Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@@H:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[NH2:13])=[O:5].[CH:14]1([CH2:17][CH:18]=O)[CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CO.ClCCl.C(O)(=O)C>[CH3:2][O:3][C:4]([C@@H:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:13][CH2:18][CH2:17][CH:14]1[CH2:16][CH2:15]1)=[O:5]
Reactant: O=CCC1CC1
Reactant: COC(=O)[C@@H]1CCCCC[C@@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1CCCCC[C@@H]1NCCC1CC1
Reaction time: 16 h

Procedure:
cis-2-Amino-cycloheptanecarboxylic acid methyl ester hydrochloride (prepared as described in Example 2a, 1.027 g, 4.96 mmol) was dissolved in methanol (23 mL), cyclopropylacetaldehyde (prepared as described in Example 19a, as a 1.40 M solution in dichloromethane, 3.54 mL, 4.96 mmol) was added at 25° C. followed by glacial acetic acid (0.94 mL). Sodium triacetoxyborohydride (2.63 g, 12.4 mmol) was added in portions at 0° C. The mixture was stirred at 0° C. to 25° C. for 16 h. Saturated aqueous sodium bicarbonate solution (40 mL) was added to neutralize the solution (pH ˜8), and the mixture was extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, filtered and concentrated and then dried at 25° C. in vacuo for 5 h to afford the crude product, cis-2-(2-cyclopropyl-ethylamino)-cycloheptanecarboxylic acid methyl ester, as a yellow oil (911.1 mg, 3.81 mmol, 76.8% crude yield over two steps) which contained neutralized unreacted cis-2-amino-cycloheptanecarboxylic acid methyl ester. This crude product was directly used in the next step without further purification. LC-MS (ESI) calcd for C14H25NO2 239.19, found 240.3 [M+H+].
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][CH2:5][C@@H:6]1[CH2:10][C@H:9]([S:11][C:12]2[C@H:18]([CH3:19])[C@H:17]3[N:14]([C:15](=[O:23])[C@@H:16]3[C@H:20]([OH:22])[CH3:21])[C:13]=2[C:24]([OH:26])=[O:25])[CH2:8][NH:7]1.Cl.[CH:28](=[NH:37])OCC1C=CC=CC=1.[OH-].[Na+].Cl>O>[F:1][CH2:2][CH2:3][O:4][CH2:5][C@@H:6]1[CH2:10][C@H:9]([S:11][C:12]2[C@H:18]([CH3:19])[C@H:17]3[N:14]([C:15](=[O:23])[C@@H:16]3[C@H:20]([OH:22])[CH3:21])[C:13]=2[C:24]([OH:26])=[O:25])[CH2:8][N:7]1[CH:28]=[NH:37]
Reactant: N=COCc1ccccc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](COCCF)C3)[C@H](C)[C@H]12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@H]3C[C@@H](COCCF)N(C=N)C3)[C@H](C)[C@H]12

Procedure:
To a solution of (4R,5S,6S)-3-[(2S,4S)-2-(2-fluoroethyloxymethyl)pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.3 g) in water (90 ml) was added benzyl formimidate hydrochloride (0.4 g) under ice-cooling with stirring, keeping the pH between 8.5-9 with 4N aqueous sodium hydroxide. After stirring for 30 minutes, the mixture was adjusted to pH 6.5 with 1N hydrochloric acid and washed with ethyl acetate (60 ml×3). The aqueous layer was subjected to a column chromatography on nonionic adsorption resin, "Diaion HP-20" (10 ml), washed with water, eluted with a mixture of acetone and water (7:93 V/V), and lyophilized to give (4R,5S,6S)-3-[(2S,4S)-2-(2-fluoroethyloxymethyl)-1-formimidoylpyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid [0.2 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=C.[Mg].Br[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1>O1CCCC1.CCOCC.[Cl-].[Cl-].[Zn+2]>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:11][CH:12]=1
Reactant: Fc1ccc(Br)cc1
Reactant: C=CCCCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCc1ccc(F)cc1
Temperature: 25 °C

Procedure:
A suspension of 6-bromo-1-hexene (10 g), magnesium (1 .5g), and lodoethane (1 drop) in anhydrous tetrahydrofuran was heated at reflux until all of the magnesium dissolved. The resulting Grignard reagent was cooled to about 0° C. and was treated with a 1M solution of ZnCl2 in ether (67 ml), and the mixture was allowed to warm to room temperature over 30 minutes. Tetraids(triphenylphosphine)palladium (0) (3.5 g) and 4-bromofluorobenzene (6.73 ml) were added to the reaction and the mixture was heated to reflux for 1 hour. The mixture was cooled to room temperature, concentrated in vacuo, diluted with hexane, filtered and concentrated once more in vacuo. Chromatography on a silica gel column eluting with ether-hexane (0-5%) afforded 5 g of a colorless oil.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[NH:20][CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:30][O:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39]Br)[CH:34]=1>CS(C)=O>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[N:20]([CH2:39][C:35]4[CH:34]=[C:33]([CH:38]=[CH:37][CH:36]=4)[C:32]([O:31][CH3:30])=[O:41])[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: O=c1[nH]cc(C2c3ccccc3C=Cc3ccccc32)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COC(=O)c1cccc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of the product from step (ii) (0.7 g) in DMSO (5 ml) was added cesium carbonate (0.75 g). After 5 minutes a solution of 3-bromomethylbenzoic acid methyl ester (0.53 g) in DMSO (5 ml) was added. The mixture was stirred at room temperature for 20 minutes and partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried (MgSO4) and evaporated. Purified by chromatography eluting with 30% ethyl acetate in isohexane. Yield 0.34 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:43])([CH2:13][C:14]2[N:15]([C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:16]=[C:17]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[N:18]=2)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[NH:44]1[CH:48]=[CH:47][N:46]=[N:45]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O.[Cu]I>[CH3:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:17]1[N:18]=[C:14]([CH2:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:45]3[N:46]=[CH:47][CH:48]=[N:44]3)=[CH:3][CH:4]=2)([OH:43])[C:9]([F:12])([F:11])[F:10])[N:15]([C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:16]=1
Reactant: CC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)(c2ccc(Br)cc2)C(F)(F)F)n1
Reactant: c1c[nH]nn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)(c2ccc(-n3nccn3)cc2)C(F)(F)F)n1

Procedure:
A mixture of copper (I) iodide (1 mg, 0.01 mmol), 2-(4-bromophenyl)-3-[4-(2,2-dimethylpropyl)-1-trityl-1H-imidazol-2-yl]-1,1,1-trifluoropropan-2-ol (50 mg, 0.08 mmol), 1,2,3-triazole (11 mg, 0.15 mmol) and potassium carbonate (21 mg, 0.15 mmol) in N-methylpyrrolidinone (1 mL) were irradiated in a microwave reactor at 195° C. for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were dried (magnesium sulfate), filtered and concentrated in vacuo. High pressure liquid chromatography (KR100-5C18 100×21.2 mm column) eluting with 10-100% acetonitrile/water containing 0.1% trifluoroacetic acid afforded 3-[4-(2,2-dimethylpropyl)-1-trityl-1H-imidazol-2-yl]-1,1,1-trifluoro-2-[4-(2H-1,2,3-triazol-2-yl)phenyl]propan-2-ol.
Reaction SMILES: [F:1][C:2]1([F:16])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[CH:12][C:13]([NH2:15])=[O:14])=[CH:10][C:4]=2[O:3]1.[Cl:17][CH:18](Cl)[C:19](=O)[CH3:20]>C1(C)C=CC=CC=1>[Cl:17][CH2:18][C:19]1[N:15]=[C:13]([CH:12]=[CH:11][C:9]2[CH:8]=[CH:7][C:5]3[O:6][C:2]([F:1])([F:16])[O:3][C:4]=3[CH:10]=2)[O:14][CH:20]=1
Reactant: CC(=O)C(Cl)Cl
Reactant: NC(=O)C=Cc1ccc2c(c1)OC(F)(F)O2
Solvent: Cc1ccccc1
Product: FC1(F)Oc2ccc(C=Cc3nc(CCl)co3)cc2O1

Procedure:
6.90 g (30.4 mmol) 3-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-acrylamide, 4.76 g (37.5 mmol) dichloro acetone and 50 ml toluene were kept at reflux temperature for 48 h with continuous removal of water by applying a Dean-Stark trap. After removal of solvents in vacuo, the residue was treated with 60 ml of a 1:1 mixture of water/isopropanol. After filtration the precipitate was washed first with isopropanol, then with heptane. Drying at 40° C. in vacuo gave 4-Chloromethyl-2-[2-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-vinyl]-oxazole.
Reaction SMILES: [Br-].C(CCC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(O)=O.[Br-].[C:28]([CH2:31][CH:32]([CH3:56])[CH:33]([CH3:55])[CH2:34][CH2:35][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:30])=[O:29].[CH2:57]([O:59][C:60]1([CH2:68][CH2:69]CC=O)[CH:64]=[CH:63][CH:62]([O:65][CH2:66][CH3:67])[O:61]1)[CH3:58].C(OC1(CC=O)C=CC(OCC)O1)C>C(O)C>[CH2:57]([O:59][C:60]1(/[CH:68]=[CH:69]\[CH2:35][CH2:34][CH:33]([CH3:55])[CH:32]([CH3:56])[CH2:31][C:28]([OH:30])=[O:29])[CH:64]=[CH:63][CH:62]([O:65][CH2:66][CH3:67])[O:61]1)[CH3:58]
Reactant: CC(CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C(C)CC(=O)O
Reactant: CCOC1C=CC(CCCC=O)(OCC)O1
Agent: CCOC1C=CC(CC=O)(OCC)O1
Agent: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCO
Product: CCOC1C=CC(/C=C\CCC(C)C(C)CC(=O)O)(OCC)O1

Procedure:
Adaption of the above-described procedures to the preparation of the other compounds of this invention essentially involves the lengthening or shortening of, or the introduction of one or two lower alkyl groups into, the side-chains in furans (I) or (XVII) or in phosphonium derivative (III). These adaptations can be accomplished by procedures well-known to the art. For example, isopropyl γ-(2-furyl)butyrate provides 2,5-dihydro-2,5-di-n-propoxy-2-(3'-carbo-isopropoxypropyl)furan in n-propanol whereas methyl δ-(2-furyl)valerate provides 2,5-dihydro-2,5-diethoxy-2-(4'-carbomethoxybutyl)furan in ethanol when treated in the manner described for the conversion of (I) to (II). Similarly, ω-(2-furyl)caproic acid and ω-(2-furyl)enanthic acid provide 2,5-dihydro-2,5-diethoxy-2-(5'-carboxyentyl)furan and 2,5-dihydro-2,5-diethoxy-2-(6'-carboxyhexyl)furan when treated in ethanol in the manner described for the conversion of (XVII) to (XVIII). Optionally, the furyl acids may be first esterified prior to oxidative alkoxylation, and all 2,5-dihydro-2,5-dialkoxy-2-(carboalkoxyalkyl)furans may be converted to the corresponding aldehydes in the manner described for the conversion of (II) to (IV). Also, the reaction of 3-carboxypropyltriphenylphosphonium bromide and 5-carboxy-3,4-dimethylamyltriphenylphosphonium bromide with 2,5-dihydro-2,5-diethoxy-2-(4'-oxobutyl)furan and 2,5-dihydro-2,5-diethoxy-2-(2'-oxoethyl)furan, respectively, provides the 2,5-dihydro-2,5-diethoxy-2-(7'-carboxy-4'-cis-heptenyl)furan and 2,5-dihydro-2,5-diethoxy-2-(7'-carboxy-5',6'-dimethyl-2-cis-heptenyl)furan.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:27]2[CH:32]=[CH:31][C:30](Br)=[CH:29][N:28]=2)([OH:26])[CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:34][S:35]([O-:37])=[O:36].[Na+].[OH-].[Na+].O>CS(C)=O.[Cu]I>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:27]2[CH:32]=[CH:31][C:30]([S:35]([CH3:34])(=[O:37])=[O:36])=[CH:29][N:28]=2)([OH:26])[CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)[O-]
Reactant: O=S(=O)(c1ccccc1)n1c(C(O)(CC2CCCC2)c2ccc(Br)cn2)cc2cccnc21
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(C(O)(CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)nc1
Temperature: 95 °C
Reaction time: 12 h
Yield: 43.1 %

Procedure:
To a mixture of 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-(5-bromo-pyridin-2-yl)-2-cyclopentyl-ethanol (0.28 g, 0.53 mmol), sodium methanesulfinate (82 mg, 0.8 mmol), and copper (I) iodide (10 mg, 0.05 mmol) in dimethylsulfoxide (5 mL) was added sodium hydroxide (4 mg, 0.106 mmol). The resulting mixture was heated at 95° C. After stirring for 12 h, the mixture was poured into water (10 mL), extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 20% ethyl acetate/hexanes) afforded 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-1-(5-methanesulfonyl-pyridin-2-yl)-ethanol (0.12 g, 43%): LC/MS m/e calcd for C26H27N3O5S2 [M+H]+ 526.65, observed 526.3.
Reaction SMILES: BrCC1CCC(O)CC1.[CH3:10][O:11][CH:12]1[CH2:17][CH2:16][CH:15]([C:18](O)=[O:19])[CH2:14][CH2:13]1>>[CH3:10][O:11][CH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]1
Reactant: COC1CCC(C(=O)O)CC1
Agent: OC1CCC(CBr)CC1
Product: COC1CCC(CO)CC1
Reaction time: 8 h
Yield: 101.3 %

Procedure:
Modified polyvinylbutryal containing a pendant group with cyclohexanol was prepared by the reaction of PVB with tetrahydropyranyl (THP) protected bromomethylcyclohexanol, followed by acid hydrolysis of the THP protection group. The THP-protected cyclohexanol-containing moiety was prepared by the following reaction sequence: 4-Methoxycyclohexanoic acid was reduced with borane-tetrahydrofuran complex to obtain 4-bromomethyl-cyclohexanol. This compound was treated with phosphorus tribromide to obtain the corresponding bromo compound. This bromo compound was reacted with trimethylsilyliodide to cleave the methoxy group to obtain 4-bromomethyl-cyclohexanol, which in turn was treated with dihyhdropyran to obtain the tetrahydropyranyl-protected bromomethylcyclohexanol. This preparation is represented by the following reaction scheme and further described in paragraphs a-d below. ##STR15## a) Preparation of 4-bromomethylcyclohexanol (C-3): 4-Methoxycyclohexanoic acid (13.0 g) was dissolved in THF (20 g), and cooled with ice. Then, borane-tetrahydrofuran complex (80 ml of 1M solution) was added and stirred overnight. Excess borane was destroyed by adding 15 ml of water dropwise until no effervescence was observed. The solution was then neutralized with potassium carbonate. The THF layer was dried over anhydrous magnesium sulfate and filtered. The solvent from the filtrate was removed under vacuum to obtain the desired 4-methoxycyclohexylmethanol (12.0 g).
Reaction SMILES: C1([Li])C=CC=CC=1.C(NC(C)C)(C)C.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>C(OCC)C>[Si:22]([CH2:21][C:17]1[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cccnc1
Agent: [Li]c1ccccc1
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: CC(C)(C)[Si](C)(C)Cc1cccnc1
Reaction time: 1 h
Yield: 89.9 %

Procedure:
In a 500 ml 3 neck round bottomed flask stirring under N2 was charged 33.1 ml of 2M phenyl lithium, in 70/30 cyclohexane diethyl ether, (0.0662 moles, 1.0 eq.), to which 6.70 g of diisopropylamine (1.0 eq. 0.0662 moles) in 10 ml of diethylether was pipetted into the flask followed by rapid addition of 6.16 g of 3-picoline (1.0 eq., 0.066 moles) in 10 ml of diethylether and 10.0 g of tert-butyldimethylsilylchloride (1.0 eq., 0.0662 moles) in 10 ml diethyl ether. The temperature of the reaction was maintained below 35° C. with an ice bath during the additions. After 1 hour of stirring GLC indicated the reaction was complete. The reaction was quenched by adding 100 ml of water, extracted with 250 ml of diethylether and washed with 2×100 ml of water. The ether was dried over magnesium sulfate and concentrated to give 12.3 g of an orange oil. GLC indicated the crude mixture was 96% product. A 7.0 g portion was purified by flash chromatography with 1:4 ethyl acetate/hexane and afforded 3.8 g (48.7% yield based on chromatographic portion) of 3-(tert-butyldimethylsilyl)pyridine.
Reaction SMILES: [CH:1]([N:4]([CH:18]([CH3:20])[CH3:19])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].Cl.[NH2:22][NH:23][C:24]([NH2:26])=[O:25].C([O-])(=O)C.[Na+].C(O)C>O>[CH:1]([N:4]([CH:18]([CH3:20])[CH3:19])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)/[C:10](=[N:22]\[NH:23][C:24]([NH2:26])=[O:25])/[C:8]1=[O:9])([CH3:3])[CH3:2]
Reactant: CC(C)N(CCN1C(=O)C(=O)c2ccccc21)C(C)C
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)N(CCN1C(=O)/C(=N/NC(N)=O)c2ccccc21)C(C)C
Yield: 74.7 %

Procedure:
A solution of 10.3 g of 1-(2-diisopropylaminoethyl)isatin, 5.1 g of semicarbazide hydrochloride and 3.7 g of sodium acetate in 150 ml of a mixture of ethanol and water (2:1) was stirred for 17 hours at room temperature. The yellow precipitates were collected by filtration and washed with aqueous ethanol. The filtrate and the washed the aqueous ethanol solution were combined and concentrated under reduced pressure. An aqueous sodium bicarbonate solution was added to the residue. The yellow precipitates were collected by filtration and washed with dichloromethane. The yellow precipitates were combined and recrystallized from aqueous methanol to obtain 9.3 g of (E)-1-(2-diisopropylaminoethyl)isatin 3-semicarbazone having a melting point of 193°-196° C.
Reaction SMILES: [N+:1]([CH:4]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:5](=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-])=O.Cl.[N:24]#[C:25][NH2:26]>[Pd]>[CH2:18]([C:4]1[NH:1][C:25]([NH2:26])=[N:24][C:5]=1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: N#CN
Reactant: CCCCCC(C(=O)CCCCCc1ccccc1)[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Product: CCCCCc1[nH]c(N)nc1CCCCCc1ccccc1

Procedure:
7-Nitro-1-phenyldodecan-6-one (0.090 g, 0.29 mmol) reacted with concentrated HCl (1.45 mmol) and palladium, 5 wt. % on activated carbon (0.125 g, 0.060 mmol) under H2, then reacted with cyanamide (0.062 g, 1.47 mmol) according to the general procedure. Purification by column chromatography gave 0.071 g (81%) over two steps as a yellow oil: 1H NMR (300 MHz, CD3OD) δ 7.20 (m, 2H), 7.14 (m, 3H), 2.59 (t, J=7.5 Hz, 2H), 2.42 (m, 4H), 1.56 (m, 6H), 1.32 (m, 6H), 0.90 (t, J=7.2 Hz, 3H) ppm; 13C NMR (75 MHz, CD3OD) δ 146.3, 142.5, 128.3, 128.1, 125.6, 122.1, 121.8, 35.5, 31.1, 31.1, 28.7, 28.7, 28.2, 23.1, 23.0, 22.3, 13.3 ppm; IR νmax (cm−1) 3169, 2928, 2857, 1680, 1453, 1202, 1030, 746, 699; HRMS (FAB) calcd for C19H29N3 (MH+) 300.2434, found 300.2441.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[O:5][C:6]=1[C:7](O)([CH3:9])[CH3:8].[CH3:21][O:22][C:23](=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([SH:31])[CH:26]=1.ClCCCl>C(OCC)(=O)C.[I-].[Zn+]>[CH3:21][O:22][C:23](=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([S:31][C:7]([CH3:9])([C:6]2[O:5][C:4]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[N:3][C:2]=2[CH3:1])[CH3:8])[CH:26]=1
Reactant: COC(=O)Cc1cccc(S)c1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1C(C)(C)O
Agent: [I-]
Agent: [Zn+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)Cc1cccc(SC(C)(C)c2oc(-c3ccc(C(F)(F)F)cc3)nc2C)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propan-2-ol (0.1 g, 0.351 mmol), (3-Mercapto-phenyl)-acetic acid methyl ester (0.070 g, 0.386 mmol), zinc (I) iodide (0.056 g, 0.176 mmol), and 1,2-dichloroethane (2 mL) is stirred at room temperature 24 hr. The reaction mixture is diluted with ethyl acetate (25 mL), and washed with aqueous saturated sodium hydrogen carbonate, water, brine (25 mL each), dried over anhydrous magnesium sulfate, filtered, concentrated, and purified via silica chromatography eluting with 8:2 hexanes:ethyl acetate to afford the product as a colorless film, 0.105 g, 66%. MS M++1 286. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([NH:40][CH3:41])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:42][CH3:43])=[O:5])[CH3:2].Br[CH2:45][CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:38])([F:39])[F:37])[CH:27]=3)[C:22]([NH:40][CH2:41][CH2:45][CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:42][CH3:43])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(NC)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCNc1cnc(N[C@H]2C[C@@H](CC)N(C(=O)OCC)c3ccc(OC)nc32)nc1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-methylaminopyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (150 mg) is dissolved in N,N-dimethylformamide (5 ml), and thereto are added ethyl 4-bromobutyrate (13 μl) and potassium carbonate (50 mg). The mixture is heated at 50° C. and stirred for 2 hours. The reaction solution is cooled to room temperature, and partitioned by adding a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer is washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=9:1→3:2) to give (2R,4S)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[(3-ethoxycarbonylpropyl)-methyl]aminopyrimidin-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (85 mg). MS (m/z): 727 [M+H]+.
Reaction SMILES: Br[C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:17][C:18]([F:50])([F:49])[C:19]1[CH:20]=[C:21]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:22][N:23]1[C:27]([CH3:28])=[C:26]([Sn](CCCC)(CCCC)CCCC)[N:25]=[N:24]1>CN(C=O)C>[F:50][C:18]([F:17])([F:49])[C:19]1[CH:20]=[C:21]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:22][N:23]1[C:27]([CH3:28])=[C:26]([C:2]2[C:7]([C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[N:25]=[N:24]1
Reactant: O=C(c1ccccc1Cl)c1cccnc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1C
Solvent: CN(C)C=O
Product: Cc1c(-c2ncccc2C(=O)c2ccccc2Cl)nnn1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 80 °C
Yield: 54.1 %

Procedure:
Dissolve (2-bromo-pyridin-3-yl)-(2-chloro-phenyl)-methanone (148 mg, 0.50 mmol) and 1-(3,5-bis-trifluoromethyl-benzyl)-5-methyl-4-tributylstannanyl-1H-[1,2,3]triazole (449 mg, 0.75 mmol) in DMF (5 mL) and degass, then add dichlorobis(triphenylphosphine) palladium (70 mg, 0.10 mmol). Seal the mixture under N2 and heat at 80° C. for 24 hours. Concentrate, dissolve in CHCl3, wash with saturated potassium fluoride solution (2×), saturated potassium bicarbonate solution, brine, dry over MgSO4 and concentrate. Purify the residue by flash chromatography on silica gel eluting with 0-40% EtOAc/hexane followed by recrystallization from EtOAc/hexane to afford the title compound (142 mg, 54%). MS(IS) 525 (M+1); TLC (60% EtOAc/hexane) Rf=0.30.