Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([CH:14]=[N:15]O)=[C:12]([CH3:17])[N:11]=[C:10]3[N:18]([CH2:21][CH3:22])[N:19]=[CH:20][C:9]=23)[CH:5]=[N:6][CH:7]=1.C(OC(=O)C)(=O)C>O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([C:14]#[N:15])=[C:12]([CH3:17])[N:11]=[C:10]3[N:18]([CH2:21][CH3:22])[N:19]=[CH:20][C:9]=23)[CH:5]=[N:6][CH:7]=1
Reactant: CCn1ncc2c(-c3cncc(Br)c3)c(C=NO)c(C)nc21
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCn1ncc2c(-c3cncc(Br)c3)c(C#N)c(C)nc21
Temperature: 150 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
A mixture of 4-(5-bromo-3-pyridyl)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde oxime (34 mg) and acetic anhydride (1 ml) was stirred at 90° C. for 2 hours and 150° C. for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a mixture of EtOAc and n-hexane (1:2). The crystalline residue was recrystallized from EtOAc and n-hexane to give 4-(5-bromo-3-pyridyl)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (15.5 mg) as a colorless crystal.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:27])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:28][Mg+].[Br-]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)([CH2:16][C:17]([OH:19])([CH3:28])[CH3:18])[O:12][C:11]2=[O:27])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2cccc(Br)c2)C(=O)O1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: C[C@@H](c1cccc(Br)c1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42 %

Procedure:
A solution of (S)-3-((S)-1-(3-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-oxopropyl)-1,3-oxazinan-2-one (18.5 mg, 0.043 mmol) in dry toluene (3 mL) was cooled to 0° C. A solution of MeMgBr (3.0M in THF, 45 μL, 3 equiv) was added. After 15 min, the mixture was warmed to rt slowly and stirred 2 h. LC-MS found reaction completed. The reaction was quenched by satd aq NH4Cl solution (2 mL), diluted with EtOAc (10 mL), washed with 1% aq HCl (3 mL), brine (3 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by preparative HPLC to afford (S)-3-((S)-1-(3-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one (8.0 mg, 42%). LC-MS (3 min) tR=1.75 min, m/z=472, 474 (M+Na); 1H NMR (CDCl3) 7.32-7.21 (m, 3H), 7.12-6.98 (m, 4H), 6.89 (m, 1H), 5.65 (q, 1H), 2.89 (m, 1H), 1.50 (d, 3H), 1.15 (d, 6H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH2:10][C:11]#[CH:12])=[O:7])([CH3:4])[CH3:3].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:37][C@H:38]([C:43]([O:45][CH3:46])=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41].Cl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:2]([O:5][C:6]([NH:8][CH:9]([CH2:10][C:11]#[CH:12])[C:13]([NH:37][CH:38]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:43]([O:45][CH3:46])=[O:44])=[O:15])=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CCC(NC(=O)OC(C)(C)C)C(=O)NC(CC(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of Boc-L-propargylglycine (26.65 g; 125 mmol) in dry DMF (170 mL) was added EDCI (29.23 g; 152.5 mmol) and HOBt (23.5 g; 122.5 mmol), and the reaction mixture was stirred at room temperature for 40 min (solution A). In a separate RB flask, (L) Leu-OMe hydrochloride (22.72 g; 125 mmol) in dry DMF (82 mL) kept at 0° C. was treated with diisopropyl ethyl amine (DIEA) (64.62 g; 500 mmol) and the solution was stirred for 25 min (solution B). Solution B was added to solution A and the reaction mixture was stirred overnight at room temperature. The solvent was removed on the rotary evaporator and the residue was taken up in dichloromethane (DCM) (600 mL) and washed sequentially with saturated sodium bicarbonate (2×200 mL), 5% HCl (2×200 mL) and brine (200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, leaving a crude product which was purified using flash chromatography (silica gel; hexane/ethyl acetate 75:25) to give 1 as a white solid (38.12 g; 89% yield); 1H NMR (CDCl3) δ 8.2 (s, 1H), 7.0 (s, 1H), 4.3 (m, 1H), 4.1 (m, 1H), 3.6 (s, 3H), 2.8 (s, 1H), 2.4 (m, 2H), 2.3 (m, 1H), 1.6 (m, 2H), 1.5 (m, 1H), 1.38 (s, 9H), 0.87 (d, 6H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH3:8][OH:9]>>[CH3:8][O:9][C:4](=[O:5])/[CH:3]=[CH:2]\[C:1]([OH:6])=[O:7]
Reactant: O=C1C=CC(=O)O1
Reactant: CO
Product: COC(=O)/C=C\C(=O)O
Reaction time: 3 h

Procedure:
The same procedure as that of process (I) of Example 1 was conducted to obtain a 50% by weight methanol solution of (A1). In the same manner, to a 1 liter flask were added 24.00 g of maleic anhydride and 39.68 g of methanol, and the resulting mixture was stirred under reflux in a water bath kept at 90° C. Thirty minutes after initiation of the stirring, solid components disappeared, 3 hours after, the temperature was lowered to room temperature to obtain a 50% by weight methanol solution of maleic monomethyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].[CH:20]12[CH2:27][NH:26][CH2:25][CH:24]1[CH2:23][CH2:22][NH:21]2>CS(C)=O>[CH:20]12[CH2:27][N:26]([C:3]3[C:2]([Cl:1])=[C:11]4[C:6]([C:7](=[O:18])[C:8]([C:15]([OH:17])=[O:16])=[CH:9][N:10]4[CH:12]4[CH2:14][CH2:13]4)=[CH:5][CH:4]=3)[CH2:25][CH:24]1[CH2:23][CH2:22][NH:21]2
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)ccc2c1=O
Reactant: C1CC2CNCC2N1
Solvent: CS(C)=O
Product: O=C(O)c1cn(C2CC2)c2c(Cl)c(N3CC4CCNC4C3)ccc2c1=O

Procedure:
650 mg (2.3 mmol) of 8-chloro-l-cyclopropyl-7-fluoro-1,4 -dihydro-4 -oxo-3 -quinolinecarboxylic acid together with 315 mg (2.8 retool) of 2,7-diazabicyclo[3.3.0]octane and 510 mg (4.6 mmol) of 1,4-diazabicyclo[2.2.21]octane are heated for six hours at 120° C. in 23 ml of dimethyl sulphoxide. All volatile components are removed under a high vacuum, and the residue is stirred thoroughly with acetonitrile and dried at approximately 100° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15](=[O:21])[O:14][CH:13]2[PH2](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[N:41]1[CH:46]=[CH:45][C:44]([CH:47]=O)=[CH:43][CH:42]=1>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15](=[O:21])[O:14][C:13]2=[CH:47][C:44]1[CH:45]=[CH:46][N:41]=[CH:42][CH:43]=1
Reactant: O=Cc1ccncc1
Reactant: COc1cc2c(cc1OC)C([PH2](c1ccccc1)(c1ccccc1)c1ccccc1)OC2=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(=Cc1ccncc1)OC2=O
Yield: 60.9 %

Procedure:
Triethylamine (20 ml, 145 mmoles) was dropwise added to a suspension of 5,6-dimethoxy-3-(triphenyl-λ6-phosphanyl)-3H-isobenzofuran-1-one (78 g, 145 mmoles), obtained as described in example 3, and 4-pyridincarboxaldehyde (13 ml, 145 mmoles) in CH2Cl2 (1 l), at room temperature under stirring. After 1.5 hours the mixture was filtered and evaporated and the residue was treated with ethanol under reflux, cooled and filtered. The mother liquors were chromatographed (eluent: 100% CH2Cl2, then with 1% CH3OH) and the residue was brought to dryness and joined to the above filtrate to give 25 g of the title compound.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[S:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])=[N:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.Cl[C:30]([O:32][CH3:33])=[O:31]>C(Cl)Cl>[CH3:33][O:32][C:30](=[O:31])[NH:2][C@@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[S:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([C:22]#[N:23])[CH:24]=4)=[N:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: COC(=O)Cl
Reactant: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4N)s2)cc1C#N
Agent: Cl
Solvent: ClCCl
Product: COC(=O)N[C@H]1CCc2c(-c3nnc(-c4ccc(OC(C)C)c(C#N)c4)s3)cccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.1 %

Procedure:
Prepared using General Procedure 8. To a stirred solution of (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 4 (15 mg, 0.03 mmol) and TEA (11 mg, 0.1 mmol) in DCM (1 mL) was added methyl chloroformate (10 mg, 0.1). The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated and water (2 mL) was added. The resulting solid was filtered, washed with water, and dried under high vacuum to afford 12 mg (92%) of (S)-methyl(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate 16 as white solid. LCMS-ESI (m/z) calculated for C23H22N4O3S: 434.1; found 435.3 [M+H]+, tR=3.69 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:26])[CH:3]=1.[O:27]=[C:28]1[NH:32][C@H:31]([CH2:33][O:34]C(=O)C2C=CC=CC=2)[CH2:30][O:29]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:32]5[C@H:31]([CH2:33][OH:34])[CH2:30][O:29][C:28]5=[O:27])=[CH:3][C:4]=4[CH3:26])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Product: Cc1cc(N2C(=O)OC[C@H]2CO)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Yield: 71.6 %

Procedure:
By reaction and treatment in the same manner as in Example 19 and using (4-bromo-2-methylphenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (347 mg) described in Preparation Example 130 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (278 mg), the title compound (270 mg) was obtained.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9].[CH3:32][N:33]1[CH2:37][CH2:36][CH2:35][CH:34]1[CH2:38][CH2:39][NH2:40]>>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:40][CH2:39][CH2:38][CH:34]4[CH2:35][CH2:36][CH2:37][N:33]4[CH3:32])=[O:27])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CN1CCCC1CCN
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCCC3CCCN3C)cn2)c1O

Procedure:
The title compound, as a TFA salt, was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 2-(1-methylpyrrolidin-2-yl)ethanamine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.60-1.83 (m, 2H) 1.83-2.08 (m, 2 H) 2.18 (dd, J=12.88, 4.29 Hz, 1 H) 2.27-2.41 (m, 1 H) 2.44 (s, 3 H) 2.84 (d, J=3.54 Hz, 3 H) 3.08 (br. s., 1 H) 3.29 (br. s., 1 H) 3.40 (q, J=6.57 Hz, 2 H) 3.58 (d, J=4.29 Hz, 1 H) 7.67 (d, J=7.58 Hz, 1 H) 7.70-7.89 (m, 2 H) 8.20 (br. s., 1 H) 8.42 (br. s., 1H) 8.50-8.71 (m, 1 H) 8.84 (br. s., 1 H) 8.89-8.95 (m, 1 H) 9.53 (br. s., 1 H) 12.81-13.56 (m, 1 H). MS m/z [M+H]+ 431.2.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:28])([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:19][CH:18]=2)[C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([OH:28])([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:21][CH:22]=2)[C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(O)(CC)c1ccc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Agent: [Pd]
Solvent: CO
Product: CCC(O)(CC)c1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Temperature: 50 °C
Yield: 56.4 %

Procedure:
A mixture of 3-{4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-phenyl}-pentan-3-ol (120 mg, 0.32 mmol) and 10% palladium on activated carbon (36 mg) in methanol (250 mL) was heated at 50° C. under hydrogen (50 psi) for 16 h. The mixture was cooled to 25° C., the solids filtered off, washed with ethyl acetate and concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 3-{4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-ethyl]-phenyl}-pentan-3-ol (68 mg, 60%): LC/MS m/e calcd for C25H32N2O [M+H]+ 377.55, observed 377.3; 1H NMR (400 MHz, CD3OD) δ ppm 8.04 (d, J=3.8 Hz, 1H), 7.87 (dd, J=7.7, 1.1 Hz, 1H), 7.25-7.34 (m, 4H), 7.02 (dd, J=7.7, 4.9 Hz, 1H), 6.31 (s, 1H), 4.15 (t, J=7.8 Hz, 1H), 2.21 (dt, J=13.7, 7.2 Hz, 1H), 2.03-2.11 (m, 1H), 1.58-1.85 (m, 9H), 1.42-1.54 (m, 2H), 1.14-1.28 (m, 2H), 0.72 (td, J=7.4, 2.1 Hz, 6H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:17])=[CH:16][N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([O:18][CH2:19][CH2:20][O:21][CH3:22])[C@H:6]([O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C@H:5]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:3])[CH3:2].C1C(=O)N([Cl:43])C(=O)C1>C(O)C>[C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:17])=[C:16]([Cl:43])[N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([O:18][CH2:19][CH2:20][O:21][CH3:22])[C@H:6]([O:23][C:24](=[O:29])[C:25]([CH3:26])([CH3:27])[CH3:28])[C@H:5]1[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COCCO[C@@H]1c2ccn3cc(C)nc3c2N(C(C)=O)[C@H](c2ccccc2)[C@H]1OC(=O)C(C)(C)C
Solvent: CCO
Product: COCCO[C@@H]1c2ccn3c(Cl)c(C)nc3c2N(C(C)=O)[C@H](c2ccccc2)[C@H]1OC(=O)C(C)(C)C
Reaction time: 2 h

Procedure:
To a of 0° C. cooled solution of 1.00 g (2.10 mmol) (7R,8R,9R)-10-acetyl-7-(2-methoxyethoxy)-2-methyl-9-phenyl-8-pivaloyloxy-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine in ethanol (20 ml) is added 0.28 g (2.10 mmol) NCS and the mixture is stirred for 2 h. Afterwards the reaction is quenched by adding of saturated aqueous sodium hydrogen carbonate solution and is extracted twice with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified by column chromatography (ethyl acetate/cylohexane: 1/1) to provide 0.89 g (1.73 mmol/82%) of the title compound as a colourless solid with a melting point of 167-170° C. (cyclohexane).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][N:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[C:21]1([C:27]2[S:28][CH:29]=[C:30]([CH:32]=O)[N:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:20][O:19][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:32][C:30]2[N:31]=[C:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[S:28][CH:29]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cncc1OC
Reactant: O=Cc1csc(-c2ccccc2)n1
Product: COc1cncc(OC)c1C1CCCCC(=O)N1Cc1csc(-c2ccccc2)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(3,5-dimethoxypyridin-4-yl)hexanoate with commercially available 2-phenylthiazole-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.61 min.; [M+H]+: 423.86 g/mol.
Reaction SMILES: O.[OH-].[Li+].[NH2:4][CH2:5][CH2:6][CH2:7][P:8]([CH:13]([O:18][CH2:19][CH2:20][CH3:21])[O:14][CH2:15][CH2:16][CH3:17])(=[O:12])[O:9]CC>O.C(O)C>[NH2:4][CH2:5][CH2:6][CH2:7][P:8]([CH:13]([O:18][CH2:19][CH2:20][CH3:21])[O:14][CH2:15][CH2:16][CH3:17])(=[O:9])[OH:12]
Reactant: CCCOC(OCCC)P(=O)(CCCN)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCOC(OCCC)P(=O)(O)CCCN
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a stirred solution of 0.05 g of lithium hydroxide monohydrate in 7.7 ml of water, is added a solution of 4.37 g of ethyl 3-aminopropyl(di-n-propyloxymethyl)phosphinate in 16.2 ml of ethanol. A slight exothermic reaction ensues and the reaction mixture becomes cloudy.A further 2 ml of water are added and the clear solution stirred at room temperature for 5 days. After: this time the mixture is concentrated in vacuo at 55° and the residue redissolved in water and extracted with 3×10 ml of dichloromethane. The aqueous layer is again evaporated to dryness and the residue dissolved in 20 ml of water and treated with 0.51 ml of 85% phosphoric acid. After stirring overnight, thesolid is removed by filtration. Evaporation of the filtrate and crystallisation of the residue from ethanol/ether affords 3-aminopropyl(di-n-propyloxymethyl) phosphinic acid, m.p. 223°-225°, as a white solid.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:19]1[N:20]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[N:21]=[C:22]([CH3:24])[CH:23]=1)=[O:4].[OH-].[Li+]>>[C:13]1([S:10]([C@H:8]2[CH2:7][N:6]([C:19]3[N:20]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:27][CH:26]=4)[N:21]=[C:22]([CH3:24])[CH:23]=3)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]2)(=[O:12])=[O:11])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1c1cc(C)nn1-c1ccc(C(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3)C[C@H]2C(=O)O)n(-c2ccc(C(F)(F)F)cc2)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-4-benzenesulfonyl-1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as yellow solid. MS (ESI): m/z=480.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([O:10][CH3:11])[CH:3]=1.CN1CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Cl)ccc1CO
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1cc(Cl)ccc1C=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
In methylene chloride (80 ml) was dissolved (4-chloro-2-methoxyphenyl)methanol (3.69 g). Under ice cooling, molecular sieve 4A (4.57 g), N-methylmorpholine (2.81 g) and tetra-n-propylammonium perruthenate (420 mg) were added to the resulting solution, followed by stirring at room temperature for 2.5 hours. The reaction mixture was distilled under reduced pressure. The residue was subjected to chromatography on a silica gel column (hexane:ethyl acetate=9:1), whereby the title compound (3.07 g) was obtained as pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:20]([O-])=O)=[C:5]([C:9]2[O:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[CH:14]=2)[CH:6]=[CH:7][CH:8]=1>CO.C1COCC1.[Ni]>[NH2:20][C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[C:9]1[O:10][C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13](=[O:15])[CH:14]=1
Reactant: COc1cccc(-c2cc(=O)c3ccccc3o2)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(-c2cc(=O)c3ccccc3o2)c1N
Yield: 58.1 %

Procedure:
2-(3-Methoxy-2-nitrophenyl)-4-oxo-4H-[1]benzopyran (1.73 g, 5.8 mmol) in methanol (50 mL) and THF (50 mL) is hydrogenated under pressure with RaNi (0.5 g). The solution is concentrated under reduced pressure and recrystallized from toluene to yield 2-(2-amino-3-methoxyphenyl)-4-oxo-4H-[1]benzopyran (900 mg, 58%) as a solid. 1H NMR (DMSO): δ8.07 (1H, d, J=8.0 Hz), 7.83 (1H, t, J=6.9 Hz), 7.70 (1H, d, J=7.7 Hz), 7.51 (1H, t, J=7.0 Hz), 7.09 (1H, d, J=8.0 Hz), 7.00 (1H, d, J=7.0 Hz), 6.71 (1H, t, J=8.0 Hz), 6.56 (1H, s), 5.30 (2H, s), 3.85 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][C:14]2[S:15][CH:16]=[C:17]([C:19]([O:21]CC)=[O:20])[N:18]=2)[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][C:14]2[S:15][CH:16]=[C:17]([C:19]([OH:21])=[O:20])[N:18]=2)[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1csc(CN(C)S(=O)(=O)c2ccc(Br)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN(Cc1nc(C(=O)O)cs1)S(=O)(=O)c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 72 h
Yield: 91.4 %

Procedure:
Ethyl 2-(N-(4-bromobenzenesulphonyl)-N-methylaminomethyl)thiazole-4-carboxylate (2.19, 5.2 mmol) was added to mixture of 1N lithium hydroxide solution (10 ml, 10 mmol) and dioxan (20 ml) and heated to 50° C. until a solution was obtained. The mixture was stirred at room temperature for a further 3 days. The mixture was evaporated, taken up in EtOAc and acidified with 1N potassium hydrogen sulphate solution. The phases were separated and the organic phase washed with water and brine, dried and reduced to afford 2-(N-(4-bromobenzenesulphonyl)-N-methylaminomethyl)thiazole-4-carboxylic acid (1.86 g, 95%) as a white solid.
Reaction SMILES: O[C@@:2]([CH3:54])([C:5](=[O:53])[C@@H:6]([NH:11][C:12](=[O:52])[C@@H:13]([NH:21][C:22](=[O:51])[C@@H:23]([N:28](C)[C:29](=[O:49])[C@@H:30]([NH:39][C:40](=[O:48])[CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:3][I:4].[CH3:55][O:56][C:57]1[CH:71]=[CH:70][C:60]([CH2:61][O:62][C:63](=[O:69])[CH2:64][CH2:65][C:66]([OH:68])=[O:67])=[CH:59][CH:58]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:66]([O:68][C@:2]([CH3:54])([CH2:3][I:4])[C:5](=[O:53])[C@H:6]([CH2:7][CH:8]([CH3:9])[CH3:10])[NH:11][C:12](=[O:52])[C@H:13]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH:21][C:22](=[O:51])[C@H:23]([CH2:24][CH:25]([CH3:27])[CH3:26])[NH:28][C:29](=[O:49])[C@H:30]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[NH:39][C:40](=[O:48])[CH2:41][N:42]1[CH2:43][CH2:44][O:45][CH2:46][CH2:47]1)(=[O:67])[CH2:65][CH2:64][C:63]([O:62][CH2:61][C:60]1[CH:59]=[CH:58][C:57]([O:56][CH3:55])=[CH:71][CH:70]=1)=[O:69]
Reactant: COc1ccc(COC(=O)CCC(=O)O)cc1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1)C(=O)[C@](C)(O)CI
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)CCC(=O)O[C@](C)(CI)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc2ccccc2)NC(=O)CN2CCOCC2)cc1
Temperature: 30 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
Referring to FIG. 43, to a solution of compound (S)—N—((S)-1-(((2S,4S)-2-hydroxy-1-iodo-2,6-dimethyl-3-oxoheptan-4-yl)amino)-1-oxo-3-phenylpropan-2-yl)-4-methyl-2-((S)—N-methyl-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide (20, 1.5 g, 1.77 mmol) in DCM (10 mL) were added 4-((4-methoxybenzyl)oxy)-4-oxobutanoic acid (2.1 g, 8.81 mmol), DCC (1.82 g, 8.82 mmol) and DMAP (1.08 g, 8.84 mmol). The reaction mixture was stirred for 3 h at 30° C. (TLC analysis showed very little of 19 was left). The mixture was diluted with DCM (100 mL) and then filtered. The filtrate was washed with saturated citric acid solution (50 mL×2) and saturated NaHCO3 solution (50 mL×3), dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography (EtOAc/DCM=1:15 to 2:1) to give product (1.7 g, 90% yield) as a yellow powder.