Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.C1C2C(COC([N:62]3[CH2:67][C@@H:66]([C:68](=[O:88])[N:69]([CH:85]4[CH2:87][CH2:86]4)[CH2:70][C:71]4[C:79]5[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=5)[N:73]([CH2:80][CH2:81][CH2:82][O:83][CH3:84])[CH:72]=4)[CH2:65][C@@H:64]([NH2:89])[CH2:63]3)=O)C3C(=CC=CC=3)C=2C=CC=1>C(Cl)Cl>[CH:85]1([N:69]([CH2:70][C:71]2[C:79]3[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=3)[N:73]([CH2:80][CH2:81][CH2:82][O:83][CH3:84])[CH:72]=2)[C:68]([C@H:66]2[CH2:65][C@@H:64]([NH:89][C:7]([CH:3]3[C:4]([CH3:5])([CH3:6])[C:2]3([CH3:1])[CH3:10])=[O:9])[CH2:63][NH:62][CH2:67]2)=[O:88])[CH2:86][CH2:87]1
Reactant: COCCCn1cc(CN(C(=O)[C@H]2C[C@@H](N)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)c2ccccc21
Reactant: CC1(C)C(C(=O)O)C1(C)C
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCCn1cc(CN(C(=O)[C@@H]2CNC[C@H](NC(=O)C3C(C)(C)C3(C)C)C2)C2CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2,2,3,3-tetramethyl-cyclopropanecarboxylic acid (50 mg, 0.35 mmol), O-(1H-6-chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU) (145 mg, 0.35 mmol), N-ethyldiisopropylamine (171 μL, 1 mmol) in CH2Cl2 (3 mL) is stirred for 10 min at RT. After the addition of (3R*,5S*)-3-amino-5-{cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (121.4 mg, 0.2 mmol) (Starting Material 6), stirring is continued for 14 h. The mixture is diluted with CH2Cl2, the organic layer washed with saturated NaHCO3 solution, dried over Na2SO4 and evaporated in vacuo. The crude product is stirred with a solution of CH2Cl2/piperidine 4:1 (5 mL) for 2 h, the mixture is evaporated and the residue purified by preparative HPLC (C18 column, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, 20 min, flow 20 mL/min). The combined pure fractions are treated with K2CO3, CH3CN is removed in vacuo, and the residual aqueous phase is extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to afford the title compound as a yellowish solid. MS: 509.6 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.68 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[NH:11][CH:12]=O)=O)C.C([O-])=O.[NH4+:17]>C(N)=O>[OH:3][C:4]1[C:6]2[CH:10]=[CH:9][S:8][C:7]=2[N:11]=[CH:12][N:17]=1
Reactant: CCOC(=O)c1ccsc1NC=O
Reactant: [NH4+]
Agent: O=C[O-]
Solvent: NC=O
Product: Oc1ncnc2sccc12
Temperature: 150 °C
Reaction time: 6 h
Yield: 71.9 %

Procedure:
2-formylaminothiophene-3-carboxylic acid ethyl ester (3.0 g, 15.3 mmol) was dissolved in formamide (12 ml), to which ammonium formate (3.0 g, 48.2 mmol) was added and the mixture was stirred at 150° C. for 6 hours. The reaction mixture was allowed to stand overnight at room temperature and the crystals that formed were filtered to obtain 4-hydroxythieno[2,3-d]pyrimidine (1.7 q, 11.0 mmol) having the following physical properties:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:6]=1[CH2:18]Br)[CH3:2].[NH:21]([S:27]([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH2:22][C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:6]=1[CH2:18][N:21]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[S:27]([C:30]1[CH:31]=[CH:32][C:33]([CH3:34])=[CH:35][CH:36]=1)(=[O:29])=[O:28])[CH3:2]
Reactant: CCOC(=O)c1ccc(Oc2ccccn2)cc1CBr
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Oc2ccccn2)cc1CN(CC(=O)OC)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A mixture of 2-bromomethyl-4-(pyridin-2-yloxy)-benzoic acid ethyl ester (855 mg, crude from previous step), Ts-Gly-OMe (502 mg), potassium carbonate (425 mg) and KI (32 mg) in DMF (10 mL) was stirred at rt overnight. Then the reaction mixture was diluted with EtOAc, washed with water, diluted NaCl sol and dried over anhydrous sodium sulfate, filtered, concentrated and the residue was column purified to give product (745 mg). LC MS ESI+: 499 (M+1)+.
Reaction SMILES: CO[C:3](=[O:14])/[C:4](=[N:11]\[O:12][CH3:13])/[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[CH3:15][NH2:16]>O>[CH3:15][NH:16][C:3](=[O:14])[C:4](=[N:11][O:12][CH3:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: CO/N=C(\C(=O)OC)c1ccccn1
Reactant: CN
Solvent: O
Product: CNC(=O)C(=NOC)c1ccccn1

Procedure:
Z-α-methoxyimino-2-pyridineacetic acid methylester (5 g) and a solution of methylamine in water (15 ml, 30%) were stirred at a temperature of 60° C. until the starting compound was completely dissolved. Water was evaporated under reduced pressure and the residue was recrystallized from toluene, yielding N-methyl-α-methoxyimino-2-pyridineacetamide (3.0 g), Z-isomer, m.p. 132°-133° C. The E-isomer was obtained in the same way, but starting from the corresponding E-ester. M.p. of the E-isomer 91°-93° C.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][C:6]([N+:8]([O-:10])=[O:9])=[C:5]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=2[F:19])[O:4][CH2:3]1.[BH4-].[Na+]>C(Cl)(Cl)Cl.C(O)(C)C>[CH2:1]=[C:2]1[CH2:3][O:4][C@@H:5]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=2[F:19])[C@H:6]([N+:8]([O-:10])=[O:9])[CH2:7]1
Reactant: C=C1COC(c2cc(F)c(F)cc2F)=C([N+](=O)[O-])C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: C=C1CO[C@@H](c2cc(F)c(F)cc2F)[C@H]([N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-methylene-5-nitro-6-(2,4,5-trifluorophenyl)-3,4-dihydro-2H-pyran (798 mg, 2.94 mmol) in chloroform (42 mL) and isopropyl alcohol (7.8 mL) was added silica gel (5.1 g), and sodium borohydride (420 mg, 11.1 mmol), and the reaction mixture stirred for 30 minutes at room temperature. The reaction mixture was then quenched by dropwise addition of hydrochloric acid (6 mL, 2N) and filtered. The resulting solid residue was washed with ethyl acetate (100 mL). The combined filtrate was washed successively with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and evaporated. The resultant amber oil (802 mg) was dissolved in tetrahydrofuran (15 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 40 μL) was added. The solution was stirred for 105 minutes and then transferred to a separatory funnel containing ethyl acetate (100 mL) and 1N hydrochloric acid (50 mL). The organic layer was washed with brine and the aqueous layer extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to yield a crude product which was purified by flash chromatography (silica, 8-10% ether in hexane) to yield trans-5-methylene-3-nitro-2-(2,4,5 trifluorophenyl)tetrahydro-2H-pyran. A portion of this product (388 mg) was resolved by HPLC (ChiralCel OD, 1.5% isopropyl alcohol in heptane) to yield the slower-moving enantiomer, (2R,3S)-5-methylene-3-nitro-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][C:13]2([S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:4][CH:3]=1.[Br:31][CH2:32][CH2:33][CH2:34]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][C:13]2([S:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)(=[O:22])=[O:21])[S:17][C:16](=[O:18])[N:15]([CH2:34][CH2:33][CH2:32][Br:31])[C:14]2=[O:19])=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)C2(CCCC#Cc3ccc(Cl)cc3)SC(=O)NC2=O)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)C2(CCCC#Cc3ccc(Cl)cc3)SC(=O)N(CCCBr)C2=O)cc1

Procedure:
The compound of Example 97 is reacted with 1,3-dibromopropane and potassium carbonate in DMF to give 5-[5-(4-chlorophenyl)pent-4-ynyl]-3-(3-bromopropyl)-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione, and this is reacted with imidazole, sodium salt in DMF, and in the presence of a catalytic amount of potassium iodide to give the title compound as a light tan solid, mp 111-113° C.
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.[NH2:13][C@H:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:16][CH2:17][CH3:18].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([NH:13][C@H:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:16][CH2:17][CH3:18])=[O:5]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCCC[C@H](N)C(=O)OCC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 0 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
Boc-Gly-OH (4.4 g, 0.025 mol.) and Nleu-OEt (3.2 g, 0.02 mol.) were dissolved in 100 ml DMF and the solution was chilled to 0° C. on a water-ice bath. BOP (11 g, 0.025 mol.) was added to the solution. Triethylamine was used to adjust the pH of the solution to about 9. The solution was stirred overnight. The DMF was removed under reduced pressure and the resulting mixture was poured into 300 ml ethyl acetate. The ethyl acetate solution was washed by H2O, saturated NaHCO3, brine, saturated Na2SO4 and brine again. The organic layer was dried by Na2SO4 and the ethyl acetate was removed under reduced pressure to get the crude product. Column chromatography (elution solvents: E/H, 2:1) was carried out to obtain the pure product (5.9 g, 94%). TLC Rf=0.52 (developing solvents: E/H, 2:1). 1H-NMR (360 MHz, DMSO-d6) δ 6.74 (m, Gly-NH), 6.68 (m, Gly-NH), 4.18 (s, Nleu-α), 4.12 (q, ethyl ester-CH2), 4.04 (q, ethyl ester-CH2), 3.94 (s, Nleu-α), 3.79 (d, Gly-α), 3.65 (d, Gly-α), 3.07 (m, Nleu-β), 1.79 (m, 1H, Nleu-γ), 1.34 (s, 9H, Boc-CH3), 1.16 (m, ethyl ester-CH3), 0.87 (d, Nleu-δ), 0.78 (d, Nleu-δ).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1.Cl[CH2:21][C:22]1[C:23]([CH3:35])=[N:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1.O>CN(C)C=O>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:25]2[N:24]=[C:23]([CH3:35])[C:22]([CH2:21][O:19][C:6]3[CH:7]=[CH:8][C:9]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]4[CH:18]=[CH:17][N:16]=[N:15]4)=[C:4]([CH3:3])[CH:5]=3)=[CH:27][CH:26]=2)=[CH:29][CH:30]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)ccc1CCl
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(-c3ccc(Cl)cc3)nc2C)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
33 mg (0.83 mmol) of 60% sodium hydride were added to at 0° C. to a solution of 172 mg (0.79 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 8.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 200 mg (0.79 mmol) 3-chloromethyl-6-(4-chloro-phenyl)-2-methyl-pyridine were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 16 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, water/methanol 1:1, ethyl acetate, and ether. 324 mg (91%) of the title compound were obtained as slightly beige powder.
Reaction SMILES: [CH:1]1([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:18]([CH3:24])([CH3:23])[C:19]([O:21]C)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CS(C)=O.CO>[CH:1]1([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:18]([CH3:24])([CH3:23])[C:19]([OH:21])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)C(C)(C)C(c1ccccc1)c1ccc2c(cnn2C2CCCCCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: CC(C)(C(=O)O)C(c1ccccc1)c1ccc2c(cnn2C2CCCCCC2)c1
Yield: 103.7 %

Procedure:
Methyl 3-(1-cycloheptyl-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoate (393 mg, 0.97 mmol) was hydrolyzed by heating with 10 equiv NaOH in 3:1 DMSO/MeOH (10 mL). Purified by HPLC to give 393 mg of 3-(1-cycloheptyl-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoic acid. (M+H)+=391.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]([O:16][C@H:17]2[CH2:25][CH2:24][C@H:23]3[C@@H:19]([CH2:20][NH:21][CH2:22]3)[C@@H:18]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH2:14][OH:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:35](Cl)(=[O:39])[CH:36]([CH3:38])[CH3:37].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([O:16][C@H:17]2[CH2:25][CH2:24][C@H:23]3[C@@H:19]([CH2:20][N:21]([C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH2:22]3)[C@@H:18]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH2:14][OH:15])[CH:4]=[C:3]([C:2]([F:33])([F:1])[F:34])[CH:8]=1
Reactant: CC(C)C(=O)Cl
Reactant: Cc1ccccc1[C@H]1[C@@H]2CNC[C@H]2CC[C@@H]1O[C@H](CO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1[C@H]1[C@@H]2CN(C(=O)C(C)C)C[C@H]2CC[C@@H]1O[C@H](CO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the compound from EXAMPLE 2 in CH2Cl2 was added isobutyric chloride, triethylamine and a catalytic amount of DMAP. The mixture was stirred at room temperature for 2 hr. The solvent was removed and the residue was heated with 10 mL 2 N NaOH in 40 mL methanol at 50° C. for 1 hr. Methanol was removed under vacuum. The residue was diluted with water and the aqueous was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and the solvent was removed. The residue was purified by preparative TLC (80:20 EtOAc:hexane), 0.07 mg. M++1: 558.16.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([OH:12])[CH2:9][C:10]#[CH:11].C1(NC2CCCCC2)CCCCC1.C(#N)C>[Cu]I.CCOCC>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][OH:12]
Reactant: C#CCCO
Reactant: Brc1ncccn1
Agent: [Cu]I
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CCOCC
Solvent: CC#N
Product: OCCC#Cc1ncccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
A mixture of 2-bromopyrimidine (5.0 g), 3-butynol (2.20 g), dicyclohexylamine (6.87 g), copper (I) iodide (50 mg), BTPC (380 mg) and acetonitrile (50 ml) was stirred at room temperature under nitrogen for 16 h. Ether (150 ml) was added, the mixture filtered and the filtrate evaporated in vacuo. Purification of the residue by FCC eluting with ether and ether-methanol (1-3%) followed by System C (5:1) afforded the title compound as a pale yellow solid (4.29 g) m.p. 58°-64°, t.l.c. (System C, 99:1) Rf 0.08
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([F:29])[C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[CH:14]([CH3:20])[C:15]([O:17]CC)=[O:16])=[CH:7][CH:6]=1.[OH-].[Na+]>C1COCC1.C(O)(C)C>[Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[C:21]([F:29])[C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[CH:14]([CH3:20])[C:15]([OH:17])=[O:16])=[CH:7][CH:6]=1
Reactant: CCOC(=O)C(C)n1ncc2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C(=O)O)n1ncc2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-[6-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)indazol-1-yl]propionate prepared as described in Example 2 (30 mgs) was dissolved in THF (0.1 cm3) and isopropanol (0.28 cm3). 1.73M sodium hydroxide (0.04 cm3) was added and the mixture stirred at room temperature for 8 hours and left to stand overnight. The solvent was removed under vacuum and the residue dissolved in water (2 cm3). 2M hydrocloric acid (0.035 cm3) was added dropwise with stirring. After 1.5 hours the solid product was filtered off, washed with water and air dried to give 2-[6-(2-chloro-6-fluoro-4-trifluoromethylphenoxy) indazol-1-yl]propionic acid (11 mgs) as a white solid. Compound No 4 was prepared by an analogous process using appropriate reactants.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:8][C:7]=1[CH3:17])=[O:5])[CH3:2].C(Cl)Cl.[Br:21]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:21][CH2:17][C:7]1[N:8]=[C:9]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[S:10][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1sc(N2CCOCC2)nc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Product: CCOC(=O)c1sc(N2CCOCC2)nc1CBr
Yield: 71.2 %

Procedure:
To a round bottom flask containing a solution of ethyl-4-methyl-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate (14.50 g, 56.57 mmol) in methylene chloride (400 mL, 6000 mmol) were added N-bromosuccinimide (10.07 g, 56.57 mmol) and 2,2′-azo-bis-isobutyronitrile (464 mg, 2.83 mmol). The mixture was stirred at reflux overnight. Reaction was quenched via addition of 10% aqueous sodium bisulfite (20 g in 200 ml water) and stirred for 20 minutes. Mixture was transferred to a separatory funnel, the layers separated, and the aqueous layer was extracted 2×DCM. Combined organic layers were dried with Na2SO4, filtered, and concentrated in vacuo. The resulting residue was dissolved in DCM and adsorbed onto silica gel. Purification via column chromatography (220 g Isco column, gradient elution 0-10% EtOAc in 1:1 DCM:hexanes) afforded ethyl 4-(bromomethyl)-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate (13.5 g, yield 71.1%). LC/MS: (FA) ES+ 335, 337; NMR (300 MHz, CDCl3) δ 4.76 (s, 2H), 4.30 (dd, J=7.1, 7.1, 2H), 3.88-3.72 (m, 4H), 3.62-3.49 (m, 4H), 1.35 (dd, J=7.1, 7.1, 3H).
Reaction SMILES: S(O)(O)(=O)=O.[NH:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH2:11].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]([C:25](OCC)=[O:26])[C:20](OCC)=[O:21].N12CCCN=C1CCCCC2>CN(C=O)C>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[C:25]([OH:26])=[N:11][C:7]2[N:6]([CH:10]=[CH:9][N:8]=2)[C:20]=1[OH:21]
Reactant: Nc1ncc[nH]1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1F
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Oc1nc2nccn2c(O)c1-c1ccccc1F
Temperature: 100 °C

Procedure:
5 g (27.5 mmol) 1H-Imidazol-2-ylamine sulfate are dissolved in 31.7 mL DMF. 7 g (27.5 mmol) diethyl (2-fluorophenyl)malonate are added. After dropwise addition of 12.3 mL (82.6 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene the reaction mixture is stirred at 100° C. over night. The DMF is evaporated and the darkbrown oily residue treated with 150 mL water (complete dissolution). 2M HCl (60 mL) is added at room temperature until a pH of 1. After stirring for 1 h at ice bath cooling the formed crystals are collected by filtration to yield the product (3.43 g=48.3%), which is used without further purification. Another crop of 0.41 g (6.1%) is obtained by evaporating the solvent, treating the oily residue with water and 2M HCl. After stirring for five hours the crystals are collected and washed with water.
Reaction SMILES: [Cl-].C[Al+]C.[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][N:7]=1.C([O:15][C:16]([C:18]1[CH:19]=[C:20]([O:28][C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=2)[C:21]2[CH:25]=[C:24]([CH3:26])[S:23][C:22]=2[CH:27]=1)=O)C>ClC(Cl)C>[CH3:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:16]([C:18]2[CH:19]=[C:20]([O:28][C:29]3[CH:30]=[CH:31][C:32]([S:35]([CH3:38])(=[O:36])=[O:37])=[CH:33][CH:34]=3)[C:21]3[CH:25]=[C:24]([CH3:26])[S:23][C:22]=3[CH:27]=2)=[O:15])=[N:7][CH:8]=1
Reactant: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(C)sc2c1
Reactant: Cc1ccc(N)nc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cc1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3cc(C)sc3c2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
Dimethylaluminum chloride (16.1 mmol, 16.1 ml of 1M in hexanes) is added to a solution of 2-amino-5-picoline (1.74g, 16.1 mmol) in dichloroethane (10 ml) at 0 C. The mixture was allowed to warm to room temperature over a period of 1 h, then recooled to 0 C and treated with 4-(4-methanesulfonyl-phenoxy)-2-methyl-benzo[b]thiophene-6-carboxylic acid ethyl ester (0.63 g, crude product from previous step) in dichloroethane (5 ml) at 0 C. The mixture was allowed to warm to room temperature, and held at room temperature for 8 h. The reaction was quenched by the drop wise addition of MeOH (2 ml) at 0 C, followed by 1M aqueous pH6 phosphate buffer (10 ml), then ethyl acetate was added (50 ml). Separation of the organic layer followed by evaporation yields 0.80 g crude product. Purification by silica gel chromatography (0-20% MeOH-CHCl3) yielded 0.39 g (68%) of product 4-(4-methanesulfonyl-phenoxy)-2-methyl-benzo[b]thiophene-6-carboxylic acid(5-methyl-pyridin-2-yl)-amide. LRMS for C23H20N2O4S2 m/z 453 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.80 (s, 1H), 8.56 (s, 1H), 8.22 (d, J=2.3, 1H), 8.08 (d, J=8.3, 1H), 7.93 (d, J=8.8, 2H), 7.74 (d, J=1.2, 2H), 7.67 (dd, J=8.6, 2.0, 1H), 7.22 (d, J=8.8, 2H), 7.09 (s, 1H), 3.21 (s, 3H), 2.59 (d, J=1.0, 3H), 2.28 (s, 3H). Anal. Calcd. for C23H20N2O4S2: C, 61.04; H, 4.45; N, 6.19; Found: C, 61.01; H, 4.47; N, 5.96.
Reaction SMILES: [Li+].[B-](CC)(CC)CC.[NH2:9][C:10]1[CH:11]=[C:12]([C:16]2[CH2:17][C@@H:18]3[N:24]([CH:25]=2)[C:23](=[O:26])[C:22]2[CH:27]=[C:28]([O:70][CH3:71])[C:29]([O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]4[C:67]([O:68][CH3:69])=[CH:66][C:39]5[C:40](=[O:65])[N:41]6[CH:56]=[C:55]([C:57]7[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][CH:58]=7)[CH2:54][C@H:42]6[C:43](=O)[N:44](COCC[Si](C)(C)C)[C:38]=5[CH:37]=4)=[CH:30][C:21]=2[N:20](COCC[Si](C)(C)C)[C:19]3=O)[CH:13]=[CH:14][CH:15]=1>C1COCC1.O>[NH2:9][C:10]1[CH:11]=[C:12]([C:16]2[CH2:17][C@@H:18]3[N:24]([CH:25]=2)[C:23](=[O:26])[C:22]2[CH:27]=[C:28]([O:70][CH3:71])[C:29]([O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]4[C:67]([O:68][CH3:69])=[CH:66][C:39]5[C:40](=[O:65])[N:41]6[CH:56]=[C:55]([C:57]7[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][CH:58]=7)[CH2:54][C@H:42]6[CH:43]=[N:44][C:38]=5[CH:37]=4)=[CH:30][C:21]=2[N:20]=[CH:19]3)[CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCOc5cc6c(cc5OC)C(=O)N5C=C(c7cccc(N)c7)C[C@H]5C(=O)N6COCC[Si](C)(C)C)cc4N(COCC[Si](C)(C)C)C(=O)[C@@H]3C2)cc1
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCOc5cc6c(cc5OC)C(=O)N5C=C(c7cccc(N)c7)C[C@H]5C=N6)cc4N=C[C@@H]3C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
A solution of superhydride (0.56 mL, 0.56 mmol, 1.0 M in THF) was added dropwise to a solution of the SEM dilactam (18) (0.271 g, 0.27 mmol) in dry THF (10 mL) at −78° C. under a nitrogen atmosphere. After 1 hr a further aliquot of superhydride solution (0.13 ml, 0.13 mmol) was added and the reaction mixture was allowed to stir for another 0.5 hr, at which time LC-MS indicated that reduction was complete. The reaction mixture was diluted with water and allowed to warm to room temperature. The reaction mixture was partitioned between chloroform and water, the layers were separated and the aqueous layer extracted with additional chloroform (emulsions). Finally the combined organic phase was washed with brine and dried over magnesium sulphate. The reduced product was dissolved in methanol, chloroform and water and allowed to stir in the presence of silica gel for 72 hours The crude product was subjected to flash column chromatography (methanol/chloroform gradient) to afford the desired imine product (150 mg, 0.21 mmol, 77%) after removal of excess eluent from selected fractions.