Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].CS[C:10]1[N:11]=[N:12][C:13]([C:27]#[N:28])=[C:14]([N:16]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[CH2:18][CH2:17]2)[N:15]=1>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:10]1[N:11]=[N:12][C:13]([C:27]#[N:28])=[C:14]([N:16]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[CH2:18][CH2:17]2)[N:15]=1
Reactant: COCCO
Reactant: CSc1nnc(C#N)c(N2CCc3ccccc3CC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1nnc(C#N)c(N2CCc3ccccc3CC2)n1
Reaction time: 0.25 h
Yield: 9 %

Procedure:
Under an argon atmosphere at 0° C., a solution of 25.6 mg (0.34 mmol) of 2-methoxy-ethanol in 2 ml of tetrahydrofurane was treated with 15 mg (0.34 mmol) of sodium hydride (55% dispersion in refined oil) and stirred during 15 min. To this mixture, a solution of 100 mg (0.34 mmol) of 3-methylsulfanyl-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile in 3 ml of tetrahydrofurane was added and stirring continued for 18 h at 40° C. The yellow solution was evaporated under reduced pressure and the residue (141 mg) was chromatographed on silica gel with a 99:1 v/v mixture of dichloromethane and methanol as eluent. Thus were obtained 10 mg (9% of theory) of 3-(2-methoxy-ethoxy)-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile as a light yellow solid; MS: 326 (M+H)+.
Reaction SMILES: Cl.C([NH:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11](=[N:35][O:36][CH3:37])[C:12]([NH:14][CH:15]2[C:33](=[O:34])[N:17]3[C:18]([C:30]([OH:32])=[O:31])=[C:19]([CH:22]([S:24][C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH3:23])[CH2:20][S:21][C@H:16]23)=[O:13])[N:6]=1)=O>CO>[NH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11](=[N:35][O:36][CH3:37])[C:12]([NH:14][CH:15]2[C:33](=[O:34])[N:17]3[C:18]([C:30]([OH:32])=[O:31])=[C:19]([CH:22]([S:24][C:25]4[NH:26][N:27]=[N:28][N:29]=4)[CH3:23])[CH2:20][S:21][C@H:16]23)=[O:13])[N:6]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1nccc(NC=O)n1
Agent: Cl
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1nccc(N)n1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 55.5 %

Procedure:
Conc. hydrochloric acid (0.36 ml) was added to a solution of 7-[2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (1.9 g) in methanol (38 ml), and the mixture was stirred at ambient temperature for 5.5 hours. The reaction mixture was concentrated, and the concentrate was diluted with water and then washed with ethyl acetate. After the ethyl acetate in the aqueous solution was removed by distillation, the aqueous solution was subjected to column chromatography on a macroporous, non-ionic adsorption resin, "Diaion HP-20" (Trade mark, manufactured by Mitsubishi Chemical Industries Ltd.) (110 ml). Elution was carried out with water (400 ml), 10% aqueous methanol (100 ml.), 20% aqueous methanol (200 ml.) and then 30% aqueous methanol (2 l.), and the fractions containing the desired compound were collected. The combined fractions were evaporated to dryness under reduced pressure to give powders (1.0 g.) of 7-[2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (a mixture of syn and anti isomer), mp. 150°-160° C. (dec.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[C:26]([NH:30][S:31]([C:34]1[CH:35]=[N:36][CH:37]=[C:38](Br)[CH:39]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[CH:35]=[N:36][CH:37]=[C:38]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:39]=1)(=[O:33])=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)NS(=O)(=O)c1cncc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)(C)NS(=O)(=O)c1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 5-bromo-pyridine-3-sulfonic acid tert-butylamide (example B.3) (439 mg, 1.3 mmol) according to general procedure II. Obtained as an orange solid (390 mg, 70%). MS (ISP) 568.2 [(M+H)+]; mp 224° C.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([Br:7])[NH:4][N:3]=1.[I-].[K+].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Br:1][C:2]1[N:6]=[C:5]([Br:7])[N:4]([CH2:16][C:15]2[CH:18]=[CH:19][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[N:3]=1
Reactant: Brc1n[nH]c(Br)n1
Reactant: COc1ccc(CCl)cc1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2nc(Br)nc2Br)cc1
Yield: 78 %

Procedure:
3,5-dibromo-1H-1,2,4-triazole (1.5 g, 6.61 mmol, Eq: 1.00), potassium iodide (110 mg, 661 μmol, Eq: 0.10), 4-methoxybenzyl chloride (1.14 g, 990 μl, 7.27 mmol, Eq: 1.1) and N,N-diisopropylethylamine (1.71 g, 2.31 ml, 13.2 mmol, Eq: 2.0) was stirred in acetonitrile (23.0 ml) overnight at room temperature. The crude material was applied on silica gel and purified by column to give 3,5-Dibromo-1-(4-methoxy-benzyl)-1H-[1,2,4]triazole (1.79 g, 78%) as white solid. MS: m/z=348.1 (M+H+)
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:11]=2[O:10][CH:9]=1)(=O)=O.[C:23]1([C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([SH:31])[CH3:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:22][O:21][C:19](=[O:20])[CH2:18][O:17][C:16]1[C:11]2[O:10][CH2:9][CH:8]([CH2:7][CH2:6][S:31][C:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH3:30])[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)COc1cccc2c(CCOS(C)(=O)=O)coc12
Reactant: CC(S)(c1ccccc1)c1ccccc1
Product: COC(=O)COc1cccc2c1OCC2CCSC(C)(c1ccccc1)c1ccccc1
Yield: 79.9 %

Procedure:
The same process as Example 17 was repeated except that methyl (3-(2-(methanesulfonyloxy)ethyl)benzofuran-7-yloxy)acetate (284 mg) and 1,1-diphenylethanethiol (240 mg) were used to obtain the object compound (310 mg, yield 95%).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][CH:4]([C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])[CH2:3]1.[C:12]([Si:16](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:15])([CH3:14])[CH3:13].N1C=CN=C1>CN(C=O)C.ClCCl>[Si:16]([O:1][CH:2]1[CH2:5][CH:4]([C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])[CH2:3]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CON(C)C(=O)C1CC(O)C1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Temperature: 25 °C
Yield: 50 %

Procedure:
Into a solution of 3-hydroxy-N-methoxy-N-methylcyclobutanecarboxamide (0.6 g, 0.004 mol in DMF (10 mL) was added tert-butylchlorodiphenylsilane (3 mL, 0.01 mol), followed by 1H-imidazole (1 g, 0.02 mol). The mixture was stirred at rt over night. The reaction was diluted with dichloromethane and washed with sat. NaHCO3, water and brine. The organic layers were dried over MgSO4, concentrated and purified with Combiflash (silica gel, 0-30% EtOAc/Hex) to give the desired product (0.7 g, 50%) as cis- and trans-isomer mixtures. LCMS calculated for C23H32NO3Si(M+H)+: 398.2; Found: 398.1.
Reaction SMILES: C(O[C:6]([N:8](C)[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:66]([CH3:69])[CH2:67][CH3:68])[C@H:25]([O:64][CH3:65])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:62][CH3:63])[C@@H:35]([CH3:61])[C:36]([NH:38][C@@H:39]([CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:40]([O:42][CH2:43][C:44]12[CH2:53][CH:48]3[CH2:49][CH:50]([CH2:52][CH:46]([CH2:47]3)[CH2:45]1)[CH2:51]2)=[O:41])=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.[C:71]([OH:77])([C:73]([F:76])([F:75])[F:74])=[O:72]>ClCCl>[F:74][C:73]([F:76])([F:75])[C:71]([OH:77])=[O:72].[CH3:6][NH:8][C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:66]([CH3:69])[CH2:67][CH3:68])[C@H:25]([O:64][CH3:65])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:62][CH3:63])[C@@H:35]([CH3:61])[C:36]([NH:38][C@@H:39]([CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[C:40]([O:42][CH2:43][C:44]12[CH2:45][CH:46]3[CH2:52][CH:50]([CH2:49][CH:48]([CH2:47]3)[CH2:53]1)[CH2:51]2)=[O:41])=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[CH:10]([CH3:12])[CH3:11]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCC12CC3CC(CC(C3)C1)C2)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCC12CC3CC(CC(C3)C1)C2)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Reaction time: 0.5 h

Procedure:
27.5 mg (28 μmol) of N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(adamantan-1-ylmethoxy)-1-oxo-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide were dissolved in 1.8 ml of dichloromethane, and 361 μl of TFA were added. The reaction mixture was stirred for 30 min and then concentrated. The residue was taken up in water and lyophilized. 22.7 mg (81% of theory) of the title compound were obtained.
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7]C(=O)[CH2:5][CH2:4]1.[CH:10](OC)([O:13][CH3:14])[O:11][CH3:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:12][O:11][C:10]1([O:13][CH3:14])[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1
Reactant: COC(OC)OC
Reactant: O=C1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: COC1(OC)CCNCC1
Reaction time: 24 h

Procedure:
Into 9 ml of methanol were dissolved 0.69 g of 4-piperidone hydrochloride monohydrate, 0.74 ml of trimethyl orthoformate and 86 mg of p-toluenesulfonic acid monohydrate, and the reaction was conducted at room temperature for 24 hours. The reaction mixture was evaporated under reduced pressure to remove the solvent. The residue was dissolved into 2 ml of N,N-dimethylacetamide and admixed with 1.4 ml of triethylamine to give a solution of 4,4-dimethoxypiperidine.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:29]=[N+:30]=[N-:31].[Na+]>>[N:29]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:15]=2[O:14]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cccc(Cl)c4)c3O2)cc1
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2cccc(-c3cccc(Cl)c3)c2O1

Procedure:
Treatment of (±)-[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (3.6 g, 8.66 mmol) with sodium azide (2.25 g, 34.65 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.125 g, 5 wt. %) generally according to the procedure described for Example 1 provided 1.91 g (74%) of (±)-1-[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a tan solid, hydrochloride salt. mp 150-154° C.; Anal. calcd. for C15H14ClNOHCl: C, 60.83; H, 5.1; N, 4.73. Found: C, 59.17; H, 5.12; N, 4.38.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[S:20][C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][CH:28]=3)=[C:22]([CH3:25])[C:23]=2[CH3:24])[O:7][C@@H:6]1[CH2:35][O:36]C(=O)C)(=O)C.C[O-].[Na+].CC(O)=O>CO>[CH2:33]([C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C:21]2[S:20][C:19]([C@H:8]3[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:35][OH:36])[O:7]3)=[C:23]([CH3:24])[C:22]=2[CH3:25])=[CH:28][CH:29]=1)[CH3:34]
Reactant: CCc1ccc(Cc2sc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c(C)c2C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCc1ccc(Cc2sc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(C)c2C)cc1
Yield: 28.3 %

Procedure:
To a solution of (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(5-(4-ethylbenzyl)-3,4-dimethylthiophen-2-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (57) (125 mg, 0.223 mmole) in MeOH (5 mL) was added NaOMe (25 wt % in MeOH, 310 μL, 1.34 mmole). The reaction mixture was stirred at ambient temperature for 2 h before AcOH (2 mL) was added. Purification by reverse phase preparative HPLC provided the title compound 60 (24.8 mg, 0.0632 mmole, 28%) as a brown solid.
Reaction SMILES: [C:1]1([CH:7](O)[C:8]#[CH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C(C)=CC=CC=1C.FC(F)(F)S([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])(=O)=O>ClCCl>[Si:25]([O:24][CH2:9][C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C#CC(O)c1ccccc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OCC#Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Phenyl-2-propyn-1-ol (7 g) was dissolved in dichloromethane at 0° C. under nitrogen. 2,6-Lutidine (6.17 ml) was added to the solution followed by dropwise addition of tert-butyldimethylsilyl trifluoromethane sulfonate (12.16 ml); the resulting solution was stirred overnight at room temperature. The dichloromethane was washed with water (2×), brine and dried (MgSO4) and solvent removed in vacuo. The residue was purified on flash silica using 100% petrol moving to 5% ethyl acetate/petrol, to afford the title compound as a yellow oil (10.31 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH2:10]O)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.O=S(Cl)[Cl:16].O>C1COCC1.[Cl-].[Cl-].[Zn+2]>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH2:10][Cl:16])[C:3]=1[O:12][CH3:13]
Reactant: COc1cc(Br)c(OC)c(CO)c1
Reactant: O=S(Cl)Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Br)c(OC)c(CCl)c1
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 52 (7.5 g, 30 mmol) and ZnCl2 (1 g) in THF (100 ml) was added SOCl2 (5.31 g, 45 mmol) dropwise. After 1 hr at rt, the reaction was poured into water and extracted with ether. The ether was dried, concentrated and the product was purified by column chromatography on silica gel (10% EtOAc/hex) to give 53 as an oil (5.5 g, 75%): 1H NMR(DMSO-d6) δ 7.21 (d, 1 H, J=3.0 Hz), 7.08 (d, 1 H, J=3.0 Hz), 4.73 (s, 2 H), 3.78 (s, 3 H), 3.75 (s, 3 H)
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)C.[B:26](OC(C)C)([O:31]C(C)C)[O:27]C(C)C.Cl>C1COCC1.C([Li])(CC)C.O>[C:1]([Si:5]([CH3:17])([CH3:16])[N:6]1[C:14]2[C:9](=[C:10]([B:26]([OH:31])[OH:27])[C:11]([F:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cc(F)ccc21
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)n1ccc2c(B(O)O)c(F)ccc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
To a solution of 1-(tert-butyl-dimethyl-silanyl)-5-fluoro-1H-indole (30.0 g, 0.12 mol) in anhydrous THF (1000 mL) were added N,N,N′,N′-tetramethylethylenediamine (36.6 mL, 0.241 mol) and a solution of s-butyl lithium (1.4 M in cyclohexane, 172 mL, 0.241 mmol) at −78° C. The resulting mixture was stirred at −78° C. for 2 h, then triisopropyl borate (37.5 mL, 162.7 mmol) was added dropwise. The resulting solution was stirred at −78° C. for 40 min, then allowed to warm to −20° C. An aqueous solution of HCl (2.4 M, 250 mL) was added and the resulting mixture was poured into H2O. The layers were separated and the aqueous layer extracted with EtOAc. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The resultant yellow solid was then crystallised from DCM and cyclohexane to give the title compound as a white solid (25.0 g, 71%).
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.[CH3:23][NH:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28](Br)[CH:27]=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>[CH3:23][NH:24][C:25]([C:26]1[CH:27]=[C:28]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C@@H:3]([CH3:14])[C@H:2]([OH:1])[CH2:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:6][CH:7]=2)[C:29]([CH3:32])=[CH:30][CH:31]=1)=[O:34]
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: CNC(=O)c1ccc(C)c(Br)c1
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
Product: CNC(=O)c1ccc(C)c(-c2ccc(O[C@@H](C)[C@H](O)CCc3cccnc3)cc2)c1
Temperature: 90 °C

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-[2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy]benzeneboronic acid (0.20 g, Example 33 (0.290 g), 3-bromo-4-methylbenzoic acid, methyl amide (0.30 g), 2M aqueous sodium carbonate (0.66 ml) and tetrakis(triphenylphosphine)palladium(0) (0.038 g) in ethanol (3 ml). The reaction mixture was heated at 90° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure, taken up in ethanol and concentrated again (twice). The residue was triturated with acetone and then filtered through silica gel. The filtrate was concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give an oil, which was further purified by column chromatography over silica gel eluting with ethyl acetate:ethanol (9:1) to give the title compound as a foam(0.20 g).
Reaction SMILES: FC1C=CC=CC=1C1N(C(=O)CNC(N[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27]C)=[O:26])[CH:20]=2)=O)C(C(=O)NCC(C)C)CC1S(C1C=CC=C(OC)C=1)(=O)=O.[OH-].[K+]>CO.O>[C:25]([OH:27])(=[O:26])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:19][CH:20]=1
Reactant: COC(=O)c1cccc(NC(=O)NCC(=O)N2C(C(=O)NCC(C)C)CC(S(=O)(=O)c3cccc(OC)c3)C2c2ccccc2F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccccc1

Procedure:
A The process is performed as described in Example 1A, but starting with 3 g of (2RS,4SR,5RS)-5-(2-fluorophenyl)-2-isobutylcarbamoyl-1-{2-[3-(3-methoxycarbonylphenyl)ureido]acetyl}-4-(3-methoxyphenyl)sulphonylpyrrolidine and 0.245 g of potassium hydroxide in a mixture of 60 cm3 of methanol and 20 cm3 of distilled water. After treatment, 0.5 g of (2RS,4SR,5RS)-3-(3-{2-[5-(2-fluorophenyl)-2-isobutylcarbamoyl-4-(3-methoxyphenyl)sulphonyl-1-pyrrolidinyl]-2-oxoethyl}ureido!benzoic acid is obtained [Rf=0.4; eluent: methylene chloride/methanol (90/10); 1H NMR spectrum (200 MHz, (CD3)2SO with addition of a few drops of CD3COOD, at a temperature of 383 K, δ in ppm): 0.95 (d, J=6.5 Hz, 6H: C (CH3)2); 1.86 (mt, 1H: CH); from 2.35 to 2.55 and 2.86 (2 mts, 1H each: CH2 at 3); 3.08 (mt, 2H: NCH2); from 3.60 to 3.80 and 3.90 (mt and d respectively, (J=17 Hz), 1H each: COCH2N); 3.91 (s, 3H: OCH3); 4.09 (mt, 1H: H4); 4.81 (t, J=7 Hz, 1H: H2); 5.72 (very broad s, 1H:H5); from 6.95 to 7.65 (mt, 10H: aromatic H); 8.00 (mt, 1H: aromatic H (H2 : ortho to the COOH)); 8.20 (broad t, J=8 Hz, 1H: H of the aromatic at 5 (H6))].
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[CH:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:25])[F:26])(=[O:17])=[O:16])[CH2:12][N:11]2[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:9])[CH2:5][CH2:6]1)#[N:3]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3C(F)(F)F)CN2)CC1
Reactant: O=Cc1ccccc1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3C(F)(F)F)CN2Cc2ccccc2)CC1

Procedure:
(2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K5 was reductively aminated with benzaldehyde in analogy to experiment L3 to give (2S,4R)-1-benzyl-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 478.1 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][CH2:4][NH:3]1.[H-].[Na+].Br[CH2:10][CH2:11][CH2:12][Cl:13]>O1CCCC1>[Cl:13][CH2:12][CH2:11][CH2:10][N:3]1[C:2](=[O:1])[CH2:6][S:5][CH2:4]1
Reactant: O=C1CSCN1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CSCN1CCCCl

Procedure:
A solution of 4-oxothiazolidine (3.00 g) in tetrahydrofuran (40 ml) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil) (1.28 g) in tetrahydrofuran (30 ml) at room temperature with stirring. 3-Bromo-1-chloropropane (3.15 ml) was added dropwise to the mixture under refluxing and the mixture was allowed to reflux for 9 hours. After the resultant precipitate was removed by filtration, the filtrate was evaporated in vacuo. The residue was chromatographed on basic alumina by eluting with ethyl acetate and then with a 10:1 mixture of toluene and ethyl acetate to give 3-(3-chloropropyl)-4-oxothiazolidine (2.60 g) as colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].CN1CCOCC1.ClC(OCC)=O.[O:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:32][CH:29]1[CH2:30][CH2:31][O:26][CH2:27][CH2:28]1)=[O:9])([O-:3])=[O:2]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: NC1CCOCC1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(NC1CCOCC1)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
Under nitrogen atmosphere, 3-nitrobenzoic acid (1.00 g, 5.98 mmol) was taken in THF (20 ml) and the mixture was cooled to 0° C. followed by addition of N-methylmorpholine (0.85 ml, 7.78 mmol) and ethyl chloroformate (6.58 mmol). The reaction mixture was stirred for 30 min at 0° C. and tetrahydro-2H-pyran-4-amine (0.6 ml, 5.98 mmol) was added and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under vacuum and the residue was taken in ethyl acetate (20 ml), washed with water and brine, dried over sodium sulfate and concentrated under vacuum to afford the solid product (1.2 gm).
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[K+].CO.I[CH2:16][CH2:17][CH2:18][CH3:19]>O.Cl>[CH2:16]([N:10]1[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]1=[O:1])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCI
Reactant: O=C(O)c1cccnc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCn1cccc(C(=O)O)c1=O
Temperature: 60 °C
Yield: 38.5 %

Procedure:
To a solution of 2-hydroxy-nicotinic acid (0.50 g, 3.59 mmol) and potassium -hydroxide (0.40 g, 7.13 mmol) in 4:1 methanol: water (6 mL) at room temperature, was added 1-iodobutane (0.74 mL, 6.42 mmol). This solution was heated at 60° C. for 30 minutes, then cooled to room temperature and diluted with water and 1N HCl. The resulting solid was filtered and dried to give the title compound (0.27 g, 39%). MS (DCI/NH3) m/z 196 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 0.91 (m, 3 H) 1.30 (m, 2 H) 1.69 (m, 2 H) 4.10 (m, 2 H) 6.73 (m, 1 H) 8.27 (dd, J=6.62, 1.84 Hz, 1 H) 8.38 (dd, J=7.35, 2.21 Hz, 1 H) 14.68 (s, 1 H).