Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:34])[N:6]2[C@H:21]1[CH2:26][CH2:25][C@H:24]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[CH2:23][CH2:22]1.[CH3:35]CN(P1(N(C)CCCN1)=NC(C)(C)C)CC.IC>CC#N>[Cl:1][C:2]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[N:8]=[C:7]2[C:3]=1[N:4]([CH3:35])[C:5](=[O:34])[N:6]2[C@H:21]1[CH2:26][CH2:25][C@H:24]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[CH2:23][CH2:22]1
Reactant: O=c1[nH]c2c(Cl)nc(-n3cnc4ccc(F)cc43)nc2n1[C@H]1CC[C@H](OC2CCCCO2)CC1
Reactant: CCN(CC)P1(=NC(C)(C)C)NCCCN1C
Solvent: CI
Solvent: CC#N
Product: Cn1c(=O)n([C@H]2CC[C@H](OC3CCCCO3)CC2)c2nc(-n3cnc4ccc(F)cc43)nc(Cl)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-chloro-2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-9-(trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl)-7H-purin-8(9H)-one (0.06 mmol) in anhydrous CH3CN (10 mL) were added BEMP on polystyrene (loading 2.2 mmol/g, 4 equiv.) and iodomethane (primary alkyl iodide/benzyl iodide or bromide to be used for alkylation) (6 equiv.) with stirring at room temperature. After 1 h, LCMS showed reaction to be complete. The reaction mixture was filtered under vacuum, the resin washed with CH3CN and methanol, and the combined filtrate and washings were concentrated in vacuo to give the desired product as a pale yellow solid, which was used in the next step without further purification. MS (EI) m/z 501.2 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:11]Br>C(O)(=O)C>[NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1ncccc1C(=O)O
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1ncc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.3 %

Procedure:
25.00 g (0.181 mol) of 2-aminonicotinic acid were dispersed in 100 ml of glacial acetic acid. To this suspension was added a solution of 12.0 ml (0.23 mol) of bromine in 50 ml of glacial acetic acid. The mixture was stirred at room temperature for 20 hours. The precipitate formed was filtered off and washed with 100 ml of glacial acetic acid in several portions until the filtrate remained colorless. The crude was dried by suction and crystallized from boiling methanol to afford 38.63 g (0.178 mol, 98% yield) of 2-amino-5-bromonicotinic acid as slightly greenish to off-white crystalline needles. 1H-NMR (d6-DMSO) δ: 8.45 [1H] d, 8.34 [1H] d.; MS: m/z 217 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[N:17]=[C:16]2[O:18][C:19]([CH3:30])([CH3:29])[CH2:20][CH:21]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:15]2=[CH:14][C:13]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C:5](OC)=[O:6].O.[NH2:39][NH2:40]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:39][NH2:40])=[O:6])[CH:9]=[CH:10][C:11]=1[C:12]1[N:17]=[C:16]2[O:18][C:19]([CH3:30])([CH3:29])[CH2:20][CH:21]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:15]2=[CH:14][C:13]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1
Reactant: COC(=O)c1ccc(-c2nc3c(cc2-c2ccc(Cl)cc2)C(NC(=O)C(C)(C)C)CC(C)(C)O3)c(Cl)c1
Reactant: NN
Solvent: CO
Solvent: O
Product: CC1(C)CC(NC(=O)C(C)(C)C)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(C(=O)NN)cc3Cl)nc2O1
Temperature: 25 °C

Procedure:
A solution of the product of Step B (22 mmol) and 2.0 mL of hydrazine hydrate in 10 mL of CH3OH was refluxed for 10 h. After cooling to rt, the reaction mixture was concentrated to give the product, which was taken into the next step without further purification.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4]1\[CH2:5][N:6]([C:11]2[N:16]=[C:15]3[N:17]([CH:25]4[CH2:27][CH2:26]4)[CH:18]=[C:19]([C:22]([OH:24])=[O:23])[C:20](=[O:21])[C:14]3=[CH:13][C:12]=2[F:28])[CH2:7][CH:8]\1[CH2:9][NH2:10].C(Cl)Cl.[C:32]([OH:37])(=[O:36])[CH:33]([CH3:35])[OH:34]>C(O)C>[CH3:1][O:2]/[N:3]=[C:4]1\[CH2:5][N:6]([C:11]2[N:16]=[C:15]3[N:17]([CH:25]4[CH2:27][CH2:26]4)[CH:18]=[C:19]([C:22]([OH:24])=[O:23])[C:20](=[O:21])[C:14]3=[CH:13][C:12]=2[F:28])[CH2:7][CH:8]\1[CH2:9][NH2:10].[C:32]([O-:37])(=[O:36])[CH:33]([CH3:35])[OH:34]
Reactant: CC(O)C(=O)O
Agent: CO/N=C1\CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1CN
Solvent: CCO
Solvent: ClCCl
Product: CC(O)C(=O)[O-]
Temperature: 10 °C
Reaction time: 1 h

Procedure:
Gemifloxacin free base (3 gm) is added to methylene dichloride (65 ml) at 25-30° C., ethanol (20 ml) is added to form a clear solution. To the solution, lactic acid (0.6ml) is added at 25-30° C., stirred for 1 hour and then cooled to 10° C. Filtered the solid and dried at 50-l 55° C. to give 3 gm of gemifloxacin lactate (HPLC Purity: 99.93%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:27][C:28]([F:39])([F:38])[C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)[CH:12]=[C:13]([O:15][C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([C:28]([F:39])([F:38])[F:27])[CH:34]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: COC(=O)C(CC(C)C)c1cc(Oc2cccc(C(F)(F)F)c2)cc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 25 %

Procedure:
The title compound was prepared in 25% yield from 2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester and 3-trifluoromethylphenylboronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)=[O:5])C.[CH3:16][C:17]1[N:18]=[C:19]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[S:20][C:21]=1[CH:22]=O>>[CH3:16][C:17]1[N:18]=[C:19]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=2)[S:20][C:21]=1[CH2:22][NH:15][C:12]1[CH:11]=[CH:10][C:9]([C@@H:7]2[CH2:8][C@H:6]2[C:4]([OH:3])=[O:5])=[CH:14][CH:13]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(N)cc1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CNc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Yield: 25 %

Procedure:
Experimental procedure analogous to that described for synthesis of compounds III-2a and III-3a but instead using (+)-(trans)-ethyl-2-(4-aminophenyl)cyclopropanecarboxylate (III-1b) (0.61 g, 2.97 mmol) and 4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carbaldehyde to give 0.30 g (25% yield) of pure title compound as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J=7.87 Hz, 2H), 7.65 (d, J=8.24 Hz, 2H), 6.97 (d, J=8.42 Hz, 2H), 6.60 (d, J=8.61 Hz, 2H), 4.46 (s, 2H), 2.51 (m, 1H), 2.50 (s, 3H), 1.79 (m, 1H), 1.59 (m, 1H), 1.35 (m, 1H). ES-MS m/z 432 (MH+). [α]25,D=+128° (chloroform, c=3.8). Product was determined to be 96% ee by chiral SFC according to Method 2.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[C@@H:12]3[CH2:25][C@@H:13]3[C:14]2=[O:24])[CH2:6]1)(=[O:3])[CH3:2].[CH2:26](O)[CH2:27][OH:28].C(OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CCOCC.N1C=CC=CC=1>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[C@@H:12]3[CH2:25][C@@H:13]3[C:14]32[O:28][CH2:27][CH2:26][O:24]3)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: OCCO
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4[C@@H]5C[C@@H]5C(=O)[C@@]4(C)CC[C@@H]32)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCOC(OCC)OCC
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4[C@@H]5C[C@@H]5C5(OCCO5)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 105 g of 3β-acetoxy-15β,16β-methylene-5-androsten-17-one in 1.05 l of methylene chloride was combined with 315 ml of ethylene glycol, 210 ml of triethyl orthoformate, and 10.5 g of p-toluene-sulfonic acid and agitated for 1 hour at room temperature. The reaction solution was combined with 40 ml of pyridine and diluted with ether, then washed with water, dried, and evaporated. The residue was triturated with pentane and vacuum-filtered, thus producing 109 mg of 3β-acetoxy-17,17-ethylenedioxy-15β,16β-methylene-5-androstene, mp 177°-178.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH:13]=O)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[CH:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][C:25]1=[O:30])([CH3:23])[CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:27]3[CH2:28][CH2:29][N:24]([CH:21]([CH3:23])[CH3:22])[C:25](=[O:30])[CH2:26]3)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: Cn1c(CC=O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC(C)N1CCNCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)N1CCN(CCc2nc3c(N4CCOCC4)nc(Cl)nc3n2C)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (167 mg, 0.57 mmol) in DCE (10 mL) was added 1-isopropylpiperazin-2-one (87 mg, 0.61 mmol) and powdered 4 Å molecular sieves. The reaction mixture was stirred at room temperature for 1 h, sodium triacetoxyborohydride (239 mg, 1.13 mmol) was added and the resulting mixture stirred for a further 16 h. The reaction mixture was filtered through Celite®, loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si—PCC, 0-10% 2 M NH3/MeOH in DCM) to give the title compound as a pale yellow oil (51 mg, 33%). LCMS (Method H): RT=3.31 min, [M+H]+ 422.5
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O)#[N:13].C(=O)([O-])[O-].[K+].[K+]>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.O1CCOCC1>[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1)#[N:13]
Reactant: N#Cc1ccccc1B(O)O
Reactant: COC(=O)c1ccc(Cl)nc1
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: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccccc2C#N)nc1
Temperature: 25 °C
Yield: 14 %

Procedure:
Methyl 6-chloronicotinate (1.00 g, 5.83 mmol) and (2-cyanophenyl)boronic acid (856 mg, 5.83 mmol) were added to 1,4-dioxane (50 mL). To this was added 14.6 mL of a 2 M solution of aqueous potassium carbonate and tetrakis(triphenylphosphine)palladium(0) (337 mg, 0.291 mmol). The above reagents were heated at reflux for 5 hours. The reaction was cooled to room temperature and partitioned between ethyl acetate (50 mL) and water (20 mL), the phases were separated and the organic layer was dried over anhydrous MgSO4, filtered and evaporated to a gum. The solid was purified using chromatography on silica eluting with a mixture of heptane: ethyl acetate 80:20, 70:30, 30:70. The product fractions were combined and evaporated to give methyl 6-(2-cyanophenyl)nicotinate as a white solid (195 mg). LCMS (ES+) 239 (M+1), 1.37 minutes; 1H NMR (400 MHz CDCl3) ppm 4.00 (s, 3H) 7.58 (t, J=7.4 Hz, 1H) 7.74 (d, J=6.2 Hz, 1H) 7.85 (d, J=7.8 Hz, 1H) 7.90 (m, 2H) 8.45 (dd, J=5.8, 2.4 Hz, 1H) 9.37 (d, J=2.0, Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[N:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1cncc(Br)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: COC(=O)c1cncc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
28 g (132 mmol) of methyl 5-bromonicotinate and 30 g (158 mmol, 1.2 eq.) of 4-trifluoromethylphenylboronic acid were reacted according to General Method 1A. Yield: 32 g (85% of theory)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([CH3:14])([CH3:13])[C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[C:15]([Cu])#[N:16]>CN1C(=O)CCC1.CCOC(C)=O>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]([CH3:14])([C:10](=[O:12])[CH3:11])[CH3:13])=[CH:3][C:2]=1[C:15]#[N:16]
Reactant: CC(=O)C(C)(C)c1ccc(F)c(Br)c1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(=O)C(C)(C)c1ccc(F)c(C#N)c1
Temperature: 160 °C
Yield: 69.2 %

Procedure:
To a solution of 3-(3-bromo-4-fluorophenyl)-3-methylbutan-2-one (13 g, 50 mmol) in NMP (100 mL) was added CuCN (17.9 g, 200 mmol, 4 eq). The mixture was heated 24 h at 160° C. After cooling, the reaction was diluted with EtOAc, washed with 2N HCl (200 mL), satd NaHCO3 (200 mL) and brine (200 mL) successively, dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography (Hex/EtOAc=4:1) to give 2-fluoro-5-(2-methyl-3-oxobutan-2-yl)benzonitrile (7.1 g, 69%). 1H NMR (400 MHz, CDCl3) δ 7.56-7.54 (m, 1H), 7.49-7.45 (m, 1H), 7.20 (t, J=8.4 Hz, 1H), 1.96 (s, 3H), 1.50 (s, 6H).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][C@H:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][CH3:18])[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([O:17][CH3:18])[CH:14]=[C:15]([CH3:16])[C:7]=2[C@@H:6]([CH2:5][C:4]([OH:19])=[O:3])[O:10]1
Reactant: CCOC(=O)C[C@H]1OB(O)c2cc(OC)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C)c2c(c1)B(O)O[C@@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (3R)-(1-hydroxy-6-methoxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.68 g, 2.57 mmol) in THF (7 mL) was added a solution of LiOH (0.31 g, 12.87 mmol) in water (7 mL) at 0° C. The resulting mixture was stirred at room temperature for 3 hours then acidified to pH 2 using 6M hydrochloric acid and extracted with EtOAc. The organic extracts were washed with water, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (0-5% MeOH in DCM) to give (3R)-(1-hydroxy-6-methoxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid as an off white solid (0.45 g, 74%). mp 48.2-50° C. 1HNMR (400 MHz, DMSO-d δ 9.10 (s, 1H), 7.02 (d, J=2.34 Hz, 1H), 6.83 (d, J=1.76 Hz, 1H), 5.42 (dd, J=9.67, 2.64 Hz, 1H), 3.73 (s, 3H), 3.01 (dd, J=15.38, 2.49 Hz, 1H), 2.24 (s, 3H), 2.03 (m, 1H). MS (ESI) m/z: 235 (M−1)−. HPLC purity: 98.31% (Maxplot), 97.78% (220 nm).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:5]2[C:10]([C:11]=1[CH2:12][C:13]([NH2:15])=[O:14])=[CH:9][C:8]([O:16][CH2:17][CH2:18][CH2:19][C:20]([NH:22]N)=[O:21])=[CH:7][CH:6]=2)[CH3:2].CO.CCOC(C)=O>C(O)C.[Ni]>[NH2:22][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][O:16][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:3]([CH2:1][CH3:2])=[C:11]2[CH2:12][C:13]([NH2:15])=[O:14]
Reactant: CCc1c(CC(N)=O)c2cc(OCCCC(=O)NN)ccc2n1Cc1ccccc1
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CO
Product: CCc1c(CC(N)=O)c2cc(OCCCC(N)=O)ccc2n1Cc1ccccc1
Yield: 47.4 %

Procedure:
A mixture of 150 mg (0.37 mmol) of 2-ethyl-5-(4-hydrazino-4-oxobutoxy)-1-(phenylmethyl)-1H-indole-3-acetamide and 200 mg of Raney Ni in 15 mL of ethanol was heated to maintain reflux for 2 hours. After cooling, the EtOH was poured off and the Raney Ni washed twice with methylene chloride. The combined washes were filtered, concentrated at reduced pressure and the residue chromatographed on silica eluting with EtOAc, then 10% MeOH/EtOAc to give 69 mg (47% yield) of 5-(4-amino-4-oxobutoxy)-2-ethyl-1-(phenylmethyl)-1H-indole-3-acetamide, mp 176°-179° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][NH:48][C:49](=[O:51])[CH3:50])=[CH:38][CH:37]=2)[CH2:9]1)=O)(C)(C)C.C(=O)(O)[O-].[Na+]>ClCCCl.[Br-].[Zn+2].[Br-]>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][CH2:23][CH2:22][CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C@H:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]2[O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][NH:48][C:49](=[O:51])[CH3:50])=[CH:38][CH:37]=2)=[CH:19][CH:18]=1
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCNC(C)=O)CCC3)cc1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCNC[C@@H]2OCc2ccc3c(c2)N(CCNC(C)=O)CCC3)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
A solution of 0.88 g (1.25 mmol) of (3R,4R)-3-[1-(2-acetylamino-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester in 9 ml of 1,2-dichloroethane was treated with 0.62 g (2.75 mmol, 2.2 equiv.) of anhydrous zinc bromide. The suspension was stirred for 2 h at 50° C. under Argon atmosphere. Subsequently, it was poured into a mixture of 100 ml of ice/water and 10 ml of sat. sodium bicarbonate solution. The aqueous phase was extracted five times with 50 ml of ethyl acetate. The combined organic phases were washed three times with 20 ml of water, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The thus-obtained crude product was purified by chromatography on silica gel using a 100:10:1 v/v/v mixture of dichloromethane/methanol/28% ammonium hydroxide solution as the eluent and yielded 0.36 g (0.60 mmol, 48.0% of theory) of (3R,4R)-N-[2-[7-[4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidin-3-yloxymethyl]-3,4-dihydro-2H-quinolin-1-yl]-ethyl]-acetamide as a light yellow oil; MS: 602 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]1[NH:13][C:14]([C:16]1[N:17]([CH2:26][CH2:27][CH2:28]O)[C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:20]([Cl:25])[CH:19]=2)=[O:15])=[O:6])#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH3:57][S:58]([O-:60])=[O:59].[Na+].[I-].[Na+]>CN(C=O)C>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]1[NH:13][C:14]([C:16]1[N:17]([CH2:26][CH2:27][CH2:28][S:58]([CH3:57])(=[O:60])=[O:59])[C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:20]([Cl:25])[CH:19]=2)=[O:15])=[O:6])#[N:2]
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1cc2ccc(Cl)cc2n1CCCO
Reactant: CS(=O)[O-]
Agent: O=C1CCC(=O)N1Br
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)CCCn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)NCC#N)cc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
To 150 mg (0.36 mmol) of 6-Chloro-1-(3-hydroxy-propyl)-1H-indole-2-carboxylic acid [(1S,2R)-2-(cyanomethyl-carbamoyl)-cyclohexyl]-amide (from Example 45) dissolved in 5 mL DMF was added 151 mg (0.58 mmol) triphenylphosphine. At 0° C., N-bromosuccinimide (104 mg, 0.58 mmol) was added in portions. After stirring at room temperature for 30 minutes, sodium methane sulfinate (88 mg, 0.73 mmol) and sodium iodide (6 mg, 0.036 mmol) were added in portions. The reaction mixture was then stirred at 70° C. for 3 hours, cooled to room temperature, partitioned between ethyl acetate and 5% aqueous sodium thiosulfate solution, washed with water, dried over magnesium sulfate, and concentrated. Column chromatography, eluting with 70% ethyl acetate in hexane, followed by recrystallization from ether provided 50 mg of 6-chloro-1-(3-methanesulfonyl-propyl)-1H-indole-2-carboxylic acid [(1S,2R)-2-(cyanomethyl-carbamoyl)-cyclohexyl]-amide. HPLC: 87% pure, yield: 30%, MS: 479 (M H+).
Reaction SMILES: [CH3:1][C:2]([S:24]([CH3:27])(=[O:26])=[O:25])([CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([B:15]2[O:19][C:18]([CH3:21])([CH3:20])[C:17]([CH3:23])([CH3:22])[O:16]2)[CH:12]=[N:11]1)[C:3]([O:5]CC)=[O:4].[Li+].[OH-]>C1COCC1.O>[CH3:1][C:2]([S:24]([CH3:27])(=[O:25])=[O:26])([CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([B:15]2[O:19][C:18]([CH3:20])([CH3:21])[C:17]([CH3:22])([CH3:23])[O:16]2)[CH:12]=[N:11]1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1)S(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OB(c2cnn(CCC(C)(C(=O)O)S(C)(=O)=O)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of ethyl 2-methyl-2-(methylsulfonyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]butanoate (28 g, 0.07 mol) in THF (100 mL) was added a solution of LiOH (4.2 g, 0.017 mol) in H2O (50 mL). The mixture was stirred at room temperature for 5 h. The THF was removed under reduced pressure and the aqueous phase was washed with EtOAc (50 mL×2) and then acidified with aqueous HCl (3 M). The solid precipitate was filtered to give the first batch of (2-methyl-2-(methylsulfonyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]butanoic acid. The mother liquid was refrigerated for 20 h, filtered to give the second batch of 2-methyl-2-(methylsulfonyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]butanoic acid. The two batches were combined the and dried to give 2-methyl-2-(methylsulfonyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]butanoic acid (13 g, 50%) as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22].[OH-].[Na+].O1CCCC1>O>[CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCN(CC)c1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)c1ccc(S(=O)(=O)NCCCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
2.5 g of 4-diethylaminobenzenesulphonyl chloride are added to a solution comprising 1.17 g of 5-aminovaleric acid and 1.2 g of sodium hydroxide dissolved in 12 cm3 of water, followed by the addition of 12 cm3 of tetrahydrofuran in order to obtain a solution. The mixture is kept stirring for 2 hours at room temperature, the tetrahydrofuran is evaporated off, the reaction medium is acidified using acetic acid and extracted with chloroform, the organic phase is dried and the solvents are removed under reduced pressure. 2.2 g of expected product are obtained. M.p. 106°-108° C. After crystallization in an isopropanol/water mixture (1:1), the product, melting point 109°-110° C., is obtained.
Reaction SMILES: [CH3:1]/[C:2](=[CH:8]\[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH3:22])[CH:16]=2)=[CH:11][CH:10]=1)/[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:23]([N:30]=[C:31]=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:23]([NH:30][C:31](=[O:32])[N:21]([C:17]1[CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9](/[CH:8]=[C:2](\[CH3:1])/[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:10][CH:11]=2)[CH:20]=[CH:19][CH:18]=1)[CH3:22])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCOC(=O)/C(C)=C/c1ccc(-c2cccc(NC)c2)cc1
Reactant: CCCCCCCN=C=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\C)C(=O)OCC)cc2)c1
Yield: 88 %

Procedure:
1.0 g (3.4 mmol) of ethyl (E)-2-methyl-3-(3′-methylaminobiphenyl-4-yl)acrylate is mixed with 2 mL of heptyl isocyanate and the medium is irradiated by microwave for 30 minutes at a temperature of 100° C. in an Emrys Optimizer machine. The residue obtained is purified by chromatography on a column of silica eluted with a 9/1 heptane/ethyl acetate mixture. 1.2 g (88%) of ethyl (E)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]-2-methylacrylate are obtained.