Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].C([O:11][CH:12]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:38][CH:37]=1)[CH:13]([C:27]([O:29]C(C)(C)C)=[O:28])[CH2:14][CH2:15][NH:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:18])(=O)C1C=CC=CC=1.Cl>O1CCCC1.CO.O.O>[C:39]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:38]=[CH:37][C:36]([CH2:35][CH2:34][CH:12]([OH:11])[CH:13]([CH2:14][CH2:15][NH:16][C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[O:18])[C:27]([OH:29])=[O:28])=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)C(CCNC(=O)Nc1ccc(F)cc1)C(CCc1ccc(-c2ccccc2)cc1)OC(=O)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCC(C(=O)O)C(O)CCc1ccc(-c2ccccc2)cc1)Nc1ccc(F)cc1
Yield: 41.7 %

Procedure:
Aqueous solution of lithium hydroxide (22 mg in 1 ml) was added to the solution of the compound (130 mg) obtained from Step 1 above, in tetrahydrofuran:methanol:water (3:1:1, 5 ml) and the reaction mixture was stirred at 40° C. overnight. The reaction mixture was concentrated and the residue thus obtained was taken in distilled water, acidified with dilute hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with distilled water and brine solution and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to furnish the title compound (40 mg)
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])[CH2:8]2.[Br:22][CH2:23][C:24](Br)=[O:25]>>[Br:22][CH2:23][C:24]([N:11]([CH:2]1[CH:3]2[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]1[CH2:8]3)[CH2:4]2)[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])=[O:25]
Reactant: O=C(Br)CBr
Reactant: O=[N+]([O-])c1ccccc1NNC1C2CC3CC(C2)CC1C3
Product: O=C(CBr)N(Nc1ccccc1[N+](=O)[O-])C1C2CC3CC(C2)CC1C3

Procedure:
1-(Adamantan-2-yl)-2-(2-nitrophenyl)hydrazine and bromoacetyl bromide were used for a similar reaction and treatment as Process 3 of Example 1, and 1-(2-bromoacetyl)-1-(adamantan-2-yl)-2-(2-nitrophenyl)hydrazine was obtained as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:28]=[C:29]([N+:31]([O-])=O)[CH:30]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:8])([O-])=O>C(OCC)(=O)C.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:28]=[C:29]([NH2:31])[CH:30]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:8]
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCOC(=O)c1cc(N)cc(N)c1
Yield: 64.7 %

Procedure:
In 300 ml of ethyl acetate was dissolved 8.0 g (0.017 mol) of stearyl 3,5-dinitrobenzoate, and 1.0 g of 5% palladium-carbon was then added thereto and catalytic reduction was carried out at ordinary temperature under atmospheric pressure. After the completion of the reaction, the catalyst was removed by filtration and the solvent was distilled off under reduced pressure to obtain a crystal. The thus obtained crystal was recrystallized from n-heptane/ethyl acetate twice to obtain 4.48 g (0.011 mol) of stearyl 3,5-diaminobenzoate. The melting point of this compound was in the range of 81.8° to 82.6° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][CH:5]=1)[CH:2]=[CH2:3]>[Os](Cl)(Cl)Cl>[CH:1](/[C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:8][CH:9]=1)=[CH:2]\[CH3:3]
Reactant: C=CCc1ccc(C(C)C)cc1
Agent: Cl[Os](Cl)Cl
Product: C/C=C/c1ccc(C(C)C)cc1
Yield: 57 %

Procedure:
A mixture of 5 g. of p-allylcumene and 5 mg. of osmium trichloride is brought to 110° C. for 71/2 hours. After distillation, a fraction weighing 4.2 g. containing (as measured by gas-liquid chromatography) 31% of p-allylcumene, 12% of cis-p-propenylcumene and 57% of trans-p-propenylcumene is obtained. The conversion rate is 74% and the yield is 78.5%, based on the converted p-allylcumene.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][NH:10]2)=[CH:6][CH:5]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[F:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][N:10]2[C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1c[nH]c2cc(F)ccc12
Reactant: Clc1ccnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(-c2ccnc3ccccc23)c2cc(F)ccc12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
0.25 g (7.8 mmol) of sodium hydride, at 75% by mass in liquid petroleum jelly, is added at a temperature in the region of 20° C. under an argon atmosphere to a solution of 1.5 g (7.76 mmol) of 6-fluoro-3-methoxycarbonyl-1H-indole in 40 cm3 of dimethylformamide. After stirring at a temperature in the region of 40° C. for 0.5 hour, 1.29 g (7.8 mmol) of 4-chloroquinoline are added. After stirring at a temperature in the region of 120° C. for 6 hours, the reaction mixture is poured into 150 cm3 of water and extracted with 150 cm3 of ethyl acetate. The organic phase is washed with 3 times 100 cm3 of water and is then dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give a brown solid which is purified by silica gel chromatography [eluent: dichloromethane and then dichloromethane/ethyl acetate (90/10 by volume)]. After concentrating the fractions under reduced pressure, 1.5 g of 6-fluoro-3-methoxycarbonyl-1-(quinol-4-yl)-1H-indole are obtained in the form of a beige-coloured solid melting at 186° C.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:16]2[C:7](=[C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:26]N1C(=O)CCC1=O.CN(C)C=O>O>[Br:26][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:7]2[C:16]=1[CH:17]=[CH:18][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1ccc2cc3ccccc3c(-c3ccc(Cl)cc3)c2c1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc2c(Br)c3ccccc3c(-c3ccc(Cl)cc3)c2c1

Procedure:
A mixed solution of 6 g of the above-mentioned 2-tert-butyl-9-(4-chlorophenyl)anthracene, 3.5 g of N-bromosuccinimide and 55 g of dimethylformamide was stirred under nitrogen gas stream at room temperature for 3 hours. 50 ml of water was injected thereto to extract 100 ml of dichloromethane therefrom. The organic layer was washed twice in 50 ml of water, dried by magnesium sulfate and thereafter concentrated by evaporation. The organic layer was purified by silica gel column chromatography to obtain 10-bromo-2-tert-butyl-9-(4-chlorophenyl)anthracene.
Reaction SMILES: O[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1>O>[N:7]1[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1cccc(O)n1
Solvent: O
Product: O=C(O)c1ccccn1

Procedure:
For isolation, the cell-free picolinic acid solution was precipitated with CaCl2 /H2SO4. For this purpose, the cell-free picolinic acid solution from Example 2 was diluted 3-fold and, while stirring, 0.5 equivalent of CaCl2 per equivalent of picolinic acid was added after the cell-free fermentation solution had been heated to 90° C. The resulting calcium/picolinic acid complex precipitated immediately. The resulting complex was cooled to 4° C. with stirring, filtered off on a glass flit (porosity 3) and washed with demineralized water. The filter cake was suspended in demineralized water and acidified to a pH of 2.5 with concentrated sulfuric acid. During this operation, the picolinic acid was dissolved out of the complex and, at the same time, insoluble calcium sulfate was formed. Since the free picolinic acid is very soluble in water it was possible to remove calcium sulfate by filtration. The picolinic acid solution was evaporated to dryness and analyzed. The crude yield was about 70 percent with a purity of 86 percent by titration. The water content was 0.7 percent measured by the Karl-Fischer method.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[N:11]=[C:10]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([C:20]([OH:23])([CH3:22])[CH3:21])[CH2:16][CH2:15]3)=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH:30]([C:33]1[NH:37][C:36]2[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=2[N:34]=1)([CH3:32])[CH3:31].CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:23][C:20]([CH:17]1[CH2:18][CH2:19][N:14]([C:12]([C:10]2[CH:9]=[CH:8][C:6]3[N:7]=[C:2]([N:34]4[C:35]5[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=5[N:37]=[C:33]4[CH:30]([CH3:32])[CH3:31])[N:3]=[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:5]=3[N:11]=2)=[O:13])[CH2:15][CH2:16]1)([CH3:22])[CH3:21]
Reactant: CC(C)(O)C1CCN(C(=O)c2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: CC(C)c1nc2ccccc2[nH]1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)N3CCC(C(C)(C)O)CC3)ccc2n1

Procedure:
(2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)(4-(2-hydroxypropan-2-yl)piperidin-1-yl)methanone from Example 118 (80 mg) was reacted with 2-isopropyl-1H-benzo[d]imidazole (1.05 eq), sodium tert-butoxide (2 eq), palladium acetate (0.1 eq) and bis(tri-t-butylphosphine)palladium (0.1 eq). The tube was flushed with nitrogen for 10 minutes before adding Toluene (2 mL). The reaction was microwaved at 145° C. for 20 minutes. The crude was loaded onto a Biotage isolute scx-2 cartridge, eluted with 2M ammonia in MeOH then purified by flash column chromatography to afford 6.6 mg of 119.
Reaction SMILES: C1C[O:4][CH2:3]C1.[CH2:6]([N:13]1[C@H:18]([CH3:19])[CH2:17][N:16]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22](F)[CH:21]=2)[C@@H:15]([CH3:29])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CC(C)([O-])C.[K+].[Cl-].[NH4+]>CO>[CH2:6]([N:13]1[C@H:18]([CH3:19])[CH2:17][N:16]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([O:4][CH3:3])[CH:21]=2)[C@@H:15]([CH3:29])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[C@@H]1CN(c2ccc(C#N)c(F)c2)[C@@H](C)CN1Cc1ccccc1
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: COc1cc(N2C[C@@H](C)N(Cc3ccccc3)C[C@@H]2C)ccc1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into 20 ml of THF and 6 ml of methanol was dissolved 5.17 g of 4-[(2S,5R)-4-benzyl-2,5-dimethylpiperazin-1-yl]-2-fluorobenzonitrile, and then 9.83 g of potassium t-butoxide was added thereto, followed by stirring at room temperature overnight. A saturated ammonium chloride aqueous solution was added to the reaction solution, followed by extraction with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by evaporation and the resulting residue was purified by silica gel column chromatography to obtain 4.72 g of the title compound from an eluate eluted with hexane-ethyl acetate (80:20, v/v).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:13]4[S:18][C:17]([CH:19]([CH3:23])C(O)=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C(N(CC)CC)C.Cl.CNC.[CH3:41][N:42]([CH:44]=[O:45])[CH3:43]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[C:13]4[S:18][C:17]([CH2:19][CH2:23][C:44]([N:42]([CH3:43])[CH3:41])=[O:45])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(C(=O)O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: CN(C)C=O
Agent: CNC
Agent: Cl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)CCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-[2-(1H-indazol-4-yl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl]-propionic acid (145 mg) in DMF (5 mL) at room temperature was added carbonyliimidazole (115 mg). The reaction mixture was then stirred at room temperature for 1 h. Then, triethylamine (0.15 mL) and dimethylamine hydrochloride (58 mg) were added and the solution was stirred at room temperature for 16 h. The reaction was then quenched with water (20 mL) and extracted into ethyl acetate (2×20 mL). The combined organics were washed with aqueous brine solution (3×20 mL), dried (MgSO4), concentrated and purified using column chromatography to give 148 as a white solid (96 mg). NMR: DMSO: 2.68-2.84 (2 H, m, CH2), 2.86 (3 H, s, Me), 3.02 (3 H, s, Me), 3.18 (2 H, t, J 7.22, CH2), 3.79-3.84 (4 H, m, CH2), 3.98-4.02 (4 H, m, CH2), 7.40 (1 H, s, Ar), 7.44 (1 H, t, J 8.0, Ar), 7.62 (1 H, d, J 8.15, Ar), 8.21 (1 H, d, J 7.35, Ar), 8.85 (1 H, s, Ar) and 13.15 (1 H, s, NH). MS: (ESI+): MH+ 437.22
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C@@H:8]([NH:18][C:19](=[O:31])[CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[NH:23][CH:22]=2)[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[C:5]([C:32]2[CH:33]=CC(F)=[C:36]([CH:40]=2)C(N)=O)=[CH:4][CH:3]=1.NC1N=C(C(NC(=O)CC2C3C(=CC=C(F)C=3)NC=2)CC2C=C(F)C=C(F)C=2)C(Br)=CC=1.[CH3:74][O:75][C:76]1C=C(B(O)O)C=C[N:77]=1>>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]([NH:18][C:19](=[O:31])[CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[NH:23][CH:22]=2)[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[C:5]([C:32]2[CH:40]=[CH:36][N:77]=[C:76]([O:75][CH3:74])[CH:33]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)c1cc(-c2ccc(N)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)ccc1F
Reactant: COc1cc(B(O)O)ccn1
Agent: Nc1ccc(Br)c(C(Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)n1
Product: COc1cc(-c2ccc(N)nc2C(Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)ccn1

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 1H of Example 1 utilizing 1G and (2-methoxypyridin-4-yl)boronic acid. 1H NMR (400 MHz, DMSO) δ 10.89 (s, 1H), 7.96 (d, J=5.2 Hz, 1H), 7.25 (dd, J=8.9, 4.3 Hz, 2H), 7.14-7.10 (m, 3H), 6.88-6.80 (m, 3H), 6.67 (d, J=5.2 Hz, 1H), 6.45-6.38 (m, 5H), 5.00 (d, J=7.3 Hz, 1H), 3.75 (s, 2H), 2.89 (m, 2H). MS (m/z) 532.4 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH:9]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[N:15]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([CH2:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=2)[C:21]#[N:22])[S:13][N:12]=1)[CH3:2].C([O-])(=O)C.[Na+].Cl.[NH:34]1[CH2:37][CH:36]([C:38]([O:40]C)=[O:39])[CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[S:13][N:12]=[C:11]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][N:34]4[CH2:37][CH:36]([C:38]([OH:40])=[O:39])[CH2:35]4)[CH:7]=[CH:6][CH:5]=3)[N:15]=2)[CH:17]=[CH:18][C:19]=1[CH2:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: CCc1c(C=O)cccc1-c1nsc(-c2ccc(CC(C)C)c(C#N)c2)n1
Reactant: COC(=O)C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1c(CN2CC(C(=O)O)C2)cccc1-c1nsc(-c2ccc(CC(C)C)c(C#N)c2)n1
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
To a solution of 5-[3-(2-ethyl-3-formylphenyl)-1,2,4-thiadiazol-5-yl]-2-(2-methylpropyl)benzonitrile (D63) (100 mg) in dichloromethane (DCM) (15 mL) was added sodium acetate (22.9 mg), hydrogen chloride-methyl 3-azetidinecarboxylate (1:1) (42.4 mg) and 5 drops of acetic acid. After stirring for 30 min, sodium triacetoxyborohydride (85 mg) was added and the reaction solution was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (30 mL), the organic phase was washed with water, dried over sodium sulphate and concentrated. The residue was dissolved in isopropanol/water (10 mL, 1:1), 0.5M sodium hydroxide (2.66 mL) was added. The reaction solution was stirred at room temperature overnight. The isopropanol was removed in vacuo and the residue was acidified to pH=3-4. The resulting solution was extracted with ethyl acetate (2*15 mL), and the combined organic phases were dried over sodium sulphate, concentrated and purified by Mass Directed AutoPrep to afford 1-[(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,2,4-thiadiazol-3-yl}-2-ethylphenyl)methyl]-3-azetidinecarboxylic acid (E27) (51 mg) as a TFA salt. δH (DMSO-d6, 400 MHz): 0.87 (6H, d), 1.04 (3H, t), 1.93 (1H, m), 2.71 (2H, d), 2.92 (2H, q), 3.58 (1H, m), 4.20 (4H, m), 4.51 (2H, s), 7.39 (1H, t), 7.52 (1H, d), 7.64 (1H, d), 7.84 (1H, d), 8.26 (1H, dd), 8.47 (1H, d). δF (DMSO-d6, 376 MHz): −73.5. MS (ES): C26H28N4O2S requires 460. found 461.1 (M+H+).
Reaction SMILES: BrC1C=CC(N=C=S)=CC=1.NC1C=C(C)C=CC=1O.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=2[OH:38])=S)=[CH:23][CH:22]=1.Cl.CN(C)CCCN=C=NCC>C(O)C.CCOCC>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]2[O:38][C:32]3[CH:33]=[CH:34][C:35]([CH3:37])=[CH:36][C:31]=3[N:30]=2)=[CH:23][CH:22]=1
Reactant: Cc1ccc(O)c(NC(=S)Nc2ccc(Br)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(O)c(N)c1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: Cc1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
In a 250-mL round-bottom flask, 1-bromo-4-isothiocyanatobenzene (4.28 g, 20 mmol) and 2-amino-4-methyl-phenol (2.46 g, 20 mmol) were stirred in 120 mL ethanol at rt overnight. The formation of N-(4-bromophenyl)-N′-(2-hydroxy-5-methylphenyl)thiourea was confirmed by LC-MS. To the mixture, 1.5 eq. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) was added, and the reaction was stirred at rt for another 2 h. The reaction mixture was then heated at reflux for 6 h. The mixture was cooled to rt and the solvent was removed under reduced pressure. The solid was dissolved in EtOAc and washed with 2 N aqueous HCl and H2O. The organic layer was dried (MgSO4) and the solvent was removed under reduced pressure. The solid obtained was ultrasonicated in 30 mL ether and filtered to give the desired compound (3.64 g, 60%). 1H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1 H), 7.70 (m, 2 H), 7.55 (m, 2 H), 7.35 (d, 1 H), 7.25 (s, 1 H), 6.95 (d, 1 H), 2.40 (s, 3 H). LC-MS m/z 303.3 (MH+), ret. time 3.46 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[F-:15].[K+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([F:15])(=[O:13])=[O:12]
Reactant: [F-]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)F)c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
2--Chloro-5-nitro benzene sulphonylchloride (40 parts) was stirred in p-dioxane (48 parts) at room temperature. Potassium fluoride (10 parts) dissolved in water (35 parts) was added, and the mixture heated to 70° C. Stirred at 70° C. for 4 hours then cooled to room temperature and poured onto ice/water. Allowed to stand for 2 days then filtered off the precipitate and dried in air to yield the product 2-chloro-5-nitro benzene sulphonylfluoride (36 parts).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[N:29]1([C:2]2[N:7]=[C:6]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[C:14]([C:17]5[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=5)[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1
Reactant: C1CNCCN1
Reactant: Fc1cccc(-c2nn(C3CCCCO3)c3cnc(-c4cccnc4)cc23)n1
Product: c1cncc(-c2cc3c(-c4cccc(N5CCNCC5)n4)n[nH]c3cn2)c1
Yield: 78 %

Procedure:
Following the procedures of Example 143, 3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and piperazine were reacted and purified via reverse phase HPLC using a gradient of MeOH in water with 0.1% NH4OH to afford 42 mg (78%) of 162. ESI MS m/z 358.1 (M+1). 1H NMR (400 MHz, DMSO): 9.24 (d, J=8.1 Hz, 1H), 8.90 (s, 1H), 8.61 (s, 1H), 8.42 (d, J=7.2 Hz, 1H), 7.74 (d, J=7.9 Hz, 1H), 7.56 (d, J=6.7 Hz, 1H), 6.96 (d, J=8.1 Hz, 1H), 3.82 (s, 2H), 3.17 (s, 2H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[C:15]2[N:14]=[CH:13][C:12](=[O:16])[NH:11][C:10]=2[N:9]=[CH:8][CH:7]=1.[C:20]([C:24]1[CH:28]=[C:27]([N:29]=[C:30]=[O:31])[N:26]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)[N:25]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:28]=[C:27]([NH:29][C:30]([NH:1][C:2]2[CH:19]=[CH:18][CH:17]=[C:4]([O:5][C:6]3[C:15]4[N:14]=[CH:13][C:12](=[O:16])[NH:11][C:10]=4[N:9]=[CH:8][CH:7]=3)[CH:3]=2)=[O:31])[N:26]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)[N:25]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)cnc23)c1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N=C=O)cc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2cccc(Oc3ccnc4[nH]c(=O)cnc34)c2)cc1
Yield: 65 %

Procedure:
Method F2 was used with 8-(3-aminophenoxy)pyrido[2,3-b]pyrazin-3(4H)-one and 3-tert-butyl-5-isocyanato-1-p-tolyl-1H-pyrazole to afford the title compound as a white solid (46 mg, 65%).
Reaction SMILES: C(OC(C)(C)C)(=O)[NH:2][NH2:3].[CH3:10][C:11]1[O:15][C:14]([C:16](Cl)=[O:17])=[CH:13][CH:12]=1>C(Cl)Cl>[CH3:10][C:11]1[O:15][C:14]([C:16]([NH:2][NH2:3])=[O:17])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: Cc1ccc(C(=O)Cl)o1
Solvent: ClCCl
Product: Cc1ccc(C(=O)NN)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl carbazate (549 mg, 4.15 mmol) was added to a methylene chloride (10 mL) solution of commercially available 5-methylfuran-2-carbonyl chloride (500 mg, 3.46 mmol) under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and then, the residue was dissolved in methylene chloride (10 mL). To the solution, trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated to obtain 5-methylfuran-2-carbohydrazide.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].C(Cl)CCl.[Br:10][C:11]1[CH:12]=[C:13]([CH:45]=[CH:46][CH:47]=1)[CH2:14][N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]([CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])[C:16]1=[N:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>C(O)(C)(C)C.ClCCl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:41]([O:40][C:38](=[O:39])[N:37]=[C:16]1[N:15]([CH2:14][C:13]2[CH:45]=[CH:46][CH:47]=[C:11]([Br:10])[CH:12]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]1[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:30]([C:31]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:32])[CH:29]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)N=c1n(CCCOc2cccc(C(=O)O)c2)c2ccccc2n1Cc1cccc(Br)c1
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N=c1n(CCCOc2cccc(C(=O)NS(C)(=O)=O)c2)c2ccccc2n1Cc1cccc(Br)c1
Reaction time: 24 h
Yield: 70.2 %

Procedure:
To a solution of methyl sulfonamide (25 mg, 0.26 mmol) in tert-butanol (2.5 ml) and dichloromethane (2.5 ml) at rt under N2 was added EDC (99 mg, 0.52 mmol), DMAP (44 mg, 0.36 mmol) and 3-(3-{3-(3-bromo-benzyl)-2-[tert-butoxycarbonylimino]-2,3-dihydro-benzoimidazol-1-yl}-propoxy)-benzoic acid (150 mg, 0.26 mmol). The reaction was stirred for 24 h and then diluted with EtOAc and washed with a solution of KHSO4. The organic layer was separated, dried (Na2SO4) and concentrated under reduced pressure to provide [1-(3-bromo-benzyl)-3-[3-(3-methanesulfonylaminocarbonyl-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-ylidene]-carbamic acid tert-butyl ester (120 mg, 71%). HPLC-MS 657, 659 [M+1]+.