Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH:19]([CH3:21])[CH3:20])[CH2:4][C@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH3:29][S:30]([O:1][CH2:2][C@H:3]([CH:19]([CH3:21])[CH3:20])[CH2:4][C@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)[C@@H](CO)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@@H](COS(C)(=O)=O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The solution of 2.84 g of tert-butyl 4(S)-(2(S)-hydroxymethyl-3-methylbutyl)-2,2-dimethyl-oxazolidine-3-carboxylate in 100 ml of dichloromethane is admixed at 0° C. successively with 1.41 ml of triethylamine and 0.76 ml of methanesulphonyl chloride. The reaction mixture is stirred at 0° C. over 1 hour and subsequently concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a slightly yellowish oil. Rf=0.30 (1:2 EtOAc-heptane); Rt=5.03 (gradient I).
Reaction SMILES: CO[C:3]([CH:5]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([F:18])[CH:16]=2)[C:11]2[C:6]1=[CH:7][C:8]([F:20])=[CH:9][C:10]=2[CH3:19])=[O:4].[H-].[Na+].I[CH2:24][C:25]([NH2:27])=[O:26]>O1CCCC1>[F:18][C:15]1[CH:16]=[C:17]2[C:5]3([CH2:24][C:25](=[O:26])[NH:27][C:3]3=[O:4])[C:6]3[C:11](=[C:10]([CH3:19])[CH:9]=[C:8]([F:20])[CH:7]=3)[C:12]2=[N:13][CH:14]=1
Reactant: COC(=O)C1c2cc(F)cnc2-c2c(C)cc(F)cc21
Reactant: NC(=O)CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(F)cc2c1-c1ncc(F)cc1C21CC(=O)NC1=O

Procedure:
Treatment of 3.7-difluoro-9-methyl-5H-indeno]1,2-b]pyridin-5-one with hydrazine in hot diethylene glycol provided 3,7-difluoro-9-methyl-5H-indeno[1,2-b]pyridine. Deprotonation using n-butyllithium in tetrahydrofuran followed by reaction with carbon dioxide and methanolic hydrogen chloride provided 3,7-difluoro-9-methyl-5H-indeno[1,2-b]pyridin-5-carboxylic acid methyl ester. The ester was then deprotonated using a slight excess of sodium hydride in tetrahydrofuran and treated with iodoacetamide to provide, after 18 hours at room temperature and 6 hours at reflux, the title compound.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][CH2:8][C:9]2[CH:23]=[CH:22][C:12]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[C:28]([OH:38])=[C:29]([S:34](Cl)(=[O:36])=[O:35])[CH:30]=[C:31]([Cl:33])[CH:32]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:26][C:27]1[C:28]([OH:38])=[C:29]([S:34]([N:7]([CH2:8][C:9]2[CH:23]=[CH:22][C:12]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[CH:11][CH:10]=2)[CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:25][CH:24]=2)(=[O:36])=[O:35])[CH:30]=[C:31]([Cl:33])[CH:32]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CNCc2ccc(F)cc2)cc1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 212.1 %

Procedure:
To a solution of tert-butyl 4-((4-fluorobenzylamino)methyl)benzylcarbamate (654 mg, 1.90 mmol, Aldrich) in CH2Cl2 (5 mL) were added 3,5-dichloro-2-hydroxybenzene-1-sulfonyl chloride (497 mg, 0.50 mmol, Aldrich) and diisopropylethylamine (1.34 mL, 9.50 mmol). The reaction mixture was stirred at rt overnight. The mixture was diluted with methylene chloride (100 mL) and washed with saturated aq sodium bicarbonate solution and brine, dried over MgSO4, concentrated and purified by flash column chromatography on silica gel eluting with CH2Cl2/EtOAc to give the title compound (604 mg, 53%) as a white solid. MS (ESI): m/z 566.9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10]O.C(N(S(F)(F)[F:21])CC)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][F:21]
Reactant: O=[N+]([O-])c1ccc(OCCO)c(Br)c1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(OCCF)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.1 %

Procedure:
To a cooled (-78° C.) suspension of 3-Bromo-4-(2-hydroxy)ethoxy nitrobenzene (7.9 g, 30 mmol) in dichoromethane (80 ml) was added diethylaminosulphur trifluoride (3.88 ml, 31.5 mmol). The solution was stirred at ambient temperature for 2 hours, then quenched by the dropwise addition of water (100 ml). The organic layer was separated, washed with brine (100 ml), dried (MgSO4), and evaporated in vacuo. Purification on silica, eluting with 15%-20% ethyl acetate in hexane afforded the title compound as a yellow oil (1.2 g, 15%). 1H NMR (250 MHz, CDCl3) δ 4.35 (1H, dd, J=4.1 Hz, J=2.4 Hz), 4.45 (1H, dd, J=2.4 Hz, J=4.1 Hz), 4.75 (1H, dd, J=4 Hz, J=5.8 Hz), 4.95 (1H, dd, J=4 Hz, J=5.8 Hz), 6.98 (1H, d, J=9.1 Hz), 8.21 (1H, dd, J=2.7 Hz, J=9 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:26]([S:33](Cl)(=[O:35])=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:33]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:35])=[O:34])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: O=S(=O)(Cl)Cc1ccccc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NS(=O)(=O)Cc4ccccc4)cc3)cc2C1=O

Procedure:
The compound of example 93 was prepared analogous to compound of example 77 by reaction of compound of example 6 with benzyl sulfonyl chloride. The compound of example 93 was used directly without isolation for the preparation of compound of example 94.
Reaction SMILES: [OH:1]O.[CH2:3]([CH:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:19][CH2:18][C:17]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([S:20][CH2:21][CH3:22])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[CH2:4][CH2:5][CH2:6][CH3:7]>C(O)(=O)C>[CH2:3]([CH:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:15][CH2:16][C:17]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([S:20]([CH2:21][CH3:22])=[O:1])[CH2:18][CH2:19]2)[CH2:10][CH2:9]1)[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCC1(SCC)CCC(C2CCC(CCCCC)CC2)CC1
Reactant: OO
Solvent: CC(=O)O
Product: CCCCCCCC1(S(=O)CC)CCC(C2CCC(CCCCC)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1 ml of 30% H2O2 is added to 3.8 g of 4-pentyl-4'-heptyl-4'-ethylthiobicyclohexane in 25 ml of glacial acetic acid and the mixture is stirred at room temperature for 3 hours. After customary working up, 4-pentyl-4'-heptyl-4'-ethylsulfinylbicyclohexane is obtained.
Reaction SMILES: C([Si](C(C)C)(C(C)C)[O:5][C@@H:6]1[C@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:8][C:7]1=[O:16])(C)C.[H][H]>CO>[CH:10]1([C@@H:9]2[NH:8][C:7](=[O:16])[C@@H:6]2[OH:5])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CC(C)[Si](O[C@H]1C(=O)N[C@H]1c1ccccc1)(C(C)C)C(C)C
Reactant: [H][H]
Solvent: CO
Product: O=C1N[C@@H](C2CCCCC2)[C@H]1O
Temperature: 90 °C
Reaction time: 120 h
Yield: 85 %

Procedure:
A suspension of 500 mg (3.06 mmol) of 4-phenyl-3-hydroxy-2-azetidinone 1a and 15 mg of Rh—C in 10 mL of methanol was heated at 90° C. under 800 psi in an autoclave. After 5 days, the hydrogen pressure was released and the catalyst filtrated on celite. Evaporation of the solvent afforded a solid which was recrystallized in ethyl acetate to give 440 mg (85%) of 3e as a white solid: White solid; mp 140-140.5° C.; [α]D20+65.1° (c 0.66, CH3OH); 1H NMR (250 MHz, MeOH-d4) δ 0.75-1.10 (m, 2H), 1.12-1.35 (m, 3H), 1.40-2.00 (m, 6H), 3.28 (dd, J=9.7, 4.6 Hz, 1H), 4.81 (d, J=4.6 Hz, 1H); 1H NMR (250 MHz, DMSO-d6) δ 0.75-1.00 (m, 2H), 1.10-1.35 (m, 3H), 1.37-1.55 (m, 1H), 1.58-1.85 (m, 5H), 3.10 (dd, J=9.6, 4.7 Hz, 1H), 4.67 (m, 1H), 5.87 (d, J=7.8 Hz, 1H), 8.21 (bs, 1H); 13C NMR (63 MHz, DMSO-d6) δ 25.08, 25.36, 26.07, 28.83, 29.17, 37.51, 59.04, 76.41, 170.21; IR (KBr) 3312, 3219, 2928, 1726 cm−1.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:46])([CH3:45])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:44])([C@@:13]3([CH3:43])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][S:38](=[O:42])(=[O:41])[CH2:37][CH2:36]1)[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.[Cl:49][C:50]1([C:65]([O:67][CH3:68])=[O:66])[CH2:55][CH2:54][C:53](B2OC(C)(C)C(C)(C)O2)=[CH:52][CH2:51]1>>[Cl:49][C:50]1([C:65]([O:67][CH3:68])=[O:66])[CH2:55][CH2:54][C:53]([C:7]2[C:8]([CH3:46])([CH3:45])[C@H:9]3[C@:22]([CH3:25])([CH2:23][CH:24]=2)[C@@H:21]2[C@:12]([CH3:44])([C@@:13]4([CH3:43])[C@H:18]([CH2:19][CH2:20]2)[C@H:17]2[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]2([NH:32][CH2:33][CH2:34][N:35]2[CH2:36][CH2:37][S:38](=[O:41])(=[O:42])[CH2:39][CH2:40]2)[CH2:15][CH2:14]4)[CH2:11][CH2:10]3)=[CH:52][CH2:51]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: COC(=O)C1(Cl)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(Cl)(C(=O)OC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the procedure described in general procedure Step 5, using (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate and methyl 1-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate as reactants. The product was isolated as a mixture of diasteroisomers. MS: m/e 743.5 (M+H)+, 3.01 min (method 4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[N:5][CH:4]=1.[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][N:39]([CH2:14][CH2:13][N:10]4[C:11]5[C:6](=[N:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=5)[CH:7]=[CH:8][C:9]4=[O:16])[CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Reactant: COc1cnc2ccc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cnc2ccc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Yield: 62 %

Procedure:
A mixture of [7-(methoxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]acetaldehyde (as the methyl hemiacetal) (530 mg, 2.431 mmol) and 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinylcarbamate (for a synthesis see WO2004/058144 Example 99(h)) (848 mg, 2.431 mmol) in chloroform (20 ml) and MeOH (1 ml) was stirred for 2 h before addition of NaBH(OAc)3 (1.546 mg, 7.293 mmol). The reaction was stirred for 0.5 h before addition of sat. aq NaHCO3 (50 ml). The reaction was then extracted with 20% MeOH in DCM (3×200 ml). The combined organic phases were dried, evaporated and the crude residue purified by chromatography on silica gel using a 0-20% MeOH/DCM gradient to provide the desired compound (833 mg, 62%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Br:10]Br>[Fe]>[Br:10][C:3]1([CH3:9])[CH:4]=[CH:5][C:6]([F:8])=[CH:7][CH:2]1[F:1]
Reactant: BrBr
Reactant: Cc1ccc(F)cc1F
Agent: [Fe]
Product: CC1(Br)C=CC(F)=CC1F

Procedure:
The title compound was prepared by a modification of a published procedure. 2,4-Difluorotoluene was treated with iron chip and bromine at 60° C. overnight under an argon atmosphere in quantitative yield.
Reaction SMILES: [NH2:1][C:2]1[C:11]([I:12])=[CH:10][C:9](C(F)(F)F)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].NC1C=CC([O:28][C:29]([F:32])([F:31])[F:30])=CC=1C(OC)=O>>[NH2:1][C:2]1[C:11]([I:12])=[CH:10][C:9]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C(F)(F)F)cc(I)c1N
Reactant: COC(=O)c1cc(OC(F)(F)F)ccc1N
Product: COC(=O)c1cc(OC(F)(F)F)cc(I)c1N

Procedure:
The title compound was prepared as in the method of compound 2 from methyl 2-amino-5-(trifluoromethoxy)benzoate to give a white solid (0.67 g, 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH:10]=1)[CH:8]=[O:9].[CH2:14](O)[CH2:15][OH:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:9]1[CH2:14][CH2:15][O:16][CH:8]1[C:7]1[CH:10]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[N+:11]([O-:13])=[O:12]
Reactant: OCCO
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(C2OCCO2)c1
Yield: 85 %

Procedure:
The mixture 5-methoxy-2-nitrobenzaldehyde (1 eq), ethylene glycol (1.4eq) and p-toluene sulfonic acid monohydrate (catalytic amount) in toluene was heated to reflux with a Dean-Stark apparatus for 16 hours. The mixture was then concentrated and passed through a plug of silica to give 2-(1,3-dioxolan-2-yl)-4-methoxy-1-nitrobenzene in 85-90% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([S:27]([NH:30][CH2:31][CH2:32][CH3:33])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([S:27]([NH:30][CH2:31][CH2:32][CH3:33])(=[O:28])=[O:29])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CCCNS(=O)(=O)c1ccc(C)c(Br)c1
Product: CCCNS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 3-bromo-4-methyl-N-propyl-benzenesulfonamide (Intermediate 150), the title compound was obtained as a yellow sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].Br[CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[OH:2][C:1]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[O:5][CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(C)Br
Reactant: Oc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)C(C)Oc1cccc(O)c1

Procedure:
A mixture of resorcinol (11.0 g), methyl 2-bromopropanoate (20 g), potassium carbonate (27.6 g) and methyl ethyl ketone (120 mL) was heated under reflux for 5 hours. The reaction mixture was filtered, evaporated and the residue was separated by chromatography. Elution with 1:3 ethyl acetate/hexane afforded the desired product.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=O)[CH2:4][C:5]#[N:6].[OH:10][NH:11]C(N)=O>CO>[F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[C:5]([NH2:6])[O:10][N:11]=1
Reactant: NC(=O)NO
Reactant: N#CCC(=O)C(F)(F)F
Solvent: CO
Product: Nc1cc(C(F)(F)F)no1
Yield: 11 %

Procedure:
Trifluoroacetoacetonitrile (5.12 g, 0.030 mole), hydroxyurea (2.51 g, 0.033 mole) and methanol were heated under reflux for 150 hours to give the title compound (0.50 g, 11.0%).
Reaction SMILES: Br.CN(C)[CH:4]=[CH:5][C:6]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[CH:8][N:7]=1.CC(O)=[O:17]>>[OH:17][C:8]1[CH:9]=[CH:10][C:11]2[C:6](=[CH:5][CH:4]=[N:13][CH:12]=2)[N:7]=1
Reactant: CN(C)C=Cc1ncccc1C#N
Reactant: CC(=O)O
Agent: Br
Product: Oc1ccc2cnccc2n1
Reaction time: 2 h
Yield: 56 %

Procedure:
A solution of 30% HBr in AcOH (200 mL) was added dropwise with mechanical stirring at 40° to a solution of N,N-dimethyl-2-(3-cyano-2-pyridyl)ethenamine (10.8 g, 0.062 m) in AcOH (100 mL). After the addition, the slurry was stirred at 55° for 2 hours. The mixture was then evaporated to dryness and the residue treated with ice and saturated aqueous Na2CO3. The aqueous layer was filtered and the filtrate extracted with Et2O. The aqueous layer was placed in a continuous extractor with CHCl3 to yield 7.0 g of a crude product. Sublimation of this product at 160°-180° (0.1 mm) yielded 5.1 g (56%) of hydroxy-1,6-naphthyridine. An analytical sample was prepared by crystallization from CH3OH: m.p. 243-244.5.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:17]2[C:26]([CH3:28])([CH3:27])[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:29]([O:31]C)=[O:30])[CH:23]=3)[NH:18]2)[CH:13]=[C:14]([Cl:16])[CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[C:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:17]2[C:26]([CH3:28])([CH3:27])[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:29]([OH:31])=[O:30])[CH:23]=3)[NH:18]2)[CH:13]=[C:14]([Cl:16])[CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(Cl)cc(NC(=O)c3ccccc3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(Cl)cc(NC(=O)c2ccccc2)c1
Yield: 88.7 %

Procedure:
To a solution of methyl 2-(3-benzamido-5-chlorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (61 mg, 0.14 mmol) in methanol (4 mL) was added a 1 M solution of sodium hydroxide (1.63 mL, 1.63 mmol). The mixture was stirred and heated to reflux for 3 h. The mixture was concentrated, dissolved in water and acidified to pH=5-6. The precipitated solid was collected by filtration, dissolved in tetrahydrofuran, and dried over anhydrous magnesium sulfate. After evaporation of the organic solvent, the residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=3:1) to afford 54 mg of 2-(3-benzamido-5-chloro phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid. Yield: 91%; MS(ESI+APCI) M+1=417.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][O:12][C@@H:11]2[C:14](=O)[CH2:15][O:16][C@H:10]12)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(OP([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])(OCC)=O)C.[H-].[Na+]>C1COCC1>[Si:1]([O:8][C@@H:9]1[CH2:13][O:12][C@@H:11]2/[C:14](=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])/[CH2:15][O:16][C@H:10]12)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@@H]2C(=O)CO[C@@H]21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C1\CO[C@H]2[C@@H]1OC[C@H]2O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 20 mL sample vial was charged (3R,3aS,6aS)-3-[tert-butyl(dimethyl)silyl]oxy-2,3,3a,6a-tetrahydrofuro[3,2-b]furan-6-one (400 mg, 1.548 mmol), ethyl 2-(diethoxyphosphoryl)acetate (521 mg, 2.322 mmol) and THF (5 ml). The vial was flushed with nitrogen and cooled in an ice bath. To the mixture was then added slowly 60% sodium hydride (93 mg, 2.3 mmol) and the resulting reaction mixture was stirred at room temperature for 6 h. The reaction was partitioned between water (10 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic phases were dried over MgSO4, filtered and concentrated. The resulting residue was then purified by MPLC (40 g silica gel, 0 to 20% ethyl acetate in hexanes) to afford the desired product as a mixture of E/Z isomers. LC-MS: calculated for C16H28O5Si, [M+H]+Calc: 328.17. Found: 329.2, Rt=2.24 and 2.31 min (E and Z mix, 4 min run).
Reaction SMILES: [CH3:1][N:2]([CH3:35])[CH2:3][CH2:4][N:5]([C@H:28]1[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]1)[C:6]([CH:8]=[CH:9][CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]CC2C=CC=CC=2)=[C:14]([O:26][CH3:27])[CH:13]=1)=[O:7].[H][H]>CO.[C].[Pd]>[CH3:35][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([C@H:28]1[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]1)[C:6](=[O:7])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:26][CH3:27])[CH:13]=1
Reactant: COc1cc(C=CC=CC(=O)N(CCN(C)C)[C@H]2CC[C@H](C)CC2)ccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCCCC(=O)N(CCN(C)C)[C@H]2CC[C@H](C)CC2)ccc1O
Reaction time: 18 h

Procedure:
3.81 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-4-(4-benzyloxy-3-methoxyphenyl)-1,3-butadiene-1-carboxamide (Example 113) was dissolved in 100 ml of methanol. 0.2 g of 10% palladium-carbon was added to the solution. The solution was vigorously stirred at room temperature under normal-pressure hydrogen gas. After 18 hours, the reaction was ceased, and the catalyst was filtered out. The solvent was removed in vacuo from the filtrate, yielding 2.1 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-5-(4-hydroxy-3-methoxyphenyl)valeramide (a compound of the present invention) as a pale yellow oil, which had the following physiochemical properties:
Reaction SMILES: C(OC([N:6]1[CH2:14][CH2:13][CH2:12][C:11]([CH3:16])([CH3:15])[CH:7]1[C:8]([OH:10])=O)=O)C.C(Cl)(=O)C(Cl)=O.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>C(Cl)Cl>[N:23]1([C:8]([CH:7]2[C:11]([CH3:15])([CH3:16])[CH2:12][CH2:13][CH2:14][NH:6]2)=[O:10])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCOC(=O)N1CCCC(C)(C)C1C(=O)O
Reactant: C1CCNC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC1(C)CCCNC1C(=O)N1CCCC1
Reaction time: 24 h
Yield: 54.9 %

Procedure:
To a stirred solution of 5.6 g (0.026 moles) of 1-ethoxy carbonyl-3,3-dimethyl pipecolic acid in 50 ml of methylene chloride at 0° C., under nitrogen, were added 5.0 g (0.041 moles) of oxalyl chloride. After the addition the solution was allowed to reach room temperature, stirred 24 hours and evaporated in vacuo to dryness. The crude oily residue was dissolved in 30 ml of methylene chloride and added to a stirred solution of 4.44 g (0.062 moles) of pyrrolidine in 30 ml of methylene chloride at 0° C. After the addition the solution was allowed to reach room temperature and stirring was continued overnight. This solution was washed with saturated sodium bicarbonate and then with 10% HCl. The aqueous layer was brought to basic pH with 10% NaOH and extracted twice with methylene chloride. The combined extractes were dried and evaporated in vacuo to give 3.0 g of the title compound.
Reaction SMILES: Cl.[NH2:2][O:3][CH2:4][CH3:5].[C:6]([CH:9]1[CH2:12][N:11]([C:13](=[O:27])/[CH:14]=[CH:15]/[C:16]2[CH:17]=[C:18]3[C:23](=[N:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]3)[CH2:10]1)(=O)[CH3:7]>CO.ClCCl>[CH2:4]([O:3]/[N:2]=[C:6](\[CH:9]1[CH2:12][N:11]([C:13](=[O:27])/[CH:14]=[CH:15]/[C:16]2[CH:17]=[C:18]3[C:23](=[N:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]3)[CH2:10]1)/[CH3:7])[CH3:5]
Reactant: CCON
Reactant: CC(=O)C1CN(C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)C1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCO/N=C(/C)C1CN(C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)C1
Reaction time: 8 h

Procedure:
1-(Aminooxy)ethane hydrochloride (23 mg, 0.23 mmol) was added to a solution of (E)-6-(3-(3-acetylazetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (50.0 mg, 0.16 mmol) in a mixture methanol/dichloromethane (8:2, 3.5 mL) at room temperature. The reaction mixture was stirred overnight. After concentration to dryness, the residue was purified by chromatography on silica gel using ethyl acetate/methanol (95:5) as eluent. The title product was obtained as a white solid (20 mg, 35%).