Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]#[C:5][CH2:6][CH3:7].Cl[C:10]1[CH:15]=[C:14]([N:16]2[CH2:21][CH:20]([CH3:22])[CH2:19][CH:18]([CH3:23])[CH2:17]2)[N:13]=[CH:12][N:11]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:23][CH:18]1[CH2:19][CH:20]([CH3:22])[CH2:21][N:16]([C:14]2[CH:15]=[C:10]([O:8][CH2:3][C:4]#[C:5][CH2:6][CH3:7])[N:11]=[CH:12][N:13]=2)[CH2:17]1
Reactant: CCC#CCO
Reactant: CC1CC(C)CN(c2cc(Cl)ncn2)C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC#CCOc1cc(N2CC(C)CC(C)C2)ncn1
Reaction time: 0.17 h
Yield: 41.3 %

Procedure:
0.07 g of sodium hydride (60% oil suspension) was suspended in 2 ml of tetrahydrofuran. 0.5 ml of tetrahydrofuran solution of 0.13 g of 2-pentyn-1-ol was added dropwise at 0° C. therein, and the mixture was stirred for 10 minutes. Into the mixture was added dropwise 0.5 ml of tetrahydrofuran solution of 0.3 g of 4-chloro-6-(3,5-dimethylpiperidino) pyrimidine obtained the Reference Production Example 6, and stirred for 6 hours at room temperature. Into the reaction mixture was added a saturated ammonium chloride aqueous solution, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.15 g of 4-(3,5-dimethylpiperidino)-6-(2-pentynyloxy)pyrimidine (hereinafter, referred to as Compound (15)). Compound (15) had the cis/trans diastereomer originated two methyls on the pyperidine ring. The ratio of the cis/trans diastereomer was about 8.2/1.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=CC=2O)C=CC=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=1>CN1CCCC1=O.[Cu-]=O.C1(C)C=CC=CC=1>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([N:10]2[CH:11]=[CH:12][C:8]([N:3]3[C:2]([CH3:1])=[CH:6][CH:5]=[C:4]3[CH3:7])=[N:9]2)=[CH:33][CH:32]=1
Reactant: Clc1ccc(I)cc1
Reactant: Cc1ccc(C)n1-c1cc[nH]n1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccn(-c2ccc(Cl)cc2)n1
Temperature: 110 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
Under argon atmosphere, to a solution of 3-(2,5-dimethylpyrrol-1-yl)-1H-pyrazole (3.06 g) prepared according to the same procedures as Preparation 4 in N-methylpyrrolidone (31 ml) were sequentially added cesium carbonate (12.37 g), 8-quinolinol (0.55 g), copper (I) oxide (0.27 g) and 1-chloro-4-iodobenzene (6.79 g) at room temperature, the mixture was stirred at 110° C. for 2 hours. This reaction mixture was cooled to room temperature, and then toluene (30 ml) was added thereto, the mixture was filtered through Celite, and further subjected to elution with toluene. The filtrate was sequentially washed with a 1N aqueous solution of sodium hydroxide, water, a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 9/1) to give the titled compound (4.98 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4](O)=[O:5].O1CCCC1.[NH3:17]>O>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([NH2:17])=[O:5]
Reactant: N
Reactant: Cc1ccc(N)c(C(=O)O)c1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(N)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 15 g of 2-amino-5-methylbenzoic acid, 16 g of 1,1-carbonyldiimidazole and 500 ml of tetrahydrofuran was stirred for 2 hours at room temperature and then saturated with anhydrous ammonia with ice bath cooling. After 24 hours, 50 ml of water was added and the mixture was concentrated under reduced pressure to a solid residue. This solid Was partially dissolved in 500 ml of dichloromethane and then washed with 200 ml of 0.1 N sodium hydroxide and 200 ml of water. The dichloromethane solution was dried and concentrated to a solid Which Was crystallized from ethyl acetate/hexane, giving 3.0 g of 2-amino-5-methylbenzamide as straw-colored crystals, mp 171°-174° C.
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]([NH2:26])=[NH:25])[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH3:43])([CH3:42])[C:35](=O)[CH:36]=[CH:37]N(C)C)=[CH:30][CH:29]=1.C(N(CC)CC)C>CN1CCCC1=O>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([C:35]2[CH:36]=[CH:37][N:26]=[C:24]([NH:23][C:13]3[CH:14]=[CH:15][C:16]([N:17]4[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]4)=[C:11]([O:10][CH3:9])[CH:12]=3)[N:25]=2)([CH3:42])[CH3:43])=[CH:30][CH:29]=1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CN(C)C=CC(=O)C(C)(C)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: O=[N+]([O-])O
Solvent: CN1CCCC1=O
Product: COc1cc(Nc2nccc(C(C)(C)c3ccc(Cl)cc3)n2)ccc1-n1cnc(C)c1
Reaction time: 2 h

Procedure:
The title compound was prepared in analogous manner as described in example 4c) from N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]guanidine dinitrate and 4-(4-chloro-phenyl)-1-dimethylamino-4-methyl-pent-1-en-3-one, and triethylamine using 1-methyl-2-pyrrolidone as solvent. The reaction was performed in a microwave oven at 200° C. for 2 h. The title compound was isolated as a brown solid in 20% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:37]1[CH2:41][CH2:40][N:39]=[C:38]1[C:42]1[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][NH2:50])=[CH:44][CH:43]=1.CCN(C(C)C)C(C)C>ClCCCl>[NH:39]1[CH2:40][CH2:41][N:37]=[C:38]1[C:42]1[CH:43]=[CH:44][C:45]([CH2:48][CH2:49][NH:50][C:21]([C:18]2[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]3[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH3:24])(=[O:12])=[O:11])[CH3:14])[O:20][CH:19]=2)=[O:22])=[CH:46][CH:47]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: NCCc1ccc(C2=NCCN2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCCc3ccc(C4=NCCN4)cc3)co2)c(C)c1
Temperature: 25 °C

Procedure:
5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (100 mg, 0.3 mmol) was dissolved in DCE (6 mL) and CDI (195 mg, 0.6 mmol) was added. The reaction was stirred at room temperature until complete as determined by LCMS. 2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethanamine (54 mg, 0.3 mmol) and DIPEA (0.63 mL, 1.8 mmol) was added and the reaction stirred for 4 days. The reaction was washed with saturated aqueous NH4Cl (6 mL) and the aqueous wash extracted with DCE (3×6 mL). The combined organic extracts were dried over MgSO4 and the solvent removed in vacuo. The resulting crude product was purified using prep method B to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C1(CN)CCCCC1.[O:17]=[C:18]1[C:26]2([CH2:30][O:29][C:28]3[CH:31]=[C:32]4[C:36](=[CH:37][C:27]2=3)[CH2:35][CH2:34][O:33]4)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]1[CH2:38][C:39]1[CH:47]=[CH:46][CH:45]=[CH:44][C:40]=1[C:41](O)=[O:42].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:41](=[O:42])[C:40]1[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=1[CH2:38][N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]2([CH2:30][O:29][C:28]3[CH:31]=[C:32]4[C:36](=[CH:37][C:27]2=3)[CH2:35][CH2:34][O:33]4)[C:18]1=[O:17]
Reactant: Nc1ccccc1F
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(Nc1ccccc1F)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-fluoroaniline to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(2-fluorophenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (57%) as a colorless solid: mp 195-197° C.; 1H NMR (300 MHz, DMSO-d6) δ10.37 (s, 1H), 7.75-7.59 (m, 2H), 7.51-7.35 (m, 2H), 7.34-7.11 (m, 6H), 7.00 (dd, J=7.4, 7.4 Hz, 1H), 6.87 (d, J=7.8 Hz, 1H), 6.52 (s, 1H), 6.40 (s, 1H), 5.19-5.00 (m, 2H), 4.85 (d, J=9.4 Hz, 1H), 4.70 (d, J=9.4 Hz, 1H), 4.47 (t, J=8.8 Hz, 2H), 2.93 (t, J=8.8 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.8, 161.6, 161.2, 142.8, 135.8, 134.6, 132.7, 131.1, 129.1, 128.6, 127.8, 127.4, 127.3, 127.0, 126.0, 125.8, 124.8, 124.7, 124.2, 123.6, 120.9, 120.4, 119.6, 116.4, 116.2, 109.7, 92.9, 80.5, 72.6, 57.5, 41.4, 28.8; MS (ES+) m/z 529.2 (M+23).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.O1CCOCC1>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:4]2[CH:3]=[C:2]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([O:25][CH3:24])[CH:31]=3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: COc1cccc(B(O)O)c1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: COc1cccc(-c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)c1
Temperature: 110 °C
Yield: 0 %

Procedure:
A suspension of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 151 mmol), 3-methoxyphenylboronic acid (46 mg, 302 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9 mg, 12 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (670 microliters of 1,4-dioxane and 330 microliters of saturated aqueous NaHCO3) was prepared in a 2 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 20 minutes. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC, 45-70% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (5.2 mg, 9%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6 H) 3.85 (s, 3 H) 6.59 (d, J=2.27 Hz, 1 H) 7.22 (dd, J=8.08, 1.77 Hz, 1 H) 7.55 (t, J=7.83 Hz, 1 H) 7.59-7.70 (m, 4 H) 7.98-8.09 (m, 3 H) 8.20 (d, J=2.02 Hz, 1 H) 11.27 (s, 1 H). ESI-MS: m/z 403.3 (M+H)+.
Reaction SMILES: C(O[C:4]([C:6]1[S:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[CH2:13][CH2:12]2)=[N:9][N:10]=1)=[O:5])C.[CH2:29]([NH2:34])[CH2:30][CH:31]([CH3:33])[CH3:32].[C-]#N.[Na+]>>[CH3:32][CH:31]([CH3:33])[CH2:30][CH2:29][NH:34][C:4]([C:6]1[S:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:25])([F:27])[F:26])[CH2:13][CH2:12]2)=[N:9][N:10]=1)=[O:5]
Reactant: CCOC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1
Reactant: CC(C)CCN
Agent: [C-]#N
Agent: [Na+]
Product: CC(C)CCNC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-[4-(2-Trifluoromethylbenzoyl)piperazin-1-yl][1,3,4]thiadiazole-2-carboxylic acid ethyl ester (0.100 g, 0.24 mmol) was added to the mixture of isoamylamine (2 mL) and sodium cyanide (0.023 g, 0.48 mmol). The reaction mixture was stirred for 16 hours at room temperature and then evaporated to dryness. The residue was redissolved in 50 mL of ethyl acetate and the solution was washed sequentially with water (2×15 mL), brine (2×15 mL), then dried over anhydrous Na2SO4, and concentrated. The title compound was obtained as a white powder in quantitative yield (0.110 g). 1H NMR (500 MHz, CDCl3) δ 7.73 (d, J=7.8 Hz, 1H), 7.62 (dd, J=7.5, 7.5 Hz, 1H), 7.55 (dd, J=7.5, 7.5 Hz, 1H), 7.34 (d, J=7.5 Hz, 1H), 7.01 (t, J=7.8 Hz, 1H), 4.03-4.08 (m, 1H), 3.85-3.91 (m, 1H), 3.62-3.74 (m, 2H), 3.51-3.55 (m, 2H), 3.40-3.46 (m, 2H), 3.32-3.35 (m, 2H), 1.61-1.69 (m, 2H), 1.45-1.51 (m, 1H), 0.92 (d, J=6.6 Hz, 6H). MS (ES+) m/z 456.4 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([OH:16])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:20][O:21][CH3:22].O>CN(C=O)C>[Br:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([O:16][CH2:20][O:21][CH3:22])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)c2c1Sc1ccccc1S2
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(Br)c2c1Sc1ccccc1S2
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.) solution of 4-Bromo-thianthren-1-ol (1.0 g, 3.21 mmol) in DMF (12 ml) was added NaH (60% dispersed in mineral oil, 0.23 g, 9.63 mmol) portionwise over 30 minutes and stirred for a further 30 minutes at this temperature. Chloromethylmethylether (0.26 g, 3.241 mmol) was then added and the reaction allowed to stir at room temperature for 2 hours. Water was added to the mixture which was then extracted using EtOAc (3×50 ml). The combined organic extracts were then dried (MgSO4), filtered and concentrated in vacuo to give a mild amber liquid. The crude residue was purified by flash chromatography (SiO2) (10:1, Hexanes/EtOAc) to give the title compound as a mild amber oil that crystallised upon standing (1.11 g, 97%). m/z (LC-MS, ESP):, RT=5.55 min, (M++1)=355.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([O:4][C:5]([NH:7][C@H:8]([C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:20]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH3:3].CN1CCOCC1.Br[CH2:36][C:37](=[O:40])[CH2:38][CH3:39]>CN(C=O)C>[CH3:3][C:2]([CH3:27])([O:4][C:5]([NH:7][C@H:8]([C:16]1[N:17]([CH2:36][C:37](=[O:40])[CH2:38][CH3:39])[CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:20]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)c1nc(-c2ccccc2)c[nH]1
Reactant: CCC(=O)CBr
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCC(=O)Cn1cc(-c2ccccc2)nc1[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a solution of 2-[1(S)-{(1,1-dimethylethoxy)carbonylamino}-2-phenylethyl]4-phenyl-1H-imidazole (100 mg, 1 eq) in DMF (2 mL) were successively added morpholinomethyl polystyrene resin (Novabiochem, loading: 3.51 mmol/g, 159 mg, 2 eq) and 1-bromo-2-butanone (28 mL, 2 eq). After about 18 hours of stirring at about 20° C., 2 mL DMF were added to the reaction mixture followed by aminomethylpolystyrene resin (Novabiochem, loading: 1.73 mmol/g, 319 mg). The mixture was stirred overnight at 20° C. and filtered. The filtrate was concentrated under reduced pressure and then purified by a rapid filtration on a silica gel pad (Alltech silica cartridges) with ethylacetate as eluent to yield 107 mg (90% yield) of the title compound. NMR (1H, 400 MHz, CDCl3) δ: 7.80-6.98 (m, 11H, arom. H), 5.45 (d, 1H, NH), 4.80 (m, 1H, CH), 4.40 (AB, J=18 Hz, NCH2CO), 3.33 (m, 2H, CH2Ph), 2.25 (m, 2H, CH2CH3), 1.0 (t, 3H, CH3). LC/MS: calculated MW=433.5, m/z=434.2 (M+H), m/z=432.2 (M−H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:8][O:9][C:5]=2[CH:4]=1.C[O-].[Na+].[H][H]>CO>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[CH:7]([CH2:10][C:11]([OH:13])=[O:12])[CH2:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(CC(=O)O)coc2c1
Reactant: [H][H]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)OCC2CC(=O)O
Temperature: 25 °C
Yield: 88.4 %

Procedure:
To a mixture of (1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (5.9 mg) and (S,S)-Et-FerroTANE (5.5 mg) was added methanol (2.5 mL) sufficiently substituted by argon gas, and the mixture was stirred at room temperature for min. This was added to a mixture of (6-methoxy-1-benzofuran-3-yl)acetic acid (51.5 mg) and sodium methoxide (7 mg), and the mixture was stirred at room temperature for 5 hr under 0.7 MPa hydrogen atmosphere. The reaction mixture was quantified by HPLC. As a result, the enantiomeric excess was 86.2%, and the yield was 88.4%.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[Cl:21][C:22]1[C:29]([F:30])=[CH:28][C:25]([C:26]#[N:27])=[C:24](F)[CH:23]=1>O1CCCC1>[Cl:21][C:22]1[C:29]([F:30])=[CH:28][C:25]([C:26]#[N:27])=[C:24]([CH:23]=1)[O:3][CH:4]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccnc1
Reactant: N#Cc1cc(F)c(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(Oc1cc(Cl)c(F)cc1C#N)c1cccnc1
Yield: 87.4 %

Procedure:
Sodium hydride (141 mg, 60% dispersion in oil) was added to a solution of the product from step (b) (785 mg, 2.96 mmol) and 4-chloro-2,5-difluorobenzonitrile (546 mg, 3.75 mmol) in tetrahydrofuran (9 ml) and the resultant suspension was stirred for 0.5 h. The mixture was quenched with saturated aqueous ammonium chloride, basified to pH 8 and extracted with ethyl acetate (three times). The combined organic extracts were dried (sodium sulphate), evaporated and purified by chromatography on silica eluting with petrol—acetone to give 1.05 g (88%) of the sub-title compound as a colourless oil.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[CH:18]1([N:13]2[C:12]([C:33]3[CH:34]=[CH:35][C:30]([CH3:29])=[CH:31][CH:32]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2c3c(nn2C2CC2)CCNCC3)cc1
Yield: 105.8 %

Procedure:
The title compound (133 mg) was prepared according to Example 281 using 200 mg of 2-cyclopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 281, Step C) and 90 mg of 4-methylphenylboronic acid. MS (ESI): exact mass calculated for C17H21N3, 267.17; found, m/z 268.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.42-7.34 (m, 4H), 4.68-4.65 (m, 2H), 3.80-3.30 (m, 6H), 2.97 (br s, 2H), 2.44 (s, 3H), 0.94-0.91 (m, 4H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[H][H]>CC(O)C>[C:4]1([C@@H:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CC(=O)c1ccccc1
Solvent: CC(C)O
Product: C[C@H](O)c1ccccc1
Reaction time: 14 h
Yield: 97 %

Procedure:
Chiral hydrogenation of acetophenone was carried out (see formula (8) below). That is, a reaction was carried out in accordance with the procedures of Example 4 using the (R,RR)-ruthenium hydride complex (45.3 mg; 0.0425 mmol) synthesized in Example 1 and using acetophenone (102.1 g; 0.85 mol) as the substrate and 2-propanol (100 mL) as the solvent. However, the hydrogen pressure was set to 10 atmosphere, the reaction temperature was set to 22˜41° C., and the reaction time was set to 14 hours. As a result, (S)-1-phenylethanol was obtained at a conversion rate of 99.8%, isolation yield of 97% (100.7 g; 0.82 mol), and enantiomeric excess of 81%.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])=[O:4].Br[CH2:39][CH2:40][O:41][C:42](=[O:44])[CH3:43]>>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C@H:9]([CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][CH2:39][CH2:40][O:41][C:42](=[O:44])[CH3:43])[CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)=[O:4])(=[O:19])=[O:18])=[CH:25][CH:24]=1
Reactant: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](N)Cc1cccc2ccccc12)S(=O)(=O)c1ccc(N)cc1
Reactant: CC(=O)OCCBr
Product: CC(=O)OCCN[C@@H](Cc1cccc2ccccc12)C(=O)NCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,4S)-2-amino-N-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentyl}-3-naphthalen-1-yl-propionamide (product of example 8) as described in example 15 using 2-bromoethylacetate. The final product was obtained in 21% yield.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH2:22])[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:12][CH2:11][CH2:10][CH2:9]1.Cl[C:28]1[N:33]=[CH:32][C:31]([CH2:34][N:35]2[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][C:36]2=[O:48])=[CH:30][CH:29]=1>>[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH:22][C:28]4[N:33]=[CH:32][C:31]([CH2:34][N:35]5[CH2:40][CH2:39][NH:38][CH2:37][C:36]5=[O:48])=[CH:30][CH:29]=4)[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Cl)nc2)C(=O)C1
Solvent: O=C(O)C(F)(F)F
Product: O=C1CNCCN1Cc1ccc(Nc2ncc3c4ccncc4n(C4CCCC4)c3n2)nc1

Procedure:
Compound 357 was prepared as a off-white solid (TFA salt) from compound 4 and compound 358 using chemistry similar to that described in example 200. 1H NMR (500 MHz, CD3OD) δ ppm 9.67 (1 H, s), 9.35 (1 H, s), 8.70 (1 H, d), 8.66 (1 H, d), 8.48 (1 H, d, J=1.7 Hz), 8.20 (1 H, dd, J=8.8, 2.2 Hz), 7.91 (1 H, d, J=8.8 Hz), 5.48 (1 H, quin, J=8.7 Hz), 4.76 (2 H, s), 3.96 (2 H, s), 3.71 (2 H, t, J=5.7 Hz), 3.53-3.62 (2 H, m), 2.46-2.61 (2 H, m), 2.14-2.33 (4 H, m), 1.82-1.98 (2 H, m). LCMS-ESI (POS), M/Z, M+1: Found 442.9.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:17][CH3:18])=[CH:6][C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][C:8]=2[CH:16]=1)([OH:3])=O.S(Cl)(Cl)=O.[NH2:23][C:24]1[C:25]([OH:43])=[CH:26][C:27]2[C:28]([CH2:40][CH2:41][CH3:42])([CH2:37][CH2:38][CH3:39])[C:29]3[C:34]([C:35]=2[CH:36]=1)=[CH:33][CH:32]=[CH:31][CH:30]=3.N1C=CC=CC=1>O1CCCC1.CN1CCCC1=O>[CH2:40]([C:28]1([CH2:37][CH2:38][CH3:39])[C:27]2[CH:26]=[C:25]([OH:43])[C:24]([NH:23][C:1]([C:4]3[C:5]([O:17][CH3:18])=[CH:6][C:7]4[C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=5[O:9][C:8]=4[CH:16]=3)=[O:3])=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:41][CH3:42]
Reactant: COc1cc2c(cc1C(=O)O)oc1ccccc12
Reactant: CCCC1(CCC)c2ccccc2-c2cc(N)c(O)cc21
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CN1CCCC1=O
Product: CCCC1(CCC)c2ccccc2-c2cc(NC(=O)c3cc4oc5ccccc5c4cc3OC)c(O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
Into a 250 ml, 2-necked, round-bottomed flask, equipped with magnetic stirring, nitrogen inlet, and reflux condenser, were placed 6.98 g (28.8 mmole) of 3-carboxy-2-methoxydibenzofuran, 50 ml of dry tetrahydrofuran, 2.20 ml (30.2 mmole) of thionyl chloride, and 0.1 to 0.2 ml of N-methylpyrrolidinone. The mixture was refluxed for 2.5 hours and then allowed to cool to room temperature. Meanwhile, into a 3-necked, 500 ml, round bottomed flask, equipped with magnetic stirring, pressure-equalizing addition funnel, nitrogen inlet, and thermometer, were placed 8.99 g (30.2 mmole) of 3-amino-9,9-dipropyl-2-hydroxyfluorene, 50 ml dry tetrahydrofuran, and 4.77 ml (60.4 mole) of pyridine. To this solution was added the cooled acid chloride over several minutes, resulting in an exotherm and the formation of a precipitate. The mixture was stirred for an additional 1 hour, quenched by pouring into 400 ml of water, and made acidic (pH ≈1). The solid was collected by vacuum filtration, washed with water, slurried in 200 ml of methanol, refiltered, and washed with an additional 100 ml of methanol, resulting in a yellow solid. After drying obtained 10.5 g (70%) of N-(9,9-dipropyl-2-hydroxy-3-fluorenyl)-2-methoxydibenzofuran-3-carboxamide, mp 252°-255°.