Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[S:8]=[C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20]C(=O)OC(C)(C)C)=[CH:16][CH:15]=2)[NH:10]1>ClCCl>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[NH:10][C:9](=[S:8])[O:13][N:12]=2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2noc(=S)[nH]2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2noc(=S)[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
At 0° C., 0.8 ml of TFA was added to a solution of 119 mg (0.40 mmol) of tert-butyl [4-(5-thioxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]carbamate in 4 ml of dichlormethane, and the mixture was stirred at RT for 40 min. Subsequently, the reaction mixture was concentrated under reduced pressure. Ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the residue. After phase separation, the aqueous phase was extracted with ethyl acetate. The aqueous phase was concentrated and the crude product was purified by preparative HPLC (water/acetonitrile/0.1% formic acid gradient). Yield: 30 mg (38% of theory)
Reaction SMILES: [Cl:1][S:2]([OH:5])(=[O:4])=[O:3].[Br:6][C:7]1[CH:16]=[CH:15][C:10]2[O:11][CH:12]([CH3:14])[CH2:13][C:9]=2[CH:8]=1>C(Cl)(Cl)Cl>[Br:6][C:7]1[CH:16]=[C:15]([O:3][S:2]([Cl:1])(=[O:5])=[O:4])[C:10]2[O:11][CH:12]([CH3:14])[CH2:13][C:9]=2[CH:8]=1
Reactant: O=S(=O)(O)Cl
Reactant: CC1Cc2cc(Br)ccc2O1
Solvent: ClC(Cl)Cl
Product: CC1Cc2cc(Br)cc(OS(=O)(=O)Cl)c2O1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61.7 %

Procedure:
470 g (4.03 moles) of chlorosulfonic acid are added dropwise over 20 minutes at -7° C. to a solution of 106 g (0.5 mole) of 5-bromo-2,3-dihydro-2-methylbenzo[b]furan in 300 ml of chloroform, and the mixture is then stirred for a further 15 minutes at 20°-25° C. The reaction mixture is taken up in ice/water, the organic phase is separated, and aqueous phase is extracted with two 500 ml portions of chloroform. The combined organic phases are washed with two 250 ml portions of water, dried over sodium sulfate, and concentrated, affording 101 g (65% of theory) of 5-bromo-2,3-dihydro-2-methyl-7-benzo[b]furanylsulfochloride.
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:9][C:10]1[C:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:13][O:12][N:11]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>CC(C)=O>[I-:2].[CH2:3]([O:9][C:10]1[C:14]([C:15]2[CH:16]=[N+:17]([CH3:1])[CH:18]=[CH:19][CH:20]=2)=[N:13][O:12][N:11]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCOc1nonc1-c1cccnc1
Reactant: CI
Solvent: CC(C)=O
Product: CCCCCCOc1nonc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (1 ml, 15 mmol) and 3-(3-hexyloxy-1,2,5-oxadiazol-4-yl)pyridine (1 mmol) in acetone (5 ml) was stirred at room temperature for 18 h and evaporated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[N:19]1([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O.C(N(CC)CC)C>[N:19]1([C:25]2[CH:26]=[C:27]([C:28]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([C@@H:8]4[CH2:10][C@H:9]4[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[CH:4][CH:3]=3)=[O:29])[CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(O)c1cccc(N2CCCCC2)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(N3CCCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (105 mg) described in a document (J. Am. Chem. Soc., 2010, 132, 6827.) in acetonitrile (3 mL) were added 3-(piperidin-1-yl)benzoic acid (105 mg) described in a document (J. Med. Chem. 1997, 40, 331.), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (81 mg), 1-hydroxybenzotriazole (57.2 mg) and triethylamine (59 μL). The mixture was stirred at room temperature overnight and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (142 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]([F:26])([F:25])[C:22](O)=O.C(N(CC)CC)C.[CH3:34][O:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1.C(Cl)(Cl)(Cl)[Cl:44]>>[F:20][C:21]([F:26])([F:25])[C:22]([Cl:44])=[N:40][C:39]1[CH:41]=[CH:42][C:36]([O:35][CH3:34])=[CH:37][CH:38]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(N)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(N=C(Cl)C(F)(F)F)cc1
Temperature: 0 °C

Procedure:
In a typical reaction, a mixture of about 3 equivalents of triphenylphosphine and trifluoroacetic acid in carbon tetrachloride is cooled to about 0° C. in an ice bath and a 20% excess of triethylamine is added. With continued cooling, about a 20% excess of p-methoxyaniline in carbon tetrachloride is slowly added. After completion of the addition, the mixture is heated to about 70° C. for several hours. After cooling, the reaction mixture is extracted with hexane and the solvent evaporated to provide crude 2,2,2-trifluoro-N-(4-methoxyphenyl)acetimidoyl chloride.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[F:20])[CH:8]=[CH:9][C:10]=1[OH:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:42]1([CH:45]([C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([CH2:58]O)[CH:53]=2)[CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:44][CH2:43]1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH:42]1([CH:45]([C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([CH2:58][O:11][C:10]3[CH:9]=[CH:8][C:7]([C:12]4[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=4[F:20])=[CH:6][C:5]=3[CH2:4][CH2:3][C:2]([CH3:22])([CH3:21])[CH3:1])[CH:53]=2)[CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:44][CH2:43]1
Reactant: COc1ccc(F)c(-c2ccc(O)c(CCC(C)(C)C)c2)c1
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)cc2CCC(C)(C)C)c1)C1CC1
Yield: 48.3 %

Procedure:
To a solution of 3-(3,3-dimethylbutyl)-2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-ol (200 mg) in THF (5.0 mL) were added triphenylphosphine (260 mg), ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (246 mg) and a 40% solution of diethyl azodicarboxylate in toluene (400 μL), and the reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (170 mg) as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=[O:4].[NH2:17][C:18]1[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][N:19]=1>>[CH3:10][C:9]1[O:8][N:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]=1[C:3](=[O:4])[CH2:2][O:24][C:23]1[C:18]2[N:19]([CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:17]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ncccc1O
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Product: Cc1onc(-c2ccccc2)c1C(=O)COc1cccn2cc(-c3c(-c4ccccc4)noc3C)nc12
Yield: 7 %

Procedure:
As described for Example 2, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (140 mg, 0.5 mmol) was converted, using 2-amino-3-hydroxypyridine instead of 2-amino-3-methylpyridine, to the title compound (18 mg, 7%) which was obtained as a yellow foam. MS: m/e=491.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:11].FC(F)(F)[C:14]([O:16]C(=O)C(F)(F)F)=[O:15]>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:14]([OH:16])=[O:15])=[CH:5][N:6]2[CH3:11]
Reactant: Cn1ccc2c(Br)cccc21
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: Cn1cc(C(=O)O)c2c(Br)cccc21
Temperature: 25 °C

Procedure:
A solution of 4-bromo-1-methyl-1H-indole (D16) (7.0 g) in tetrahydrofuran (50 ml) was treated with a solution of trifluoroacetic anhydride (5.65 ml) in tetrahydrofuran (20 ml) at 0° C. The reaction mixture was allowed to warm to room temperature over 6 h, whilst stirring. The reaction mixture was concentrated in vacuo and then re-suspended in ethanol (25 ml). The solution was treated with 5N sodium hydroxide solution (50 ml) and heated under reflux for 18 h. The reaction mixture was washed with diethyl ether and the aqueous phase acidified with 5N hydrochloric acid solution. The precipitate was filtered, washed with water and concentrated in vacuo to afford the title compound (4.88 g). TLC, Silica (cyclohexane-ethyl acetate-acetic acid [3:1:0.1]), Rf=0.35.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]([C:5]1[N:30]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:28][CH:27]5[NH:29][CH:24]([CH2:25][CH2:26]5)[CH2:23]4)=[O:21])=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:37]([N:44]1[CH2:51][CH2:50][CH2:49][C@H:45]1[C:46](O)=[O:47])([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>>[C:40]([O:39][C:37]([N:44]1[CH2:51][CH2:50][CH2:49][CH:45]1[C:46]([N:29]1[CH:24]2[CH2:25][CH2:26][CH:27]1[CH2:28][N:22]([C:20]([C:17]1[CH:16]=[N:15][C:14]([NH:13][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:36])[CH3:1])[N:30]([CH:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[C:8]=4[N:9]=3)=[CH:19][CH:18]=1)=[O:21])[CH2:23]2)=[O:47])=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5)cn3)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)C4CCCN4C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1
Yield: 67.6 %

Procedure:
Following general amide formation method 1, 7-cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.205 mmol, 1.0 eq) was combined with BOC-Proline (48.5 mg, 0.225 mmol, 1.1 eq) which gave 2-{3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carbonyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (95 mg) in 64% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36-1.57 (m, 12H) 1.63-1.86 (m, 5H) 1.91 (br. s., 4H) 1.99-2.29 (m, 10H) 2.45-2.67 (m, 2H) 3.18 (s, 7H) 3.43 (d, J=6.57 Hz, 2H) 3.60 (br. s., 3H) 4.42 (br. s., 2H) 4.56 (br. s., 2H) 4.68-4.94 (m, 2H) 6.53 (s, 1H) 7.83 (d, J=8.08 Hz, 1H) 8.41 (br. s., 1H) 8.58 (d, J=8.59 Hz, 1H) 8.76-8.80 (m, 1H). HRMS m/z, (M+H)+: 686.3769.
Reaction SMILES: [CH2:1]([C:4]([CH2:35][CH:36]=C)([CH:8]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:9]([NH:11][CH:12]1[C:18](=[O:19])[N:17]([CH3:20])[C:16]2[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=2[C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:13]1)=[O:10])[C:5]([NH2:7])=[O:6])[CH:2]=C.C>C1(C)C=CC=CC=1.C(Cl)Cl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl.C=CC1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru]Cl>[CH3:34][CH:32]([CH3:33])[CH2:31][C@H:8]([C:4]1([C:5]([NH2:7])=[O:6])[CH2:35][CH:36]=[CH:2][CH2:1]1)[C:9](=[O:10])[NH:11][CH:12]1[N:13]=[C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:15]2[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=2[N:17]([CH3:20])[C:18]1=[O:19]
Reactant: C=CCC(CC=C)(C(N)=O)C(CC(C)C)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Agent: Cl[Ru]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O)C1(C(N)=O)CC=CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.2 %

Procedure:
To a solution of 31 (110 mg, 0.22 mmol) in 20 ml of toluene and CH2Cl2 (1:1) at 100 degree was added (bis(tricyclohexylphosphine)-benzylidine ruthenium (IV) dichloride) (24 mg, 0.029 mmol). The mixture was stirred at 100 degree for 4 hrs and another 24 mg Grubbs' catalyst was added. The mixture was then stirred at 100 degree for another 4 hrs. Then the solution was cooled to RT, after which 100 mg of charcoal was added. The mixture was filtered through ceslite to provide a slightly yellow solution, then concentrated. The residue was purified in silica gel chromatography with CH2Cl2/methanol (10:0.5) to give 48 mg of 32 (46%). 1H NMR (CDCl3) 0.97-0.90 (dd, 6H), 1.30-1.25 (m, 1H), 1.65-1.57 (m, 1H), 2.00-1.85 (m, 1H), 2.40-2.30 (d, 1H), 2.80-2.65 (m, 2H), 3.00-2.80 (d, 1H), 3.40-3.20 (m, 1H), 3.47 (s, 3H), 5.40-5.20 (s, 1H), 5.52-5.49 (d, 1H), 5.80-5.71 (m, 2H), 7.63-7.20 (m, 9H), 7.90 (s, 1H). API AP+ 473.1 (M+1).
Reaction SMILES: [NH:1]([C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:22][C@H:23]([C:28]([NH:30][C@H:31]([C:35]([OH:37])=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:48]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][NH-:58])([OH:50])=[O:49].[OH-:59].[Na+].[CH2:61](O)C>>[NH:1]([C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:22][C@H:23]([C:28]([NH:30][C@H:31]([C:35]([OH:37])=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[C:41]([O:40][CH2:38][O:49][C:48]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][NH-:58])=[O:50])(=[O:59])[C:42]([CH3:47])([CH3:61])[CH3:43]
Reactant: CCO
Reactant: [OH-]
Reactant: [NH-]CCCCCCCC(=O)O
Agent: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)C
Agent: [Na+]
Product: CC(C)(C)C(=O)OCOC(=O)CCCCCCC[NH-]

Procedure:
40 mg of Z-Phe-His-Leu-Val-7-carboxyheptyl amide (Example 29) are made into a slurry in 1 ml of ethanol and 100 μl of 1N NaOH are added. The solution is concentrated by evaporation and dried by twice making into a slurry in toluene/ethanol and concentrating by evaporation. The residue is dissolved in 0.5 ml of DMF; at 0° while stirring 12 mg of pivalic acid iodomethyl ester in 0.2 ml of DMF are added twice at an interval of 1 hour, the whole is further stirred for 16 hours at 0° and for 1 hour at room temperature and then evaporated to dryness in a high vacuum. The title compound is obtained by flash chromatography (5.5 g of silica gel, eluant methylene chloride/methanol/conecentrated ammonia 700:50:1) of the residue. Rf (B11)=0.81 Rf (methylene chloride/methanol/concentrated ammonia 700:50:1)=0.23.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:5]2[C:6]([CH:14]=O)=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.C1(C)C=CC(S(=O)=O)=CC=1.S1(CCCC1)(=O)=O.C([BH3-])#N.[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2c1c(C=O)cn2C(C)C
Agent: Cc1ccc([SH](=O)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Temperature: 100 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
To a stirred solution of methyl 6-bromo-3-formyl-1-isopropyl-1H-indole-4-carboxylate (60 g, 185 mmol) in DMF (220 mL) was added p-toluenesulfonic acid mono hydride (4.57 g, 24 mmol), p-toluenesulfonyl hydrazide (44.8 g, 240 mmol) followed by sulfolane (220 mL). The mixture was stirred at 100° C. for 1 h. The contents were cooled to room temperature and then sodium cyanoborohydride (46.5 g, 740 mmol) was added portion wise over a period of 25 min. Then the mixture was stirred at 100° C. for 2 h. Then the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with water and extracted with 20% EtOAc: Pet ether, finally organic layer was washed with cold water, brine solution dried over anhydrous Na2SO4 and concentrated. Crude compound was purified by column chromatography using silica gel (100-200 mesh) and 20% DCM: Pet ether as an eluent to afford desired product methyl 6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxylate (24 g, 89.2% purity), (16 g, and 62.2% purity). 1H NMR (CDCl3, 400 MHz) δ 1.486 (d, J=6.4 Hz, 6H), 2.361 (s, 3H), 3.947 (s, 3H), 4.535-4.602 (m, 1H), 7.080 (s, 1H), 7.619 (s, 1H), 7.684 (s, 1H). LCMS (ES+) m/z=310.07 (M+H)
Reaction SMILES: C(O[C:4](=[O:22])[CH2:5][N:6]1[CH2:10][C@H:9]([O:11][CH3:12])[C@@H:8]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:7]1)C.[CH3:23][CH:24]1[CH2:29][CH2:28][C:27]2[S:30][C:31]([NH2:33])=[N:32][C:26]=2[NH:25]1>>[CH3:12][O:11][C@H:9]1[CH2:10][N:6]([CH2:5][C:4](=[O:22])[NH:33][C:31]2[S:30][C:27]3[CH2:28][CH2:29][CH:24]([CH3:23])[NH:25][C:26]=3[N:32]=2)[CH2:7][C@@H:8]1[NH:13][C:14]([C:16]1[S:17][C:18]([Cl:21])=[CH:19][CH:20]=1)=[O:15]
Reactant: CCOC(=O)CN1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](OC)C1
Reactant: CC1CCc2sc(N)nc2N1
Product: CO[C@H]1CN(CC(=O)Nc2nc3c(s2)CCC(C)N3)C[C@@H]1NC(=O)c1ccc(Cl)s1

Procedure:
In analogy to example 25.3 {(3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-methoxy-pyrrolidin-1-yl}-acetic acid ethyl ester (example 25.2) was reacted with 5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4]pyridin-2-ylamine (CAS 17899-48-8) to give 5-chloro-thiophene-2-carboxylic acid {(3S,4S)-4-methoxy-1-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4]pyridin-2-ylcarbamoyl)-methyl]-pyrrolidin-3-yl}-amide as yellow solid. MS 470.5 ([M+H]+)
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]1[NH:17][C:18]1[N:19]=[CH:20][C:21]2[CH2:27][N:26]([C:28](=[O:45])[CH2:29][CH2:30][CH2:31][CH2:32][C:33]3[N:37](C(OC(C)(C)C)=O)[CH:36]=[N:35][CH:34]=3)[CH2:25][CH2:24][C:22]=2[N:23]=1>ClCCl>[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]1[NH:17][C:18]1[N:19]=[CH:20][C:21]2[CH2:27][N:26]([C:28](=[O:45])[CH2:29][CH2:30][CH2:31][CH2:32][C:33]3[N:37]=[CH:36][NH:35][CH:34]=3)[CH2:25][CH2:24][C:22]=2[N:23]=1
Reactant: CC(C)(C)OC(=O)n1cncc1CCCCC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCCCc1c[nH]cn1)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Yield: 82.8 %

Procedure:
Add trifluoroacetic acid (1.5 mL) to a solution of tert-butyl 5-[5-[2-(indan-2-ylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-5-oxo-pentyl]imidazole-1-carboxylate (0.030 g; 0.058 mmoles) in dichloromethane (8 mL). Stir the reaction at room temperature for 2 hr. Concentrate the mixture and add saturated sodium bicarbonate (10 mL) and water (20 mL), then extract with dichloromethane (3×20 mL). Wash the combined organic extracts with brine, dry over sodium sulfate, filter, and concentrate. Purify the crude product by column chromatography (0 to 10% methanol in dichloromethane) to afford 1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-5-(1H-imidazol-4-yl)pentan-1-one (0.020 g; 83%) as a white solid: MS (m/z): 417 (M+1).
Reaction SMILES: [OH:1]N1[C:6](=O)[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[O-]O.[C:15]1(C(C)C)[CH:20]=CC=[CH:17][CH:16]=1.[CH2:24]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.O=O>>[CH:3]1([OH:12])[CH2:4][CH2:11][CH2:10][CH2:9][CH2:8][CH2:5][CH2:6][CH2:17][CH2:16][CH2:15][CH2:20]1.[C:24]1(=[O:1])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[CH2:24]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CC(C)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: C1CCCCCCCCCCC1
Agent: O=O
Agent: [O-]O
Product: O=C1CCCCCCCCCCC1
Product: OC1CCCCCCCCCCC1

Procedure:
2 mmol of N-hydroxyphthalimide and 4 mmol of cumene hydroperoxide are added at a temperature of 130° C. to 200 mmol of cyclododecane in a round-bottomed flask having an attached reflux condenser. Oxygen at approximately 15 l/h is passed through the reaction mixture for 8 hours at said temperature. Cyclododecanol is obtained at a selectivity of 17% and cyclododecanone at a selectivity of 43%, at a cyclododecane conversion rate of 49%.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][CH:22]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.B(F)(F)F.[C:34]1([OH:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:19][CH2:20][C:21]([C:37]4[CH:38]=[CH:39][C:34]([OH:40])=[CH:35][CH:36]=4)([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:22][CH2:23]3)=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CC=C(c2ccccc2)CC1
Reactant: Oc1ccccc1
Agent: FB(F)F
Solvent: O
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC(c2ccccc2)(c2ccc(O)cc2)CC1

Procedure:
4-Phenyl-3,6-dihydro-2H-pyridine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (200 mg, 0.52 mmol) was treated with a drop of BF3*H3PO4 and phenol (200 mg, 2.1 mmol) at 60° C. for 6 h. Water (10 mL) was added and aqueous phase was extracted dichloromethane (2×10 mL). The combined organic phase was concentrated. 1H nmr indicated full conversion of the starting material. The desired product was isolated after flash chromatography. Yield: 270 mg. LC/MS purity (UV/MS): 96/91%, Rt 7.32 min. M+1: 432.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC1C=CC=CC=1)=O)=NC(OCC1C=CC=CC=1)=O.[NH:54]1[C:62]2[C:57](=[CH:58][C:59](O)=[CH:60][CH:61]=2)[CH:56]=[N:55]1>O1CCCC1>[NH:54]1[C:62]2[C:57](=[CH:58][C:59]([O:1][CH:2]3[CH2:3][CH2:4][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]3)=[CH:60][CH:61]=2)[CH:56]=[N:55]1
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: Oc1ccc2[nH]ncc2c1
Agent: O=C(N=NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(Oc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
Ethyl 4-hydroxycyclohexylcarboxylate (1.44 ml, 8.95 mmol), triphenylphosphine (2.15 g, 8.20 mmol) and dibenzyl azodicarboxylate (3.34 g, 11.18 mmol) were added at 0° C. to a solution of the 1H-indazol-5-ol (1.0 g, 7.45 mmol) obtained in Reference Example 4 in tetrahydrofuran (40 ml). After 1 hour, the mixture thus obtained was warmed up to room temperature. After stirring overnight, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/ethyl acetate, hexane/ethyl acetate) to obtain ethyl 4-(1H-indazol-5-yloxy)cyclohexanecarboxylate (928 mg, 43%).