl acetate/hexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a yellow oil (100 mg, 40%). ESI-MS m/z [M+H]+ calc'd for C13H17ClN4O, 281.1. found 281.3.
Reaction SMILES: [I-:1].[Na+].[C:3]([O:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15]Cl)=[CH:11][CH:10]=1)([CH3:6])([CH3:5])[CH3:4]>CC(C)=O>[C:3]([O:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][I:1])=[CH:11][CH:10]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)c1ccc(CCl)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(CI)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
Sodium iodide (229.2 g) was added to a solution of 4-chloromethyl benzoic acid tert-butyl ester (315.2 g) in acetone (1.5 L). The reaction mixture was heated to reflux for about 2 h and then allowed to cool to room temperature. The precipitate was removed by filtration and the filtrate concentrated under reduced pressure. The residue was partitioned between water (500 mL) and MTBE (1500 mL). The organic phase was washed with saturated sodium bicarbonate and dried over magnesium sulfate. Concentration under reduced pressure afforded 442.2 g (97% yield) dark oil. HNMR: CDCl3, 1.59 ppm (s, 9H), 4.47 (s, 2H), 7.42 (d, 2H), 7.91 (d, 2H)
Reaction SMILES: C([Li])CCC.[CH2:6]([N:8]([CH2:12][CH3:13])[CH2:9][C:10]#[CH:11])[CH3:7].[C:14](=[O:16])=[O:15].O>CCCCCC.O1CCCC1.CO>[CH2:6]([N:8]([CH2:12][CH3:13])[CH2:9][C:10]#[C:11][C:14]([OH:16])=[O:15])[CH3:7]
Reactant: O=C=O
Reactant: C#CCN(CC)CC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)CC#CC(=O)O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyl lithium in hexane (54 mL, 2.5M in n-hexane) was slowly added to 1-diethylamino-2-propyne (15 g, 135 mmol) in 60 mL of tetrahydrofuran under nitrogen. The mixture was stirred for 1 hr at −78° C., then dry carbon dioxide was passed through overnight. The resulting solution was poured into water and washed with ethyl acetate. The aqueous layer was evaporated under reduced pressure to give the crude acid. The dry acid was dissolved in methanol, and the insoluble salt was removed via filtration. The filtrate was collected and dried in vacuo to give 9.2 g of 4-diethylamino-but-2-ynoic acid: mass spectrum (m/e):M+H 156.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][N:11]=[C:12]([C:18](=[O:30])[C:19]2[C:24]([O:25][CH:26]([F:28])[F:27])=[CH:23][CH:22]=[CH:21][C:20]=2F)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:20]3[C:19](=[C:24]([O:25][CH:26]([F:28])[F:27])[CH:23]=[CH:22][CH:21]=3)[C:18](=[O:30])[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:11]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(=NNc1ccc(OC(F)(F)F)cc1)C(=O)c1c(F)cccc1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)c2cccc(OC(F)F)c2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
Ethyl 2-[(4-trifluoromethoxyphenyl)-1,1-diazanediyl]-(2-fluoro-6-difluoromethoxybenzoyl)acetate (530 mg), and potassium carbonate (157 mg) were added to N,N-dimethylformamide (10 ml), and the resultant mixture was heated at 100° C. for 1 hour. The mixture was cooled to room temperature, and was poured into ice-water (about 50 ml). After allowing it to stand for 2 hours, the precipitated crystals were collected by filtration. The crystals were washed with water (5 ml) two times and were dried under reduced pressure to give 478 mg of desired ethyl 1-(4-trifluoromethoxyphenyl)-1,4-dihydro-4-oxo-5-difluoromethoxycinnoline-3-carboxylate (yield: 94.3%). m.p., 145° C.