Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](F)[CH:15]=2)[CH:10]=[CH:9][C:8]1=[O:18].[OH-:19].[Na+].O>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[CH:10]=[CH:9][C:8]1=[O:18]
Reactant: O=c1ccc2ncc(F)cc2n1CC1OCCO1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1ccc2ncc(O)cc2n1CC1OCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.50 g of 1-(1,3-dioxolan-2-ylmethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one in 3 mL of tetrahydrofuran, 3 mL of a 20% aqueous sodium hydroxide solution was added, and the mixture was heated under reflux while stirring for 1 hour. Thereto was added 3 mL of water, and the mixture was heated under reflux while stirring for 3 hours 30 minutes. Thereto was added 3 mL of a 20% aqueous sodium hydroxide solution, and the mixture was heated under reflux while stirring for 4 hours. Tetrahydrofuran was distilled off under reduced pressure, and the mixture was then heated under reflux while stirring for 1 hour 30 minutes. After cooling to room temperature, the reaction mixture was added with 2 mol/L hydrochloric acid and adjusted to pH 5. Thereto was added ethyl acetate, the organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diethyl ether was added to the resultant residue, and the solid was filtered off to obtain 0.32 g of 1-(1,3-dioxolan-2-ylmethyl)-7-hydroxy-1,5-naphthyridin-2(1H)-one as a yellow solid.
Reaction SMILES: [C:1]([S:4][CH:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])[CH2:7]/[C:6]/1=[CH:24]\[C:25]1[CH:29]=[CH:28][N:27]([CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[N:26]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.[Cl:45]CCl>>[ClH:45].[C:1]([S:4][CH:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])[CH2:7]/[C:6]/1=[CH:24]\[C:25]1[CH:29]=[CH:28][N:27]([CH2:30][C:31]([OH:33])=[O:32])[N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1ccn(CC(=O)OC(C)(C)C)n1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1ccn(CC(=O)O)n1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of (E)-4-(acetylsulfanyl)-3-{[1-(t-butoxycarbonylmethyl)-1H-pyrazol-3-yl]methylidene}-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]piperidine (770 mg) in dichloromethane (10 ml) was added trifluoroacetic acid (10 ml) under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, and the residue was diluted with ethyl acetate and washed saturated aqueous sodium hydrogencarbonate solution. The organic layer was neutralized with 1N hydrochloric acid and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo, and the residue was dissolved in dichloromethane (10 ml) and a 4N solution of hydrogen chloride in dioxane (1.1 ml) was added to the resulting mixture. The reaction mixture was removed in vacuo, and the residue was purified by chromatography on a silica gel column using methanol and dichloromethane (1:40) as the eluent to afford the title compound (640 mg, yield: 80%) as a pale yellow amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9](=[O:14])[N:8]([CH3:15])[C:7]=2[CH:6]=[CH:5][CH:4]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.[N+:29]([O-])([O-:31])=[O:30].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9](=[O:14])[N:8]([CH3:15])[C:7]=2[CH:6]=[CH:5][C:4]=1[N+:29]([O-:31])=[O:30]
Reactant: COc1cccc2c1CCCC(=O)N2C
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: COc1c([N+](=O)[O-])ccc2c1CCCC(=O)N2C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.8 %

Procedure:
To a solution of 6-Methoxy-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (INT-1) (538 mg, 2.62 mmol) in acetonitrile brought to 0° C. in an ice bath was added 1.8 mL TFAA (2.7 g, 13.1 mmol), followed by KNO3 (320 mg, 3.14 mmol). After approximately 5 minutes, the reaction was allowed to warm to room temperature. Conversion of starting material to product was monitored by LC/MS. Upon completion, the reaction was cooled to 0° C. in an ice bath and quenched with sat. NaHCO3 (aq), 1N NaOH (aq), and ice until pH ˜9-10 was achieved. The aqueous mixture was extracted 3× with EtOAc and the organic layers were washed with brine, dried with MgSO4, and concentrated to give 6-Methoxy-1-methyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (INT-2) as an orange solid (530 mg, 82%). By NMR, the product showed a 4:1 mixture of nitration products, 80% of which was the desired product. By TLC, the products appeared inseparable, so the material was taken on for reduction crude. Data for Major Isomer: 1H-NMR (CDCl3) δ 7.83 (d, J=8.8 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 3.94 (s, 3H), 3.37 (s, 3H), 2.87 (br m, 2H), 2.36 (t, J=7.1 Hz, 2H), 2.24 (m, 2H); LC/MS (ESI-pos) m/z 251.03 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[N:25]1([C:30]2[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=2)[CH:29]=[CH:28][CH:27]=[N:26]1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([N:25]5[CH:29]=[CH:28][CH:27]=[N:26]5)[CH:35]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: OB(O)c1cccc(-n2cccn2)c1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(-n5cccn5)c4)cc23)CC1
Yield: 10 %

Procedure:
To 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (20 mg, 0.048 mmol) was added [3-(1H-pyrazol-1-yl)phenyl]boronic acid (36 mg, 0.193 mmol), dioxane (2.8 mL) and a solution of potassium carbonate (20 mg) in water (1.2 mL). To this mixture was added chloro-2-(dimethylaminormethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (3 mg, 0.005 mmol). The resulting mixture was reacted in a CEM microwave for 10 min at 160° C. then concentrated under a stream of nitrogen (greenhouse) at 80° C. The crude product was partitioned between water (2 mL) and CH2CL2 (2 mL). The layers were separated with a hydrophobic frit, and the aqueous layer was extracted with CH2CL2 (2×2 mL). The organic layers were pooled and concentrated under a stream of nitrogen at 80° C. Dimethyl sulfoxide (0.8 mL) was added to residue, which was sonicated for 10 sec, filtered through a cotton plug, and then filtered through a 0.2 μm filter. The crude product was purified on an Agilent MDAP using a Zorbax Eclipse XDB 610 21.2×50 mm column to afford 2.3 mg of the title compound (10%).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=2[O:23][CH3:24])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[CH3:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[CH3:34])[CH2:29][NH2:30]>>[CH3:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[CH3:34])[CH2:29][NH:30][C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:16]([O:23][CH3:24])=[CH:17][CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5]
Reactant: Cc1ccc(CN)cc1C
Reactant: CCOC(=O)c1nc(-c2c(OC)cccc2OC)n(C)c(=O)c1O
Product: COc1cccc(OC)c1-c1nc(C(=O)NCc2ccc(C)c(C)c2)c(O)c(=O)n1C

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-dimethoxy-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (50 mg, 0.15 mmol) and 3,4-dimethylbenzylamine (102 mg, 0.75 mmol). The title product was obtained as a brown solid (52 mg, 82% yield). 1HNMR (500 MHz, CDCl3) δ: 12.28 (1H, s), 7.88 (1H, t, J=5.50 Hz), 7.38 (1H, t, J=8.24 Hz), 7.10–7.03 (3H, m), 6.61 (2H, d, J=8.54 Hz), 4.48 (2H, d, J=6.11 Hz), 3.75 (6H, s), 3.28 (3H, s), 2.23 (3H, s), 2.22 (3H, s). HRMS (ESI) calcd for C23H26N3O5 (M+H): 424.1873; found: 424.1863.
Reaction SMILES: [ClH:1].Cl[C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[C:5]([NH:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)=[O:6].C(O)C.[C:23]1([N:29]=[C:30]=[S:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])(=O)C.[Na+]>O>[Cl:1][C:18]1[CH:17]=[CH:16][C:4]([C:5]([NH:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:30]([NH:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[S:31])=[CH:11][CH:10]=2)=[O:6])=[CH:3][CH:19]=1
Reactant: Nc1ccc(NNC(=O)c2ccccc2Cl)cc1
Reactant: S=C=Nc1ccccc1
Reactant: Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(NNc1ccc(NC(=S)Nc2ccccc2)cc1)c1ccc(Cl)cc1

Procedure:
1-(Chlorobenzoyl)-2-(4-aminophenyl)hydrazine hydrochloride (2.0 g, 0.0067 mole) was mixed with ethanol (125 ml) and water (25 ml). Phenyl isothiocyanate (1.1 g, 0.01 mole) was added to the mixture along with sodium acetate (0.82 g, 0.01 mole) in water (10 ml). The reaction mixture was stirred and refluxed for 5 minutes, then was stirred at room temperature for one and one half hours. The mixture was chilled in ice and then filtered. The product was washed with ethanol and dried to give an off-white solid. Yield 1.9 g (71%), m.p. 197.5°-199° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:17]([OH:19])=[O:18])[N:16]=[C:11]2[C:10]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:30][O:18][C:17]([C:15]1[N:16]=[C:11]2[C:10]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:12]2=[N:13][CH:14]=1)=[O:19]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cnc2c(n1)c(-c1ccc3ccccc3c1)nn2Cc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cnc2c(n1)c(-c1ccc3ccccc3c1)nn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
20 mg of 1-benzyl-3-(naphthalen-2-yl)-1H-pyrazolo[3,4-b]pyrazine-5-carboxylic acid was dissolved in 5 mL of N,N-dimethylformamide, added with 10 mg of potassium carbonate and 20 μl methyl iodide, and stirred at room temperature for 3 hours. The reaction solution was partitioned between water and ethyl acetate, and the organic layer was extracted and washed with water. The organic layer was dried over magnesium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10), to afford 20 mg the title compound as a colorless powder.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23](OC)=[O:24])[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:28][C:29]([CH3:33])([CH3:32])[CH2:30][NH2:31]>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([NH:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH3:28])=[O:24])[N:17]=[CH:16]4)[CH:12]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)ccc3C)ccc21
Reactant: CC(C)(C)CN
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2CC(=O)NCC(C)(C)C)c1

Procedure:
Example 130 was prepared by General Method D using methyl (5-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-1H-indazol-1-yl)acetate (Example 117) and 2,2-dimethyl-1-propanamine to give the title compound (0.015 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([NH2:11])=[S:10])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)(=[O:14])=[O:13].Br[CH2:22][C:23](=O)[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1>CN(C=O)C.CC(O)=O>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C:23]2[N:11]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][C:3]([S:12]([NH:15][C:16]4[S:17][CH:18]=[CH:19][N:20]=4)(=[O:13])=[O:14])=[C:2]([F:1])[CH:7]=3)[S:10][CH:22]=2)=[CH:26][CH:27]=1
Reactant: O=C(CBr)Cc1ccc(Cl)cc1
Reactant: NC(=S)Nc1ccc(S(=O)(=O)Nc2nccs2)c(F)c1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=S(=O)(Nc1nccs1)c1ccc(Nc2nc(Cc3ccc(Cl)cc3)cs2)cc1F
Temperature: 95 °C
Yield: 46.8 %

Procedure:
The mixture of the 2-fluoro-N-thiazol-2-yl-4-thioureido-benzenesulfonamide (32 mg, 0.000048 mol) and 1-bromo-3-(4-chloro-phenyl)-propan-2-one (14 mg, 0.000058 mol) in DMF/AcOH (1:1) was heated at 95° C. for 20 min. The crude product was purified using Gilson preparative HPLC (reverse phase, Phenomenex 250×30 min, 15 micron C18 column, 40 mL/min. Gradient, 85% A to 100% B over 25 min. Solvent A: 7800 water/200 acetonitrile/8 TFA. Solvent B: 7200 acetonitrile/800 water/8). Fractions were checked by LC/MS. The appropriate fractions were combined and dried on a lyophilizer to give the desired product as a light yellow powder (10.8 mg, 47%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](N(OC)C)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[O:43]1[CH2:48][CH2:47][CH2:46][O:45][CH:44]1[CH2:49][CH2:50][Mg]Br.Cl>O1CCCC1>[O:43]1[CH2:48][CH2:47][CH2:46][O:45][CH:44]1[CH2:49][CH2:50][CH:36]([OH:37])[CH2:35][O:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([N:18]2[C:17](=[O:42])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][N:27]=[C:19]23)[CH2:29][CH2:30]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2ncnn12
Reactant: Br[Mg]CCC1OCCCO1
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)CCC3OCCCO3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-[(trans-4-{6-[(2′-Cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide (1.5 g) was dissolved in tetrahydrofuran (15 mL), 2-(1,3-dioxan-2-yl)ethylmagnesium bromide (15 mL, 0.5M tetrahydrofuran solution) was added dropwise, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was dissolved in tetrahydrofuran (5 mL) and methanol (10 mL), and sodium tetrahydroborate (0.16 g) was added at 0° C. The reaction mixture was stirred at 0° C. for 2 hr and then at room temperature for 18 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, the solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.71 g, 44%).
Reaction SMILES: [C:1]1([CH2:7][C@:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([OH:21])[CH2:9]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:28]1[CH:32]=[N:31][CH:30]=[N:29]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:1]1([CH2:7][C@:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([OH:21])[CH2:9][N:28]2[CH:32]=[N:31][CH:30]=[N:29]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1nc[nH]n1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@](O)(Cc2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O[C@@](Cc1ccccc1)(Cn1cncn1)c1ccccc1
Yield: 50.6 %

Procedure:
A mixture of 87 g (0.23 mol) of (2R)-1,2-diphenyl-2-hydroxy-3-tosyloxy-propane, 70 g (1 mol) of 1,2,4-triazole, 70 g (0.5 mol) of potassium carbonate and 800 ml of acetonitrile is refluxed for 16 hours with stirring. The reaction mixture is then poured into water, and the product which precipitates out is filtered off under suction. In order to remove any undesired biproducts which are still present, the product is dissolved in chloroform and filtered through a silica gel column, a mixture of chloroform/ethyl acetate=1:1 being used as eluent. The eluate is evaporated under reduced pressure. In this fashion, 32.5 g (51% of theory) of (2R)-1,2-diphenyl-2-hydroxy-3-(1,2,4-triazol-1-yl)-propane are obtained in the form of a solid of melting point 134° C. [α]D20 =-2.7° (c=2.75/CHCl3)
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:18]([CH3:31])=[C:19]([CH3:30])[C:20]4[O:24][C:23]([CH3:26])([CH3:25])[C:22](=[O:27])[C:21]=4[C:28]=3[CH3:29])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.CO>C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[C:18]([CH3:31])=[C:19]([CH3:30])[C:20]4[O:24][C:23]([CH3:26])([CH3:25])[CH:22]([OH:27])[C:21]=4[C:28]=3[CH3:29])[CH2:15][CH2:16]2)=[CH:9][CH:10]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)C(C)(C)O4)CC2)cc1
Yield: 89.9 %

Procedure:
Sodium borohydride (300 mg, 7.93 mmol) was added to a solution of 4-(4-methoxyphenyl)-1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-on-5-yl)piperazine (740 mg, 1.88 mmol) obtained in Reference Example 13 in THF (7 ml) and methanol (7 ml) at room temperature and stirred for 2 hours. The resulting mixture was concentrated under reduced pressure, and the residue was diluted 1 N potassium carbonate and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residual crystals were washed with hexane to obtain 670 mg (yield 90%) of the title compound. mp. 159–161° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=NC2N(O)N=NC=2C=1.[NH2:29][C@H:30]([CH2:47][C:48]1[CH:57]=[CH:56][C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:49]=1)[C:31]([N:33]([CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[O:43][CH2:44][CH2:45][OH:46])[CH3:34])=[O:32].C(OCC)(=O)C>CN(C)C=O.ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13](=[O:15])[NH:29][C@@H:30]([C:31](=[O:32])[N:33]([CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH2:44][CH2:45][OH:46])[CH3:34])[CH2:47][C:48]2[CH:57]=[CH:56][C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[CH:49]=2)[CH:11]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(CCc1ccccc1OCCO)C(=O)[C@H](N)Cc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)O)c1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CCc1ccccc1OCCO)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC(=O)c1cccc(CNC(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.9 %

Procedure:
3-(tert-Butoxycarbonylaminomethyl)benzoic acid (113 mg, 0.45 mmol) and 7-aza-1-hydroxybenzotriazole (61 mg, 0.45 mmol) were dissolved in N,N-dimethylformamide (1 ml) and dichloromethane (1 ml). The solution was cooled to 0° C. N-(3-Dimethylaminopropyl)-N′-ethylcarbodilmide hydrochloride (86 mg, 0.45 mmol) was added. The reaction mixture was stirred for 15 min at 0° C. A solution of (2R)-2-amino-N-{2-[2-(2-hydroxyethoxy)phenyl]ethyl}-N-methyl-3-(2naphthyl)propionamide (175 mg, 0.45 mmol) and ethylduisopropylamine (0.08 ml, 0.45 mmol) were added successively. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted %With ethyl acetate (50 ml) and washed with a 10% aqueous solution of sodium hydrogen sulfate (50 ml). The aqueous phase was extracted with ethyl acetate (2×15 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (50 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using ethyl acetate/heptane 3:1 as eluent, to give 211 mg of ((3-((1R)-1-(N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethylcarbamoyl)phenyl)methyl)carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][NH:7]2.[CH2:15](O)[CH3:16]>O>[CH2:15]([O:13][C:12]([C:11]1[C:3]([O:2][CH3:1])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2)=[O:14])[CH3:16]
Reactant: CCO
Reactant: COc1c(C(=O)O)ccc2[nH]ncc12
Solvent: O
Product: CCOC(=O)c1ccc2[nH]ncc2c1OC
Temperature: 95 °C
Reaction time: 11 h

Procedure:
2 g of 4-methoxy-1H-indazole-5-carboxylic acid was added to a mixed solvent of 40 mL ethanol/2.2 mL concentrated sulfuric acid, and stirred at 95° C. for 11 hours. After cooling the reaction solution on ice, water was slowly added under ice cooling, and the precipitated crystals were collected by filtration and washed with water. Thereafter, the crystals were dried under reduced pressure, to afford 1.52 g of the title compound as pale brown crude crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10](Br)=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])[CH3:2].[C:24]([Si:28]([O:31][C:32]([CH3:36])([CH3:35])[C:33]#[CH:34])([CH3:30])[CH3:29])([CH3:27])([CH3:26])[CH3:25]>C(NC(C)C)(C)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10]([C:34]#[C:33][C:32]([O:31][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:30])[CH3:29])([CH3:36])[CH3:35])=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])[CH3:2]
Reactant: CCOC(=O)c1c(Br)cc(-c2c(CC)cccc2CC)nc1C
Reactant: C#CC(C)(C)O[Si](C)(C)C(C)(C)C
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1c(C#CC(C)(C)O[Si](C)(C)C(C)(C)C)cc(-c2c(CC)cccc2CC)nc1C
Temperature: 105 °C

Procedure:
A mixture of 4-bromo-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic ethyl ester (274 mg, 0.73 mmol), tert-butyl-(1,1-dimethyl-prop-2-ynyloxy)-dimethyl-silane (724 mg, 0.37 mmol), Pd(PPh3)4 (84 mg, 0.082 mmol), and copper iodide (7 mg, 0.037 mmol) in diisopropylamine (8 mL) is heated at 105° C. in a sealed tube. The filtrate is concentrated in vacuo. The residue is purified by flash chromatography to give 4-[3-(tert-butyl-dimethyl-silanyloxy)-3-methyl-but-1-ynyl]-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic acid ethyl ester as a pale yellow oil. 1H NMR (CDCl3) 7.38-7.31 (m, 2H), 7.17-7.12 (m, 2H), 4.43 (q, 2H), 2.62 (s, 3H), 2.38-2.25 (m, 4H), 1.56 (s, 6H), 1.44 (t, 3H), 1.06 (t, 6H), 0.83 (s, 9H), 0.15 (s, 6H).