Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[N:5]=[CH:6][C:7]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[NH2:16])=[N:8][CH:9]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[N:50]1([C:55]2[CH:63]=[CH:62][CH:61]=[CH:60][C:56]=2[C:57](O)=[O:58])[CH:54]=[CH:53][CH:52]=[N:51]1>>[N:50]1([C:55]2[CH:63]=[CH:62][CH:61]=[CH:60][C:56]=2[C:57]([NH:16][C@H:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[NH:10][C:7]2[CH:6]=[N:5][C:4]([C:3]([F:2])([F:17])[F:18])=[CH:9][N:8]=2)=[O:58])[CH:54]=[CH:53][CH:52]=[N:51]1
Reactant: O=C(O)c1ccccc1-n1cccn1
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ccccc1-n1cccn1

Procedure:
A solution of (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14, 213 mg, 0.75 mmol), HATU (430 mg, 1.13 mmol), triethylamine (0.315 ml, 2.26 mmol) and 2-(1H-pyrazol-1-yl)benzoic acid (CAS number 55317-53-8; 156 mg, 0.83 mmol) was stirred at room temperature overnight. This was then partitioned between DCM and a saturated solution of sodium bicarbonate, filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].S(Cl)([Cl:16])(=O)=O.O.C(OCC)(=O)C>O1CCCC1>[Cl:16][CH2:11][C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:12]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCl)c1cccc([N+](=O)[O-])c1
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
3′-Nitroacetophenone (2.00 g) was dissolved in tetrahydrofuran (24.2 ml), and sulfuryl chloride (4.90 g) was dropwise added thereto at 22° C. over 15 minutes. After stirring for 2 hours, water (150 ml) was added to the reaction mixture and stirred for 1 hour. Ethyl acetate was added, and the separated organic layer was washed with aqueous saturated sodium bicarbonate/aqueous saturated sodium chloride mixed solvent. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue and stirred, and the precipitated crystal was then filtered and dried under reduced pressure to yield the desired 2-chloro-3′-nitroacetophenone (1.41 g; 58.3%).
Reaction SMILES: [CH2:1]1[O:5][C@@H:4]2[C@@H:6]([OH:9])[CH2:7][O:8][C@@H:3]2[C@@H:2]1[OH:10].[C:11]([OH:20])(=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>[OH-].[Na+].O>[CH2:1]1[O:5][C@@H:4]2[C@@H:6]([OH:9])[CH2:7][O:8][C@@H:3]2[C@@H:2]1[OH:10].[C:11]([O-:20])(=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC(=O)O
Agent: O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCC(=O)[O-]
Temperature: 180 °C

Procedure:
In a stirred apparatus with distillation head, 190.0 g (1.3 mol) of isosorbide (“Sorbon” from Ecogreen Oleochemicals) and 187.5 g (1.3 mol) of octanoic acid (caprylic acid) are initially charged at 80° C. together with 0.38 g of aqueous sodium hydroxide solution (18% by weight strength, aqueous) as catalyst. With stirring and under a flow of nitrogen (10-12 liters per hour), the reaction mixture is initially heated to 180° C., where the water of reaction begins to distill off. The reaction is then heated to 190° C. over a period of 1 hour and to 210° C. over a further 2 hours. After 210° C. is reached, the esterification is continued until an acid value of <1 mg KOH/g is reached. This gives 345.7 g of amber isosorbide caprylate (97% of theory). The pH (5% by weight in ethanol/water 1:1) is 5.9. The pH was measured according to DIN EN 1262.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:19]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]2[N:18]=[CH:17][NH:16][C:13]2=[N:14][CH:15]=1)=[O:8].N1C=CC=CC=1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:19]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]2[N:18]=[CH:17][NH:16][C:13]2=[N:14][CH:15]=1)=[O:8])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(N)cc1C(=O)Nc1cnc2[nH]cnc2c1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2ccccc2)cc1C(=O)Nc1cnc2[nH]cnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.8 %

Procedure:
50 mg of 5-Amino-N-(3H-imidazo[4,5-b]pyridin-6-yl)-2-methyl-benzamide (from example k) were dissolved in 0.5 ml dry DMF and 0.5 ml pyridine and treated dropwise at room temperature with 66 mg benzoyl chloride. After 16 hrs the solvents were removed under vacuum and the residue was stirred for 1 hr at room temperature in a mixture of 2 ml methanol and 1 ml concentrated ammonia. Solvents were removed under vacuum and the residue was purified by HPLC/MS in methanol/water/acetic acid. Product containing fractions were pooled and concentrated under vacuum. Precipitated product was collected by filtration and washed with dilute ammonia to yield 11 mg of the title product.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1O.COC1C=CC(C(Cl)(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1>N1C=CC=CC=1.ClCCl>[F:1][C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:8]1
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1F
Agent: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.244 gins. (20 mMoles) of 5-fluorouridine is dissolved in 20 mL anhydrous pyridine and then dried under vacuum. This procedure is repeated at least one more time in order to make 5-fluorouridine devoid of moisture. The dried 5-fluorouridine is then dissolved in 20 mL of pyridine. 8.131 gms (24 mMoles, 1.2 eq.) of 4,4'-dimethoxy trityl chloride is added as solid in 4 fractions over a period of 2 hours. The reaction mixture is then stirred at room temperature overnight and is then diluted with 25 mL of dichloromethane and washed with saturated sodium bicarbonate solution. The aqueous layer is then washed with 20mL dichloromethane. The organic layers are mixed and washed with saturated bicarbonate solution two more times. The organic layer is then dried over anhydrous sodium sulphate. The solvent is removed under vacuum to yield a yellow foam which is purified on a silica gel column using 90:10 chloroform:methanol as eluent. The 4, 4'-dimethoxytrityl derivative of 5-fluorodeoxyuridine is prepared in an analogous manner.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([C:10]([O:12][CH3:13])=[O:11])#[C:5][C:6](OC)=[O:7]>C1(C)C=CC=CC=1>[OH:7][C:6]1[CH:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[NH:3][N:2]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: NN
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc(O)n[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
Hydrazine monohydrate (6.7 g, 210 mmol) was added to a solution of dimethyl acetylenedicarboxylate (24.7 g, 175 mmol) in toluene (90 ml) at 0° C., and the thus-obtained mixture was gradually temperature-increased up to room temperature, stirred for 2 hours and further stirred under heating at 130° C. for 4 hours. After completion of the reaction, a precipitated solid was filtered and washed with diethyl ether, to give a white solid of methyl 3-hydroxypyrazole-5-carboxylate (18.2 g, yield: 73.8%). mp: 229-231° C.; 1H-NMR (DMSO-d6, DMSO, ppm): δ 3.79 (s, 3H), 5.91 (s, 1H), 10.10-10.45 (br s, 1H). (Hydroxy proton was not assigned.)
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:18]1
Reactant: ICC1CCCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCNC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCCN(CC4CCCC4)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[2-(3-piperidinyl)ethyl]-9H-purin-6-amine and (1-iodomethyl)cyclopentane.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([O:11]C)=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:14])(=[O:13])[N:3]=1.[C-]#N.[K+].C(Cl)Cl>CS(C)=O>[NH2:1][C:2]1[C:6]2[C:7]([OH:11])=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:14])(=[O:13])[N:3]=1
Reactant: COc1cccc2c1C(N)=NS2(=O)=O
Agent: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: NC1=NS(=O)(=O)c2cccc(O)c21
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
A mixture of 5 gm of 3-amino-4-methoxy-1,2-benzoisothiazole-1,1-dioxide and 1.63 gm of potassium cyanide in 15 ml of dimethyl-sulfoxide was heated to 130°-140° C. (bath temperature 160° C.) and kept at this temperature for 1.5 hours. After cooling, the reaction mixture was stirred into 250 ml of methylene chloride, and the resulting precipitate was filtered off, dried and dissolved in 30 ml of water. At 60° C. the solution was treated with charcoal and filtered while hot. The hot filtrate was adjusted to pH 1 with concentrated aqueous hydrochloric acid. After cooling, the resulting crystals were suction-filtered off, washed with a little ice water and dried in vacuo.
Reaction SMILES: [CH:1]1([C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([OH:10])[C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:17](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C.C(Cl)Cl>[CH:1]1([C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([OH:10])[C:7]([O:9][CH3:17])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C(O)(c1ccccc1)C1CCCC1
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C(O)(c1ccccc1)C1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a mixture of racemic cyclopentylmandelic acid R/S(±)1 (4.47 g, 20 mmol) and potassium carbonate (7.01 g, 50 mmol) in DMF (50 ml), methyl iodide (8.64 g, 60 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 h, and then poured into water and extracted with hexanes three times. Evaporation of the dried hexanes extract gave a crude product. Flash chromatography of the crude product on silica gel with 1.5:1 hexanes:methylene chloride gave the pure product 2 (3.02 g, 64%). 1H NMR (CDCl3, 300 MHz): 1.32-1.37, 1.43-1.69 [8H, m, (CH2)4], 2.90 [1H, p, CHC(OH)], 3.74 (1H, s, OH), 3.77 (3H, s, CH3), 7.25-7.37, 7.63-7.65 (5H, m, Ph) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[C:14]([C:17](=[O:22])[C:18](=[CH2:21])[CH2:19][CH3:20])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][CH2:6]1.C(=O)(O)[O-].[Na+:27]>O>[Cl:1][C:2]1[C:15]([Cl:16])=[C:14]([C:17](=[O:22])[C:18](=[CH2:21])[CH2:19][CH3:20])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1([C:9]([O-:11])=[O:10])[CH2:8][CH2:7][CH2:6]1.[Na+:27]
Reactant: C=C(CC)C(=O)c1ccc(OC2(C(=O)O)CCC2)c(Cl)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C=C(CC)C(=O)c1ccc(OC2(C(=O)[O-])CCC2)c(Cl)c1Cl

Procedure:
0.103 g of 1-[2,3-Dichloro-4-(2-methylenebutyryl)phenoxy]cyclobutane-1-carboxylic acid is dissolved 33 ml of 0.1N sodium bicarbonate and with isotonic saline to make a final volume of 100 ml. The water from all sources was pyrogen free. The solution is sterilized by filtration. This solution is 3 mM in active antisickling agent.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17]Cl)[N:9]=[CH:8][CH:7]=[C:6]2[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[O:28])=[CH:22][CH:21]=1)#[N:2].[CH3:38][NH:39][CH3:40]>CN(C)C=O.[Cl-].[Na+].O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:39]([CH3:40])[CH3:38])[N:9]=[CH:8][CH:7]=[C:6]2[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[O:28])=[CH:22][CH:21]=1)#[N:2]
Reactant: CNC
Reactant: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OCCCCCl)c(C#N)cc34)cc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OCCCCN(C)C)c(C#N)cc34)cc2)cc1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
N-(4-(6-Cyano-7-(4-chlorobutoxy)-4-quinolyl)oxyphenyl-N′-(4-methoxyphenyl)urea (120 mg) was dissolved in dimethylformamide (3 ml), and then a 50% dimethylamine solution (93 μl) was added and the mixture was heated and stirred at 70° C. for 5 hours. The reaction solution was poured into saturated brine and extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate and concentrated. The residue was passed through NH silica gel (Fuji Silysia Chemical) and eluted with a solvent (ethyl acetate), and then further eluted with another solvent (ethyl acetate:methanol=10:1) and concentrated. The obtained solid was passed through Merck Silica Gel using tetrahydrofuran, and after eluting the insoluble portion with tetrahydrofuran and ethyl acetate, it was further eluted with solvents (tetrahydrofuran:methanol:triethylamine=10:1:1, ethyl acetate:methanol:triethylamine=10:1:1) and concentrated to obtain 10 mg of the title compound as a solid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: C1CNCCN1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: Clc1cc(Nc2ncnc3[nH]nc(OCCN4CCNCC4)c23)ccc1OCc1ccccn1
Yield: 42 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and piperazine to give the title compound in 42% yield; NMR Spectrum: 2.40 (br s, 4H), 2.64-2.65 (m, 4H), 2.75 (t, 2H), 4.41 (t, 2H), 5.28 (s, 2H), 7.24 (d, 1H), 7.36 (t, 1H), 7.55-7.58 (m, 2H), 7.86-7.91 (m, 2H), 8.29 (s, 1H), 8.51 (br s, 1H), 8.59 (d, 1H); Mass Spectrum: 481 (MH+).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].CI.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:28]1[C:32]2([CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1.C(OCC)(=O)C>O1CCCC1.O>[CH2:1]=[C:35]1[CH2:36][CH2:37][C:32]2([O:31][CH2:30][CH2:29][O:28]2)[CH2:33][CH2:34]1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CI
Solvent: C1CCOC1
Product: C=C1CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Potassium tert-butoxide (3.230 gm, 28.812 mmol) and triphenylphosphine methyl iodide (10.286 gm, 28.812 mmol) were dissolved in dry tetrahydrofuran (30 ml). The mixture was cooled to −78° C. and stirred at the same temperature for about 15 minutes. 1,4-Dioxaspiro[4.5]decan-8-one (3.0 gm, 19.208 mmol) in tetrahydrofuran was added drop wise and the mixture was stirred at the same temperature for about 30 minutes and then it was warmed to room temperature and stirred overnight, extaction was done with ethyl acetate and water. The organic layer was dried over sodium sulphate and concentrated. Purification was done by column chromatography.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH2:34][CH2:35]CS([O-])(=O)=O)[CH2:19][CH2:18][N:17]([C:20](=[O:33])[C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[CH2:16]2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[C:42]1([C:48]2([C:54]([NH2:56])=[O:55])[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2([CH2:34][CH2:35][N:51]3[CH2:50][CH2:49][C:48]([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)([C:54]([NH2:56])=[O:55])[CH2:53][CH2:52]3)[CH2:19][CH2:18][N:17]([C:20](=[O:33])[C:21]3[CH:22]=[C:23]([O:31][CH3:32])[C:24]([O:29][CH3:30])=[C:25]([O:27][CH3:28])[CH:26]=3)[CH2:16]2)=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-[4-(tert-butyldimethylsilyloxy)-phenyl]-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (8 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (12 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:46])[CH2:7][CH2:6][CH2:5][N:4]([C:8]([CH:10]2[CH:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]([C:21](=[O:38])[CH2:22][NH:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([O:35]CC)=[O:34])[CH:28]=3)=[O:25])[CH:12]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:11]2)=[O:9])[CH2:3]1.[OH-].[K+]>O.CO>[C:42]([O:41][C:39]([CH:12]1[CH2:11][CH:10]([C:8]([N:4]2[CH2:5][CH2:6][CH2:7][C:2]([CH3:46])([CH3:1])[CH2:3]2)=[O:9])[CH:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:13]1[C:21](=[O:38])[CH2:22][NH:23][C:24](=[O:25])[NH:26][C:27]1[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=1)[C:33]([OH:35])=[O:34])=[O:40])([CH3:43])([CH3:44])[CH3:45]
Reactant: CCOC(=O)c1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CC(C(=O)N3CCCC(C)(C)C3)C2c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)CCCN(C(=O)C2CC(C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc3cccc(C(=O)O)c3)C2c2ccccc2)C1
Yield: 52.8 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 2.3 g of tert-butyl (2RS,4SR,5SR)-4-(3,3-dimethylpiperidinocarbonyl)-1-{2-[3-(3-(ethoxycarbonyl)phenyl]ureido]acetyl}-5-phenylpyrrolidine-2-carboxylate and 0.2 g of potassium hydroxide in a mixture of 20 cm3 of distilled water and 50 cm3 of methanol. After treatment, there are obtained 1.16 g of (2RS,4SR,5SR)-3-{3-[2-(2-tert-butoxycarbonyl-4-(3,3-dimethylpiperidinocarbonyl)-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoic acid [Rf =0.2; eluent=methylene chloride/methanol (97.5/2.5)].
Reaction SMILES: [CH:1]1([C:5]2[C:14](I)=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH3:16])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:17][N:18](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[C:17]([C:14]1[C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:6][C:7]([CH3:16])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])#[N:18]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(I)c(C2CCC2)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1cc(C#N)c(C2CCC2)cc1C
Temperature: 100 °C
Yield: 88 %

Procedure:
A mixture of methyl 4-cyclobutyl-5-iodo-2-methylbenzoate (compound 6.3, 4.17 g, 12.6 mmol), Zn(CN)2 (2.96 g, 25.2 mmol) and Pd(PPh3)4 (0.73 g, 0.63 mmol) in DMF (30 mL) was degassed and the flask was charged with argon. The mixture was heated at 100° C. under argon overnight. After cooling to ambient temperature, the mixture was quenched with saturated aq. FeSO4 (20 mL) and diluted with EtOAc (200 mL). The greenish solid was removed by filtration through Celite® and the filtrate was partitioned between water and EtOAc. The organics was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (hexanes:EtOAc 30:1 to 20:1) to yield the title compound as a white solid (2.55 g, 88%). 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.28 (s, 1H), 3.90 (s, 3H), 3.86-3.82 (m, 1H), 2.68 (s, 3H), 2.55-2.45 (m, 2H), 2.27-2.04 (m, 3H), 1.89-1.87 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3[N:7]=[C:8]([CH:14]=O)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[N+](=[C:20](P(OC)(OC)=O)C(OC)=O)=[N-].C(=O)([O-])[O-].[K+].[K+]>CO>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3[N:7]=[C:8]([C:14]#[CH:20])[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: O=Cc1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: COC(=O)C(=[N+]=[N-])P(=O)(OC)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1nc2c(s1)CCOc1cc(Br)ccc1-2
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.6 %

Procedure:
8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbaldehyde (0.688 g, 2.2 mmol) was dissolved in methanol (8 mL) and methyl 2-diazo-2-(dimethoxyphosphoryl)acetate (0.923 g, 4.44 mmol) was added followed by potassium carbonate (0.613 g, 4.44 mmol). The resulting mixture was stirred 12 h at ambient temperature and quenched by the addition of sat. NH4Cl aqueous solution and stirred 5 min. Diluted with H2O and EtOAc, extracted the aqueous layer with EtOAc (2×) and the combined organic portions were washed with brine. Dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by ISCO chromatography (24 g column, 0-25% EtOAc/heptane) to provide 8-Bromo-2-ethynyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene as an oil (0.26 g, 38% yield). 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J=8.5, 1H), 7.31-7.18 (m, 2H), 4.37 (t, J=5.1, 2H), 3.49 (s, 1H), 3.33 (t, J=5.1, 2H)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][C:3]=1[F:12].C=O.F[C:16](F)(F)C([O-])=O.C[NH2+]C1C=CC=CC=1>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[CH2:16])[C:8]2=[O:11])=[CH:4][C:3]=1[F:12]
Reactant: O=C1CCc2cc(F)c(Br)cc21
Reactant: O=C([O-])C(F)(F)F
Agent: C=O
Agent: C[NH2+]c1ccccc1
Solvent: C1CCOC1
Product: C=C1Cc2cc(F)c(Br)cc2C1=O
Temperature: 25 °C
Yield: 71 %

Procedure:
6-Bromo-5-fluoro-2,3-dihydro-1H-inden-1-one (commercially available), 4 g, 17.5 mmol), paraformaldehyde (2.48 g, 78.6 mmol) and N-methylanilinium trifluoroacetate (5.79 g, 26.2 mmol) were dissolved in anhydrous THF (80 mL) and refluxed overnight. The mixture was cooled to r.t. and concentrated. The residue was re-dissolved in EtOAc and brine. The phases were separated and the organic phase was dried over sodium sulfate and concentrated. The product was purified by flash column chromatography using heptane/EtOAc 7:1 as eluent affording the title compound (2.99 g, 71% yield). 1H NMR (400 MHz, CDCl3) δ ppm 3.73 (s, 3 H) 5.69 (m, 1 H) 6.39 (m, 1 H) 7.25 (s, 2 H) 8.10 (d, 1 H); MS (EI) m/z 240, 242 M+.
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][CH2:4][CH2:3]1.[NH2:22][C:23]1([CH2:29][C:30]([NH2:32])=[O:31])[CH2:26][S:25](=[O:28])(=[O:27])[CH2:24]1>>[NH2:32][C:30](=[O:31])[CH2:29][C:23]1([NH:22][C:12]([C:9]2[CH:8]=[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])[C:6]([C:2]3([F:1])[CH2:3][CH2:4][CH2:5]3)=[CH:11][N:10]=2)=[O:14])[CH2:24][S:25](=[O:27])(=[O:28])[CH2:26]1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1(F)CCC1)C(F)(F)F
Reactant: NC(=O)CC1(N)CS(=O)(=O)C1
Product: C[C@H](Oc1cc(C(=O)NC2(CC(N)=O)CS(=O)(=O)C2)ncc1C1(F)CCC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(1-fluorocyclobutyl)-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carboxylic acid (example 305e) and 2-(3-amino-1,1-dioxo-thietan-3-yl)acetamide (example 160d) as starting materials and isolated (19 mg, 49%); MS (ESI, m/z): 468.3 (M+H+).