Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:19]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:15]2[CH:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[S:26][C:16]=2[N:17]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-methylenedioxyphenethylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: ClC1C=C(CC[CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)C=CC=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH2:42][CH2:43][CH2:44]C(O)=O)[CH:37]=[CH:38][C:39]=1[O:40][CH3:41].C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH2:42][CH2:43][CH2:44][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:37]=[CH:38][C:39]=1[O:40][CH3:41]
Reactant: COc1ccc(CCCC(=O)O)cc1OC
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: COc1ccc(CCCCN(C(=O)Nc2ncc(SCC(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1OC

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 4-(3,4-dimethoxy-phenyl)-butyric acid and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][C@:10]3([CH2:16][CH2:15][NH:14][C:13]3=[O:17])[N:9]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:4][CH:3]=1.F[C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[C:28]#[N:29]>>[C:28]([C:27]1[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=1[O:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][C@:10]3([CH2:16][CH2:15][NH:14][C:13]3=[O:17])[N:9]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:4][CH:3]=1)#[N:29]
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(O)cc2)CC[C@]12CCNC2=O
Reactant: N#Cc1ccccc1F
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(Oc3ccccc3C#N)cc2)CC[C@]12CCNC2=O
Yield: 66 %

Procedure:
1,1-Dimethylethyl (2R,5R)-2-{4-[(2-cyanophenyl)oxy]phenyl}-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate (D28, 58 mg, 66%) was synthesized using a similar procedure as set out earlier in Description 13 using 1,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-5-(4-hydroxyphenyl)-2-methyl-1-pyrrolidinecarboxylate (D25, 66 mg, 0.198 mmol) and 2-fluoro-benzonitrile; Rt (HPLC): 5.34 min; MS: (ES/+) m/z: 456 [M+Na+]; C25H27N3O4 requires 433.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].C(N(CC)CC)C.C([O:43][CH:44]=[CH:45][CH3:46])C>O>[CH3:8][C:7]1[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=2)[C:5](=[O:19])[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][CH:25]=2)=[O:21])=[CH:3][C:2]=1[C:44](=[O:43])[CH2:45][CH3:46]
Reactant: CC=COCC
Reactant: Cc1c(I)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(=O)c1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
A solution of 5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (Example 1 (d), 1500 mg, 2.5 mmol), bis[1,2-bis(diphenylphosphino)ethanelpalladium(0) (230 mg, 0.25 mmol), triethylamine (7.5 ml, 54 mmol) and ethylpropenyl ether (900 μl, 7.5 mmol) in DMP (45 ml) was heated at 100° C. overnight. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate and the solvent was removed under reduced pressure. The crude product was then dissolved in DMP (25 ml) and 2M HCl (25 ml) and then stirred for 1.5 h. The reaction mixture was then poured into aqueous NaHCO3 and extracted with ethyl acetate. The extracts were separated, evaporated under reduced pressure, and the residue was chromatographed on silica using ethyl acetate/heptane (2/1, 4/1, 10/1) as eluent. Fractions containing the product were combined and evaporated to give the title compound (1.3 g, >99%).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].C(OC(=O)C)(=O)C.[Cl:12][C:13]([F:26])([F:25])[C:14]1([C:21]([Cl:24])([F:23])[F:22])[O:18][CH:17]([CH2:19]O)[CH2:16][O:15]1>O>[N+:1]([O-:4])([O:3][CH2:19][CH:17]1[CH2:16][O:15][C:14]([C:13]([Cl:12])([F:25])[F:26])([C:21]([Cl:24])([F:22])[F:23])[O:18]1)=[O:2]
Reactant: OCC1COC(C(F)(F)Cl)(C(F)(F)Cl)O1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=[N+]([O-])OCC1COC(C(F)(F)Cl)(C(F)(F)Cl)O1
Reaction time: 0.5 h

Procedure:
34 ml nitric acid (96%) is added slowly to 43 ml chilled acetic anhydride. Then, 14.8 grams of 2,2-bis(chlorodifluoromethyl)-4-hydroxymethyl-1,3-dioxolane, is added dropwise with magnetic stirring over a 30 minute period to the chilled mixed acid (0° to -10° C.). An additional 25 minutes of stirring is allowed. The reaction mixture is drowned in 250 ml of cold tap water forming a small lower liquid layer. Ether extraction (3 × 75 ml) removed the lower layer and all of the yellow coloration. The ether solution is washed several times with water and then dried over Na2SO4, filtered and evaporated on a rotary evaporator. The cloudy residue is redissolved in ether, treated with Na2SO4, decanted and evaporated as before. The bright yellow liquid is redissolved in ether and treated with activated carbon (DARCO G-60), then filtered (colorless), and reevaporated to yield the above named product.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]([CH:24]([CH3:26])[CH3:25])[C:12]([C:14]1[N:15]=[C:16]([N:19]2[CH2:22][CH:21]([OH:23])[CH2:20]2)[S:17][CH:18]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:27][S:28](Cl)(=[O:30])=[O:29].C(N(CC)CC)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH:24]([CH3:26])[CH3:25])[C:12]([C:14]1[N:15]=[C:16]([N:19]2[CH2:22][CH:21]([O:23][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:20]2)[S:17][CH:18]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1csc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 0 °C
Yield: 42.1 %

Procedure:
To a solution of 1-(4-{N-[2-(t-butyldimethylsilyloxy)ethyl]-N-isopropyl-carbamoyl}-1,3-thiazol-2-yl)-3-hydroxyazetidine (1.24 g, 3.23 mmol) (obtained as described in Reference Example 59(3)) in methylene chloride (62 ml) were added methanesulfonyl chloride (0.30 ml, 3.88 mmol) and triethylamine (0.54 ml, 3.88 mmol) in an ice bath, and then the mixture was stirred in the ice bath for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:1) ethyl acetate as the eluant to afford 1-(4-{N-[2-(t-butyldimethylsilyloxy)-ethyl]-N-isopropyl-carbamoyl}-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (649 mg, yield 42%) as a pale yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[N:8]=2)[CH:2]=1.[H-].[Na+].[CH2:23](Br)[CH:24]=[CH2:25]>CN(C)C=O>[CH2:25]([O:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:9]2[N:8]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:12]=[CH:11][N:10]=2)=[CH:15][CH:16]=1)[CH:24]=[CH2:23]
Reactant: C=CCBr
Reactant: Oc1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Reaction time: 0.75 h

Procedure:
A 2.73 g portion of dry 4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenol was dissolved in 50 ml of dry dimethylformamide. A 528 mg portion of sodium hydride (50% in oil) was added, the reaction was sealed and stirred for 45 minutes. A solution of 1.33 g of allyl bromide in 10 ml of dimethylformamide was added, the sealed mixture was stirred overnight and then evaporated at 80° C. The residue was partitioned between water and chloroform. The organic phase was separated, dried and filtered. The filtrate was evaporated and the residue crystallized from chloroform-hexane, giving 1.7 g of the desired product as yellow crystals, mp 105°-108° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH:16]=O)=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.NO.C([N:23](CC)CC)C.[N+](C1C=C2C(=O)OC(=O)C2=CC=1)([O-])=O>C(#N)C.O>[CH2:1]([O:8][C:9]1[C:10]([C:16]#[N:23])=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: Cc1ccc(OCc2ccccc2)c(C=O)n1
Agent: Cl
Agent: NO
Agent: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Solvent: CC#N
Solvent: O
Product: Cc1ccc(OCc2ccccc2)c(C#N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
3-Benzyloxy-6-methyl-pyridine-2-carbaldehyde (100 mg) was dissolved in acetonitrile (5 ml) to prepare a solution. Hydroxylamine hydrochloride (72 mg) and triethylamine (0.25 ml) were added to the solution, and the mixture was stirred at room temperature for one hr. 4-Nitrophthalic anhydride was added to the reaction solution, and the mixture was stirred at 100° C. overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using ethyl acetate-hexane to give 3-benzyloxy-6-methylpyridine-2-carbonitrile (53 mg, yield 54%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH:25]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26]1>>[C:32]([O:31][C:29]([N:27]1[CH2:28][CH:25]([NH:24][C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:23][CH:22]=2)=[O:21])[CH2:26]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CN(C(=O)OC(C)(C)C)C2)cn1
Yield: 86 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using 3-amino-1-N-Boc-azetidine instead of 2-aminoethyl isopropylether, to the title compound (257 mg, 86%) which was obtained as a white solid. MS: m/e=463.3 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.N1C=CC=CC=1.Cl>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:18][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=S(=O)(NC1CCCCC1)c1ccccc1Br
Reaction time: 3 h

Procedure:
To a 20 mL vial were added a stirbar, 2-bromobenzene-1-sulfonyl chloride (1.053 g, 4.12 mmol), cyclohexylamine (431 mg, 4.34 mmol) and dry pyridine (5 mL). The mixture was stirred for 3 hours before adding it to a separatory funnel containing 1 N HCl and EtOAc. The layers were mixed thoroughly and then separated. The organic layer was then washed with water followed by sat. NaHCO3, dried over MgSO4, filtered and evaporated to dryness to give the title compound. MS (ESI): mass calcd. for C12H16NO2SBr 317.01, m/z found 318.0 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.14 (dd, J=7.9, 1.7, 1H), 7.71 (dd, J=7.9, 1.2, 1H), 7.49-7.42 (m, 1H), 7.42-7.35 (m, 1H), 5.05 (d, J=7.7, 1H), 3.19-3.04 (m, 1H), 1.79-1.66 (m, 2H), 1.66-1.57 (m, 2H), 1.52-1.44 (m, 1H), 1.28-1.04 (m, 5H).
Reaction SMILES: [CH:1]1([C@H:5]([NH:13][C:14]([CH2:16][C:17]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[C:18]=2[C:19]([OH:21])=[O:20])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.[C:28](C1C2C=C(F)C=C(F)C=2C(=O)OC=1N[C@@H](C1CCC1)C1C=CC=C(F)C=1)(=[O:30])[CH3:29].C1([C@H](NC(C2C3C=C(F)C=C(F)C=3C(=O)OC=2C)=O)C2C=CC=C(F)C=2)CCC1.[OH-].[Na+]>C(OC(=O)C)(=O)C.O1CCCC1>[CH:1]1([C@H:5]([NH:13][C:14]([CH:16]([C:17]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[C:18]=2[C:19]([OH:21])=[O:20])[C:28](=[O:30])[CH3:29])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)c1c(N[C@H](c2cccc(F)c2)C2CCC2)oc(=O)c2c(F)cc(F)cc12
Reactant: O=C(Cc1cc(F)cc(F)c1C(=O)O)N[C@H](c1cccc(F)c1)C1CCC1
Agent: Cc1oc(=O)c2c(F)cc(F)cc2c1C(=O)N[C@H](c1cccc(F)c1)C1CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)C(C(=O)N[C@H](c1cccc(F)c1)C1CCC1)c1cc(F)cc(F)c1C(=O)O
Reaction time: 0.5 h
Yield: 42 %

Procedure:
2-({[(S)-Cyclobutyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-methyl)-4,6-difluoro-benzoic acid (3.4 g, 9.0 mmol in acetic anhydride (60 mL) was stirred at 100° C. overnight then evaporated and co-evaporated with toluene twice in vacuo to give a mixture of 4-acetyl-3-{[(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amino}-6,8-difluoro-2-benzopyran-1-one and 6,8-difluoro-3-methyl-1-oxo-1H-2-benzopyran-4-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide. The obtained residue was dissolved in tetrahydrofuran (15 mL), allowed to cool on an ice-water bath and 2M aqueous NaOH (18 mL) was added. The cold bath removed and the reaction mixture was stirred for 30 min. The obtained mixture was diluted with water (20 mL) and extracted with isopropyl acetate (40 mL) which was washed with water (40 mL). The combined aqueous phase was cooled on ice bath and the pH was adjusted to 1 with conc. HCl. The title product was separated by extraction with isopropylacetate (2×40 mL) and purified by flash chromatography (50 g SiO2, the product was eluted with 1:1 ethyl acetate-heptane, 1.58 g, yield 42%). LC-MS (m/z) 420.6 (MH+); tR=1.35.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:16]I>CN(C=O)C>[F:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]([CH3:16])[C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)oc(=O)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
A solution of Compound 35 (3 g, 16.57 mmol) in DMF was added slowly to a suspension of NaH (60% in mineral oil, 0.729 g, 18.23 mmol) in DMF and further stirred at room temperature for 1 h. Then, neat methyl iodide (1.14 mL, 18.23 mmol) was added and the solution further stirred at room temperature for 3 h. The solution was poured into ice water and the solids formed were filtered, washed several times by water, and dried. The solids were suspended in hexane, sonicated briefly, filtered, and washed by hexane to yield 1.84 g (57%) of white solids. M.P. 133° C. 1H NMR (DMSO-d6): δ 3.90 (s, 3H), 7.51 (dd, J=4.0, 8.8 Hz, 1H), 7.77 (m, 12). Anal. (C9H6FNO3) C, H, N.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:19](Br)[CH:20]=[CH2:21]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:16][C@H:14]([O:15][CH2:21][CH:20]=[CH2:19])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCO[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.1 %

Procedure:
N-tert-Butoxycarbonyl (4R)-hydroxyproline (9.25 g, 40 mmol) was added to a solution of 60% sodium hydride (3.36 g, 84 mmol) in 100 ml of anhydrous tetrahydrofuran and stirred for 2 hours at room temperature. Allyl bromide (6.9 ml, 80 mmol) was added to the mixture and refluxed for 6 hours. The mixture was quenched with the addition of ice chips, then additional water was added and the mixture was washed with hexane. The aqueous layer was acidified with 10% sodium hydrogen sulfate and extracted with ethyl acetate (2×150 ml). The combined extracts were dried over anhydrous sodium sulfate, filtered and evaporated to give 5 g of the title product with no further purification. 1NMR (CDCl3 ; exist as rotamers) δ 5.92-5.82 (1H, m), 5.3-5.14 (2H, m) 4.5-4.31 (1H, m), 4.16-4.05 (1H, m), 4.04-3.9 (1H, m), 3.79-3.5 (3H, m), 2.43-2.2 (1.5H, m), 2.15-2.10 (0.5H, m), 1.45 (4.5H, s), 1.35 (4.5H, s).
Reaction SMILES: C([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[CH2:16][CH2:17][C:18](=[CH:20][C:21]#[N:22])[C:19]=3[C:11]=2[N:10]=[C:9]1[CH3:23])C1C=CC=CC=1.C(N(CC)CC)C.[C:31](OC(=O)C)(=[O:33])[CH3:32]>N.C(O)C.[Co]>[CH3:23][C:9]1[NH:10][C:11]2[C:19]3[CH:18]([CH2:20][CH2:21][NH:22][C:31](=[O:33])[CH3:32])[CH2:17][CH2:16][C:15]=3[CH:14]=[CH:13][C:12]=2[N:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc2c3c(ccc2n1Cc1ccccc1)CCC3=CC#N
Agent: [Co]
Agent: N
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)NCCC1CCc2ccc3nc(C)[nH]c3c21
Temperature: 25 °C
Reaction time: 14 h
Yield: 31 %

Procedure:
(3-Benzyl-2-methyl-6,7-dihydroindeno[4,5-d]imidazol-8(3H)-ylidene)acetonitrile was dissolved in 2M ammonia/ethanol solution (14 mL), Raney cobalt (10 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 14 hr. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (3 mL), triethylamine (34.9 μL, 0.25 mmol) and acetic anhydride (18.9 μL, 0.20 mmol) were added, and the mixture was stirred at room temperature for 30 min. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=5/95→15/85). The purified product was dissolved in methanol (3 mL), palladium-carbon powder (20 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 5 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=5/95→20/80) to give the title compound (13.4 mg, yield 31%).
Reaction SMILES: Br[C:2]1[C:3](=[O:16])[C:4]([CH3:15])([CH3:14])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.CC1(C)C(C)(C)OB([C:25]2[CH:42]=[CH:41][C:28]([O:29][CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=3)=[CH:27][CH:26]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[O:5][C:4]([CH3:15])([CH3:14])[C:3](=[O:16])[C:2]=2[C:25]2[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=3)=[CH:41][CH:42]=2)=[CH:8][CH:9]=1
Reactant: CC1(C)OB(c2ccc(OCc3ccc4ccccc4n3)cc2)OC1(C)C
Reactant: CC1(C)OC(c2ccc(Cl)cc2)=C(Br)C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)OC(c2ccc(Cl)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Yield: 34.6 %

Procedure:
A solution of 4-bromo-5-(4-chlorophenyl)-2,2-dimethylfuran-3(2H)-one (1.0 g, 3.30 mmol), 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (1.30 g, 3.60 mmol), and Cs2CO3 (5.37 g, 16.50 mmol) in toluene (10 mL) and water (5 mL) was degassed. Then, Pd(dppf)C2 (0.54 g, 0.601 mmol) was added under an inert atmosphere and the solution was degassed again. The reaction mixture was then refluxed for 2 h, filtered through a pad of Celite®, and the filtrate was diluted with EtOAc (40 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(4-chlorophenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl) furan-3(2H)-one (520 mg, 35%) as a pale yellow solid. 1H NMR (500 MHz, d6-DMSO): δ 8.44 (d, J=8.5 Hz, 1H), 8.02 (t, J=7.9 Hz, 2H), 7.81 (t, J=8.4 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.63 (t, J=8.2 Hz, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.52 (d, J=8.5 Hz, 2H), 7.18 (d, J=7.4 Hz, 2H), 7.11 (d, J=7.5 Hz, 2H), 5.39 (s, 2H), 1.44 (s, 6H). MS: [M+Na]: m/z=478.1, [M+H]: m/z=456.1. HPLC: 97%, Column: Acquity BEH-C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), AcN (B), Flow rate: 0.5 ml/min (Gradient).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](=[S:21])[NH:18][C:17]3=[O:22])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.I[CH3:34]>>[F:32][C:2]([F:31])([F:1])[C:3]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([S:21][CH3:34])=[N:18][C:17]3=[O:22])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CI
Reactant: O=C1NC(=S)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Product: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-one and iodomethane following General Procedure C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1.[CH3:15][CH2:16][OH:17].[H-].[Na+].O>C1COCC1>[CH2:16]([O:17][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1)[CH3:15]
Reactant: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ncc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
To a mixture of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (500 mg, 2.207 mmol) in THF (10 mL) was added EtOH (0.155 mL, 2.65 mmol) and NaH (132 mg, 3.31 mmol). Then the mixture was stirred at 0° C. for 30 min, then warmed to rt and stirred for 16 h. The mixture was added to H2O and extracted with EA (2×50 mL) to give the organic layer. The combined organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated to yield a brown oil of 2-ethoxy-5-nitro-3-(trifluoromethyl)pyridine (120 mg, 0.457 mmol, 20.7% yield): 1H NMR (400 MHz, CD3OD) δ 9.27 (d, J=2.5 Hz, 1H), 8.75 (d, J=2.5 Hz, 1H), 4.67 (m, 2H), 1.47 (t, J=7.0 Hz, 3H).