Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)=O.Cl.[NH2:12]O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:1]([C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)#[N:12]
Reactant: O=Cc1ccc(C(=O)O)o1
Reactant: NO
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: N#Cc1ccc(C(=O)O)o1
Temperature: 85 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
A 250-mL, three-neck, round-bottom flask equipped with a mechanical stirrer, a heating mantle, and a condenser was charged with 5-formyl-2-furancarboxylic acid (9.18 g, 65.6 mmol) and pyridine (60 mL). Hydroxylamine hydrochloride (5.01 g, 72.2 mmol) was added and the mixture was heated to 85° C. Acetic anhydride (40 mL) was added and the reaction was stirred at 85° C. for 3 h, after which time the solvent was evaporated at 40° C. under reduced pressure. The residue was dissolved in water, basified with 2.0 N NaOH solution to pH 9, and extracted with 4:1 dichloromethane/2-propanol until the pyridine was completely removed (5×200 mL). The aqueous solution was then acidified with 2.0 N HCl solution to pH 2, saturated with solid NaCl, and extracted with 4:1 dichloromethane/2-propanol (5×200 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to dryness. The residue was crystallized from dichloromethane to give 6.80 g of the title compound as a white solid (76%). Mass spectrum (ESI-neg, m/z) Calcd. for C6H3NO3, 136.0 (M−H), found 136.1. The 1H NMR spectrum was consistent with the assigned structure.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[N:16]=[C:15]([O:17][CH3:18])[C:14]([NH2:19])=[C:13]([O:20][CH3:21])[N:12]=1.N1C=CC=CC=1.[C:28]([CH2:32][C:33](Cl)=[O:34])([CH3:31])([CH3:30])[CH3:29]>ClCCl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[N:16]=[C:15]([O:17][CH3:18])[C:14]([NH:19][C:33](=[O:34])[CH2:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:13]([O:20][CH3:21])[N:12]=1
Reactant: COc1nc(N2CCc3ccccc3C2)nc(OC)c1N
Reactant: CC(C)(C)CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1nc(N2CCc3ccccc3C2)nc(OC)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a mixture of 4c (0.219 g, 0.76 mmol) and pyridine (0.06 g, 0.76 mmol) in dichloromethane (5 ml) was added tert-butylacetyl chloride (0.102 g, 0.76 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was washed with brine and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated and chromatographed to yield the title compound (0.262 g, 0.73 mmol, 96%). 1H NMR (CDCl3, 400 MHz) δ 1.10 (s, 9H), 2.20 (s, 2H), 2.90 (t, J=5.8 Hz, 2H), 3.92 (s, 6H), 4.01 (t, J=5.8 Hz, 2H), 4.87 (s, 2H), 6.14 (s, 1H), 7.15-7.19 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:40]=[CH:39][C:8]([O:9][C:10]2[CH:11]=[C:12]([C:22]3[N:23](C(OC(C)(C)C)=O)[C:24]([C:27]4[S:28][CH:29]=[CH:30][N:31]=4)=[CH:25][CH:26]=3)[CH:13]=[C:14]([O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[CH:15]=2)=[CH:7][CH:6]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:20][O:19][CH2:18][C@H:17]([CH3:21])[O:16][C:14]1[CH:15]=[C:10]([CH:11]=[C:12]([C:22]2[NH:23][C:24]([C:27]3[S:28][CH:29]=[CH:30][N:31]=3)=[CH:25][CH:26]=2)[CH:13]=1)[O:9][C:8]1[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:40][CH:39]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)OC)cc2)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)OC)cc2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Reaction time: 2 h
Yield: 112.8 %

Procedure:
t-Butyl 2-{3-[4-(methoxycarbonyl)phenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (70 mg, 0.124 mmol) synthesized in Example (38e) was dissolved in dichloromethane (1.0 mL). Trifluoroacetic acid (2.0 mL) was added dropwise with stirring under nitrogen atmosphere, and stirring was carried out at room temperature for 2 hours. The solvent was distilled off under reduced pressure, followed by dilution with ethyl acetate (30 mL), a saturated aqueous sodium hydrogencarbonate solution (20 mL) was added, and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-50%) to afford the desired compound (65 mg, yield ˜100%) as a pale yellow liquid.
Reaction SMILES: [CH2:1](OC(OCC)OCC)C.[NH2:11][C:12]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:30][C:13]=1[C:14]([NH:16][C:17]1[CH:22]=[C:21]([C:23]([NH:25][CH:26]2[CH2:28][CH2:27]2)=[O:24])[CH:20]=[CH:19][C:18]=1[CH3:29])=[O:15].C(O)(=O)C>C(O)C>[CH:26]1([NH:25][C:23](=[O:24])[C:21]2[CH:20]=[CH:19][C:18]([CH3:29])=[C:17]([N:16]3[C:14](=[O:15])[C:13]4[C:12](=[CH:33][CH:32]=[C:31]([N:34]5[CH2:35][CH2:36][O:37][CH2:38][CH2:39]5)[CH:30]=4)[N:11]=[CH:1]3)[CH:22]=2)[CH2:28][CH2:27]1
Reactant: CCOC(OCC)OCC
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2CCOCC2)ccc1N
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(N3CCOCC3)cc2c1=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Triethylorthoformate (0.969 ml) was added to a stirred mixture of 2-amino-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-morpholin-4-ylbenzamide (0.67 g) and glacial acetic acid (0.05 ml) in ethanol (5 ml). The mixture was heated to 80° C. and stirred for 16 hours. The reaction mixture was evaporated, dissolved in methylene chloride and washed with a saturated NaHCO3 solution. The organic phase was evaporated and the residue was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give the title compound (0.172 g); NMR Spectrum: (DMSOd6) 0.53 (m, 2H), 0.66 (m, 2H), 2.11 (s, 3H), 2.83 (m, 1H), 3.22 (m, 4H), 3.75 (m, 4H), 7.48 (m, 2H), 7.64 (m, 2H), 7.80 (s, 1H), 7.87 (m, 1H), 8.09 (s, 1H), 8.43 (m, 1H); Mass Spectrum: M+H+ 405.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[C:6]=1[CH3:23])[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=3)[C:13]=2[CH3:22])[C:6]=1[CH3:23])[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1C
Reactant: CCn1cc(Br)cn1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(CC)c3)c3cc(Cl)ccc23)c1C

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-2-methyl-benzoic acid ethyl ester and 4-bromo-1-ethylpyrazole.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CO.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[OH-].[Na+].S([O-])([O-])(=O)=O.[Cu+2]>[NH2:1][C@@H:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][CH:9]=1)[C:11]([OH:13])=[O:12]
Reactant: BrCc1ccccc1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Temperature: 60 °C

Procedure:
To a solution of L-tyrosine of the formula (21) (18.1 g) in 2N NaOH solution (115 ml), copper sulphate solution (12.5 g of CuSO4 in 50 ml of water) was added and heated at 60° C. for 1.5 h. The reaction mixture was cooled to room temperature and methanol (350 ml) and 2N NaOH (12.5 ml) was added and then benzyl bromide (12 ml) was added drop wise. The reaction mass was allowed to warm to room temperature. The precipitate was filtered and washed to give the title compound as white to off-white solid (18.5 g, 66.8%) (Ref. Bodansky & Bodansy pp50).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14]([OH:16])=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH2:24]([O:26][C:27]([CH:29]1[CH2:38][CH2:37][C:32]2[N:33]=[C:34]([NH2:36])[S:35][C:31]=2[CH2:30]1)=[O:28])C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>CN(C=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14]([NH:36][C:34]3[S:35][C:31]4[CH2:30][CH:29]([C:27]([O:26][CH3:24])=[O:28])[CH2:38][CH2:37][C:32]=4[N:33]=3)=[O:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1CCc2nc(N)sc2C1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)C1CCc2nc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)sc2C1
Yield: 41.1 %

Procedure:
The compound of example A6 was obtained by similar method described in example A1 using 2-(4-cyclopropanesulfonyl-phenyl)-2-[(tetrahydro-pyran-4-yloxy)]-acetic acid (Preparation 4, 0.340 g, 1.0 mmol), 2-Amino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester (Preparation 49; 0.286 g, 1.0 mmol), HOBt (0.162 g, 1.2 mmol), and EDCl (0.229 g, 1.2 mmol), N-methyl morpholine (0.36 g, 3.58 mmol) in DMF (6 mL) to provide the title compound (0.22 g).
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH2:11][CH2:12][C:13]([CH3:17])([NH:15][CH3:16])[CH3:14])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30]Br)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH2:11][CH2:12][C:13]([N:15]([CH2:30][CH2:29][C:28]2[CH:32]=[CH:33][C:25]([F:24])=[CH:26][CH:27]=2)[CH3:16])([CH3:17])[CH3:14])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNC(C)(C)CCC(C(N)=O)(c1ccccc1)c1ccccc1
Reactant: Fc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCc1ccc(F)cc1)C(C)(C)CCC(C(N)=O)(c1ccccc1)c1ccccc1

Procedure:
A mixture containing 2,2-diphenyl-5-methyl-5-methylaminohexanamide (0.31 g--see Preparation 13), 4-fluorophenethyl bromide (0.2 g), anhydrous potassium carbonate (0.5 g) and acetonitrile (15 ml) was heated under reflux for 5 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous potassium carbonate (20 ml), the layers separated and the aqueous layer extracted with dichloromethane (3×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield 0.1 g.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])Cl)=[CH:7][C:6]=1[O:18][CH3:19])(=[O:3])[CH3:2].[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][SiH:14]([CH3:17])[CH3:16])=[CH:7][C:6]=1[O:18][CH3:19])(=[O:3])[CH3:2]
Reactant: COc1cc(CCC[Si](C)(C)Cl)ccc1OC(C)=O
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(CCC[SiH](C)C)ccc1OC(C)=O
Yield: 63.8 %

Procedure:
A 100 mL round bottomed flask was charged with eugenol acetate (16.5 g, 80 mmol), which had been prepared from the reaction of eugenol with acetic anhydride, and 25 microliters of Karstedt's catalyst. Dimethylchlorosilane (7.56 g, 80 mmol) was added slowly over 20 minutes. After 1.5 hr the reaction was complete (as judged by 1H-NMR) and 3-(4-acetoxy-3-methoxyphenyl)prop-1-yl dimethylchlorosilane (21.1 g, 88% yield) was isolated by vacuum distillation (boiling point (bp)=150° C./0.5 mmHg). A 100 mL round bottomed flask was charged with 3-(4-acetoxy-3-methoxyphenyl)prop-1-yl dimethylchlorosilane (15.0 g, 50 mmol) and 25 mL of toluene. A 65 weight percent solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene (7.0 mL, 50 mmol) was added over 30 minutes. After quenching in 6N HCl (100 mL), the product in toluene was washed 3 times with water, dried over MgSO4 and the toluene removed under reduced pressure. Vacuum distillation gave 3-(4-acetoxy-3-methoxyphenyl)prop-1-yl dimethylsilane (8.5 g, bp 90° C./0.5 mmHg). A 100 mL Morton flask was charged with 3-(4-acetoxy-3-methoxyphenyl)prop-1-yl dimethylsilane (8.0 g, 30 mmol), eugenol (6.56 g, 40 mmol), toluene (25 mL) and platinum on carbon (5% Pt on C, 0.05 g). After heating at reflux for 1.5 hr, the reaction mixture was cooled and filtered. The toluene was removed and the crude product stripped of volatiles at 125° C. at a pressure of 0.5 mmHg. Residual acetate groups were removed by treating the coupled product with K2CO3 in methanol/water, diluting the reaction mixture to 5 weight percent HCl, extracting with ether, drying the organic layer over MgSO4 and concentrating under reduced pressure to afford eugenol siloxane bisphenol (8.0 g) wherein p is zero.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[C:22]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[C:3]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=3)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Product: CC(C)(C)c1ccc(-c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)cc1

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, using methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) and 4-tert-butylphenylboronic acid (83 mg, 0.47 mmol, 1.50 equiv) as reactants. Purification via prep-TLC resulted in 30 mg (27%) of 3-(4-tert-butylphenyl)-2-phenylquinoxaline-6-carboxylic acid as a white solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([S:16][CH3:17])[CH:11]=1)[C:4]1[N:8]([CH3:9])[N:7]=[N:6][N:5]=1.Cl[CH2:19][C:20]1[N:21]=[C:22]([NH2:25])[S:23][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C>[CH3:17][S:16][C:12]1[CH:11]=[C:10]([C:3](=[N:2][O:1][CH2:19][C:20]2[N:21]=[C:22]([NH2:25])[S:23][CH:24]=2)[C:4]2[N:8]([CH3:9])[N:7]=[N:6][N:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Nc1nc(CCl)cs1
Reactant: CSc1cccc(C(=NO)c2nnnn2C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: CSc1cccc(C(=NOCc2csc(N)n2)c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 26 h
Yield: 44.1 %

Procedure:
To a stirred suspension of N-hydroxy-1-[3-(methylsulfanyl)phenyl]-1-(1-methyl-1H-tetrazol-5-yl)methanimine (2.00 g, 6.90 mmol), in dry acetonitrile (115 mL) were added 4-(chloromethyl)-1,3-thiazol-2-amine (1.13 g, 7.59 mmol), cesium carbonate (4.72 g, 14.5 mmol) and potassium iodide (0.57 g, 3.45 mmol). The reaction mixture was stirred at room temperature for 26 h, then insolubles were removed by filtration and washed with dichloromethane (3×40 mL) and ethyl acetate (3×40 mL). The filtrates were combined and concentrated in vacuo. The residue was dissolved in dichloromethane (100 mL), washed with water (50 mL), the aqueous layer was extracted with dichloromethane (50 mL) and the combined organic layers were dried over MgSO4 and concentrated in vacuo to afford 4-{[({[3-(methylsulfanyl)phenyl](1-methyl-1H-tetrazol-5-yl)methylene}amino)oxy]methyl}-1,3-thiazol-2-amine [1.10 g, yield 42%; HPLC/MS: m/z=362 (M+H); logP(HCOOH)=1.76].
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[C:7]([C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Li+].[OH-].[Na+].Cl>C1COCC1.O.C(OCC)(=O)C.CO>[F:12][C:2]([F:1])([F:13])[C:3]1[N:8]=[C:7]([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1cccc(C(F)(F)F)n1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: OCc1cccc(C(F)(F)F)n1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 32.5 %

Procedure:
To a suspension of 6-trifluoromethylpyridine-2-carboxylic acid (2.53 g, 13.2 mmol) in THF (50 mL) cooled to −5° C. was added triethylamine (1.84 mL, 13.2 mmol) followed by addition of ethyl chloroformate (1.26 mL, 13.2 mmol) and the reaction mixture was stirred for 30 min at 0° C. Lithium borohydride (718 mg, 33 mmol) was added in portions, maintaining the temperature below −5° C. After the addition was complete, the reaction was allowed to warm to room temperature and stirred for 1 h. Temperature was lowered to −5° C. and methanol (10 mL) was added followed by addition of aqueous sodium hydroxide (10 mL, 10%). After the addition of ethyl acetate (50 mL) and water (40 mL), dilute hydrochloric acid was added to obtain pH=5.0. After washing aqueous layer thoroughly with ethyl acetate the combined organic extracts were dried over MgSO4 and concentrated. Purification by flash column (30% EtOAc-Hexane) gave (6-trifluoromethylpyridin-2-yl)methanol (760 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C[Al](C)C.[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][C:19]([C:25](OCC)=[O:26])=[C:18]2[OH:30].Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:25]([C:19]2[CH:20]=[N:21][C:22]3[C:17]([C:18]=2[OH:30])=[CH:16][C:15]([F:14])=[CH:24][CH:23]=3)=[O:26])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2ccc(F)cc2c1O
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(F)cc2c1O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a 0° C. solution of 4-chlorobenzylamine (0.52 mL) in 5 mL of toluene is added 2.13 mL of a 2.0 M solution of trimethylaluminum in tolune. The solution is stirred for 5 min at 0° C. and then a suspension of 0.50 g of ethyl 6-fluoro-4-hydroxy-3-quinolinecarboxylate (J. Amer. Chem. Soc., 69, 371 (1947)) in 5 mL of toluene is added. The solution is stirred at 0° C. for an additional 10 min and then it is stirred 18 h at 90° C. The mixture is cooled to 25° C. and it is poured onto a mixture of a large excess of 3 M hydrochloric acid and ice. After stirring the mixture vigorously for 30 min it is filtered. The solid is dissolved in 50 mL of warm glacial acetic acid and distilled water is added to the resulting solution until it is cloudy. The mixture is then allowed to stand for several hours at 5° C. Filtration of this mixture gives the desired amide as 390 mg of a solid.
Reaction SMILES: C[O:2][CH:3]=[CH:4][C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2(OCC[O:15]2)[CH2:6]1.Cl>O1CCCC1>[O:15]=[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][C@@H:5]([CH2:4][CH:3]=[O:2])[CH2:6]1
Reactant: COC=C[C@@H]1Cc2ccccc2C2(C1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: O=CC[C@H]1CC(=O)c2ccccc2C1
Reaction time: 16 h
Yield: 67.3 %

Procedure:
To a stirred solution of (R)-3′-(2-methoxyvinyl)-3′,4′-dihydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalene] (step-4) (3.5 g, 14.21 mmol) in tetrahydrofuran (20 mL) was added HCl (2.159 mL, 71.1 mmol) at 25° C. and reaction was stirred for 16 h. Reaction was monitored by TLC. After completion solvent was evaporated at reduced pressure. Crude obtained was purified by column chromatography (Biotage) using eluent 30% ethyl acetate/hexane to give (S)-2-(4-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)acetaldehyde (1.8 g, 9.56 mmol, 67.3% yield) as colourless sticky compound; GCMS 188.10.
Reaction SMILES: [C:1]([C:3]1([C:7]2[CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)#[N:2]>CCO.[Pd]>[C:1]([C:3]1([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)[CH2:4][CH2:5][CH2:6]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(C2(C#N)CCC2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C2(C#N)CCC2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.4 %

Procedure:
The solution of Example 265B (0.8 g, 3.2 mmol) in EtOH (15 mL) was hydrogenated in the presence of Pd/C (320 mg). The resulting mixture was stirred at room temperature for 12 hours. After the filtration to remove Pd/C, the filtrate was concentrated under reduced pressure to give title compound (780 mg, 92% yield) as a colorless oil, which was used in the next step without further purification. 1H NMR: (400 MHz, CDCl3): δ 3.68-3.38 (m, 2H), 3.33-3.03 (m, 2H), 2.77-2.33 (m, 3H), 2.26-2.12 (m, 2H), 1.90-1.62 (m, 4H), 1.49 (s, 9H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].Br[CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[C:21]#[N:22])[C:13]1=[O:23]>ClCCl>[C:21]([C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH2:20][CH:12]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:13]2=[O:23])#[N:22]
Reactant: CCOC(=O)c1ncc[nH]1
Reactant: N#Cc1cccc2c1CC(Br)C2=O
Solvent: ClCCl
Product: CCOC(=O)c1nccn1C1Cc2c(C#N)cccc2C1=O
Temperature: 130 °C
Yield: 35.3 %

Procedure:
Ethyl 1-[(4-cyano-1-oxoindan-2-yl)]imidazole-2-carboxylate can be obtained in the following way: a mixture of 3.92 g of ethyl imidazole-2-carboxylate and 3.4 g of 2-bromo-4-cyano-1-indanone is heated at 130° C. for 20 minutes, cooled to 20° C. and dissolved in 20 ml of dichloromethane. The mixture is then concentrated to dryness under reduced pressure (15 mm Hg; 2 kPa) at 40° C. The residue thus obtained is purified by flash chromatography on a silica column, under a nitrogen stream at medium pressure (0.5 bar), with a dichloromethane/methanol (95/5 by volume) mixture as eluent. 1.5 g of ethyl 1-[(4-cyano-1-oxoindan-2-yl)]imidazole-2-carboxylate are thus obtained, which product melts at 159° C.
Reaction SMILES: Cl[CH2:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12][C:13]([Cl:16])([Cl:15])[F:14])=[CH:4]1.[F:17][C:18]([F:27])([F:26])[CH2:19][CH2:20][CH:21]([C:24]#[N:25])[C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:15][C:13]([Cl:16])([F:14])[S:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:3]([CH2:2][C:21]([CH2:20][CH2:19][C:18]([F:17])([F:26])[F:27])([C:22]#[N:23])[C:24]#[N:25])[CH:4]=1
Reactant: FC(Cl)(Cl)Sc1cn(CCl)c2ccccc12
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cc(SC(F)(Cl)Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
0.61 g of 1-(chloromethyl)-3-{[dichlorofluoromethyl]thio}-1H-indole and 0.35 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 2 ml of N,N-dimethylformamide. 0.28g of potassium carbonate was added to the solution under ice cooling, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.65 g of [(3-{[dichlorofluoromethyl]thio}-1H-indole-1-yl) methyl](3,3, 3-trifluoropropyl) malononitrile (referred as the compound of the present invention (44), hereinafter) shown by below formula.