Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[CH:34][CH:33]=1>C1COCC1>[CH3:29][N:24]1[C:23]([C:21]([NH:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[C:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:3](=[CH:2][NH:31][C:32]4[CH:33]=[CH:34][C:35]([CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[CH:36][CH:37]=4)[C:4](=[O:30])[NH:5]3)=[CH:10][CH:9]=2)=[O:13])=[O:22])=[CH:27][C:26]([CH3:28])=[N:25]1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Reactant: Nc1ccc(CCC(=O)O)cc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CCC(=O)O)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 15.3 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 100 mg, 0.249 mmol) and THF (2 mL). To the resulting solution was added 3-(4-Amino-phenyl)-propionic acid (45.2 mg, 0.274 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was redissolved into EtOAc. Hexanes were added to the EtOAc solution causing a precipitate to form. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 15.4% (0.021 g, 0.038 mmol) of the title compound.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11](Cl)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:18]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:20][CH2:21][CH3:22])=[O:19]>O>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([N:26]3[CH2:25][CH2:24][N:23]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:28][CH2:27]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(Cl)c([N+](=O)[O-])cc2s1
Reactant: CCOC(=O)N1CCNCC1
Solvent: O
Product: CCOC(=O)N1CCN(c2cc3nc(C(C)(C)C)sc3cc2[N+](=O)[O-])CC1

Procedure:
A mixture of 3.5 g of 2-tert.-butyl-5-chloro-6-nitrobenzothiazole, described in Example 5, and 5.8 g of N-carbethoxypiperazine is heated at 180° for 2 hours, cooled and poured into water. The solid is filtered, washed with water and crystallised from isopropyl alcohol to give 2-tert-butyl-5-[4-carbethoxypiperazin-1-yl]-6-nitrobenzothiazole, melting at 100°-102°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[NH:12][N:13]=[C:14]([CH3:16])[CH:15]=2)[CH:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[CH3:9][S:8][C:6]1[N:5]=[C:4]([NH:10][C:11]2[NH:12][N:13]=[C:14]([CH3:16])[CH:15]=2)[CH:3]=[C:2]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:7]=1
Reactant: C1COCCN1
Reactant: CSc1nc(Cl)cc(Nc2cc(C)n[nH]2)n1
Product: CSc1nc(Nc2cc(C)n[nH]2)cc(N2CCOCC2)n1

Procedure:
The above-prepared [6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (2.42 g, 9.46 mmol) is heated in morpholine (10 mL) at 130° C. for 15 hours. The solvent is then removed in vacuo and the solid residue is triturated in EtOH and collected by, filtration to give [2-methylsulfanyl-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11](O)=O)=[CH:5][CH:4]=1)#[N:2].[C:14]1([N:20]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:21](=[O:31])[C:22]2[CH:27]=[CH:26][C:25]([NH:28][CH3:29])=[C:24]([NH2:30])[CH:23]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[C:14]1([N:20]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:21]([C:22]2[CH:27]=[CH:26][C:25]3[N:28]([CH3:29])[C:11]([CH2:10][NH:9][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)=[N:30][C:24]=3[CH:23]=2)=[O:31])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N#Cc1ccc(NCC(=O)O)cc1
Reactant: CCOC(=O)CCN(C(=O)c1ccc(NC)c(N)c1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccc1

Procedure:
6.17 g (0.035 mol) of N-(4-cyanophenyl)glycine and 5.68 g (0.035 mol) of N,N′-carbonyldiimidazole were refluxed in 300 mL of tetrahydrofuran for 30 minutes, then 10.6 g (0.032 mol) of 3-amino-4-methylaminobenzoic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide were added, and the mixture was refluxed for a further five hours. Then the solvent was distilled off in vacuo, the residue was dissolved in 150 mL of glacial acetic acid and refluxed for one hour. Then the glacial acetic acid was distilled off in vacuo, the residue was dissolved in about 300 mL of dichloromethane, the solution was washed twice with about 150 mL water and then dried over sodium sulfate. After evaporation of the solvent, the crude product thus obtained was purified by column chromatography (800 g silica gel; eluant: dichloromethane with 1-2% ethanol). Yield: 8.5 g (57% of theory); Rf value: 0.51 (silica gel; dichloromethane/ethanol=19:1).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[N:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:31]#[C:32][C:33](OCC)=[O:34])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1>C1COCC1>[C:1]1([N:7]2[C:31]([C:28]3[CH:29]=[C:30]4[C:25](=[CH:26][CH:27]=3)[N:24]=[CH:23][CH:22]=[C:21]4[C:18]3[CH:17]=[CH:16][N:15]=[CH:20][CH:19]=3)=[CH:32][C:33](=[O:34])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)C#Cc1ccc2nccc(-c3ccncc3)c2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=c1cc(-c2ccc3nccc(-c4ccncc4)c3c2)n(-c2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.8 %

Procedure:
A solution of phenylhydrazine (0.093 ml, 0.95 mmol) in anhydrous THF (4.0 ml) was treated with a 1M solution of potassium tert-butoxide in THF (1.89 ml, 1.89 mmol). The resulting solution was added to a solution of ethyl 3-[4-(4-pyridinyl)-6-quinolinyl]-2-propynoate (0.268 g, 0.95 mmol) in THF (10 ml). The resulting brown solution was stirred at room temperature for 1 hour then at 65° C. for 1 hour. The resulting orange slurry was cooled to room temperature then concentrated under reduced pressure. The resulting residue was taken into saturated aqueous NaHCO3 then extracted into methylene chloride and the extracts were dried over sodium sulfate then evaporated under reduced pressure. The resulting oil was purified by HPLC (acetonitrile/water, 5-80% gradient). The product was concentrated to a residue then recrystallized from ethanol to give the title compound (0.020 g, 6%) as a white solid. MS(ES)+ m/e 365 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:10][CH2:11][C:12](Cl)=[O:13].O>ClCCl>[Cl:10][CH2:11][C:12]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])=[O:13]
Reactant: Nc1ccccc1C=O
Reactant: O=C(Cl)CCl
Solvent: O
Solvent: ClCCl
Product: O=Cc1ccccc1NC(=O)CCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
2-Aminobenzaldehyde (650 mg) was dissolved in dichloromethane (20 ml) to prepare a solution. Chloroacetyl chloride (728 mg) was added to the solution, and the mixture was stirred at room temperature overnight. Water was added thereto, and the mixture was extracted with dichloromethane. The dichloromethane layer was washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform to give 2-chloro-N-(2-formylphenyl)-acetamide (1.05 g, yield 99%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[O:20][CH3:21].[Al+3].[Cl-].[Cl-].[Cl-]>>[Cl:19][C:18]1[C:13]([Cl:12])=[C:14]([O:20][CH3:21])[CH:15]=[CH:16][C:17]=1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=1[CH3:1])=[O:5]
Reactant: COc1cccc(Cl)c1Cl
Reactant: Cc1cccc(C(=O)Cl)c1C
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)c2cccc(C)c2C)c(Cl)c1Cl

Procedure:
The Friedel-Crafts procedure of Example 24a is repeated with 33.7 g of 2,3-dimethylbenzoyl chloride, 54 g of 2,3-dichloroanisole and 26.7 AlCl3 being reacted to form 2,3-dichloro-4-methoxy-2',3'-dimethylbenzophenone.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4].[O:12]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[O:12]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4])=[O:22])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Product: O=C(N[C@H](CO)Cc1ccccc1)c1ccccc1Oc1ccccc1
Yield: 103.7 %

Procedure:
7.3 g (48 mmol) of (S)-2-amino-3-phenyl-1-propanol were reacted with 10.7 g (50 mmol) of 2-phenoxybenzoic acid by the method of procedure 3c. 17.3 g (100%) of the product were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[C:19]([O:26][CH3:27])=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[C:19]([O:26][CH3:27])=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)c1cc(OC)c(OC)c(OC)c1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(OC)c(OC)c(OC)c1NC(=O)c1ccc(Cl)cc1

Procedure:
A solution of 20.3 g of 4-chlorobenzoyl chloride in 60 ml of THF was added dropwise to the solution of 25.3 g of methyl 2-amino-3,4,5-trimethoxybenzoate and 16 ml of triethylamine in 100 ml of THF. The mixture was refluxed for 1 hour (h), cooled in an ice bath and filtered. After concentration, a colorless residue remained. Yield: 34.1 g. Melting point (m.p.): 116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([C:15]([O:17]C)=O)[CH:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:25]=1.[NH3:26]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([C:15]([NH2:26])=[O:17])[CH:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:25]=1
Reactant: N
Reactant: COC(=O)c1cc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Solvent: CO
Product: NC(=O)c1cc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 16 h

Procedure:
A solution of 750 mg. (2.13 mmol) of the end product of Example 9 in 50 ml. methanol in a glass bomb was cooled to 3° and saturated with ammonia. The glass bomb was then sealed and the reaction heated to 70° with stirring, for 16 hours. After cooling to 5°, the bomb was opened, the contents transferred to a r.b. flask and concentrated in vacuo. Recrystallization from acetone/hexane yielded end product, mp 216°-218°. An analytical sample was prepared by an additional recrystallization from acetone/hexane and obtained as pale yellow needles: mp 217°-219°.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C(=O)(O)[O-].[Na+].Br[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19]>O>[CH3:19][C:18]([CH3:20])=[CH:17][CH2:16][CH2:15][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: CC(C)=CCCBr
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)=CCCn1ccnc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 16 h

Procedure:
To a solution of 2-nitroimidazole (3.0 g, 27 mmol) in dry dimethylformaide (25 mL), was added anhydrous sodium bicarbonate (4.2 g, 50 mmol) followed by 5-bromo-2-methyl-2-pentene (5.0 g, 30.67 mmol). The reaction mixture was heated at 60-70° C. with stirring under nitrogen for 16 hours. Solvent dimethylformamide and the unreacted bromide were removed under reduced pressure (<1 mm) at 50-60° C. to yield a paste which was dissolved in water (50 mL) and extracted with ethyl acetate (5×50 mL). The combined organic extracts were dried and concentrated to give a brown oil which was recrystallized from petroleum ether (b.p. 40-60° C.) to yield a yellow solid. Yield: 4.8 g, m.p. 51-52° C. 1H NMR (CDCl3) δ 1.55 (s, 3H, CH3), 1.75 (s, 3H, CH3), 2.7 (q, 2H, olefinic CH2), 4.5 (t, 2H, N—CH2), 5.2 (t, 1H, olefinic H), 7.1 (s, 1H, imidazole H), 7.2 (s, 1H, imidazole H). M.S. [M+H]+ 196, [M+NH4]+ 213.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[O:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.Cl[CH2:20][C:21]([NH:23][CH3:24])=[O:22].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([O:3][CH3:2])=[C:5]([CH:6]=1)[O:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:20][C:21]([NH:23][CH3:24])=[O:22])[CH2:15][CH2:14]1)#[N:9]
Reactant: COc1ccc(C#N)cc1OC1CCNCC1
Reactant: CNC(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CNC(=O)CN1CCC(Oc2cc(C#N)ccc2OC)CC1
Temperature: 20 °C
Yield: 96.2 %

Procedure:
4-Methoxy-3-(piperidin-4-yloxy)benzonitrile hydrochloride salt (3, 28.36 g, 95.82 mmoles), 2-chloro-N-methylacetamide (12.37 g, 114.98 mmoles) and potassium carbonate (33.11 g, 239.55 mmoles) were suspended in acetonitrile (161.36 g). The reaction mixture was heated at reflux for 3 hours. The reaction mixture was cooled to 20° C. and water (386.26 g) was charged. The reaction was heated to 75° C. and the volume reduced by distillation. Upon cooling crystallisation occurred. The resulting solid was isolated by filtration, washed twice with water (77.25 g and 128.75 g) and then dried to give the title compound (27.95 g, 94% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.68 (m, 2H) 1.91 (m, 2H) 2.29 (m, 2H) 2.61 (d, J=4.7 Hz, 3H) 2.67 (m, 2H) 2.88 (s, 2H) 3.83 (s, 3H) 4.41 (tt, J=8.3, 4.0 Hz, 1H) 7.11 (d, J=8.4 Hz, 1H) 7.40 (dd, J=8.4, 1.9 Hz, 1H) 7.47 (d, J=1.9 Hz, 1H) 7.68 (q, J=4.7 Hz, 1H); Mass Spectrum: m/z (M+H)+ 304.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][N:3]=1.[F-:14].[Cs+]>CS(C)=O.O>[F:14][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][N:3]=1
Reactant: [F-]
Reactant: COc1cnc(Cl)c2ccccc12
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cnc(F)c2ccccc12
Temperature: 145 °C
Yield: 30.6 %

Procedure:
To a solution of 1-chloro-4-methoxyisoquinolin (2.5 g, 12.91 mmol) in DMSO was added cesium fluoride (4.01 g, 25.82 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (700 mg, 62%) as a white solid. 1H NMR (400 MHz, CD3OD): δ ppm 8.10 (m, 1H), 8.08 (m, 1H), 7.78-7.75 (m, 1H), 7.69-7.65 (m, 1H), 7.49 (m, 1H), 4.04 (s, 3H); 19F NMR: δ ppm −78.66 (1 F); MS: MS m/z 178.1 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@@H:4]([O:22][CH2:23][CH3:24])[C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:8]=1[Cl:21])O.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3](=[O:25])[C@@H:4]([O:22][CH2:23][CH3:24])[CH2:5][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:8]=1[Cl:21]
Reactant: CCO[C@H](C(=O)OC)[C@H](O)c1ccc(OCc2ccccc2)cc1Cl
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1Cl)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 c], (2S,3R)-3-(4-benzyloxy-2-chloro-phenyl)-2-ethoxy-3-hydroxy-propionic acid methyl ester was treated with triethylsilane in trifluoroacetic acid to yield (2S)-3-(4-benzyloxy-2-chloro-phenyl)-2-ethoxy-propionic acid methyl ester as colorless liquid.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:36])[CH2:20][NH:21][C:22](=[O:35])[NH:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([O:33]C)=[O:32])[CH:27]=[CH:28][CH:29]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>CO.O>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:36])[CH2:20][NH:21][C:22](=[O:35])[NH:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([OH:33])=[O:32])[CH:27]=[CH:28][CH:29]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3)CC[C@H]2C(=O)OC(C)(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H]1CC[C@H](c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(CC(=O)O)c1
Yield: 35.2 %

Procedure:
The operation is carried out as in Example 9, but starting from 1.9 g of methyl (2S,5R)-3-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenylacetate in solution in 60 cm3 of methanol and 0.22 g of potassium hydroxide dissolved in 30 cm3 of water. After treatment, 0.65 g of (2S,5R)-3-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenylacetic acid, melting at 112° C., [α]D20 =+30.6°±0.8° (c=1; methanol) is obtained.
Reaction SMILES: [F:1][C:2]1[C:3]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=O)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([OH:14])=[N:10][CH:11]=[N:12][CH:13]=1.Cl.[NH2:25][OH:26]>N1C=CC=CC=1>[F:1][C:2]1[C:3](/[C:15](/[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[N:25]\[OH:26])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([OH:14])=[N:10][CH:11]=[N:12][CH:13]=1
Reactant: O=C(c1ccc(F)cc1)c1nccc(-c2cncnc2O)c1F
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O/N=C(/c1ccc(F)cc1)c1nccc(-c2cncnc2O)c1F
Temperature: 25 °C
Yield: 69.2 %

Procedure:
A solution of (3-fluoro-4-(4-hydroxypyrimidin-5-yl)pyridin-2-yl)(4-fluorophenyl)methanone (0.168 g, 0.536 mmol) and hydroxylamine hydrochloride (0.039 g, 0.563 mmol) in Pyridine (Volume: 2.68 ml) was refluxed for 1.5 hr, allowed to cool to room temperature, and then concentrated in vacuo. Solvent was evaporated. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed (required a few drops of MeOH). Purification of the crude material by silica gel chromatography using an ISCO machine (24 g column, 35 mL/min, 1-25% MeOH in CH2Cl2 over 19 min, tr=12 min) gave the title compound (0.123 g, 0.371 mmol, 69.2% yield) as a tan solid. ESI MS (M+H)+=329.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][C@H:16]([CH:29]([CH3:31])[CH3:30])[CH2:17][C@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=[O:20])[CH:13]=2)[CH:8]=[N:7]1.[CH2:32]([O:39][CH2:40][C@H:41]([CH:45]([CH3:47])[CH3:46])[CH2:42][Mg]Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[NH4+].[Cl-]>C1COCC1>[CH2:32]([O:39][CH2:40][C@H:41]([CH:45]([CH3:47])[CH3:46])[CH2:42][CH:19]([OH:20])[C@@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:17][C@H:16]([CH2:15][C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[N:7][N:6]2[CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:10][CH:11]=1)[CH:29]([CH3:31])[CH3:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)[C@@H](COCc1ccccc1)C[Mg]Br
Reactant: COCCCn1ncc2ccc(C[C@@H](C[C@@H](C=O)NC(=O)OC(C)(C)C)C(C)C)cc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCCn1ncc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(O)C[C@H](COCc3ccccc3)C(C)C)C(C)C)cc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
A 250-mL, three-neck, round-bottom flask equipped with a condenser under N2 was charged with Mg powder (1.36 g, 56.7 mmol). The mixture was warmed briefly with a heat gun and a solution (S)-((2-(bromomethyl)-3-methylbutoxy)methyl)benzene (10.5 g, 37.8 mmol) in anhydrous THF (100 mL) was added dropwise. When the reaction mixture reached reflux temperature the heat gun was stopped. The mixture was stirred for an additional 30 min to afford a solution of (S)-(2-(benzyloxymethyl)-3-methylbutyl)magnesium bromide. A second 250-mL, three-neck round-bottom flask was charged with a solution of tert-butyl (2S,4S)-4-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-5-methyl-1-oxohexan-2-ylcarbamate (2.7 g, 6.3 mmol) in anhydrous THF (50 mL) and cooled to −78° C. under N2 and the solution was stirred for 30 min. The freshly prepared solution of (S)-(2-(benzyloxymethyl)-3-methylbutyl)magnesium bromide prepared above was added dropwise and the mixture was warmed to rt and stirred overnight. 10% aq NH4Cl was added and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed brine, dried and evaporated. The residue was purified by flash chromatography on silica gel to afford the crude tert-butyl (3S,5S,8S)-8-(benzyloxymethyl)-6-hydroxy-3-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-2,9-dimethyldecan-5-ylcarbamate (1.3 g, 33% yield) as an 11:5 mixture of diastereomers at the alcohol center.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]1)[CH2:10][C:9]2=[O:28].I[CH:31]([CH3:33])[CH3:32].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][CH2:14][N:13]([CH:31]([CH3:33])[CH3:32])[CH2:12]1)[CH2:10][C:9]2=[O:28]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(=O)OC(C)(C)C)C1)O2
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(C)C)C1)O2
Temperature: 75 °C
Reaction time: 24 h
Yield: 82.6 %

Procedure:
A mixture of (±)-(E)-3-[4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester hydrochloride (Intermediate 2, 300 mg, 0.888 mmol), 2-iodopropane (302 mg, 1.76 mmol) and K2CO3 (491 mg, 3.55 mmol) in CH3CN (40 ml) was stirred at 75° C. for 24 h. The solvent was removed and the residue was partitioned between EtOAc and H2O. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude mixture was purified by column chromatography (eluent: DCM/MeOH 98:2) to give (±)-(E)-3-[1′-isopropyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester (252 mg).
Reaction SMILES: [S:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:12]([F:13])=[CH:11][C:10]([NH2:14])=[CH:9][C:8]=2[F:15])[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[C:21](=[O:28])([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])N>C1COCC1.O>[S:1]1[CH2:2][CH:3]=[C:4]([C:7]2[C:8]([F:15])=[CH:9][C:10]([NH:14][C:21](=[O:28])[O:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:11][C:12]=2[F:13])[CH2:5][CH2:6]1
Reactant: Nc1cc(F)c(C2=CCSCC2)c(F)c1
Reactant: CC(C)COC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)COC(=O)Nc1cc(F)c(C2=CCSCC2)c(F)c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a stirred, biphasic mixture of 4-(3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorobenzenamine (Step 4, 3.90 g, 17.2 mmol) in THF/water (2:1, 103 mL) is added sodium bicarbonate (2.88 g, 34.3 mmol) followed by isobutyl carbamate (2.45 mL, 18.9 mmol) dropwise. The reaction mixture is stirred at ambient temperature for 7 h and is then concentrated under reduced pressure, diluted with EtOAc (100 mL) and H2O (50 mL), and the layers are separated. The organic phase is washed with H2O (25 mL) and saline (25 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification of the residue by chromatography on a Biotage Flash 40M 90 g silica gel cartridge, eluting with 5-10% EtOAc/Hexanes, affords the title compound, mp 136-137° C.; MS (ESI−) for C16H19F2NO2S m/z 326 (M−H)−.