Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C=C2C(C(C)(C)C(=O)NC2=O)=CC=1.[C:16]([NH:18][C:19](=[N:27][C:28]1[CH:37]=[C:36]2[C:31]([C:32]([CH3:41])([CH3:40])[C:33](=[O:39])[NH:34][C:35]2=[O:38])=[CH:30][CH:29]=1)[O:20]C1C=CC=CC=1)#[N:17]>C(O)(C)C>[C:16]([NH:18][C:19]([NH:27][C:28]1[CH:37]=[C:36]2[C:31]([C:32]([CH3:41])([CH3:40])[C:33](=[O:39])[NH:34][C:35]2=[O:38])=[CH:30][CH:29]=1)=[O:20])#[N:17]
Reactant: CC1(C)C(=O)NC(=O)c2cc(N=C(NC#N)Oc3ccccc3)ccc21
Agent: CC1(C)C(=O)NC(=O)c2cc(N)ccc21
Solvent: CC(C)O
Product: CC1(C)C(=O)NC(=O)c2cc(NC(=O)NC#N)ccc21

Procedure:
5.5 g. (23 mMole) N-cyanodiphenoxyimidocarbonate and 4.7 g. (23 mMole) 7-amino-4,4-dimethylisoquinoline-1,3-dione were stirred in 110 ml. isopropanol for 16 hours at 50° C. Subsequently, the reaction mixture was cooled, filtered off with suction and washed with isopropanol. The residue was recrystallised from ethanol. There were obtained 4.1 g. (51% of theory) N-cyano-N'-(4,4-dimethyl-1,2,3,4-tetrahydro-1,3-dioxo-7-isoquinolinyl)-O-phenylisourea; m.p. 214°-216° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.O.[NH2:12][NH2:13]>C(O)C.O>[Br:1][C:2]1[CH:9]=[C:8]2[C:5]([C:6]([NH2:7])=[N:12][NH:13]2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Br)cc1F
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1n[nH]c2cc(Br)ccc12
Reaction time: 22 h

Procedure:
A solution of 10 g of 4-bromo-2-fluorobenzonitrile in 300 mL of ethanol is admixed with 7.29 mL of hydrazine hydrate. The reaction mixture is stirred for 22 hours at reflux and then concentrated under reduced pressure. The residue obtained is stirred for 30 minutes in 200 mL of distilled water. The suspended solid is isolated by filtration, washed with water and treated with suction. After drying under vacuum, 10 g of 6-bromo-3-amino-1H-indazole are obtained, whose characteristics are as follows:
Reaction SMILES: [CH3:1][C:2]([CH3:6])([OH:5])[C:3]#[CH:4].[Cl:7][CH:8]([CH3:12])[C:9](Cl)=[O:10].Cl>O>[Cl:7][CH:8]([CH3:12])[C:9]([O:5][C:2]([CH3:6])([CH3:1])[C:3]#[CH:4])=[O:10]
Reactant: C#CC(C)(C)O
Reactant: CC(Cl)C(=O)Cl
Agent: Cl
Solvent: O
Product: C#CC(C)(C)OC(=O)C(C)Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
0.84 g of 1,1-dimethyl-2-propynol and solution F were mixed and stirred for 15 minutes at 0° C. To the mixture was added 0.97 ml of 2-chloropropionyl chloride and the solution was stirred for 5 minutes at 0° C., additional 5 hours at room temperature. Then, to the reaction mixture was added 1N hydrochloric acid and water, and extracted with ethyl acetate. The organic layer was washed successively with water and aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography to give 1.06 g of (1,1-dimethyl-2-propynyl) 2-chloropropionate.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([O:11]C)[C:3]=1[CH:4]=[O:5].B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5]
Reactant: COc1cc(F)cc(F)c1C=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1c(O)cc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
To a solution of 2,4-difluoro-6-methoxybenzaldehyde (Description 69, 11.2 g; 77.8 mmol) in anhydrous dichloromethane (500 ml) cooled at −78° C. was added boron tribromide (9.47 ml; 85.58 mmol) dropwise over 10 minutes. After complete addition the mixture was allowed to warm to room temperature and stirred overnight. The mixture was poured onto ice/water (1 litre) and extracted with DCM (3×400 ml). The combined organic layers were washed with water (1 litre), saturated NaCl (500 ml), dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica elution with 10% diethyl ether/isohexanes to give the title compound (9.2 g, 75%) as an orange oil.
Reaction SMILES: [Li]C(C)(C)C.CCCCC.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([N:21]([C:28]1[O:32][N:31]=[C:30]([CH3:33])[C:29]=1[CH3:34])[CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])(=[O:20])=[O:19].C[O:36][B:37](OC)[O:38]C.Cl>C1COCC1>[B:37]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([N:21]([C:28]1[O:32][N:31]=[C:30]([CH3:33])[C:29]=1[CH3:34])[CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])(=[O:20])=[O:19])([OH:38])[OH:36]
Reactant: COB(OC)OC
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1Br
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1B(O)O
Temperature: -100 °C
Reaction time: 0.08 h
Yield: 70.1 %

Procedure:
A 1.7 M solution of t-BuLi in pentane (5.0 ml; 8.50 mmol) was added over ~10 minutes to a solution of 2-bromo-N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl]benzenesulfonamide (1.62 g; 3.86 mmol) in THF at -100° C. The temperature was kept below -80° C. during the addition. After stirring 5 minutes at -100° C., trimethylborate (0.53 ml; 4.63 mmol) was added in one portion and the reaction mixture was allowed to warm to room temperature over several hours. At this time, 15 ml of 10% HCl was added and the mixture was extracted with methylene chloride (3×50 ml). The combined organic layers were washed with water (50 ml) and brine (50 ml). Drying (MgSO4), and concentration afforded a yellow oil. The residue was then partitioned between ether (50 ml) and 0.5 N NaOH (20 ml). The ether layer was extracted with 10 ml of 0.5N NaOH. The combined basic layers were washed with ether (50 ml), acidified to pH ~1.5 with saturated KHSO4 solution and extracted with methylene chloride (3×50 ml). Drying (MgSO4) and concentration afforded 1.04 g (70%) of the title product of this step as a light yellow foamy oil.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:34](=[O:35])[N:6]2[C:7]([C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])=[C:8](OP(OC3C=CC=CC=3)(OC3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@@H:5]12)[CH3:3].[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([SH:47])[CH2:44][C@H:43]1[CH2:48][CH:49]1[CH2:53][N:52]([C:54]([O:56][CH2:57][CH:58]=[CH2:59])=[O:55])[C@H:51]([C:60](=[O:63])[NH:61][CH3:62])[CH2:50]1)=[O:41])[CH:37]=[CH2:38].C(N(CC)C(C)C)(C)C>>[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([S:47][C:8]2[C@H:9]([CH3:10])[C@@H:5]3[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:34](=[O:35])[N:6]3[C:7]=2[C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])[CH2:44][C@H:43]1[CH2:48][CH:49]1[CH2:53][N:52]([C:54]([O:56][CH2:57][CH:58]=[CH2:59])=[O:55])[C@H:51]([C:60](=[O:63])[NH:61][CH3:62])[CH2:50]1)=[O:41])[CH:37]=[CH2:38]
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CC1C[C@@H](C(=O)NC)N(C(=O)OCC=C)C1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CC3C[C@@H](C(=O)NC)N(C(=O)OCC=C)C3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12

Procedure:
The same procedure as in Example 8-1 was carried out by using allyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-diphenoxyphosphoryloxy-1-carbapen-2-em-3-carboxylate (204 mg, 0.41 mmol), (2R,4S)-N-allyloxycarbonyl-2-[(2S)-N-allyloxycarbonyl-2-(methylcarbamoyl)pyrrolidin-4-ylmethyl]-4-mercaptopyrrolidine (168 mg, 0.41 mmol) and N,N-diisopropylethylamine (71 μl, 0.41 mmol) to obtain allyl (1R,5S,6S)-2-[(2R,4S)-N-allyloxycarbonyl-2-[(2S)-N-allyloxycarbonyl-2-(methylcarbamoyl)pyrrolidin-4-ylmethyl]pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (180 mg, yield:
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].[C:13]1([C:19]#[C:20][CH2:21][OH:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[I:23]Cl.C(O)(=O)C(C(C(O)=O)O)O.[Na].[K]>C1(C)C=CC=CC=1.C(OCC)C>[I:23][C:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:20][CH2:21][OH:22]
Reactant: ClI
Reactant: OCC#Cc1ccccc1
Agent: COCCO[AlH2-]OCCOC
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [K]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: OCC=C(I)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Red-Al™ (3.4M in toluene, 33 ml) was dissolved in diethyl ether (100 ml) and cooled to −10° C. to which 3-phenyl-2-propyn-1-ol (10 g, 0.076 mol) dissolved in diethyl ether (10 ml) was added dropwise, causing the solution to turn a dark red/brown colour. The reaction was stirred for 1 hour. The solution was cooled to −78° C. and iodine monochloride (1.0M solution in dichloromethane, 114 ml) was added causing the solution to turn a dark brown colour. The mixture was allowed to warm to room temperature and stirred for 1 hour. A 10% solution of potassium sodium tartaric acid (800 ml) was added, producing a white precipitate, this was removed by filtration and the filtrate was extracted with diethyl ether (3×75 ml). The combined organic extracts were washed with sodium thiosulphate (5×60 ml), brine, dried (MgSO4) and the solvent removed in vacuo to afford the crude title compound as a light brown oil (19.5 g, 95%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](=[O:28])[CH2:26]Cl)[N:17]=[CH:16]2)[C@@H:6]1[F:29])(=[O:3])[CH3:2].[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C)C=O>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](=[O:28])[CH2:26][N:30]=[N+:31]=[N-:32])[N:17]=[CH:16]2)[C@@H:6]1[F:29])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)CCl)c2N=CN(C)C)[C@H](F)[C@@H]1OC(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)CN=[N+]=[N-])c2N=CN(C)C)[C@H](F)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
The compound (21) (177 mg) obtained in item (10) above was dissolved in N,N-dimethylformamide (3.5 ml), to which sodium azide (80 mg) was added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction solution as formed was concentrated and the residue thus obtained was extracted with chloroform. The solution in chloroform was washed with water, dried over anhydrous sodium sulfate and concentrated to yield the titled compound (22) (153 mg) as a syrup. Yield: 85%.
Reaction SMILES: [C:1]([S:4][CH:5]1[N:8]([CH:9](O)[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:24])[CH2:6]1)(=[O:3])[CH3:2].N1C=CC=CC=1.O=S(Cl)[Cl:33]>O1CCCC1.O1CCOCC1>[C:1]([S:4][CH:5]1[N:8]([CH:9]([Cl:33])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)SC1CC(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC(=O)SC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
To a cooled (0°) and stirred solution of p-nitrobenzyl 2-(4-acetylthio-2-oxo-1-azetidinyl)-2-hydroxy-acetate (3.79 g., 10.7 mmole) in tetrahydrofuran (40 ml.) and dioxane (40 ml.) was added pyridine (0.97 ml., 12 mmole) followed by SOCl2 (1.43 g., 0.88 ml., 12 mmole). The mixture was stirred 30 minutes at 0°, the precipitate was removed and washed with toluene, and the combined filtrates were concentrated on a rotary evaporator to leave a yellow oil. Partial purification was achieved by filtering the residue over a silica gel pad and washing with chloroform. δ (ppm, CDCl3): 8.2 (2H, m, aromatic), 7.55 (2H, m, aromatic), 6.12 (1H, s, CHCl), 5.65 (1H, m, H-4), 5.35 (2H, two s, benzylic H), 3.62 (1H, dd, J3-3 =16, J3-4 cis =6, H-3), 3.08 (1H, m, H-3), 2.35 (3H, two s, CH3). The product was obtained as a mixture of two epimers.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][C@@H:5]([OH:29])[C@@H:6]2[N:12]1[C:20]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]=2[C:14]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])=[N:13]1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][C@@H:5]([OH:29])[C@@H:6]2[N:12]1[C:20]2[CH2:19][CH2:18][N:17]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:16][C:15]=2[C:14]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])=[N:13]1
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1cccc(-c2nn([C@@H]3c4cc(Cl)cc(Cl)c4C[C@H]3O)c3c2CNCC3)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2[C@@H]2c3cc(Cl)cc(Cl)c3C[C@H]2O)C1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-[1-((1R,2R)-4,6-Dichloro-2-hydroxy-indan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (13e) (0.02 g, 0.047 mmol) in dry tetrahydrofuran at −70° C. was added slowly and portionwise 100 μl of a solution of methanesulfonyl chloride (100 μl in 10 ml dry tetrahydrofuran) and after 5 min triethylamine (21 mg, 0.208 mmol). The mixture was stirred at −70° C. for 15 min and then a second portion of the methanesulfonyl/tetrahydrofuran solution above was added (100 μl). The mixture was stirred at −70° C. for 15 min and then a third portion of the methanesulfonyl/tetrahydrofuran solution above was added (50 μl). The mixture was stirred at −70° C. for 3 min, quenched with aqueous NaHCO3 and extracted 3 times with CH2Cl2. The combined organic layers were evaporated to dryness and the residue was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 15 mg of 3-[1-((1R,2R)-4,6-Dichloro-2-hydroxy-indan-1-yl)-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (23a).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].[CH:18](OCC)(OCC)OCC>>[Br:17][C:14]1[CH:13]=[C:3]2[C:2](=[CH:16][CH:15]=1)[N:1]=[CH:18][N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]2=[O:5]
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccc(Br)cc1C(=O)Nc1ccccc1
Product: O=c1c2cc(Br)ccc2ncn1-c1ccccc1
Temperature: 130 °C
Reaction time: 15 h
Yield: 50 %

Procedure:
A mixture of 2-amino-5-bromo-N-phenylbenzamide (2.82 g, 9.7 mmol) and triethyl orthoformate (20 mL) was stirred at 130° C. for 15 h. The reaction mixture was cooled to RT and petroleum ether was added. After filtration, the filtrate was extracted with ethyl acetate (100 mL*3), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified with silica gel column chromatograph (PE:EtOAc=5:1) to give 6-bromo-3-phenylquinazolin-4(3H)-one (1.5 g, yield: 50%) as white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.50 (d, J=2.4 Hz, 1H), 8.13 (s, 1H), 7.87˜7.90 (m, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.55˜7.58 (m, 2H), 7.51˜7.53 (m, 1H), 7.41˜7.43 (m, 2H). MS (M+H)+:301/303.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][C:29](O)=[O:30])[CH:27]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1.[CH3:34][NH:35][CH3:36]>>[CH3:34][N:35]([CH3:36])[C:29](=[O:30])[CH2:28][N:26]1[CH:27]=[C:23]([C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:18]=[C:9]([C:8]5[N:4]([CH2:3][C:2]([F:32])([F:1])[F:33])[N:5]=[CH:6][N:7]=5)[S:10][C:11]=4[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[CH:24]=[N:25]1
Reactant: CNC
Reactant: O=C(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Product: CN(C)C(=O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1

Procedure:
Following the procedure for 240, (4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-acetic acid was reacted with dimethylamine to give 241. MS(ESI+) 504.1. 1H NMR (400 MHz, DMSO) δ 8.31-8.26 (m, 2H), 8.16 (s, 1H), 7.97 (s, 1H), 7.44 (dd, J=8.3, 1.6, 1H), 7.31 (d, J=1.4, 1H), 5.87 (q, J=8.7, 2H), 5.12 (s, 2H), 4.40 (t, J=4.9, 2H), 3.47 (t, J=4.9, 2H), 3.05 (s, 3H), 2.87 (s, 3H)
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[C:16]([OH:20])(=O)[C:17]#[CH:18].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>ClCCl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:16](=[O:20])[C:17]#[CH:18])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1
Reactant: C#CC(=O)O
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C#CC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 0.5 h

Procedure:
36 mL of a 1 molar DCC solution in dichloromethane is added dropwise at −10° C. to a solution of 4.9 g (70 mmol) of propynoic acid in 120 mL of dichloromethane and the mixture is stirred for 30 minutes. Then 7 g (34.37 mmol) 4′-chlorobiphenyl-4-ylamine, dissolved in dichloromethane, is slowly added dropwise and the mixture is stirred for 2 hours at −8° C. The reaction mixture is then filtered through CELITE®E filter aid, washed again with methanol, and the filtrate is evaporated down. The purification is carried out by column chromatography on silica gel (eluant: cyclohexane/ethyl acetate (6:1 to 2:1)). Yield: 7.6 g (95% of theory); C15H10ClN0 (M=255.70); calc.: molecular ion peak (M+H)+: 256/8 (Cl); found: molecular ion peak (M+H)+: 256/8 (Cl); Rf value: 0.2 (silica gel, cyclohexane/ethyl acetate (1:1)).
Reaction SMILES: [F:1][C:2]([O:10][C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])([C:6]([F:9])([F:8])[F:7])[C:3]([OH:5])=[O:4].[Br-].[C:22]([C:26]1[CH:31]=[CH:30][C:29]([S+:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[F:1][C:2]([O:10][C:11]([F:19])([F:20])[C:12]([F:18])([F:17])[C:13]([F:14])([F:15])[F:16])([C:6]([F:9])([F:8])[F:7])[C:3]([O-:5])=[O:4].[C:22]([C:26]1[CH:31]=[CH:30][C:29]([S+:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:28][CH:27]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: O=C(O)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Agent: CC(C)(C)c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: O=C([O-])C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Yield: 36.6 %

Procedure:
Synthesis was carried out as in Synthesis Example 1 aside from using 13.2 g (0.04 mol) of 2,3,3,3-tetrafluoro-2-(1,1,2,2,3,3,3-heptafluoropropoxy)propionic acid and an amount (0.06 mol) of 4-tert-butylphenyldiphenylsulfonium bromide aqueous solution. There was obtained 9.5 g of white crystals (yield 37%). The compound thus obtained was analyzed by spectroscopy.
Reaction SMILES: [Cl-].[O:2]=[C:3]1[N:8]2[CH:9]=[CH:10][S:11][C:7]2=[N:6][C:5]([CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:4]1.[H-].[Na+].[CH:34]1([CH2:37][O:38][C:39]2[C:46]([O:47][CH3:48])=[CH:45][CH:44]=[CH:43][C:40]=2[CH:41]=O)[CH2:36][CH2:35]1>CS(C)=O.C(OCC)(=O)C>[CH:34]1([CH2:37][O:38][C:39]2[C:46]([O:47][CH3:48])=[CH:45][CH:44]=[CH:43][C:40]=2/[CH:41]=[CH:12]/[C:5]2[N:6]=[C:7]3[S:11][CH:10]=[CH:9][N:8]3[C:3](=[O:2])[CH:4]=2)[CH2:35][CH2:36]1
Reactant: COc1cccc(C=O)c1OCC1CC1
Reactant: O=c1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)nc2sccn12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cccc(/C=C/c2cc(=O)n3ccsc3n2)c1OCC1CC1
Reaction time: 0.5 h

Procedure:
To a stirred suspension of Step 2 intermediate (13.0 g, 28.08) was added NaH (1.2 g, 30.88) in dry DMSO (75 ml) and stirred for 0.5 h. A solution of 2-(cyclopropylmethoxy)-3-methoxybenzaldehyde (6.3 g, 30.88 mmol) in DMSO was added dropwise to this solution at room temperature and stirred for 2 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous Na2SO4 to yield a crude solid which was purified by column chromatography using 10% ethyl acetate in DCM to afford 7.5 g of the desired compound as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 0.30-0.33 (m, 2H), 0.52-057 (m, 2H), 1.10-1.20 (br m, 1H), 3.72-3.90 (m, 5H), 6.29 (s, 1H), 7.00-7.11 (m, 3H), 7.34 (d, J=6.3 Hz, 1H), 7.44-7.50 (m, 1H), 7.90-8.00 (m, 1H), 8.14 (d, J=6.2 Hz, 1H); ESI-MS (m/z) 355.17 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:13])[C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:14][C@H:15]([C:17]([NH:19][CH:20]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]2[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=2[N:22]([CH3:37])[C:21]1=[O:38])=[O:18])[CH3:16]>>[F:8][C:6]1[CH:5]=[C:4]([C:9](=[O:13])[C:10]([NH:14][C@H:15]([C:17]([NH:19][CH:20]2[N:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:24]3[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=3[N:22]([CH3:37])[C:21]2=[O:38])=[O:18])[CH3:16])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)C(=O)c1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Product: C[C@H](NC(=O)C(=O)c1cc(F)cc(F)c1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3,5-difluoro-α-oxoacetic acid (Example O) and 3-(L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-B), the title compound was prepared as a solid (mp.=128-129° C.). The product was purified by LC 2000 chromatography, eluting with hexanes/ethyl acetate (30:70).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[CH3:21][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: COCCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 27.5 h
Yield: 76.6 %

Procedure:
To a mixture of 7-methoxy-1-heptanol (18.1 g) and p-toluenesulfonyl chloride (28.4 g) in dichloromethane (180 ml) was added triethylamine. After stirring for 27.5 hours at room temperature, the solvent was evaporated in vacuo. Then the residue was poured into a mixture of ethyl acetate and water. The organic layer was successively washed with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (8:1→5:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give 7-methoxyheptyl 4-methylbenzenesulfonate (28.5 g).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([NH:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][CH3:22])[CH2:35][CH2:34]2)=[O:21])[C:11]([NH:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(NC)nc1C
Reactant: COc1ccccc1N1CCNCC1
Product: CCc1cc(NC(=O)N2CCN(c3ccccc3OC)CC2)c(NC)nc1C
Yield: 73 %

Procedure:
Phenyl-N-(5-ethyl-6-methyl-2-methylaminopyridin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:17]1[CH:18]=[N:19][N:20]([CH:22]2[CH2:24][CH2:23]2)[CH:21]=1>O1CCCC1>[Si:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:17]2[CH:18]=[N:19][N:20]([CH:22]3[CH2:24][CH2:23]3)[CH:21]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Brc1cnn(C2CC2)c1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Nc2cnn(C3CC3)c2)cc1

Procedure:
4-[tert-Butyl(dimethyl)silyl]oxyaniline (1.64 g, 7.3 mmol) and 4-bromo-1-cyclopropyl-1H-pyrazole (1.4 g, 7.3 mmol) dissolved in anhydrous tetrahydrofuran (30 mL) are stirred for 3 hours at ambient temperature in the presence of sodium tert-butylate (3.7 mL, 2M solution in THF) and chloro(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (101 mg, 0.146 mmol). The reaction mixture is filtered over Celite and then evaporated to dryness. The residue is purified by chromatography over silica gel using heptane and ethyl acetate as eluants to yield the expected product.