Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[Si:22]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCOC1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCCCCCOC1CCNCC1
Reaction time: 8 h
Yield: 98.3 %

Procedure:
Intermediate 22 (157 mg, 0.387 mmol) was dissolved in MeOH (5 mL) then added 10% (w/w) Pd/C (41 mg, 0.0387 mmol). The reaction vessel was attached to 3-way valve with balloon containing hydrogen gas. The vessel was evacuated 3 times then back flushed with hydrogen. The resulting suspension was stirred overnight, filtered, and concentrated to give the title compound (120 mg) as clear oil. The compound was used with no further purification. ES/MS calcd for C17H38NO2Si+ 316.3. Found m/z=316.3 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]1(O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccccc1
Reaction time: 16 h

Procedure:
A 2.01 g (10 mmol) sample of (S)-1-BOC-2-pyrrolidinemethanol (from Example 1a) and 1.41 g (15 mmol) of phenol (Aldrich) were added to a complex of TPP and DEAD, (prepared as in Example 5b above, 15 mmol of each) in 100 mL of THF. The reaction was stirred for 16 hr, the solvents were removed under vacuum, and the residue was extracted with hexane and chromatographed on silica gel to give 0.7 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[C:5]([OH:10])=[C:4]([CH2:11]O)[CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[OH:21]>C(O)(=O)C.OS(O)(=O)=O>[Cl:13][C:14]1[C:15]([OH:21])=[C:16]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[CH2:11][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([CH2:8][C:16]2[CH:17]=[C:18]([Cl:20])[CH:19]=[C:14]([Cl:13])[C:15]=2[OH:21])[C:5]=1[OH:10]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: OCc1cc(F)cc(CO)c1O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Oc1c(Cl)cc(Cl)cc1Cc1cc(F)cc(Cc2cc(Cl)cc(Cl)c2O)c1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-fluoro-2,6-bis(hydroxymethyl)phenol (2.0 g) was dissolved in glacial acetic acid (20 ml) and added slowly to 2,4-dichlorophenol (3.8 g) in concentrated H2SO4 at 60°-70°. The mixture was held at 65°-70° for 1 hr, cooled, acetic acid (20 ml) was added to dissolve the solids and the solution was poured into ice-water. The solid precipitate was purified by column chromatography over silica gel using hexane-ethyl acetate as eluent. The title compound was obtained in yield of 1.3 g, mp 168°.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:18][CH2:19][CH2:20]O)[N:6]=1)[CH:2]=[CH2:3].S(Cl)([Cl:24])=O>ClCCl>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:18][CH2:19][CH2:20][Cl:24])[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(NCCO)nc2ccc([N+](=O)[O-])cc12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: C=CCNc1nc(NCCCl)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 47 %

Procedure:
To a solution of 50 mg (0.173 mmol) of 4-allylamino-2-(2-hydroxyethylamino)-6-nitroquinazoline in dichloromethane was added 1.63 g (13.7 mmol) of thionyl chloride, and then the resulting mixture was stirred at room temperature for 4 hours. After the mixture was subjected to heating under reflux for further one hour, the solvent was distilled off under reduced pressure. The residue was purified by a silica gel chromatography to give 25 mg (yield: 46.8%) of the title compound.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[N:15]1([CH2:19][C@@H:20]([NH2:35])[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[CH2:18][CH2:17][CH2:16]1>>[N:15]1([CH2:19][C@@H:20]([NH:35][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[C:23]([C:31]([F:32])([F:33])[F:34])[CH:22]=2)[CH2:18][CH2:17][CH2:16]1
Reactant: N[C@H](CN1CCC1)c1ccc(C(F)(F)F)c(C(F)(F)F)c1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Product: NC(=O)c1ccnc2c(N[C@H](CN3CCC3)c3ccc(C(F)(F)F)c(C(F)(F)F)c3)ncnc12

Procedure:
Compound 63 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with (S)-2-Azetidin-1-yl-1-(3,4-bis-trifluoromethyl-phenyl)-ethylamine to give the title compound as a white solid. LC/MS [485 (M+H)].
Reaction SMILES: [CH2:1]([N:7]1[C:12](=O)[CH:11]2[CH:9]([C:10]2([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:14]#[N:15])[C:8]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].B.O1CCCC1>O1CCCC1>[CH2:1]([N:7]1[CH2:8][CH:9]2[CH:11]([C:10]2([CH2:14][NH2:15])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1C(=O)C2C(C1=O)C2(C#N)c1cccc([N+](=O)[O-])c1
Agent: B
Solvent: C1CCOC1
Product: CCCCCCN1CC2C(C1)C2(CN)c1cccc([N+](=O)[O-])c1
Yield: 116.2 %

Procedure:
To a solution of 3-hexyl-6-(3-nitrophenyl)-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carbonitrile (Preparation 111, 250 mg, 0.732mmol) in anhydrous tetrahydrofuran (3 ml) stirred under nitrogen was added dropwise borane-tetrahydrofuran complex (1.0 M in tetrahydrofuran, 2.9 ml, 2.9 mmol). The reaction mixture was heated at reflux for 2 h, before cooling and quenching with dry methanol (2 ml). The solution in methanol was heated under reflux for 18 h before concentrating in vacuo. The residue was again dissolved in methanol (ca 5 ml) and heated at reflux for 3 hours, followed by evaporation to dryness in vacuo. This process was repeated once more and extensive drying gave a brown oil (270 mg) which was purified by column chromatography on silica gel (13 g) eluting with dichloromethane:ethanol:0.88 ammonia (150:8:1). This gave the title compound as an orange oil (124 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[S:17][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:4]=2[C:3]=1[CH3:18].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1>>[F:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][N:14]1[CH2:13][CH2:12][CH:11]([NH:10][C:9]2[C:4]3[C:3]([CH3:18])=[C:2]([Cl:1])[S:17][C:5]=3[N:6]=[CH:7][N:8]=2)[CH2:16][CH2:15]1
Reactant: Fc1cccc(CBr)c1
Reactant: Cc1c(Cl)sc2ncnc(NC3CCNCC3)c12
Product: Cc1c(Cl)sc2ncnc(NC3CCN(Cc4cccc(F)c4)CC3)c12

Procedure:
The title compound was prepared (119 mg, 91%) from 6-chloro-5-methyl-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine (95 mg, 0.336 m. mol) and 1-(bromomethyl)-3-fluorobenzene (70 mg, 0.37 m. mol) by following the general procedure described for Preparation 12. 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.30 (m, 1H), 7.10 (m, 2H), 6.95 (m, 1H), 5.30 (d, 1H), 4.05 (m, 1H), 3.55 (s, 2H), 2.95 (m, 2H), 2.50 (s, 3H), 2.25 (m, 2H), 2.15 (m, 2H), 1.60 (m, 2H). MS (ESI) m/z: Calculated: 390.91; Observed: 391.2 (M++1).
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:15]2[CH2:20][CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][CH:16]=2)[CH:9]=1)(=[O:5])=[O:4].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:48]([C:50]1[N:51]=[C:52]([C:63]([O-])=[O:64])[N:53]([CH2:55][O:56][CH2:57][CH2:58][Si:59]([CH3:62])([CH3:61])[CH3:60])[CH:54]=1)#[N:49].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:21][C:18]1([CH3:22])[CH2:19][CH2:20][C:15]([C:10]2[CH:9]=[C:8]([CH2:7][CH2:6][S:3](=[O:4])(=[O:5])[NH:2][CH3:1])[CH:13]=[CH:12][C:11]=2[NH:14][C:63]([C:52]2[N:53]([CH2:55][O:56][CH2:57][CH2:58][Si:59]([CH3:62])([CH3:61])[CH3:60])[CH:54]=[C:50]([C:48]#[N:49])[N:51]=2)=[O:64])=[CH:16][CH2:17]1
Reactant: CNS(=O)(=O)CCc1ccc(N)c(C2=CCC(C)(C)CC2)c1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNS(=O)(=O)CCc1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCC(C)(C)CC2)c1
Yield: 83.1 %

Procedure:
A solution of 65.0 mg (0.202 mmol) of 2-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-ethanesulfonic acid methylamide (as prepared in the previous step) in CH2Cl2 (5 mL) was treated with 141 mg (0.303 mmol) of PyBroP, 67.7 mg (0.222 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)), and 105 μL (0.605 mmol) of DIEA at RT for 2 h. The mixture was diluted with CH2Cl2 (10 mL) and washed with saturated aqueous NaHCO3 (1×10 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 50% EtOAc-hexane afforded 96.0 mg (83%) of the title compound as a white solid: Mass spectrum (ESI, m/z): Calcd. for C28H41N5O4SSi, 572.3 (M+H). found 572.0.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[Br:12][CH2:13][CH2:14][C:15](OC)=[O:16]>>[Br:12][CH2:13][CH2:14][C:15]([NH:7][C:6]1[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=1)=[O:16]
Reactant: COC(=O)CCBr
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: O=C(CCBr)Nc1ccc(C(F)(F)F)cc1

Procedure:
22.3 ml of 4-(trifluoromethyl)aniline (29 g, 179.6 mmol, 1 equivalent) were reacted with 19.6 ml (30 g, 179.6 mmol, 1 equivalent) of methyl 3-bromopropanoate and worked up analogously to Example 152A. The crude product obtained was then purified on a silica gel column (mobile phase: dichloromethane). This gave 20.3 g (37% of theory) of the title compound.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:25])=[C:11]([NH:13][C:14](=[O:24])[C:15]3[CH:20]=[C:19]([F:21])[C:18](F)=[C:17]([F:23])[CH:16]=3)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][OH:33].CC(C)([O-])C.[K+]>CN1C(=O)CCC1.C(OCC)(=O)C>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:25])=[C:11]([NH:13][C:14](=[O:24])[C:15]3[CH:20]=[C:19]([F:21])[C:18]([O:33][CH2:32][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=4)=[C:17]([F:23])[CH:16]=3)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: OCc1ccccn1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)c(F)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)c(OCc2ccccn2)c(F)c1
Temperature: 180 °C
Yield: 23 %

Procedure:
A mixture of N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3,4,5-trifluorobenzamide (100 mg, 0.29 mmol), 2-pyridinylmethanol (400 μl) and potassium t-butoxide (32 mg, 0.29 mmol) in NMP (600 μl) was heated in the microwave at 180° C. for 1.5 hrs. The reaction mixture was cooled and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic phase was washed with dilute aqueous citric acid. Evaporation of the ethyl acetate gave impure product which was purified on silica column chromatography eluting with 0 to 100% ethyl acetate in isohexane. The solvents were evaporated to give a residue which was dissolved in ethyl acetate, then extracted with dilute hydrochloric acid. The aqueous extracts were basified with saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate to give the title compound as a solid (29 mg, 23%); NMR Spectrum: (DMSOd6) 0.58 (m, 2H), 0.69 (m, 2H), 2.25 (s, 3H), 2.85 (m, 1H), 5.36 (s, 2H), 7.37 (m, 2H), 7.64 (m, 2H), 7.84 (m, 4H), 8.40 (m, 1H), 8.56 (m, 1H), 10.14 (s, 1H); Mass Spectrum: M−H− 436.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH:13]=[C:12]([C:14]([O:16]C)=[O:15])[N:11]=[CH:10]2)[CH:4]=1.[OH-].[Na+]>CO.O>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[N:11]=[CH:10]2)[CH:4]=1
Reactant: COC(=O)c1cn(-c2cc(C(F)(F)F)ccn2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cn(-c2cc(C(F)(F)F)ccn2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106 %

Procedure:
To a solution of methyl 1-[4-(trifluoromethyl)pyridin-2-yl]-1H-imidazole-4-carboxylate (120 mg, 0.44 mmol) in methanol (2.5 mL) was added a 5 M solution of sodium hydroxide in water (2.5 mL) and the mixture was stirred at room temperature for 1 h. After removal of methanol under vacuum, the resulting solution was acidified with concentrated HCl (pH=5) and concentrated. The residue was taken up in acetone and insolubles were filtered off. The filtrate was evaporated to give the title compound (120 mg). MS (M+H) 258.2.
Reaction SMILES: [Cl:1][C:2]1[C:3](O)=[N:4][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[N:6][CH:7]=1.P(Br)(Br)([Br:16])=O.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Br:16][C:3]1[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[N:4]=1
Reactant: Oc1nc(-c2cccs2)ncc1Cl
Reactant: O=P(Br)(Br)Br
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: Clc1cnc(-c2cccs2)nc1Br
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 5-chloro-2-(thiophen-2-yl)pyrimidin-4-ol (90 mg, 0.42 mmol, 1.0 equiv.), POBr3 (364 mg, 1.27 mmol, 3.0 equiv.) and N,N-dimethylbenzenamine (103 mg, 0.85 mmol, 2.0 equiv.) in toluene (5 mL) was stirred at 100° C. for 1 h, then poured into crashed ice. The mixture was extracted with ethyl acetate. The combined organic layers were washed over saturated NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to afford 4-bromo-5-chloro-2-(thiophen-2-yl)pyrimidine, which was directly used for the next step. LC-MS (m/z)=275.0 [M+H]+.
Reaction SMILES: [CH:1]([N:4]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)([CH3:3])[CH3:2].[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24]([OH:29])=[CH:23][C:22]=2[O:21]1>N1C(C)=CC(C)=CC=1C.C(OCC)(=O)C>[CH:14]1([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:13])[C:6]2[CH:11]=[CH:10][C:9]([O:29][C:24]3[CH:25]=[CH:26][C:27]4[O:28][CH2:20][O:21][C:22]=4[CH:23]=3)=[CH:8][CH:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)N(C(=O)c1ccc(Br)cc1)C1CCCCC1
Reactant: Oc1ccc2c(c1)OCO2
Solvent: CCOC(C)=O
Solvent: Cc1cc(C)nc(C)c1
Product: CC(C)N(C(=O)c1ccc(Oc2ccc3c(c2)OCO3)cc1)C1CCCCC1

Procedure:
The reaction was carried out in the same manner as described in Example 1 using p-bromobenzoic acid N-isopropyl-N-cyclohexyl amide (2.904 g, 8.96 mmol), 3,4-methylenedioxyphenol (1.354 g, 9.80 mmol) and cuprous oxide (641 mg, 4.48 mmol) in 2,4,6-collidine (15 ml). After 24 hr of refluxing, the reaction was cooled, diluted with ethyl acetate, and extracted with 0.5N HCl. A precipitate that formed on extraction was filtered and the aqueous filtrate was re-extracted with ethyl acetate. The organic layers were combined and washed three times with 6N HCl, twice with H2O, three times with 5% NaOH, twice with H2O and dried (Na2SO4) The drying agent was removed by filtration, and the filtrate concentrated in vacuo to give the crude product as a black oil. This was chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:3]=1[C:4]([C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([O:14][CH3:15])=[CH:8][C:7]=1[O:16][CH3:17])=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[NH2:1][C:2]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:3]=1[CH:4]([OH:5])[C:6]1[C:7]([O:16][CH3:17])=[CH:8][C:9]([O:14][CH3:15])=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1cc(OC)c(C(=O)c2cc(Cl)ccc2N)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)c(C(O)c2cc(Cl)ccc2N)c(OC)c1
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a solution of 3.0 g of 2-amino-5-chloro-2',4',6'-trimethoxybenzophenone in 50 ml of tetrahydrofuran, 0.43 g of lithium aluminum hydride was added, followed by stirring for 1 hour. After water was added, the solution was extracted with ethyl acetate and dried over anhydrous sodium sulfate, after which the solvent was removed and the residue was subjected to silica gel column chromatography to yield 2.9 g of a crystal.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:19][C@@H:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][C@H:16]1[CH2:27][O:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1)=O)(C)(C)C>C(Cl)Cl>[O:20]([C@@H:18]1[CH2:19][NH:15][C@H:16]([CH2:27][O:28][C:29]2[CH:30]=[CH:31][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:37][CH:38]=2)[CH2:17]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccccc3)CN2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccccc3)CN2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.2 %

Procedure:
Trifluoroacetic acid (20 ml) was added to a solution of methyl 4-((2S,4S)-1-tert-butoxycarbonyl-4-phenoxy-2-pyrrolidinylmethoxy)benzoate (2.02 g, 3.25 mmol) in methylene chloride (100 ml). The resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was then concentrated under reduced pressure. The residue was diluted with methylene chloride (50 ml), followed by washing with 1N NaOH. The organic layer was fractionated, followed by washing with saturated brine, drying over anhydrous sodium sulfate and distillation under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 70 g), whereby from chloroform/acetone (10/1) chloroform/methanol (10/1) eluate fractions, the title compound (970 mg, 91%) was obtained as a brown oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)=[CH2:2]>CO.C(O)(=O)C.[Pd]>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH3:2]
Reactant: C=Cc1cc(CC(=O)OC)ccc1OCc1ccc2ccccc2n1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CCc1cc(CC(=O)OC)ccc1OCc1ccc2ccccc2n1

Procedure:
14.3 g (0.0429 mol) of the compound from Example XXXII are dissolved in 150 ml of methanol and 15 ml of glacial acetic acid, 1.5 g of 5% strength Pd-C are added, and the reaction mixture is heated to 30°-35° C. and hydrogenated. It is filtered through silica gel, the filtrate is concentrated in vacuo and the residue is recrystallised from isopropanol.
Reaction SMILES: [O:1]=[C:2]1[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:5](=[O:12])[CH2:4][S:3]1.[F:13][C:14]([F:40])([F:39])[C:15]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([CH:27]=O)=[CH:24][CH:25]=2)[C:20]([C:29]#[N:30])=[N:19]1>>[F:40][C:14]([F:13])([F:39])[C:15]1[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[CH:31][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23](/[CH:27]=[C:4]3/[C:5](=[O:12])[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:2](=[O:1])[S:3]/3)=[CH:24][CH:25]=2)[C:20]([C:29]#[N:30])=[N:19]1
Reactant: CS(=O)(=O)NN1C(=O)CSC1=O
Reactant: N#Cc1nn(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c2ccc(C=O)cc12
Product: CS(=O)(=O)NN1C(=O)S/C(=C\c2ccc3c(c2)c(C#N)nn3Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C1=O

Procedure:
N-[(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-3-cyano-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methanesulfonamide was prepared from N-(2,4-dioxothiazolidin-3-yl)methanesulfonamide (from Example 360) and 1-[2,4-bis(trifluoromethyl)benzyl]-3-cyano-1H-indazol-5-carbaldehyde following General Procedure F.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])=[S:10])=[C:4]([OH:19])[C:3]=1[S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21].[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].N1C=CN=C1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])=[S:10])=[C:4]([O:19][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C:3]=1[S:20]([N:23]([CH3:25])[CH3:24])(=[O:21])=[O:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2ccccc2Br)c1O
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2ccccc2Br)c1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.7 %

Procedure:
To a solution of N-[4-chloro-2-hydroxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]-N′-(2-bromophenyl)thiourea (500 mg, 1.07 mmol) in THF (20 mL), tert-butyldimethylsilyl chloride (810 mg, 5.35 mmol) and imidazole (144 mg, 2.14 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. Then it was partitioned between ethyl acetate and water. The combined organic phase was dried and concentrated. Chromatography of the residue on silica gel (30% Ethyl acetate/Hexane) gave desired product (240 mg, 40%) and recovered starting material (280 mg). EI-MS m/z 580 (M+).
Reaction SMILES: [C:1]([NH:20][C@@H:21]([CH2:24][CH3:25])[CH:22]=[O:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([Mg]Br)[CH3:27].O>CCOCC>[C:1]([NH:20][C@@H:21]([CH2:24][CH3:25])[CH:22]([OH:23])[CH2:26][CH3:27])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[Mg]Br
Reactant: CC[C@@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: O
Product: CCC(O)[C@H](CC)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-2-(trityl-amino)-butyraldehyde (1.5 g, 1 eq, 4.53 mmol) in ether (150 mL) under an argon atmosphere at −78° C., was added ethylmagnesium bromide (3 M in ether, 1.51 mL, 1 eq, 4.53 mmol) dropwise. The solution was stirred at −78° C. for 2 h, then allowed to warm to room temperature over 16 h. The mixture was re-cooled to 0° C., H2O (150 mL) added, and the organic phase separated. The aqueous phase was extracted with more ether (2×50 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluted with hexane:ether (90:10) to afford the title compound as a light yellow oil; Yield: 1.19 g (73%). (65% de 3R,4S: 35% de 3S,4S) 1H-NMR(d6-DMSO, 250 MHz): δ 0.46+0.69 (t+m, 6H, J=7.34 Hz, —NHCH(CH2CH3)CH(CH2CH3)OH), 1.13-1.29 (m, 4H, —NHCH(CH2CH3)CH(CH2CH3)OH), 2.17 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 2.55 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 3.20-3.39 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 4.29+4.39 (2×d, 1H, J=4.74+5.53 Hz, —NHCH(CH2CH3)CH(CH2CH3)OH), 7.15-7.52 (m, 15H, 3×Bz).