Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C>ClCCl>[C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][O:15][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:12][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@H]1CC[C@H](CO)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[SiH2]OC(C)(C)[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Temperature: 0 °C

Procedure:
To an ice-cooled solution of 27.6 g (107 mmol) of trans-[4-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohexyl]-methanol and 9.99 ml (128 mmol) of methanesulfonyl chloride in 350 ml of dichloromethane was added under stirring at 0–10° C. 29.6 ml (213 mmol) of triethylamine within 20 minutes. The reaction-mixture was stirred for 1 hour at room temperature. It was then partitioned between dichloromethane, 1N HCl and water. The dichloromethane-phase was dried over magnesium sulfate and concentrated to yield 38.2 g crude trans-methanesulfonic acid 4-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohexylmethyl ester as colorless viscous oil, MS: 354 (M+NH4+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=O)[NH:12][N:13]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:17])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([Cl:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1ccc(-c2ccc(Br)cc2)n[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc(-c2ccc(Br)cc2)nn1

Procedure:
A mixture of 20.0 g. of 6-(p-bromophenyl)-3(2H)-pyridazinone (prepared as described in Example 1) in 100 ml. of phosphorus oxychloride is heated at reflux temperature for 41/2 hours. The excess phosphorus oxychloride is removed under reduced pressure and the residue is stirred with water-cracked ice to decompose the remaining phosphorus oxychloride. The product is recovered by filtration and recrystallized from dilute dimethylformamide yielding tan crystals, m.p. 201°-203° C.
Reaction SMILES: [CH2:1]([CH:3]([C:6](=O)[CH3:7])[CH:4]=O)[CH3:2].[Na].[N+:10]([CH2:13][C:14]([NH2:16])=[O:15])([O-:12])=[O:11].C([O-])(=O)C.[NH2+]1CCCCC1>O>[CH2:6]([C:3]1[CH:4]=[C:13]([N+:10]([O-:12])=[O:11])[C:14](=[O:15])[NH:16][C:1]=1[CH3:2])[CH3:7]
Reactant: NC(=O)C[N+](=O)[O-]
Reactant: CCC(C=O)C(C)=O
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Agent: [Na]
Solvent: O
Product: CCc1cc([N+](=O)[O-])c(=O)[nH]c1C
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 2-ethyl-3-oxobutanal, sodium salt (7.5 g, 55 mmol), nitroacetamide (6.6 g, 63 mmol), aqueous piperidinium acetate (4.4 mL) [prepared from glacial acetic acid (42 mL), water (100 mL) and piperidine (72 mL)] in water (45 mL) was stirred at room temperature for 22 hours. The yellow precipitate was collected by filtration and air dried to yield 8.0 g (80%) of 5-ethyl-6-methyl-3-nitro-2-(1H)-pyidinone.
Reaction SMILES: NC(N)=O.C[O:6][C:7](=[O:24])[CH2:8][C:9]1[C:10]([CH3:23])=[N:11][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:13]=1[CH3:14].[CH2:25]([N:32]=[C:33]=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[CH2:25]([NH:32][C:33](=[O:34])[NH:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:12]2[C:13]([CH3:14])=[C:9]([CH2:8][C:7]([OH:6])=[O:24])[C:10]([CH3:23])=[N:11]2)=[CH:17][CH:18]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(N)cc2)c1C
Reactant: O=C=NCc1ccccc1
Agent: NC(N)=O
Solvent: ClCCl
Product: Cc1nn(Cc2ccc(NC(=O)NCc3ccccc3)cc2)c(C)c1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Urea formation: To a solution of [1-(4-amino-benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-acetic acid methyl ester (intermediate 1.1.3, 160 mg, 0.59 mmol) in dichloromethane (2 mL) was added benzyl isocyanate (94 μL, 0.76 mmol). The reaction mixture was stirred for 1 h at room temperature. Saponification: After removing the volatiles under reduced pressure, the remaining residue was dissolved in methanol (1 mL) and treated with aqueous LiOH solution (1 M, 1.5 mL). After 18 h, the mixture was neutralized and purified via preparative reversed phase HPLC (gradient of methanol in water+0.1% NH3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+]>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:10][CH2:9][N:8]([CH3:13])[CH3:6])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(F)c3)c[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)CCn1cc(-c2ccc(F)c(F)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 166.8 %

Procedure:
Add 4-[4-(3,4-difluoro-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (500 mg; 1.38 mmol) to a solution of NaH (110 mg; 2.76 mmol) in DMSO (50 mL) at 0° C., and stir for 1 h at RT. Add (N,N-dimethyl)ethyl chloride hydrochloride (238 mg; 1.65 mmol) to the resulting mixture and allow to stir at RT for 18 h. Monitor the reaction by thin layer chromatography (TLC). Quench the reaction mixture with ice water and extract with EA. Separate the organic layer, wash twice with brine (2×50 mL), dry over anhydrous Na2SO4 and evaporate under reduced pressure. Purify the residue by column chromatography on silica gel (60/120 mesh) using DCM:Methanol (98:2) as eluent to give 0.5 g (86%) of the title compound. LCMS=484(M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:11]3[S:16][C:15]([CH2:17][N:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]4)=[C:14]([CH3:31])[C:12]=3[N:13]=2)=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>>[CH3:31][C:14]1[C:12]2[N:13]=[C:8]([C:5]3[CH:6]=[N:7][C:2]([NH2:1])=[N:3][CH:4]=3)[N:9]=[C:10]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[C:11]=2[S:16][C:15]=1[CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: Cc1c(CN2CCN(C(=O)OC(C)(C)C)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Yield: 122.5 %

Procedure:
Tert-butyl 4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate (75 mg) was treated with TFA and purified via reverse phase HPLC to give 74.4 mg of 358. MS (Q1) 427.2 (M)+.
Reaction SMILES: [NH:1]([C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34])[C@@H:2]([C:4]([NH:6][C@H:7]([C:15]([NH:17][C@H:18]([C:30]([OH:32])=[O:31])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:3].[CH3:39][C:40]([NH:51][CH2:52][CH:53]([OH:69])[CH2:54][O:55][C:56]1[C:61]2[C:62]3[C:67]([NH:68][C:60]=2[CH:59]=[CH:58][CH:57]=1)=[CH:66][CH:65]=[CH:64][CH:63]=3)([C:42]1[CH:47]=[CH:46][C:45]([N:48]=[N+:49]=[N-:50])=[CH:44][CH:43]=1)[CH3:41].[CH3:70][C:71]([NH:82][CH2:83][CH:84]([OH:100])[CH2:85][O:86][C:87]1[C:92]2[C:93]3[C:98]([NH:99][C:91]=2[CH:90]=[CH:89][CH:88]=1)=[CH:97][CH:96]=[CH:95][CH:94]=3)([C:73]1[CH:78]=[CH:77][C:76]([N:79]=[N+:80]=[N-:81])=[CH:75][CH:74]=1)[CH3:72].[NH2:101][C:102]1[CH:109]=[CH:108][C:105]([CH2:106][OH:107])=[CH:104][CH:103]=1.[OH:110]N1C2C=CC=CC=2N=N1>C(N(CC)C=O)C.CC(O)C.C(OCC)(=O)C>[NH:1]([C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34])[C@@H:2]([C:4]([NH:6][C@H:7]([C:15]([NH:17][C@H:18]([C:30]([OH:32])=[O:31])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])=[O:16])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:3].[CH3:41][C:40]([NH:51][CH2:52][CH:53]([OH:69])[CH2:54][O:55][C:56]1[C:61]2[C:62]3[C:67]([NH:68][C:60]=2[CH:59]=[CH:58][CH:57]=1)=[CH:66][CH:65]=[CH:64][CH:63]=3)([C:42]1[CH:47]=[CH:46][C:45]([N:48]=[N+:49]=[N-:50])=[CH:44][CH:43]=1)[CH3:39].[CH3:72][C:71]([NH:82][CH2:83][CH:84]([OH:100])[CH2:85][O:86][C:87]1[C:92]2[C:93]3[C:98]([NH:99][C:91]=2[CH:90]=[CH:89][CH:88]=1)=[CH:97][CH:96]=[CH:95][CH:94]=3)([C:73]1[CH:78]=[CH:77][C:76]([N:79]=[N+:80]=[N-:81])=[CH:75][CH:74]=1)[CH3:70].[CH:104]1[C:105]([C:106]([OH:110])=[O:107])=[CH:108][CH:109]=[C:102]([NH2:101])[CH:103]=1
Reactant: Nc1ccc(CO)cc1
Reactant: On1nnc2ccccc21
Agent: C=CCOC(=O)NCCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)OCC=C)C(=O)O
Agent: CC(C)(NCC(O)COc1cccc2[nH]c3ccccc3c12)c1ccc(N=[N+]=[N-])cc1
Agent: CCN(C=O)CC
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Nc1ccc(C(=O)O)cc1
Temperature: -8 °C
Reaction time: 48 h

Procedure:
100 mg (0.105 mmol) of Aloc-D-Ala-Phe-Lys(Aloc)-PABC-PABC-PNP 18 was dissolved in dry N,N-diethylformamide under an argon atmosphere and cooled to −8° C. 4-Aminobenzylalcohol (14.2 mg, 1.1 equiv), dipea (18.3 μl, 1.0 equiv) and 1-hydroxybenzotriazole (HOBt) (4 mg, 0.3 equiv) were added. The reaction mixture was stirred for 48 hours at room temperature, and diluted with 10% 2-propanol/ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate, 0.5 N potassium bisulfate, and brine, dried over sodium sulfate (Na2SO4), and evaporated to yield the desired product 34 as a cream colored powder 86 mg (88%). 1H NMR (300 MHz CDCl3) δ 0.95–2.05 (m, 9H, 3CH2-Lys and CH3-Ala), 2.88–3.11 (m, 4H, 2H Bn-Phe and N—CH2-Lys), 3.95–4.62 (m, 7H, 3Hα and 4H Aloc), 4.75 (s, 2H, CH2—OH), 5.12–5.21 (m, 6H, 4 Aloc and CH2-Bn), 5.09 (s, 2H, CH2-Bn), 5.65–6.00 (m, 2H, Aloc), 6.79–7.41 (m, 15H, aromatic) 7.62 (d, 2H, aromatic) ppm; MS (FAB) m/e 959 (M+Na)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][O:25][NH2:26])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].Cl.[N:29]1([C:34]([NH2:36])=O)C=CC=N1>CO>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][O:25][NH:26][C:34]([NH2:36])=[NH:29])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CC(c1ccccc1)n1ccc2cc(OCCON)ccc21
Reactant: NC(=O)n1cccn1
Agent: Cl
Solvent: CO
Product: CCOC(=O)CC(c1ccccc1)n1ccc2cc(OCCONC(=N)N)ccc21
Reaction time: 120 h
Yield: 97 %

Procedure:
3-[5-(2-aminooxy-ethoxy)-indol-1-yl]-3-phenyl-propionic acid ethyl ester (0.28 g, 0.75 mmol) and 1H-pyrazole-1-carboxamide hydrochloride (0.99 g, 0.67 mmol) were dissolved in methanol (3 mL) and stirred for 5 days. The solvent was evaporated under vacuum and the crude mixture was purified via column chromatography with silica gel, eluting with 10% methanol/dichloromethane to afford the title compound (97% yield). 1H NMR (CDCl3), δ 7.11–7.26 (m, 7H), 7.00 (d, 1H, J=2.3 Hz), 6.75 (dd, 1H, J=2.3, 8.8 Hz), 6.43 (d, 1H, J=3.2 Hz), 5.98 (t, 1H, J=7.6 Hz), 4.08 (m, 2H), 3.99 (m, 4H), 3.23 (m, 2H), 1.05 (t, 3H, J=7.2 Hz).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:8]=[C:7]([O:17][CH3:18])[C:6]=12.[C:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)#[CH:20].C(N(CC)CC)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I>[CH3:18][O:17][C:7]1[C:6]2[N:5]([N:4]=[CH:3][C:2]=2[C:20]#[C:19][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[CH:8]=1
Reactant: C#Cc1cccnc1
Reactant: COc1cc(-c2cnn(C)c2)cn2ncc(I)c12
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(-c2cnn(C)c2)cn2ncc(C#Cc3cccnc3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-iodo-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (20.0 mg, 0.056 mmol), 3-ethynylpyridine (17.5 mg, 0.169 mmol), tetrakis(triphenylphosphine)palladium (0) (6.5 mg, 5.7 mmol), and copper (I) iodide (6.5 mg, 0.034 mmol) were suspended in DMF (1 ml). Triethylamine (0.016 ml, 0.113 mmol) was added, the mixture was sparged with argon for 10 minutes then allowed to stir at ambient temperature. After 1 h, the reaction mixture was diluted in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA. The fractions containing product were combined and diluted in ethyl acetate, then washed with aqueous sodium bicarbonate and dried over sodium sulfate, filtered and concentrated to give 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)-3-(pyridin-3-ylethynyl)pyrazolo[1,5-a]pyridine. 1H NMR (600 MHz, DMSO-d6) δ 8.68 (s, 1H); 8.65 (d, 1H); 8.51 (dd, 1H); 8.30 (s, 1H); 8.17 (s, 1H); 8.03 (s, 1H); 7.85-7.88 (m, 1H); 7.40-7.43 (m, 1H); 7.02 (s, 1H); 4.02 (s, 3H); 3.85 (s, 3H). LRMS (ESI) calculated for C19H16N5O [M+H]+, 330.1; found 330.0.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9].[NH3:12].CO>>[NH2:12][CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1sccc1CBr
Reactant: N
Solvent: CO
Product: COC(=O)c1sccc1CN
Temperature: 25 °C
Reaction time: 14 h
Yield: 57 %

Procedure:
A 2-L single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was purged with nitrogen and charged with 116c (7.50 g, 32.0 mmol) and a 7 M solution of ammonia in methanol (915 mL, 6.40 mol). The solution was stirred at room temperature for 14 h. After that time, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (150 mL) and extracted with methyl tert-butyl ether (2×25 mL). The aqueous layer was basified with sodium hydroxide (5.00 g) and extracted with methyl tert-butyl ether (3×150 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford a 57% yield (3.14 g) of 116d as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.45 (d, 1H, J=5.1 Hz), 7.14 (d, 1H, J=5.1 Hz), 4.11 (s, 2H), 3.88 (s, 3H), 1.72 (br s, 2H); MS (ESI+) m/z 172.0 (M+H). The material was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([N:13]([CH3:19])[CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.N1C=CC=CC=1.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:32]>C(Cl)Cl.O>[C:34]1([O:33][C:31](=[O:32])[NH:1][C:2]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([N:13]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[CH3:19])[CH:8]=3)[N:5]=[C:4]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN(C)CCN(C)c1cccc(-n2nc(C(C)(C)C)cc2N)c1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CN(C)CCN(C)c1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
A solution of Intermediate 150b (50 mg, 0.16 mmol) in DCM (2 mL) was treated with pyridine (26 μL, 0.32 mmol) and phenyl chloroformate (32 μL, 0.25 mmol). The resulting mixture was stirred at RT for 2 h. Further pyridine (26 μL, 0.32 mmol) and phenyl chloroformate (32 μL, 0.25 mmol) were added and the mixture stirred at RT for 16 h. The mixture was diluted with water and the phases separated. The aqueous layer was extracted with DCM and the combined organic phase was washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by FCC, using 0-20% MeOH in DCM, to give the title compound (30 mg, 43%). LCMS (Method 3): Rt 2.97 min, m/z 436 [MH+].
Reaction SMILES: C(NC(C)C)(C)C.[C:8]1([CH3:17])[CH:13]=[CH:12][C:11]([S@:14]([CH3:16])=[O:15])=[CH:10][CH:9]=1.[CH2:18]([O:25][C:26]([N:28]1[CH2:41][CH2:40][CH2:39][C@H:29]1[C:30]([N:32]1[CH2:38][CH2:37][CH2:36][C@H:33]1[CH:34]=[O:35])=[O:31])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>C1COCC1>[CH2:18]([O:25][C:26]([N:28]1[CH2:41][CH2:40][CH2:39][C@H:29]1[C:30]([N:32]1[CH2:38][CH2:37][CH2:36][C@H:33]1[CH:34]([OH:35])[CH2:16][S@@:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:17])=[CH:9][CH:10]=1)=[O:15])=[O:31])=[O:27])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: Cc1ccc([S@](C)=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1ccc([S@@](=O)CC(O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
To diisopropylamine (0.26 ml) in THF (6 ml) was dropwise added 1.62M n-butyllithium-hexane solution (1.12 ml) at -78° C., and the mixture was stirred at 0° C. for 0.5 hour. The reaction mixture was cooled to -30° C., dropwise added with (S)-(-)-methyl p-tolyl sulfoxide (255 mg) in THF (6 ml), and stirred at 0° C. for 0.5 hour. The reaction mixture was cooled to -78° C. and dropwise added with known N-benzyloxycarbonyl-L-prolyl-L-prolinal (300 mg) in THF (6 ml). After stirring for 0.5 hour, an aqueous solution of saturated ammonium chloride was added thereto, followed by stirring at room temperature for 10 minutes. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine order, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluate; chloroform-methanol) to give 388 mg of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[CH3:9][C:10]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[O:11]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[C:17]1([C:10]2([CH3:9])[C:14](=[O:15])[CH:13]=[C:12]([CH:16]=[CH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[O:11]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=Cc1cccnc1
Reactant: CC1=CC(=O)C(C)(c2ccccc2)O1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(c2ccccc2)OC(C=Cc2cccnc2)=CC1=O
Temperature: 60 °C
Yield: 54.3 %

Procedure:
To a solution of 3-pyridinecarboxaldehyde (1.03 g, 9.6 mM) and 2,5-dimethyl-2-phenyl-3(2H)-furanone (1.0 g, 8 mM) in ethanol (50 mL), was added 1N aqueous sodium hydroxide (2.4 mL, 2.4 mM). The reaction solution was heated at 60° C. for 8 hours. After the reaction solution cooled to room temperature, saturated aqueous sodium chloride (200 mL) was added. The aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a brown solid. The crude product was purified by chromatography (silica gel, pet. ether-ethyl acetate) to afford a yellow crystalline solid (0.8 g, 36.3% yield), m.p. 106°-108° C.
Reaction SMILES: [H-].[Na+].CCCCCC.CS(O[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][C:24]#[N:25])(=O)=O.[Cl-].[Na+]>CN(C)C=O>[C:24]([CH:23]1[CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][CH:20]=[C:19]12)#[N:25]
Reactant: CS(=O)(=O)OCCCCn1cccc1CC#N
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: N#CC1CCCCn2cccc21
Reaction time: 1 h
Yield: 69 %

Procedure:
To a stirred suspension of sodium hydride (obtained from 2.5 g. of 50% sodium hydride in mineral oil which had been freed of the carrier with hexane) in anhydrous dimethylformamide (60 ml.), maintained in an atmosphere of nitrogen and cooled to -5°, is added a solution of 1-(4-methansulfonyloxybutyl)pyrrol-2-acetonitrile (10 g, 0.062 moles) in dimethylformamide (40 ml.) at a rate such that the temperature is maintained at 10°-15° C. After the addition, stirring at this temperature is continued for 1 hours, and then a dilute sodium chloride solution (500 ml.) is added. The product is extracted into benzene (4×200 ml.), the extract is washed with water (4×500 ml.), dried, and evaporated in vacuo. The residue is purified by column chromatography on silica gel using hexane-ethyl acetate (95:5) as the eluting solvent to give a crude product in a 69% yield. Crystallization from acetone-hexane gives 9-cyano-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine (Formula (XIX) where n is 1), m.p. of 70°-72° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].CC(C)([O-])C.[K+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>CN(C)C=O>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)=[O:10]
Reactant: O=C(O)Cc1ccccc1O
Reactant: COc1ccc(CCl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)Cc2ccccc2O)cc1
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
2-hydroxyphenylacetic acid (10 g, 66 mmol) was dissolved in N,N-dimethyl-formamide (100 ml) and cooled on ice-bath. Potassium tert-butoxide (8.85 g, 78 mmol) was added. The mixture was left for 30 min and allowed to reach room temperature. 4-Methoxy-benzylchloride (11.7 g, 72 mmol) in N,N-dimethyl-formamide (30 ml) was then added dropwise, under nitrogen atmosphere and left over-night. The solvent was evaporated under reduced pressure and the crude mixture was dissolved in ether (100 ml) and washed with water (25 ml), brine and dried over sodium sulphate. Chromatography (hexane-ethyl acetate, 2:1) followed by recrystallization (hexane-ethyl acetate) gave the title compound (7.6 g, 42%).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][SiH:10]([CH:12]([SiH:17]([Cl:19])[Cl:18])[Si:13]([Cl:16])([Cl:15])[Cl:14])[Cl:11]>C1C=CC=CC=1>[Cl:11][Si:10]1([Cl:9])[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[Si:17]([Cl:18])([Cl:19])[CH:12]1[Si:13]([Cl:16])([Cl:14])[Cl:15]
Reactant: Cl[SiH](Cl)C([SiH](Cl)Cl)[Si](Cl)(Cl)Cl
Reactant: C#Cc1ccccc1
Solvent: c1ccccc1
Product: Cl[Si](Cl)(Cl)C1[Si](Cl)(Cl)C=C(c2ccccc2)[Si]1(Cl)Cl
Reaction time: 15 h
Yield: 43.9 %

Procedure:
Hydrosilation of phenylacetylene with bis(dichlorosilyl)trichlorosilylmethane in the presence of Pt(C2H4)(PPh3)2. Into the same apparatus as described in Example 1 were add 0.99 g of bis(dichlorosilyl)trichlorosilylmethane, 0.101 g of Pt(C2H4)(PPh3)2, and 25 ml of dried benzene forming a mixture. To this mixture at reflux was added 0.32 ml of phenylacetylene over a 10 minute period. The resulting mixture was stirred for an additional 15 hours at reflux temperature and then the solvent removed. The residue was vacuum distilled at 67 Pa to give a mixture comprising 0.58 g of 1,1,3,3-tetrachloro-2-trichlorosilyl-4-phenyl-1,3-disilacyclopent-4-ene (TCD-GC area 43.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH:10]([CH3:12])[CH3:11])[CH3:9])[C:4](=[O:13])[C:3]=1[C:14]#[N:15].[Br:16]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:16][C:7]1[C:2]([Cl:1])=[C:3]([C:14]#[N:15])[C:4](=[O:13])[N:5]([CH:8]([CH:10]([CH3:11])[CH3:12])[CH3:9])[CH:6]=1
Reactant: CC(C)C(C)n1ccc(Cl)c(C#N)c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C(C)n1cc(Br)c(Cl)c(C#N)c1=O
Temperature: 50 °C
Yield: 93.7 %

Procedure:
To a solution of 4-chloro-1-(3-methylbutan-2-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step E (305 mg) in N,N-dimethylformamide (3.0 mL) was added N-bromosuccinimide (296 mg) at room temperature. The reaction mixture was heated at 50° C. for 4 hr, and cooled to room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (386 mg).