Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[CH2:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:2]([CH3:4])[CH3:3].CO.O1CCCC1.[BH4-].[Na+]>C(OCC)(=O)C>[CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][C:7]=1[CH2:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COc1ccc(C=O)cc1Cn1c(-c2ccccc2)cc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)COc1ccc(CO)cc1Cn1c(-c2ccccc2)cc2ccccc21
Temperature: 0 °C
Yield: 99.8 %

Procedure:
To a mixture of 4-isobutoxy-3-[(2-phenyl-1H-indol-1-yl)methyl]benzaldehyde (0.6 g, 1.56 mmol), methanol (3 mL) and tetrahydrofuran (6 mL) was added sodium borohydride (30 mg, 0.78 mmol) with stirring at 0° C., and the mixture was stirred at the same temperature for 1.5 hr. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, and the mixture washed with 5% aqueous potassium hydrogensulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=1/1) to give the title compound (0.60 g, yield 99%) as a colorless oil. 1H NMR (CDCl3) δ: 1.00 (6H, d, J=6.6 Hz), 1.37 (1H, t, J=6.0 Hz), 2.09 (1H, m), 3.79 (2H, d, J=6.6 Hz), 4.40 (2H, d, J=6.0 Hz), 5.36 (2H, s), 6.62 (1H, d, J=1.8 Hz), 6.68 (1H, s), 6.88 (1H, d, J=8.1 Hz), 7.10-7.18 (3H, m), 7.23 (1H, d, J=2.1, 8.4 Hz), 7.29-7.48 (5H, m), 7.68 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][CH2:13][CH3:14])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[F:15][B-:16]([F:19])([F:18])[F:17].[CH2:20]([O+](CC)CC)[CH3:21]>>[F:15][B-:16]([F:19])([F:18])[F:17].[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][CH2:13][CH3:14])=[C:6]([CH:10]=1)[C:7](=[NH:9])[O:8][CH2:20][CH3:21]
Reactant: CC[O+](CC)CC
Reactant: CCCOc1ccc(F)cc1C(N)=O
Agent: F[B-](F)(F)F
Product: CCCOc1ccc(F)cc1C(=N)OCC

Procedure:
reaction of 5-fluoro-2-propoxybenzamide (16.40 g) with triethyloxonium tetrafluoroborate yielded ethyl 5-fluoro-2-propoxybenzimidate tetrafluoroborate which on reaction with a saturated solution of ethanolic ammonia yielded 5-fluoro-2-propoxybenzamidine (8.40 g);
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][N:6]([CH2:13]P(O)=O)[C:7](=[O:12])[C:8]([F:11])([F:10])[F:9])C.[P:18]([Cl:21])(Cl)[Cl:19].[CH:22]1C=CC=C[CH:23]=1>>[CH2:22]([CH:5]([C:4]([OH:3])=[O:17])[N:6]([C:7](=[O:12])[C:8]([F:9])([F:10])[F:11])[CH2:13][P:18]([Cl:21])[Cl:19])[CH3:23]
Reactant: ClP(Cl)Cl
Reactant: CCOC(=O)CN(C[PH](=O)O)C(=O)C(F)(F)F
Reactant: c1ccccc1
Product: CCC(C(=O)O)N(CP(Cl)Cl)C(=O)C(F)(F)F

Procedure:
Ethyl-N-(hydroxyphosphinylmethyl)-N-(trifluoroacetyl)glycinate (2.8 g.) was dissolved in benzene and added dropwise to excess phosphorus trichloride with stirring. The solution was filtered and the supernatant liquid decanted and evaporated under vacuum to yield ethyl-N-(trifluoroacetyl)-N-[bis(chloro)phosphinomethyl]glycine as a clear oil. The clear oil was dissolved in tetrahydrofuran and a solution of methane thiol (0.96 g.) and triethylamine (2.05 g.) dissolved in tetrahydrofuran added with stirring. After stirring for an additional one hour, sulfur (0.32 g.) was added and the solution stirred overnight. The reaction mixture was then filtered and the solvent removed under vacuum. The residue was chromatographed on silica gel employing dichloromethane to yield ethyl-N-(trifluoroacetyl)-N-[bis(methanethio)phosphinothioylmethyl]glycine as an oil, ND25 =1.5132 and having the following analysis.
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]3[CH:25]=[CH:26][CH:27]=[C:17]3[CH2:16]2)=[O:14])=[CH:9][CH:8]=1)=[O:5].[Cl:32]N1C(=O)CCC1=O>O1CCCC1>[CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]3[C:25]([Cl:32])=[CH:26][CH:27]=[C:17]3[CH2:16]2)=[O:14])=[CH:11][CH:12]=1)=[O:5]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3-c3ccccc32)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccc(Cl)n3-c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To an ice-water cooled suspension of 5 mmol of 2-methyl-N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)-phenyl]benzamide in 5 ml of tetrahydrofuran is added 5.5 mmol of N-chlorosuccinimide followed by continued stirring in the cold for 10 minutes. The bath is removed and stirring continued for 2.25 hours. The reaction mixture is added to ice-water and extracted with ether. The organic layer is dried and concentrated in vacuo to give the desired product as a solid.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH3:11][NH2:12].C(O)(=O)C.[BH4-].[Na+]>CO>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:1][NH:12][CH3:11]
Reactant: CN
Reactant: COc1ccccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1ccccc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.7 %

Procedure:
To a solution of 2-anisaldehyde (5.56 g, 40 mmol) in methanol (40 mL) was added methylamine (40 wt % solution in water, 6.9 mL, 80 mol) and acetic acid (240 mg, 4 mmol). The reaction mixture was stirred at room temperature for 16 hours and then cooled in an ice bath. To this ice-cooled mixture was added sodium borohydride (1.51 g, 40 mmol) in portions. The reaction mixture was stirred at room temperature for 3 hours. Most of the solvent was removed under the reduced pressure. The residue was diluted with water (100 mL) and ethyl acetate (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate twice. The combined extracts were washed with brine, dried over sodium sulfate and concentrated to provide the desired 2-methoxybenzyl methylamine (4.7 g, 79%): 1H NMR (CDCl3, 500 MHz) δ 7.23 (d, J=7.4 Hz, 2H), 6.91 (t, J=7.4 Hz, 1H), 6.86 (d, J=7.9 Hz, 1H), 3.83 (s, 3H), 3.75 (s, 2H), 2.42 (s, 3H); ESI MS m/Z=152 [M+H]+. This crude product was used in the next step without further purification.
Reaction SMILES: C([C:4]1[C:8](C)=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:6][C:5]=1[NH:16][C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18])(O)=O.[Li]I.O.O.C1(C(O)=O)CCCCC1>N1C(C)=CC(C)=CC=1C>[C:10]1([C:7]2[S:6][C:5]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[O:18])=[CH:4][CH:8]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1c(-c2ccccc2)sc(NC(=O)C2CCCCC2)c1C(=O)O
Agent: [Li]I
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Solvent: O=C(O)C1CCCCC1
Product: O=C(Nc1ccc(-c2ccccc2)s1)C1CCCCC1

Procedure:
This compound (m.p. 174° C.) was prepared from N-(3-carboxy-methyl-5-phenyl-2-thienyl)-cyclohexane carboxamide (31.1 g, 0.1 mole) and LiI.2H2O (48.1 g, 0.32 mole) by refluxing in collidine (125 ml.) according to the procedure of Example 53 (a). This compound was also prepared according to the procedure of Example 53(b), using cyclohexane carboxylic acid as the acylating agent. The products of the two processes were spectrally identical and had a melting point of 175° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([S:9]([F:12])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.Cl.[N:14]([O-])=O.[Na+].[Cl:18][C:19]1[C:20]([OH:27])=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[O:23]>O.N1C=CC=CC=1>[Cl:18][C:19]1[C:20]([OH:27])=[C:21]([CH:24]=[C:25]([N:14]=[N:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([S:9]([F:12])(=[O:11])=[O:10])[CH:4]=2)[CH:26]=1)[CH:22]=[O:23]
Reactant: O=N[O-]
Reactant: Nc1cccc(S(=O)(=O)F)c1
Reactant: O=Cc1cccc(Cl)c1O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: O=Cc1cc(N=Nc2cccc(S(=O)(=O)F)c2)cc(Cl)c1O
Temperature: 0 °C
Reaction time: 72 h

Procedure:
m-Aminobenzenesulfonyl fluoride hydrochloride (21.1 g, 0.099 mol) was slurried in hot 10% HCl (300 ml) and then cooled to 0° C. Sodium nitrite (7.0 g, 0.1 mol) was dissolved in 30 ml water and added dropwise to the acidic solution. Vigorous stirring was required to prevent the slurry from coagulating. The diazonium slurry was then added slowly to 500 ml of pyridine containing 3-chloro-2-hydroxy-benzaldehyde (16.0 g, 0.10 mol) at 0° C. The mixture was stirred 30 minutes and then slowly added to 1500 ml ice and hydrochloric acid. The resulting precipitate coagulated into one lump. The liquid was decanted off and the remaining tarry solid crushed and slurried in 50% HCl. The resulting solid was filtered off, washed with water and air dried, (21.1 g). Upon standing 72 hours, the decanted solution yielded an additional 2.8 g. Yield: 23.8 g (70%).
Reaction SMILES: [Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O[K])(C)(C)C.[CH2:30]([CH2:33][O:34][CH3:35])OC.C1(C)C=CC=CC=1.[CH3:43][C:44]1[N:49]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=2)[C:48](=[O:60])[N:47]([C@H:61](C)[CH:62]=O)[C:46](=[O:65])[C:45]=1[C:66]1[N:70]([C:71]2[CH:78]=[CH:77][C:74]([C:75]#[N:76])=[CH:73][CH:72]=2)[N:69]=[CH:68][CH:67]=1>C(OCC)(=O)C.O>[CH3:35][O:34][CH:33]=[CH:30][C@H:61]([N:47]1[C:46](=[O:65])[C:45]([C:66]2[N:70]([C:71]3[CH:72]=[CH:73][C:74]([C:75]#[N:76])=[CH:77][CH:78]=3)[N:69]=[CH:68][CH:67]=2)=[C:44]([CH3:43])[N:49]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:59])([F:57])[F:58])[CH:51]=2)[C:48]1=[O:60])[CH3:62]
Reactant: COCCOC
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n([C@H](C)C=O)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: CC(C)(C)O[K]
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COC=C[C@@H](C)n1c(=O)c(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
To (methoxymethyl)triphenylphoshonium chloride (1.74 g) and tertiary-butoxy potassium (853 mg) was added at 0° C. glyme/toluene (10 ml/10 ml) and the resulting mixture was stirred for fifteen minutes. To the reaction mixture was added at 0° C. (R)-4-(5-(6-methyl-2,4-dioxo-3-(1-oxopropane-2-yl)-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 373) (500 mg) and the resulting mixture was stirred at room temperature for fifteen hours. To the reaction mixture was added water (20 ml) followed by an addition of ethyl acetate (30 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford (R)-4-(5-(3-(4-methoxy-3-buten-2-yl)-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (350 mg). UPLC/MS 522 (M+H)/1.00 min. (measurement condition 9)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][NH:20][CH3:21])=[C:13]([C:22]([F:25])([F:24])[F:23])[CH:12]=3)[N:7]=[C:6]([C:26]#[N:27])[C:5]=2[N:4]=[CH:3]1.CCN(C(C)C)C(C)C.[C:37](Cl)(=[O:40])[CH2:38][CH3:39]>C1COCC1>[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]([C:37](=[O:40])[CH2:38][CH3:39])[CH3:21])=[C:13]([C:22]([F:23])([F:25])[F:24])[CH:12]=3)[N:7]=[C:6]([C:26]#[N:27])[C:5]=2[N:4]=[CH:3]1
Reactant: CCC(=O)Cl
Reactant: CNCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(=O)N(C)CCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-methyl-6-(4-(2-(methylamino)ethoxy)-3-(trifluoromethyl)-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (0.053 mmol, 20 mg) in THF (1 mL) was added DIPEA (0.266 mmol, 47 μL) and propionyl chloride (0.16 mmol, 15 mg). The mixture was stirred at r.t. for 16 h and the product was then purified by HPLC to give 1-methyl-6-(4-(2-(N-propionyl-N-methylamino)ethoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile. 1H NMR (CD3OD) δ: 8.37-8.46 (m, 4H), 7.31 (d, 1H), 4.31-4.37 (m, 2H), 3.90 (s, 3H), 3.82-3.90 (m, 2H), 3.01, 3.30 (2xs, 3H), 2.42-2.58 (m, 2H), 1.10-1.15 (m, 3H). MS m/z 432 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]([F:29])([F:28])[F:27])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:15](O)=[O:16])[C:10](=[O:25])[CH:9]=2)[CH:7]=1.[NH2:30][C:31]1[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]([F:27])([F:29])[F:28])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:15]([NH:30][C:31]3[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[CH:33][CH:32]=3)=[O:16])[C:10](=[O:25])[CH:9]=2)[CH:7]=1
Reactant: O=C(O)C(Cc1ccncc1)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)C(Cc2ccncc2)n2ccc(-c3cc(Cl)ccc3C(F)(F)F)cc2=O)cc1

Procedure:
626 mg (purity 50%, 0.74 mmol) of 2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-4-yl)propanoic acid (racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 155 mg (purity 94%, 33% of theory)
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[N:19]=[C:18]([C:28]([N:30]3[CH2:34][C:33](=[O:35])[NH:32][CH2:31]3)=[O:29])[CH:17]=2)[CH:11]=1)(=O)=O.[CH3:36][NH:37][CH3:38].[O:39]1CCCC1>C(O)C>[CH:33]([OH:35])=[O:39].[Cl:27][C:23]1[CH:22]=[C:21]([N:20]2[C:16]([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:37]([CH3:38])[CH3:36])[CH:11]=3)=[CH:17][C:18]([C:28]([N:30]3[CH2:34][C:33](=[O:35])[NH:32][CH2:31]3)=[O:29])=[N:19]2)[CH:26]=[CH:25][CH:24]=1
Reactant: CNC
Reactant: C1CCOC1
Reactant: CS(=O)(=O)OCCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Solvent: CCO
Product: CN(C)CCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Product: O=CO

Procedure:
49.6 mg (0.096 mmol) of the compound of Example 120A and 0.48 ml (0.96 mmol) of a 2M solution of dimethylamine in tetrahydrofuran are stirred in 3 ml of ethanol at 80° C. overnight. The reaction mixture is subsequently purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with the addition of 0.1% formic acid). 6.2 mg (23% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:41](=[NH:43])[NH2:42])[CH:37]=2)[CH:32]=1)(=O)=O.C(OCC)C>N1C=CC=CC=1>[C:1]1([CH2:7][C:8]([O:10][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([C:41](=[NH:42])[NH2:43])[CH:37]=3)[CH:32]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Solvent: c1ccncc1
Product: N=C(N)c1ccc2cc(OC(=O)Cc3ccccc3)ccc2c1
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
To a solution of 2.4 g of phenylacetic acid in 50 ml of anhydrous pyridine, while being cooled and stirred, was added 4.4 g of DCC. After 30 minutes, to the mixture was added 5.0 g of 6-amidino-2-naphthol methanesulfonate. The mixture was stirred at room temperature for 24 hours, mixed with ethyl ether, and the precipitate was collected by filtration. The precipitate was dissolved in DMF and the insolubles were filtered off. The filtrate containing the DMF-soluble substances was mixed with ethyl ether, the resulting precipitate was collected by filtration and recrystallized from a mixture of DMF and ethyl ether to obtain 3.0 g of a white powder of 6-amidino-2-naphthyl phenylacetate methanesulfonate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:15][C:16]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:17]=1[NH2:18].O>C1COCC1>[F:15][C:16]1[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:19][C:17]=1[NH:18][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Nc1cc(C(F)(F)F)ccc1F
Reactant: O=[N+]([O-])c1cccc2c(Cl)ncnc12
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cccc2c(Nc3cc(C(F)(F)F)ccc3F)ncnc12
Yield: 98.6 %

Procedure:
A solution of 4-chloro-8-nitroquinazoline (Intermediate-7, step-2, 150 mg, 0.72 mmol) and 2-fluoro-5-(trifluoromethyl)aniline (387 mg, 2.16 mmol) in THF (4 mL) was heated at 50° C. for 2 h. Then water was added to the reaction mixture and it was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 250 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 10.46 (s, 1H), 8.74-8.71 (d, J=8.7 Hz, 1H), 8.63 (s, 1H), 8.43-8.40 (d, J=7.2 Hz, 1H), 8.01 (d, 1H), 7.86-7.81 (m, 2H), 7.66-7.63 (t, J=9.3 Hz, 1H); MS [M+H]+: 353.14.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:21]C)[CH:19]=4)[CH2:14][CH2:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.B(Br)(Br)Br.CO.C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([OH:21])[CH:19]=4)[CH2:14][CH2:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CC1)=NCC2
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Oc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CC1)=NCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-[1-(4-chlorophenyl)cyclopropyl]-7-methoxy-3,4-dihydroisoquinoline (700 mg, 2.2 mmol) in methylenehloride (10 ml) under nitrogen was cooled to −78° C. Borontribromide (BBr3, 4.2 ml 1M in methyleneloride, 4.2 mmol) was added dropwise. The reaction was allowed to warm up to room temperature and stirred overnight. Methanol was added (5 ml) and the resulting mixture poured into water neutralized with 1M sodiumbi-carbonate and extracted consecutively with methylenehloride and water. The organic layer was dried (Na2SO4), the solvents removed and the black residue purified by chromatography. Yield: 320 mg, (1.1 mmol, 48%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C@H:13]([O:28][C:29](=O)[CH2:30][C@H:31]([OH:40])[C:32]([CH3:39])([CH3:38])/[C:33](/[CH2:36][CH3:37])=[CH:34]/[CH3:35])[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[OH:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)C>[C:22]1([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:15])[C@H:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[OH:28])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1.[CH3:39][C:32]([CH3:38])(/[C:33](/[CH2:36][CH3:37])=[CH:34]/[CH3:35])[C@@H:31]([OH:40])[CH2:30][CH2:29][OH:28]
Reactant: C/C=C(\CC)C(C)(C)[C@@H](O)CC(=O)O[C@@H](c1ccccc1)C(O)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C/C=C(\CC)C(C)(C)[C@@H](O)CCO
Product: O[C@@H](c1ccccc1)C(O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %
Yield: 99 %

Procedure:
Lithium aluminium hydnde (1.325 g, 35.0 mmol, 7.0 equiv) is added portionwise to a refluxing solution of (1S)-2,2,1-triphenyl-2-hydroxyethyl (3S,E)-4,4-dimethyl-5-ethyl-3-hydroxy-5-heptenoate 26 (2.364 g, 5.0 mmol) in diethyl ether (50 ml) within a period of 2 h. Refluxing is continued for 30 min. After cooling to 0° C., the reaction is quenched dropwise with 1.35 ml water and 1.35 ml of aqueous NaOH (15%). Diethyl ether (40 ml) and water (2.0 ml) is added. The mixture is stirred for 1 h at r.t. until a white precipitate forms which is filtered off by suction through a small plug of celite. The precipitate is washed with diethyl ether (4×40 ml). The filtrate and the washings are combined and concentrated in vacua. Purification of the residue by flash column chromatography (pentane/diethyl ether 2:1) affords (S)-2,2,1-Triphenyl-ethane-1,2-diol (922 mg, 99%) as a colourless, crystalline solid and (S)-(E)-4,4-Dimethyl-5-ethyl-5-heptene-1,3-diol 28 (836 mg, 90%) as a colourless oil. 13C-NMR (100 MHz, CDCl3): δ=146.2; 121.1; 75.8; 62.6; 44.4; 32.7; 22.8; 21.1; 20.1; 14.3; 13.6
Reaction SMILES: Cl[Ni:2]Cl.[C:4]([OH:23])(=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[OH-].[Na+]>CO>[C:4]([O-:23])(=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[Ni+2:2].[C:4]([O-:23])(=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: Cl[Ni]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Product: [Ni+2]
Reaction time: 1 h

Procedure:
1.30 g of NiCl2 was dissolved in 100 mL of methanol, and then 5.5 mL oleic acid was added. A NaOH solution with 0.8 g of NaOH in 200 mL of methanol was dropped into the solution under magnetic stirring conditions. The reaction was carried out for one hour. The observed green precipitate of Ni (II) oleate was extracted with hexane. The solvents were removed under vacuum overnight.
Reaction SMILES: [NH2:1][P:2]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[OH:3].[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)C.Cl>O>[CH2:13]([O:20][C:21]([NH:1][P:2]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:3])[OH:4])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NP(=O)(O)CCc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: O=C(NP(=O)(O)CCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Compound 2 (1.1 g, 6 mmole) is dissolved in 10 ml of water and then the pH of this solution is adjusted to 9.5 with the aid of a 4N soda solution. To this mixture cooled in an icebath is gently added benzylchloroformate (1.2 ml, 7.5 mmole), whilst maintaining the pH of the reaction at 9.5 by successive soda additions. Stirring of the reaction mixture is maintained at 0° C. for 30 min. and then for 1 h at ambient temperature. After diethyl ether treatment, the mixture is cooled, and then acidified by the addition of hydrochloric acid. The product which precipitates is filtered, washed with cold water and dried. The expected compound 3 is obtained with a 76% yield (1.5 g), RF(1)=0.57, RF(2)=0.76, m.p. 110° C.
Reaction SMILES: O[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])=[C:7]([CH3:13])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:18][C:19]1[O:20][C:21](C)=[N:22][N:23]=1.CN(C)[CH:27]=[O:28]>>[CH3:13][C:7]1[C:8](=[O:12])[O:9][C:10]2[C:5]([C:6]=1[CH3:14])=[C:4]([O:28][CH3:27])[CH:3]=[C:2]([C:21]1[O:20][C:19]([CH3:18])=[N:23][N:22]=1)[CH:11]=2
Reactant: Cc1c(C)c2ccc(O)cc2oc1=O
Reactant: Cc1nnc(CCl)o1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COc1cc(-c2nnc(C)o2)cc2oc(=O)c(C)c(C)c12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
5.0 g of 7-hydroxy-3,4-dimethylcoumarin in 20 ml of diemthylformamide were added dropwise to a suspension of 0.9 g of NaH (80%) in 50 ml of dimethylformamide at room temperature. After 45 minutes, 3.5 g of 2-chloromethyl-5-methyl-1,3,4-oxadiazole, dissolved in 20 ml of dimethylformamide, were added and the mixture was stirred overnight at room temperature. The reaction solution was hydrolyzed with ice water, and the precipitated solid was filtered off under suction and recrystallized from methanol.