Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.[NH4+:15].[OH-]>O>[NH2:15][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1
Reactant: Brc1cccc(CN2CCCCC2)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Product: Nc1cccc(CN2CCCCC2)n1
Temperature: 95 °C

Procedure:
To a solution of 2-bromo-6-(piperidylmethyl)pyridine (5.21 g, 20 mmol) in IpOH (30 mL) in a sealed tube at RT, a catalytic amount of Cu (100 mg) and 28–30% NH4OH (35 mL) were added. The stirred suspension was heated to 95° C. for 40 h. After cooling to RT, the reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (4×80 mL). The organic layers were combined, then washed with H2O (50 mL) followed by brine (50 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to yield the title compound as a dark yellow oil. This was used as crude. MS m/z: 193 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][NH2:3].C([O:6][C:7](=O)[CH2:8][C:9](=O)[C:10]([CH3:13])([CH3:12])[CH3:11])C.C[O-].[Na+]>CO>[CH3:1][N:2]1[C:7]([OH:6])=[CH:8][C:9]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:3]1
Reactant: CCOC(=O)CC(=O)C(C)(C)C
Reactant: CNN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cn1nc(C(C)(C)C)cc1O
Yield: 87.5 %

Procedure:
9.2 g (0.2 mol) of methylhydrazine were added dropwise to a mixture of 34.4 g (0.2 mol) of pivaloylacetic acid ethyl ester, 10.8 g (0.2 mol) of sodium methylate and 100 ml of methanol at 20° C. When the exothermic reaction had subsided, the reaction mixture was heated for 2 hours under reflux and then concentrated, the residue was taken up in 200 ml of water and this solution was acidified with concentrated hydrochloric acid to a pH of ca. 6. The resulting precipitate was filtered off, dried and recrystallized from isopropanol. 27 g (87% of theory) of 1-methyl-3-tert.-butyl-5-hydroxy-pyrazole were obtained in the form of colorless crystals of melting point 150° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9](C(O)=O)[S:8][C:7]=2[CH:14]=1)#[N:2].N12CCCN=C1CCCCC2.Cl>CN(C)C(=O)C>[S:8]1[CH:9]=[CH:10][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:14][C:7]1=2
Reactant: N#Cc1ccc2cc(C(=O)O)sc2c1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc2ccsc2c1

Procedure:
A microwave vial was charged with 6-cyanobenzo[b]thiophene-2-carboxylic acid (1.90 g, 9.35 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (5.6 mL, 37.4 mmol) and N,N-dimethylacetamide (15 mL) and the reaction was subjected to microwave irradiation at 190° C. for 1 hour. After cooling, the reaction mixture was poured into 1N aq. HCl and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to get the product as light brown solid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](=[O:44])[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:42][CH3:43])([C:27]3[CH:32]=[CH:31][C:30](OS(C(F)(F)F)(=O)=O)=[C:29]([CH3:41])[CH:28]=3)[CH2:25][CH3:26])=[CH:20][CH:19]=2)[CH:17]=1.[C:45]([C:47]1([OH:53])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1)#[CH:46]>C(#N)C.[Cu]I>[CH3:8][O:9][C:10](=[O:44])[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([CH2:42][CH3:43])([C:27]3[CH:32]=[CH:31][C:30]([C:46]#[C:45][C:47]4([OH:53])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]4)=[C:29]([CH3:41])[CH:28]=3)[CH2:25][CH3:26])=[CH:22][CH:23]=2)[CH:17]=1
Reactant: C#CC1(O)CCCCC1
Reactant: CCC(CC)(c1ccc(-c2cncc(CC(=O)OC)c2)cc1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC(CC)(c1ccc(-c2cncc(CC(=O)OC)c2)cc1)c1ccc(C#CC2(O)CCCCC2)c(C)c1
Temperature: 160 °C
Yield: 67.1 %

Procedure:
Triethylamine (0.156 mL, 1.12 mmol), tetrakistriphenylphosphine palladium (43.0 mg, 0.036 mmol) and copper (I) iodide (7.0 mg, 0.037 mmol) were added to a solution of (5-{4-[1-ethyl-1-(3-methyl-4-trifluoromethanesulfonyloxy-phenyl)-propyl]-phenyl}-pyridin-3-yl)-acetic acid methyl ester (Example 144-(2); 0.1 g, 0.186 mmol) and 1-ethynyl-cyclohexanol (69.6 mg, 0.56 mmol) in acetonitrile (0.9 mL), and the mixture was stirred with microwave heating at 160° C. for five minutes. The reaction solution was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (63.6 mg, 66%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]([C:10]1[S:11][C:12]([S:25][CH3:26])=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[CH3:28][C:29]1[C:34]2B(O)[O:36][CH2:37][C:33]=2[CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)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.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]([C:10]1[S:11][C:12]([S:25][CH3:26])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:34]3[C:33]([CH2:37][OH:36])=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:28])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Reactant: Cc1cccc2c1B(O)OC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2CO)c1
Yield: 39.4 %

Procedure:
The procedure used in Example 1: step c was followed using {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (Example 27 (50 mg, 0.1 mmol)), 7-methyl-3H-benzo[c][1,2]oxaborol-1-ol ((Example 5: step b) 59 mg, 0.4 mmol), Na2CO3 (2M, 0.8 mL, 1.6 mmol), Pd(PPh3)4 (29.4 mg, 0.025 mmol), ethanol (0.8 mL) and toluene (1.6 mL). Analogous aqueous workup and purification of the crude material by preparative TLC (40% EtOAc in hexanes) yielded the title compound (21 mg, 40%) as a light-yellow glass. 1H-NMR (CDCl3): δ 7.96 (m, 2H), 7.86 (m, 1H), 7.54 (m, 1H), 7.43 (m, 1H), 7.18–7.38 (m, 3H), 4.53 (d, 1H, J=13.3 Hz), 4.45 (d, 1H, J=13.3 Hz), 2.54 (s, 3H), 1.96 (s, 3H), 1.49 (s, 9H). ESI-MS (m/z): Calcd. for C25H28N2O5S3: 532.7; found: 532.9.
Reaction SMILES: [CH3:1][O-:2].[Na+].[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1>CO>[CH2:1]([O:2][C:15](=[O:17])[C:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=2)=[CH:19][CH:18]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[O-]
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: [Na+]
Solvent: CO
Product: O=C(OCc1ccccc1)c1ccc(-c2ccc(O)cc2)cc1
Reaction time: 0.08 h

Procedure:
2.25 g of methanol solution including 28% sodium methylate was added to 2.50 g of 4-(4-hydroxyphenyl)benzoic acid suspended in 10 ml of methanol. After the mixture was stirred for 5 minutes, it was concentrated under reduced pressure. 10 ml of N,N-dimethylformamido and 2.43 g of benzyl-bromoamide were added to the residue. The mixture was stirred during night at room temperature and poured into 30 ml of ice water, and extracted with 50 ml of toluene. The organic layer was washed with in order saturated sodium hydrogen and water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. Obtained crude crystals were purified by silica gel column chromatography with toluene-ethyl acetate eluent, and hexane was added to them. Precipitated crystals were collected by filtration, and washed with hexane. 4-(4-hydroxyphenyl)benzoate benzylester 2.60 g was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[NH2:12].[CH3:13][C:14]1[CH:15]=[N:16][C:17]2[N:18]([N:20]=[C:21]([S:23](Cl)(=[O:25])=[O:24])[N:22]=2)[CH:19]=1>N1C=CC=CC=1>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[NH:12][S:23]([C:21]1[N:22]=[C:17]2[N:16]=[CH:15][C:14]([CH3:13])=[CH:19][N:18]2[N:20]=1)(=[O:24])=[O:25]
Reactant: COC(=O)c1cccc(C)c1N
Reactant: Cc1cnc2nc(S(=O)(=O)Cl)nn2c1
Solvent: c1ccncc1
Product: COC(=O)c1cccc(C)c1NS(=O)(=O)c1nc2ncc(C)cn2n1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Methyl 3-methylanthranilate (2.1 g, 13 mmol) was dissolved in 4 ml pyridine and 6-methyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonyl chloride was added. After a mild exothermic reaction subsided the reaction mixture was stirred at 50° C. for 24 hours. The pyridine was removed by evaporation at reduced pressure and the residue was treated with in 10% aqueous sodium bicarbonate. Insouble material was collected by filtration, washed with ether and dried to yield 2.9 (63%) of the desired product as a solid, mp 198.5°-205° C. An analytical sample was prepared by recrystallization from ethanol to yield a crystalline solid, mp 208.5°-210.5° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: O.O.O.[C:4]1([O-:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Na+].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH2:12]([O:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [O-]c1ccccc1
Reactant: ClCc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: c1ccc(COc2ccccc2)cc1
Yield: 66.9 %

Procedure:
A mixture of sodium phenolate trihydrate (10.2 g; 60 mmole) and benzyl chloride (6.4 ml; 56 mmole) in methanol (150 ml) was pumped through the system (15 ml/minute; 146°-7° C.; 1000-1050 kPa). The MeOH was rotary evaporated off and the residue recrystallised from EtOH to afford colourless needles of phenyl benzyl ether (6.9 g; 67% yield), m.p. 36°-36.3° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O>C1C=CC=CC=1>[CH3:6][CH:5]([CH2:4][CH3:3])[CH2:9][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CCC(C)COC(=O)c1ccc(O)cc1
Yield: 64.4 %

Procedure:
To p-hydroxybenzoic acid (113 g, 0.82 mol) were added S(-)-2-methyl-butanol (273 g, 3.1 mols), conc. sulfuric acid (25 ml) and benzene (300 ml), followed by refluxing the mixture for 16 hours, cooling, thereafter adding toluene (1 l), washing the toluene layer with 2% NaHCO3 aqueous solution and further with water till the washing water became neutral, distilling off toluene and recrystallizing from ethanol to obtain optically active p-hydroxy-benzoic acid 2-methyl-butyl ester (55 g).
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][N:5]=1.O>C(O)(=O)C>[NH2:3][C:4]1[C:9]([Br:1])=[CH:8][C:7]([Cl:10])=[CH:6][N:5]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Nc1ncc(Cl)cc1Br
Temperature: 25 °C
Yield: 63.8 %

Procedure:
A solution of 257 g (1.61 mol) of bromine in 380 ml of acetic acid was added dropwise over a period of one hour to a solution of 187 g (1.45 mol) of 2-amino-5-chloropyridine in 1.5 l of acetic acid. The reaction mixture was refluxed for 3 h and then allowed to cool to ambient temperature. 1.9 l of demineralized water were added and the mixture was concentrated in vacuo. The residue was partitioned between 4 l of ethyl acetate and 1.8 l of water. The mixture was basified with 3 l of a 10% by weight aqueous sodium hydroxide solution. The organic layer was separated and washed with brine (2×1.5 l), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was filtered, washed with hexane (2×100 ml) and dried in vacuo to give 192 g of 2-amino-3-bromo-5-chloropyridine. The mother liquor was concentrated in vacuo, filtered, washed with hexane and dried to give further 75 g of the same product.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[Br:16]Br>C(Cl)Cl>[NH2:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][C:12]=1[Br:16]
Reactant: BrBr
Reactant: CCOC(=O)c1ccc(N)c([N+](=O)[O-])c1
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)c(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
To a solution of ethyl 4-amino-3-nitrobenzoate (D212) (21.0 g, 100 mmol, 1 equiv) in CH2Cl2 (500 ml) at room temperature was added bromine (6.7 ml, 130 mmol, 1.3 equiv) and the resulting mixture was refluxed for 4 h then bromine (2 ml, 40 mmol, 0.4 equiv) was added and the resulting mixture refluxed for another 3 h then cooled to room temperature. The organic phase was washed twice with a 10% aqueous Na2S2O3 solution and twice with H2O, dried over MgSO4 and concentrated in vacuo to give ethyl 4-amino-3-bromo-5-nitrobenzoate (D213) (27.1 g, 94%) as a yellow solid which was used in the next step without further purification.
Reaction SMILES: [NH3:1].C[O:3][C:4]([C:6]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH:14]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)[CH2:13]2)[CH:9]=[CH:8][CH:7]=1)=O>CO>[F:31][C:28]1[CH:27]=[CH:26][C:25]([O:24][C:21]2[CH:22]=[CH:23][C:18]([CH:14]3[O:15][CH2:16][CH2:17][N:12]([C:10]4[CH:9]=[CH:8][CH:7]=[C:6]([C:4]([NH2:1])=[O:3])[N:11]=4)[CH2:13]3)=[CH:19][CH:20]=2)=[CH:30][CH:29]=1
Reactant: COC(=O)c1cccc(N2CCOC(c3ccc(Oc4ccc(F)cc4)cc3)C2)n1
Reactant: N
Solvent: CO
Product: NC(=O)c1cccc(N2CCOC(c3ccc(Oc4ccc(F)cc4)cc3)C2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 50 ml of 2M NH3 in methanol was added the crude compound 9 and the resulting solution was stirred for 12 hours at room temperature. The mixture was then concentrated to dryness and the resulting solid was recrystalized in methanol to give 1.1 g of compound 10. 1H NMR (DMSO-D6): δ 8.05 (b, 1H), 7.93 (d, 2H, J=8.8 Hz), 7.62 (d, 1H, J=2.5 Hz), 7.14 (d, 1H, J=2.5 Hz), 7.08 (m, 6H), 5.56 (b, 1H), 4.15 (t, 4H, J=5.1 Hz), 3.47 (t, 4H, J=5.1 Hz). MS: 394.2 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[CH:25]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[CH2:26]C(=O)[CH2:28][CH2:29][N:23]4[N:22]=3)=[CH:16][C:15]=2[O:39][CH3:40])[CH:13]=1.[CH:41]([O:46][CH3:47])([O:44][CH3:45])OC.S(O)(C1C=CC(C)=CC=1)(=O)=O>CO>[Cl:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[CH:25]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[CH2:26][C:41]([O:44][CH3:45])([O:46][CH3:47])[CH2:28][CH2:29][N:23]4[N:22]=3)=[CH:16][C:15]=2[O:39][CH3:40])[CH:13]=1
Reactant: COC(OC)OC
Reactant: COc1cc(Nc2nc3n(n2)CCC(=O)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Nc2nc3n(n2)CCC(OC)(OC)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.4 %

Procedure:
To a stirred solution of 2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (200 mg, 0.428 mmol, from example 137) in MeOH (2 mL) was added trimethyl orthoformate (0.469 mL, 4.28 mmol) followed by Ts-OH (8.15 mg, 0.043 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction was concentrated in vacuo. The crude product was purified using reverse phase preparatory HPLC (AcCN/water/ammonium acetate) to afford the titled compound (104 mg, 46% yield). LC-MS (M+H)+ 513.3. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.51 (1 H, d, J=1.5 Hz), 7.40 (1 H, d, J=2.4 Hz), 7.31-7.35 (2 H, m), 7.06-7.14 (3 H, m), 7.02 (1 H, d, J=1.5 Hz), 6.78 (1 H, dd, J=8.5, 2.4 Hz), 6.59 (1 H, s), 4.39 (1 H, ddd, J=14.7, 5.9, 2.3 Hz), 4.20-4.28 (1 H, m), 4.11-4.17 (1 H, m), 3.76 (3 H, s), 3.29 (3 H, s), 3.26 (3 H, s), 2.35-2.43 (2 H, m), 2.05-2.12 (1 H, m), 1.89 (1 H, ddd, J=14.5, 11.9, 2.3 Hz).
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]=[C:8](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[O:9][CH:10]=1)(=O)C.[OH-].[Na+].O>CS(C)=O>[OH:4][CH2:5][C:6]1[N:7]=[C:8](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[O:9][CH:10]=1
Reactant: CC(=O)OCc1coc(/C=C/c2ccc(C(F)(F)F)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: OCc1coc(/C=C/c2ccc(C(F)(F)F)cc2)n1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
4-(Acetoxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole (20.0 g, 64.3 mmol) was dissolved in dimethyl sulfoxide (200 ml), and 2N-aqueous sodium hydroxide solution (35 mL 70.0 mmol) was added at 50° C. The mixture was stirred at about 40° C. for 15 min. Water (200 ml) was added at the same temperature. After allowing to cool to room temperature and stirring, the mixture was stirred at the same temperature for 1 hour. The precipitated crystals were collected by filtration, washed with water (60 ml) and dried under reduced pressure to give 4-(hydroxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole (16.4 g, 61.1 mmol, yield 95%).
Reaction SMILES: [C:1]1([CH:7](O)[CH:8]=[CH:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CC[O:15]CC.C(=O)(O)[O-].[Na+]>O1CCOCC1>[C:1]1([CH:7]=[CH:8][CH:9]([OH:15])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOCC
Reactant: CC=CC(O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(O)C=Cc1ccccc1
Reaction time: 8 h
Yield: 96.8 %

Procedure:
1-Phenyl-2-buten-1-ol (135.88 g) was dissolved in 2300 mL of dioxane and treated with 2750 mL of dilute hydrochloric acid (2.3 mL of concentrated hydrochloric acid in 2750 mL of water) at room temperature. The mixture was stirred overnight and then poured into 4333 mL of ether and neutralized with 2265 mL of saturated aqueous sodium bicarbonate. The aqueous phase was extracted with 1970 mL of ether. The combined extract was dried over anhydrous potassium carbonate. Evaporation of the solvent followed by Kugelrohr distillation at 30° C. for 30 minutes afforded 131.73 g (96.8%) of the desired 4-phenyl-3-buten-2-ol as an oil which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11](OCC)=[O:12])[C:6]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:5]=2[S:4][C@H:3]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH3:27]>CO>[NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([NH2:27])=[O:12])[C:6]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:5]=2[S:4][C@H:3]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N
Reactant: CCOC(=O)CN1C(=O)[C@@H](N)[C@H](c2ccccc2)Sc2cc(Cl)ccc21
Solvent: CO
Product: NC(=O)CN1C(=O)[C@@H](N)[C@H](c2ccccc2)Sc2cc(Cl)ccc21
Reaction time: 8 h

Procedure:
In the same manner as in (iv) of Example 23, 1.7 g of ethyl trans-3-amino-8-chloro-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate is dissolved in 50 ml of methanol, into which ammonia gas is blown to the level of saturation under ice-cooling. The reaction temperature is slowly elevated to room temperature, and the mixture is allowed to stand still overnight. Then, the reaction mixture is concentrated under reduced pressure. The separated crystals are collected by filtration to give 1.4 g of trans-3-amino-8-chloro-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide, m.p. 225°-228° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-])=O.[H][H].C>CO.O=[Pt]=O>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10]
Reactant: [H][H]
Reactant: COCc1ccccc1[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: CO
Product: COCc1ccccc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A solution of 1-(methoxymethyl)-2-nitrobenzene (4.30 g, 25.7 mmol) and PtO2 (0.29 g, 1.29 mmol) in MeOH (30 mL) was charged with 1 atmosphere hydrogen and stirred at ambient temperature for 1 hour. Charcoal (5 g) was added and the reaction mixture was stirred for 10 minutes. The solid was removed by filtration and washed with methanol. The filtrate was concentrated under reduced pressure to give 2-(methoxymethyl)aniline (3.42 g, 96.9%) as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[NH:10][C@H:11]1[CH2:15][CH2:14][N:13]([C@H:16]2[CH2:21][CH2:20][C@@H:19]([NH:22]C(OC(C)(C)C)=O)[CH2:18][C@H:17]2[CH2:30][CH2:31][CH3:32])[C:12]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:22][C@@H:19]1[CH2:20][CH2:21][C@H:16]([N:13]2[CH2:14][CH2:15][C@H:11]([NH:10][C:9](=[O:34])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:12]2=[O:33])[C@H:17]([CH2:30][CH2:31][CH3:32])[CH2:18]1
Reactant: CCC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC[C@@H]1C[C@H](N)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reaction time: 5 h

Procedure:
To a solution of {(3S)-1-[(1S,2R,4R)-4-tert-butoxycarbonylamino-2-propyl-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-carbamic acid benzyl ester (3.88 g, 8.2 mmol) in CH2Cl2 (90 mL) was added TFA (45 mL) at RT. The reaction was stirred for 5 h and concentrated in vacuo. The residue was partitioned between 1N NaOH (100 mL) and EtOAc (150 mL). The aqueous layer was extracted with EtOAc (2×50 mL) and the organic phases were combined, washed with brine (25 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give benzyl (S)-1-[(1S,2R,4R)-4-amino-2-propylcyclohexyl]-2-oxopyrrolidin-3-ylcarbamate. MS found: (M+H)+=374.3.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Cl:32])[C:16]=1[NH:17][C:18]1[C:27]2[C:22](=[C:23]([OH:30])[C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[O:21][C:20](=[O:31])[CH:19]=1>>[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Cl:32])[C:16]=1[NH:17][C:18]1[C:27]2[C:22](=[C:23]([O:30][CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[O:21][C:20](=[O:31])[CH:19]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Reactant: BrCCc1ccccc1
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCc1ccccc1

Procedure:
The title compound was prepared from (2-bromoethyl)benzene and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, DMSO-d6): δ 9.51 (s, 1H), 8.81 (s, 2H), 7.94 (d, 1H), 7.35-7.23 (m, 4H), 7.19 (d, 2H), 4.64 (s, 1H), 4.22 (t, 2H), 3.89 (s, 3H), 3.03 (t, 2H); MS (ESI): 456.9.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][C:37]([CH2:41][OH:42])([CH3:40])[CH2:38][OH:39])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[OH:39][CH2:38][C:37]([NH:36][S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34])([CH2:41][OH:42])[CH3:40]
Reactant: CC(CO)(CO)NS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(CO)(CO)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-(2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-benzenesulfonamide (example B.9) according to general procedure II. Yellow solid. MS (ISP) 600.4 [(M+H+]; mp 246° C.