Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C1CCNC1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Solvent: CN(C)C=O
Product: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1N1CCCC1
Temperature: 150 °C
Yield: 18.7 %

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (0.010 g, 0.025 mmol) and pyrrolidine (0.03 ml, 0.4 mmol) were dissolved in DMF (1 ml) and heated in a sealed vial at 150° C. for 3 h. The excess amine and the solvent were removed under reduced pressure, and the solid residue was washed with CH3CN, giving the title product (0.002 g, 19%).
Reaction SMILES: [S:1]([CH2:4][C:5]([CH2:12][S:13]C#N)([CH2:8][S:9]C#N)[CH2:6][CH3:7])C#N.S1C=CSS1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH2:6]([C:5]([CH2:12][SH:13])([CH2:8][SH:9])[CH2:4][SH:1])[CH3:7]
Reactant: CCC(CSC#N)(CSC#N)CSC#N
Agent: C1=CSSS1
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CCC(CS)(CS)CS
Temperature: -5 °C

Procedure:
Compound 3 was converted to the trithiol by reduction with lithium aluminum hydride. Under N2, compound 3 (1.0 g, 3.9 mmol) and LiAlH4 (0.89 g, 23.4 mmol) were added to a 50 mL three necked round bottom flask. After the reaction was cooled to −5° C., cold ethyl ether (30 mL) was added by syringe while stirring. The reaction continued stir for 3 h at −5° C., brought to room temperature and stirred overnight. Upon return, grey solids were present. The reaction was cooled then quenched by the slow addition of saturated ammonium chloride (20 mL). Solids were removed via vacuum filtration, and 2 M HCl (20 mL) was added to the mother liquor. The product, 4, was extracted into ethyl ether (3×50 mL), dried over anhydrous Na2SO4, filtered, and taken to dryness to yield a light yellow oil, which crystallized upon cooling. Yield: 584 mg, 82%. 1H NMR (CDCl3; 500 MHz) δ ppm: 0.82 (t, 3H, CH3), 1.18 (t, 3H, SH), 1.46 (q, 2H, CCH2), 2.58 (d, 6H, SCH2). 13C NMR (CDCl3; 125.8 MHz) δ ppm: 7.85 (CH3), 25.10 (CCH2), 28.80 (SCH2), 41.66 (C). ESI-MS (m/z) 181.12 (181.03 calcd for [M−H]− of [C6H14S3]).
Reaction SMILES: Br[C:2]1[C:8](=[O:9])[C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20](Cl)=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1[C:31](=[O:32])C(N2CCNCC2)=CC=CC=1.ClC1C=CC(CBr)=CC=1>>[CH3:31][O:32][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:13]1[CH2:14][CH2:15][N:10]([C:7]2[C:8](=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][CH2:12]1
Reactant: O=c1c(Br)ccccc1N1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=c1c(Br)ccccc1N1CCNCC1
Agent: Clc1ccc(CBr)cc1
Product: COc1cccc(CN2CCN(c3cccccc3=O)CC2)c1

Procedure:
7-bromo-2-[4-(4-chlorobenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, from 7-bromo-2-(1-piperazinyl)-2,4,6-cycloheptatriene-1-one of example 2b and 4-chlorobenzyl bromide.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Cl:13][C:14]1[C:15]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:16]([NH:20][NH2:21])[N:17]=[N:18][CH:19]=1.O>C1COCC1>[Cl:13][C:14]1[CH:19]=[N:18][N:17]2[C:1](=[O:2])[NH:21][N:20]=[C:16]2[C:15]=1[C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1
Reactant: NNc1nncc(Cl)c1-c1ccc(Cl)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(Cl)cnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
To a solution of 1,1′-carbonyldiimidazole (1.78 g, 11 mmol) in THF (10 mL) at RT was added a suspension of 1-(5-chloro-4-(4-chlorophenyl)pyridazin-3-yl)hydrazine (560 mg, 2.19 mmol) in THF (10 mL). After addition, the reaction became a clear solution and was stirred at RT for 1 h. The reaction mixture was then poured into water and extracted with EtOAc (3×50 mL). The combined organic layers were washed with saturated NaCl. The organic layer was dried (Na2SO4), filtered and concentrated. To the obtained residue was added EtOAc (20 mL), and the resulting yellow precipitate was collected by filtration and washed with hexane to give the title compound, 7-chloro-8-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one as a yellow solid (300 mg, 61%). LC/MS (method A): RT=2.86 min, (M+H)+=281.
Reaction SMILES: [CH3:1][CH:2]([CH2:40][CH3:41])[CH:3]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:32](=[O:33])[CH2:31][O:30][C:29]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:28]2)=[CH:22][CH:21]=1)[C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH:10]([C:16]([O:18]C)=[O:17])[CH2:11]2)=[O:5].[OH-].[Na+]>C1COCC1>[CH3:1][CH:2]([CH2:40][CH3:41])[CH:3]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:32](=[O:33])[CH2:31][O:30][C:29]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[N:28]2)=[CH:22][CH:21]=1)[C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH:10]([C:16]([OH:18])=[O:17])[CH2:11]2)=[O:5]
Reactant: CCC(C)C(C(=O)Nc1cccc2c1CC(C(=O)OC)C2)c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC(C)C(C(=O)Nc1cccc2c1CC(C(=O)O)C2)c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1

Procedure:
A solution of 180 mg (0.31 mmol) of methyl 4-[(3-methyl-2-{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}pentanoyl)amino]-2,3-dihydro-1H-indene-2-carboxylate (Example 147A) in 3.6 ml of THF and 1.3 ml (1.3 mmol) of 1 N aqueous sodium hydroxide solution was stirred at room temperature overnight. After the reaction had gone to completion, the THF was removed under reduced pressure and the reaction solution was diluted with water and then adjusted to pH 2 with 1 M hydrochloric acid. The precipitated solid was filtered off, washed with water and dried under reduced pressure at 45° C. overnight. This gave 159 mg (0.29 mmol, 91% of theory) of the title compound as a mixture of isomers.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH:22](O)([CH3:24])[CH3:23]>>[CH:22]([O:20][C:19](=[O:21])[CH2:18][O:17][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:16][N:15]=1)([CH3:24])[CH3:23]
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: CC(C)O
Product: CC(C)OC(=O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Yield: 92 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using isopropanol (100 μL, 1.3 mmol) as the coupling partner. Concentration (no chromatography) yielded 52 mg (92%) of the titled compound.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=O)=[CH:12][CH:13]=2)[C:8]([Cl:17])=[N:7]1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41]2[S:42][CH2:43][C:44](=[O:46])[N:45]=2)[CH2:37][C@@H:36]1[CH2:47][OH:48])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41]2[S:42][C:43](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:18]=[CH:19][C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:3]=3[C:2]([F:26])([F:1])[F:27])[N:7]=[C:8]4[Cl:17])[C:44](=[O:46])[N:45]=2)[CH2:37][C@@H:36]1[CH2:47][OH:48])=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)CS2)C[C@@H]1CO
Reactant: O=Cc1ccc2c(c1)c(Cl)nn2Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(c3)c(Cl)nn4Cc3ccc(C(F)(F)F)cc3C(F)(F)F)S2)C[C@@H]1CO

Procedure:
4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-chloro-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 1-(2,4-Bis-trifluoromethyl-benzyl)-3-chloro-1H-indazole-5-carbaldehyde and 2-(R)-Hydroxymethyl-4-(4-oxo-4,5-dihydro-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester following general procedure D.
Reaction SMILES: O[C@@H:2]([CH3:35])[CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:13]=2)=[CH:10][CH:11]=1)=[O:6].CS(O)(=O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:33][O:32][CH2:31][C@H:30]([CH3:34])[O:29][C:14]1[CH:13]=[C:12]([C:9]2[NH:8][C:7]([C:5]3[O:6][C@H:2]([CH3:35])[CH2:3][N:4]=3)=[CH:11][CH:10]=2)[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][CH:20]=2)[CH:15]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NC[C@H](C)O)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NC[C@@H](C)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 56.4 %

Procedure:
N-[(2S)-2-Hydroxypropyl]-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxamide (285 mg, 0.567 mmol) synthesized in Example (33a) was dissolved in tetrahydrofuran (10 mL), and anhydrous methanesulfonic acid (130 mg, 0.746 mmol) and triethylamine (0.24 mL, 1.72 mmol) were added, followed by stirring at room temperature for 21 hours under nitrogen atmosphere. A saturated aqueous sodium hydrogencarbonate solution (10 mL) was added, and the solution was separated with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium 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%-70%) to afford the desired product (155 mg, yield 56%) as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]([O:10]C)=O.CO.[CH3:14][NH2:15]>>[CH3:14][NH:15][C:8](=[O:10])[CH2:7][CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCc1ccco1
Reactant: CN
Solvent: CO
Product: CNC(=O)CCc1ccco1

Procedure:
A solution of methyl 3-(furan-2-yl)propanate (4.0 g) in 40% methylamine methanol solution (50 ml) was stirred for 5 hours at room temperature. The solvent was removed under reduced pressure to afford N-methyl-3-(furan-2-yl)propanamide (4.0 g).
Reaction SMILES: C(O[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[CH:14]=2)[C:9]([OH:25])=[C:8]([C:26]([O:28][CH3:29])=[O:27])[N:7]=1)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>[Pd].C(OCC)(=O)C>[OH:25][C:9]1[C:10]2[C:15](=[CH:14][C:13]([O:16][C:17]3[CH:18]=[C:19]([F:24])[CH:20]=[C:21]([F:23])[CH:22]=3)=[CH:12][CH:11]=2)[C:6]([CH3:5])=[N:7][C:8]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)c1nc(COC(C)=O)c2cc(Oc3cc(F)cc(F)c3)ccc2c1O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(C)c2cc(Oc3cc(F)cc(F)c3)ccc2c1O
Temperature: 60 °C
Reaction time: 7 h

Procedure:
A glass lined Parr pressure reactor vessel equipped with a 4-blade impeller can be charged with 7c, Pd/C (about 0.4 to 0.5 molar equivalents), anhydrous Na2CO3 (about 0.5 molar equivalents), and ethyl acetate. The flask can then be vacuum-purged with nitrogen (3×) and vacuum-purged with hydrogen (3×). The flask can then be pressurized with hydrogen to set point 60 psi and stirred at 60° C. for 6-8 hrs until completion of reaction (7c <0.5%). The flask can then be cooled to 20-25° C., the pressure released to ambient, the head space purged with nitrogen three times and filtered through glass microfiber filter paper. The filtrate can be concentrated and precipitated from cold methanol and dried under vacuum at 50±5° C.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[CH:16]=O)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][CH:18]=[C:15]([CH2:16][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH:14]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: O=Cc1cccc(N2CCC(CN3CCCC3)CC2)c1
Product: c1cc(CN2CCCC2)cc(N2CCC(CN3CCCC3)CC2)c1

Procedure:
Prepared from the product of Example 20 and pyrrolidine.
Reaction SMILES: Cl.[F:2][C:3]([F:17])([F:16])[C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.[C:18]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:19]([CH:24]=O)=[CH:20][CH:21]=[CH:22][CH:23]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:18]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][N:13]1[CH2:14][CH2:15][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([F:2])([F:16])[F:17])[CH:5]=2)[CH2:11][CH2:12]1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: O=Cc1ccccc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: FC(F)(F)c1cccc(N2CCN(Cc3ccccc3-c3ccccc3)CC2)c1

Procedure:
19.2 mg of the target compound (0.05 mmol, 5.6%) was obtained using 1-(3-trifluoromethylphenyl)piperazine hydrochloride (437 mg, 1.64 mmol), biphenyl-2-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[N:15]=1.C[O:22][B:23](OC)[O:24]C.Cl>C1COCC1>[F:13][C:14]1[C:19]([B:23]([OH:24])[OH:22])=[CH:18][CH:17]=[C:16]([F:20])[N:15]=1
Reactant: COB(OC)OC
Reactant: Fc1cccc(F)n1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OB(O)c1ccc(F)nc1F

Procedure:
0,6 M of n-butyllithium are added at -10° to 0,6 M of diisopropylamin in 600 ml THF. The mixture is cooled to -70°, 0,6 M of 2,6-difluoropyridin are added and after stirring for 15 minutes 0,6 M of trimethylborate are added at the same temperature. The mixture is allowed to warm up to -30°. Then the borate ester is hydrolysed with dilute HCl, the product extracted with ether, washed, dried and the solvent removed. Thus, 2,6-difluoro-pyridine-3-boronic acid is obtained.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:18](=[O:26])[C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:34][CH2:35][CH3:36])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:27]([N:17]([C:18](=[O:26])[C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:15]1[CH:14]=[CH:13][C:12]2[N:8]([CH2:7][C:6]([OH:37])=[O:5])[C:9]([CH2:34][CH2:35][CH3:36])=[N:10][C:11]=2[CH:16]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3ccc(Cl)cc3)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3ccc(Cl)cc3)ccc2n1CC(=O)O

Procedure:
{5-[Benzyl-(4-chloro-benzoyl)-amino]-2-propyl-benzoimidazol-1-yl}-acetic acid tert-butyl ester (0.12 mmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. MS calculated for C26H24ClN3O3+H: 462, observed: 462.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2([C:17]#[N:18])[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+]>C(O)(=O)C.O.[Cl-].[Na+].O>[O:11]=[C:10]1[CH2:15][CH2:16][C:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)([C:17]#[N:18])[CH2:8][CH2:9]1
Reactant: N#CC1(C2CCOCC2)CCC2(CC1)OCCO2
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#CC1(C2CCOCC2)CCC(=O)CC1
Temperature: 100 °C
Yield: 70.4 %

Procedure:
A solution of 10.3 g (40.8 mmol) of 8-(tetrahydropyran-4-yl)-1,4-dioxa-spiro[4.5]decane-8-carbonitrile (5) in a mixture of 90 mL of acetic acid and 18 mL of water was heated at 100° C. for 24 h. The mixture was cooled to room temperature and slowly poured onto 1.2 L of cold saturated aqueous sodium bicarbonate solution. The mixture was diluted with 600 mL of brine and extracted six times with methyl-tert-butyl ether. The combined organic phases were washed with water and brine, dried over magnesium sulphate, filtered and concentrated in vacuo. The residue was lyophilized from acetonitrile and water, taken up in water and lyophilized again to give 5.95 g of the ketone, which was used directly in the next step. Rt=0.82 min (Method O). Detected mass: 208.1 (M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([NH:11][C:12]1[CH:13]=[C:14]([NH:18][C:19]2[CH:31]=[C:30]([CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:29]=[CH:28][C:20]=2[C:21]([O:23]C(C)(C)C)=[O:22])[CH:15]=[CH:16][CH:17]=1)(=[O:10])[CH3:9]>>[C:8]([NH:11][C:12]1[CH:13]=[C:14]([NH:18][C:19]2[CH:31]=[C:30]([CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:29]=[CH:28][C:20]=2[C:21]([OH:23])=[O:22])[CH:15]=[CH:16][CH:17]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)Nc1cccc(Nc2cc(CCc3ccccc3)ccc2C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cccc(Nc2cc(CCc3ccccc3)ccc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid 7.5 mL was added to the obtained tert-butyl 2-((3-(acetamido)phenyl)amino)-4-phenethylbenzoate, and it was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure,diisopropyl ether was added to the obtained residue, and solid matter was filtrated to give 2-((3-(acetamido)phenyl)amino)-4-phenethylbenzoic acid 0.12 g of a white solid.
Reaction SMILES: CO.CS(O)(=O)=O.C(OC([NH:18][CH2:19][C:20]1[CH:41]=[CH:40][C:23]([C:24]([O:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([C:37](=[NH:39])[NH2:38])[CH:33]=3)[CH:28]=2)=[O:25])=[CH:22][CH:21]=1)=O)C1C=CC=CC=1.CS(O)(=O)=O.[H][H]>[Pd].CN(C=O)C>[NH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([C:37](=[NH:38])[NH2:39])[CH:33]=3)[CH:28]=2)=[O:25])=[CH:40][CH:41]=1
Reactant: [H][H]
Reactant: N=C(N)c1ccc2cc(OC(=O)c3ccc(CNC(=O)OCc4ccccc4)cc3)ccc2c1
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CN(C)C=O
Solvent: CO
Product: N=C(N)c1ccc2cc(OC(=O)c3ccc(CN)cc3)ccc2c1
Reaction time: 3 h
Yield: 103.3 %

Procedure:
To a solvent mixture comprising100 ml of methanol and 20 ml of DMF, were added 5.0 g 6-amidino-2-naphthyl 4-benzyloxycarbonylaminomethylbenzoate methanesulfonate, 1.0 g of 10% Pd-C and 1.1 g of methanesulfonic acid. Hydrogen was introduced into the mixture with vigorous stirring for 3 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to about half the volume. Ethyl ether was added to the concentrate and the precipitated crystals were collected by filtration to obtain 3.0 g of a white powder of 6-amidino-2-naphthyl 4-aminomethylbenzoate dimethanesulfonate.
Reaction SMILES: C[Si](C#N)(C)C.C(=O)C1C=CC=CC=1.[C:15]([CH:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)#[N:16]>ClCCl.[Ti]>[C:15]([C@H:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)#[N:16]
Reactant: N#CC(O)c1ccccc1
Agent: [Ti]
Agent: C[Si](C)(C)C#N
Solvent: O=Cc1ccccc1
Solvent: ClCCl
Product: N#C[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
To a solution of L(+)-diisopropyl tartarate (235 mg) in absolute dichloromethane (10 ml), tetaraisopropyl titanate (284 mg) was dropwise added and stirred at room temperature for 30 minutes. After evaporating volatile components off in the same manner as in Example 1, dichloromethane (10 ml) was added to the residue and stirred at room temperature to obtain a homogeneous solution. To the resulting solution, trimethylsilylcyanide (436 mg) and then benzaldehyde (424 mg) were added and stirred at room temperature for 15 hours. Thereafter, the reaction mixture was treated in the same manner as in Example 1 and analyzed by HPLC to reveal that α-cyanobenzyl alcohol containing the R(+) isomer in the enantiomer excess percentage of 88% was produced in the yield of 37% based on the amount of the used benzaldehyde and 148% based on the amount of the used catalyst.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH:33]1([CH2:36][NH2:37])[CH2:35][CH2:34]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH:33]1([CH2:36][NH:37][C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:32])[F:31])=[CH:4][CH:5]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:30])[CH2:35][CH2:34]1
Reactant: NCC1CC1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1CC1)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with cyclopropylmethylamine (29 mg, 0.27 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to afford 101 mg of the title compound as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21](CN4CCOCC4)=[CH:20][CH:19]=3)[NH:15][C:12]2=[N:13][CH:14]=1.NC1[C:48]([NH2:49])=[C:47]([NH:50][C@@H:51]2[C@@H:56]3C[C@@H](C=C3)[C@@H]2C(N)=O)C(Cl)=CN=1.C(OC(N1CCN(C2C=CC(C=O)=CC=2)CC1)=O)(C)(C)C.C(=O)(OC(C)(C)C)N.Cl>O1CCOCC1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([N:49]4[CH2:48][CH2:47][NH:50][CH2:51][CH2:56]4)=[CH:22][CH:23]=3)[NH:15][C:12]2=[N:13][CH:14]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Agent: CC(C)(C)OC(N)=O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(N5CCNCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 43 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 4-(4-Formyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester were reacted to produce an initial tert-butyl carbamate condensation product. This material was treated with 4N hydrochloric acid in dioxane at 40° C. overnight. Concentration followed by reverse phase chromatography on a Gilson chromatograph afforded fractions which were lyophilized to afford the title compound (43%). 1H NMR (d6-DMSO): 13.19 (br s, 1H), 8.77 (m, 2H), 8.04 (s, 1H), 8.02 (s, 1H), 7.95 (s, 1H), 7.78 (s, 1H), 7.13-7.45 (m, 4H), 6.38 (m, 2H), 5.17 (t, J=8 Hz, 1H), 3.49 (m, 4H), 3.26 (m, 4H), 2.91 (s, 1H), 2.80 (s, 1H), 2.62 (d, J=8 Hz, 1H), 2.23 (d, J=9 Hz, 1H), 1.40 (d, J=9 Hz, 1H). MS: 465.09 (M+H). HPLC retention time: 1.79 minutes (G Method).