Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH2:8][F:9])[C:3](=O)[CH2:4][S:5][CH3:6].Cl.[NH2:12][OH:13].C(N(CC)CC)C>C(O)C>[CH3:1][C:2]([CH3:10])([CH2:8][F:9])[C:3](=[N:12][OH:13])[CH2:4][S:5][CH3:6]
Reactant: CSCC(=O)C(C)(C)CF
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CSCC(=NO)C(C)(C)CF
Yield: 74.4 %

Procedure:
99 g (0.6 mol) of 3,3-dimethyl-4-fluoro-1-methylthiobutan -2-one, 46 g (0.66 mol) of hydroxylamine hydrochloride and 66.7 g (0.66 mol) of triethylamine in 300 ml of ethanol were heated under reflux for 6 hours. The solvent was then removed in vacuo, the residue was partitioned between methylene chloride and water and the methylene chloride phase was separated off and dried with sodium sulphate. After distilling off the solvent, the residue was distilled in vacuo. 80 g (75% of theory) of 3,3-dimethyl-4-fluoro-1-methylthio-2-hydroximino-butane of boiling point 133° C./13 mm Hg were obtained. ##STR31## 78 g (0.43 mol) of 3,3-dimethyl-4-fluoro-1-methylthio-hydroximinobutane were dissolved in 300 ml of methylene chloride, and 26 g (0.46 mol) of methyl isocyanate were added dropwise. During this addition, the temperature of the reaction solution rose to about 35° C.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([CH2:11]Br)[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1NC(=O)OC(C)(C)C.BrC1C=CC=CC=1[C:30]#[N:31]>COCCOC.C([O-])(O)=O.[Na+].CCOCC>[CH3:11][C:8]1[CH:9]=[CH:10][C:5]2[O:4][C:3]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:30]#[N:31])=[CH:2][C:6]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1-c1oc2ccc(CBr)cc2c1Br
Reactant: N#Cc1ccccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: Cc1ccc2oc(-c3ccccc3C#N)cc2c1
Temperature: 25 °C
Yield: 109.1 %

Procedure:
Intermediate 1 (20 g) was added to a stirred solution of 2-bromobenzonitrile (10.34 g) and tetrakistriphenylphosphine palladium (0) (1.5 g) in DME (200 ml) and 8% aqueous NaHCO3 (50 ml) at reflux under nitrogen. Further catalyst (1.5 g) was added and the reaction was heated overnight. The reaction was cooled to room temperature and diluted with ether (200 ml). The organic layer was separated, washed with water (3×100 ml) and dried. Filtration and evaporation gave a white solid which was purified by chromatography eluting with System A (1:9) to give the title compound (10.58 g) as a white solid.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27](O)=[O:28])[CH:20]=1>>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]4[CH:18]=[N:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=4)[CH2:3]3)[CH2:6]2)=[O:28])[CH:20]=1
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Reactant: O=C(O)c1ccccc1-c1cccnc1
Product: O=C(c1ccccc1-c1cccnc1)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 2-pyridin-3-yl-benzoic acid. MS (ESI): mass calculated for C26H23N5O, 421.51; m/z found 422.3 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.C1COCC1>[CH3:1][S:2][C:3]1[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:29]([NH:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:30])=[CH:11][CH:10]=2)=[N:7][CH:8]=1
Reactant: CSc1cnc(-c2ccc(N)cc2)nc1N1CCOCC1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CSc1cnc(-c2ccc(NC(=O)Nc3ccccc3)cc2)nc1N1CCOCC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 30.3 %

Procedure:
A mixture of 4-(5-(methylthio)-4-morpholinopyrimidin-2-yl)benzeneamine (0.1 g, 0.33 mmole), co-solvent (5 ml, DMF/THF=6/40) and phenyl isocyanate (0.2 ml, 0.92 mmole) was heated to 80° C. After 12 hrs, the reaction mixture was cooled, and the THF removed in vacuo. Then the mixture was diluted with EA, washed with brine, and dried (MgSO4). The solvent was removed in vacuo. Purification of the residue on silica gel (EA/Hex=1/2) yielded the desired compound (42.2 mg, 30.4%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].N1C=CN=C1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CCCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(Br)cc2)c1C(CCCc1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-butan-1-ol (4.2 g, 10.9 mmol) was dissolved in DMF (60 mL). tert-Butyldimethylsilyl chloride (4.92 g, 7.93 mmol) and imidazole (2.22 g, 32.6 mmol) were added and the reaction stirred at room temperature until completion. The reaction was submitted to aqueous workup to afford the title compound.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]([O:19][CH3:20])=[N:14][C:15]([NH2:18])=[N:16][CH:17]=2)=[CH:8][C:7]=1[N+:21]([O-])=O)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.[Zn]>[NH2:18][C:15]1[N:14]=[C:13]([O:19][CH3:20])[C:12]([C:9]2[CH:8]=[C:7]([NH2:21])[C:6]([NH:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:11][CH:10]=2)=[CH:17][N:16]=1
Reactant: COc1nc(N)ncc1-c1ccc(NC(C)(C)C)c([N+](=O)[O-])c1
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: COc1nc(N)ncc1-c1ccc(NC(C)(C)C)c(N)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a round bottom flask is added 5-(4-tert-Butylamino-3-nitro-phenyl)-4-methoxy-pyrimidin-2-ylamine (150 mg, 0.473 mmol) in MeOH (5 mL), followed by the addition of ammonium formate (268 mg, 4.25 mmol) and of zinc dust (154 mg, 2.37 mmol). The reaction mixture is stirred at 50° C. for 1 hour. The reaction mixture is filtered through diatomaceous earth, washing with MeOH. The filtrate is concentrated in vacuo. The residue is diluted with EtOAc, washed with water, dried with Na2SO4, filtered and concentrated to afford 4-(2-amino-4-methoxy-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (118 mg, 87%) as a light brown solid. LCMS (ESMS): m/z 288.48 (M++1)
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][N:11]=2)=[CH:6][CH:5]=1.[C:21]([O:25][C:26](=[O:41])[CH:27]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39]Br)=[CH:35][CH:34]=1)[CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)([CH3:24])([CH3:23])[CH3:22].O>C1COCC1.CN(C=O)C>[C:21]([O:25][C:26](=[O:41])[CH:27]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39][N:12]2[N:11]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=3)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:20])=[CH:35][CH:34]=1)[CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(c1ccc(Cn2nc(-c3ccc(Cl)cc3)c3ccccc3c2=O)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0° C., 54 mg (2.14 mmol) of sodium hydride were added a little at a time to a solution of 500 mg (1.95 mmol) of 4-(4-chlorophenyl)phthalazin-1(2H)-one [CAS Reg. No. 51334-86-2] in 7.6 ml of THF. After the evolution of gas had ended, 688 mg (1.95 mmol) of tert-butyl[4-(bromomethyl)phenyl](cyclopentyl)acetate, dissolved in 4.5 ml of DMF, were slowly added dropwise at 0° C., and the reaction solution was then stirred at room temperature overnight. Water was then added carefully to the reaction mixture. The reaction mixture was extracted three times with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent was removed to dryness under reduced pressure. The crude product obtained was purified by flash chromatography on silica gel (mobile phase: initially cyclohexane/ethyl acetate 3:1, then ethyl acetate). This gave 630 mg (93% pure, 1.11 mmol, 57% of theory) of a colorless solid.
Reaction SMILES: CC1C=CC(S(O[CH:12]2[CH2:17][O:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:14][CH2:13]2)(=O)=O)=CC=1.CN(C=O)C.[N-:29]=[N+:30]=[N-:31].[Na+]>O>[N:29]([CH:12]1[CH2:17][O:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:14][CH2:13]1)=[N+:30]=[N-:31]
Reactant: Cc1ccc(S(=O)(=O)OC2COC(c3ccccc3)OC2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1COC(c2ccccc2)OC1
Temperature: 105 °C
Reaction time: 48 h
Yield: 84.1 %

Procedure:
To a 1 L round bottom flask was added 2-phenyl-1,3-dioxan-5-yl 4-methylbenzenesulfonate (40 g, 120 mmol) and DMF (500 mL). NaN3 (31.3 g, 478 mmol) was added as a solution in water (150 mL). The reaction was stirred at 105° C. for 2 days. The reaction was then concentrated to dryness. The solid was dissolved in water (700 mL) and extracted into EtOAc (3×500 mL). The combined organic layers were washed with water (5×) and concentrated to dryness to afford an orange solid. The material was then recrystallized from hexanes to afford 20.7 g (84% yield) of 22 as a pale brown solid. 1H NMR (CDCl3, 400 MHz), δ: 3.67 (2H, pseudo t, J=11.59 Hz), 3.78-3.88 (1H, m), 4.36-4.04 (2H, m), 7.36-7.39 (3H, m), 7.45-7.47 (2H, m). Mass Spec (lo-res): Calc'd for C10H11N3O2: 205.09; found: 178.1 (M+H−N2).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:13](=[O:14])[N:12]2[C:7]([S:8][CH2:9][CH2:10][CH2:11]2)=[N:6][C:5]=1[CH3:15].[BrH:16]>C(O)(=O)C>[BrH:16].[Br:16][CH2:2][CH2:3][C:4]1[C:13](=[O:14])[N:12]2[C:7]([S:8][CH2:9][CH2:10][CH2:11]2)=[N:6][C:5]=1[CH3:15]
Reactant: Cc1nc2n(c(=O)c1CCO)CCCS2
Agent: Br
Solvent: CC(=O)O
Product: Cc1nc2n(c(=O)c1CCBr)CCCS2
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 20 parts of 3,4-dihydro-7-(2-hydroxyethyl)-8-methyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one, 50 parts of acetic acid and 180 parts of a hydrobromic acid solution 67% in acetic acid was stirred and heated to reflux. Stirring was continued overnight at reflux temperature. The reaction mixture was evaporated and the solid residue was triturated in 2-propanone. The product was filtered off and dried, yielding 24 parts (100%) of 7-(2-bromoethyl)-3,4-dihydro-8-methyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one monohydrobromide; mp. 215° C. (intermediate 10).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](OC(=O)C(C)(C)C)[N:6]=[C:5]2[C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28].C(N(CC)CC)C>C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1)=[O:28]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CC(C)(C)C(=O)On1nc(-c2ccc[nH]2)c2cc(N)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2[nH]nc(-c3ccc[nH]3)c2c1)c1cccc(Cl)c1
Yield: 32 %

Procedure:
2,2-Dimethyl-propionic acid 5-amino-3-(1H-pyrrol-2-yl)-indazol-1-yl ester (0.38 mmol) (From Example 28) was coupled with 3-chloro-benzoyl chloride (0.4 mmol) and triethylamine in DCM at 0° C. to give 41 mg of the titled compound as a white solid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([NH2:12])=[O:11])=[CH:9][C:4]=2[CH2:3]1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:25]([CH:26]=O)=[CH:24][NH:23][N:22]=2)=[CH:17][CH:16]=1>N1CCCCC1.CC(O)C>[O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([NH2:12])=[O:11])=[CH:9][C:4]=2/[C:3]/1=[CH:26]/[C:25]1[C:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[N:22][NH:23][CH:24]=1
Reactant: NC(=O)c1cc2c(s1)NC(=O)C2
Reactant: COc1ccc(-c2n[nH]cc2C=O)cc1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: COc1ccc(-c2n[nH]cc2/C=C2\C(=O)Nc3sc(C(N)=O)cc32)cc1
Temperature: 75 °C
Yield: 52.6 %

Procedure:
5,6-Dihydro-5-oxo-4H-thieno[2,3-b]pyrrole-2-carboxamide (25 mg, 0.14 mmol) was dissolved in a solution of 1% piperidine in 2-propanol (2 ml). 3-(4-Methoxyphenyl)-1H-pyrazole-4-carboxaldehyde (0.15 mmol, 28 mg) was added in one portion and the mixture heated at 75° C. for 1 hour. The reaction mixture was poured into an ice/water mixture (2 ml) and the precipitated solid was collected by filtration and washed with water to give 27 mg of (Z)-5,6-dihydro-5-oxo-4-[[3-(4-methoxyphenyl)-1H-pyrazol-4-yl]methylene]-4H-thieno [2,3-b]pyrrole-2-carboxamide as a brown solid. MS(ES): m/e 367 [M+H].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][C:12](=O)[C:11]=2[CH:10]=[CH:9][C:8]=1Br)[CH3:2].[C:20](=[S:23])([S-:22])[NH2:21].[NH4+]>C(O)C>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[CH2:15][CH2:14][C:13]1[S:22][C:20]([SH:23])=[N:21][C:12]=12)[CH3:2]
Reactant: NC(=S)[S-]
Reactant: CCOC(=O)COc1c(Br)ccc2c1CCCC2=O
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Yield: 75.8 %

Procedure:
A mixture of ethyl[(2-bromo-5,6,7,8-tetrahydro-5-oxo-1-naphthalenyl)oxy]acetate (2.63 g, 8.04 mmol), ammonium dithiocarbamate (1.06 g, 9.60 mmol), and ethanol (30 mL) was refluxed for 14 hours. After cooling, the solid precipitate was recovered by filtration to provide 1.96 g of the title compound. Amorphous solid. Yield 76%.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[F:18][C:19]([F:44])([F:43])[C:20]([C:26]1[CH:42]=[CH:41][C:29]([CH2:30][N:31]2[CH2:36][CH2:35][NH:34][CH:33]([C:37]([O:39][CH3:40])=[O:38])[CH2:32]2)=[CH:28][CH:27]=1)([OH:25])[C:21]([F:24])([F:23])[F:22].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:34]3[CH2:35][CH2:36][N:31]([CH2:30][C:29]4[CH:41]=[CH:42][C:26]([C:20]([OH:25])([C:21]([F:22])([F:23])[F:24])[C:19]([F:44])([F:18])[F:43])=[CH:27][CH:28]=4)[CH2:32][CH:33]3[C:37]([O:39][CH3:40])=[O:38])=[O:14])=[CH:15][CH:16]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)C1CN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CCN1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CCN1C(=O)c1ccc(NC(=O)NCC2CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.3 %

Procedure:
4-(3-(Cyclopropylmethyl)ureido)benzoic acid (0.213 mmol, 0.05 g), methyl 4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-2-carboxylate (0.213 mmol, 0.085 g) and triethylamine (0.640 mmol, 0.089 mL, 0.065 g) were combined and stirred in dichloromethane. 1-Propanephosphonic acid cyclic anhydride (0.320 mmol, 0.191 mL, 0.204 g) was added and the reaction stirred for 2 hours at room temperature. This was washed with water and the resulting residue purified by acidic prep HPLC to afford the title compound (45 mg). MS (ESI) m/z 617.2 [M+H]+
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:36]C(Br)(Br)Br>C(Cl)Cl>[Br:36][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)COc1cccc(CCCO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)COc1cccc(CCCBr)c1
Yield: 66 %

Procedure:
To a stirred solution of methyl 3-(3-hydroxypropyl)phenoxyacetate (2.00 g) in methylene chloride (20 ml) were added successively triphenylphosphine (2.81 g) and tetrabromomethane (3.55 g) at room temperature. The mixture was evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=7:1) to give the title compound (1.69 g) having the following physical data.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[O:8])=[C:5]([CH3:17])[CH:4]=1)=O.Cl.[OH:19][NH2:20].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:19][N:20]=[CH:1][C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[O:8])=[C:5]([CH3:17])[CH:4]=1
Reactant: Cc1cc(C=O)ccc1C(=O)NCC(F)(F)F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C=NO)ccc1C(=O)NCC(F)(F)F
Temperature: 25 °C
Yield: 58.9 %

Procedure:
In a solution of 0.8 g of 4-formyl-2-methyl-N-(2,2,2-trifluoroethyl) benzoic acid amide in 10 ml of ethanol and 5 ml of water, 0.3 g of hydroxyamine hydrochloride and 0.4 g of anhydrous sodium acetate were added with stirring at room temperature, and stirred at the same temperature for 30 minutes. After the completion of the reaction, the solvent was distilled off under reduced pressure, and precipitated crystal was filtered off, washed with water and dried to obtain 0.5 g of the aimed product as white crystal.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[C:13]1[C:18]([O:19]CC2C=CC=CC=2)=[CH:17][CH:16]=[CH:15][N:14]=1>C(O)C.[Pd]=O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: BrCCCCCCOCC/C=C\c1ncccc1OCc1ccccc1
Agent: O=[Pd]
Solvent: CCO
Product: Oc1cccnc1CCCCOCCCCCCBr
Yield: 99.7 %

Procedure:
(Z)-2-[4-[(6-Bromohexyl)oxy]-1-butenyl]-3-(phenylmethoxy)pyridine (1.5 g) was hydrogenated over pre-reduced 10% palladium oxide on carbon (50% aqueous paste, 300 mg) in ethanol (15 ml). The catalyst was removed by filtration through hyflo and the solvent was evaporated to give the title compound as a yellow oil (1.18 g).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][N:13]=[C:12]3[NH2:19])O1.Br[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH2:29][CH2:30][N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O1CCOCC1>[N:31]1([CH2:30][CH2:29][NH:28][C:24]2[CH:23]=[C:22]([C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][CH:18]=3)[N:15]=[CH:14][N:13]=[C:12]4[NH2:19])[CH:27]=[CH:26][N:25]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC1(C)OB(c2ccc3ncnc(N)c3c2)OC1(C)C
Reactant: Brc1ccnc(NCCN2CCCC2)c1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Nc1ncnc2ccc(-c3ccnc(NCCN4CCCC4)c3)cc12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To an 8 mL screw-cap vial was added 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-amine (26 mg; 0.096 mmol, 26 mg) followed by 4-bromo-N-(2-pyrrolidin-1-ylethyl)pyridin-2-amine (2 equiv., 0.19 mmol, 52 mg, Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.05 equiv., 0.005 mmol, 4 mg, dioxane (0.4 mL), and potassium phosphate tribasic (2M in water, 4 equiv., 0.38 mmol, 0.19 mL). The reaction was capped and shaken for 1 h at 100° C. The reaction was then cooled to room temperature, then extracted. The aqueous was further extracted with dichloromethane, and combined with the dioxane extract and concentrated. The crude was purified by reverse phase HPLC, yielding 5 mg of desired product. 1H NMR (400 MHz, DMSO) δ 8.62-8.56 (s, 1H), 8.42-8.38 (s, 1H), 8.32-8.16 (m, 2H), 8.11-8.02 (m, 2H), 7.77-7.72 (d, J=8.7 Hz, 1H), 6.98-6.92 (d, J=5.4 Hz, 1H), 6.90-6.84 (s, 1H), 6.53-6.44 (t, J=5.4 Hz, 1H), 3.49-3.40 (t, J=6.7 Hz, 2H), 2.73-2.65 (t, J=6.7 Hz, 2H), 2.64-2.55 (m, 4H), 1.80-1.63 (m, 4H). LCMS M/Z (M+H)=335.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[CH:24]([S:27][C:28]1[CH:32]=[C:31]([Si](C)(C)C)[O:30][C:29]=1[C:37]([NH:39][C:40]1[NH:44][N:43]=[N:42][N:41]=1)=[O:38])([CH3:26])[CH3:25]>O1CCCC1>[CH:24]([S:27][C:28]1[CH:32]=[CH:31][O:30][C:29]=1[C:37]([NH:39][C:40]1[NH:44][N:43]=[N:42][N:41]=1)=[O:38])([CH3:26])[CH3:25]
Reactant: CC(C)Sc1cc([Si](C)(C)C)oc1C(=O)Nc1nnn[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)Sc1ccoc1C(=O)Nc1nnn[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5.0 mL (5.0 mmol, 1.1 equiv) of 1.0 M tetra-n-butylammonium fluoride/tetrahydrofuran is added to a room temperature solution of 1.51 g (4.64 mmol) of 3-isopropylthio-5-trimethylsilyl-N-1H-tetrazol-5-yl-2-furancarboxamide in 15 mL of tetrahydrofuran. The resulting mixture is stirred at room temperature for 18 hours and concentrated in vacuo. The residue is suspended in water (100 mL) and acidified with 10% aqueous hydrochloric acid. The precipitate is isolated by vacuum filtration and recrystallized from toluene affording 1.26 g (1.77 g theo., 71%) of the carbamoyltetrazole as a tan solid; mp 201°-203° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[C:5]([C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].S(OC)(O[CH3:27])(=O)=O.C(=O)(O)[O-].[Na+].O>CC(C)=O>[CH3:27][O:7][C:6](=[O:8])[C:5]1[C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[C:4]=1[NH:16][C:17](=[O:22])[C:18]([CH3:19])([CH3:21])[CH3:20]
Reactant: COS(=O)(=O)OC
Reactant: COc1ccc(C(F)(F)F)c(C(=O)O)c1NC(=O)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1c(C(F)(F)F)ccc(OC)c1NC(=O)C(C)(C)C
Yield: 95 %

Procedure:
A mixture of 3-methoxy-2-pivalamido-6-(trifluoromethyl)benzoic acid (1 eq), dimethyl sulfate (1 eq) and sodium bicarbonate (1.3 eq) in acetone was refluxed for 4 h. The reaction mixture was poured to water and extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with brine and dried over sodium sulfate. Filtered, evaporated and dried under vacuum to provide product as yellow solid in 95% yield. ES/MS m/z 334.1 (MH+). Proceeds for next step without any purification.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[C:15]3[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=3[CH:13]=[C:12]([C:21]([OH:23])=O)[CH:11]=2)=[CH:7][C:6]=1[F:26])=[O:4].[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1>>[CH3:35][C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:21]([C:12]2[CH:11]=[C:10]([O:9][C:8]3[CH:24]=[CH:25][C:5]([C:3](=[O:4])[N:2]([CH3:1])[CH3:27])=[C:6]([F:26])[CH:7]=3)[C:15]3[CH2:16][C:17]([CH3:19])([CH3:20])[O:18][C:14]=3[CH:13]=2)=[O:23])=[N:30][CH:31]=1
Reactant: CN(C)C(=O)c1ccc(Oc2cc(C(=O)O)cc3c2CC(C)(C)O3)cc1F
Reactant: Cc1ccc(N)nc1
Product: Cc1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N(C)C)c(F)c3)c3c(c2)OC(C)(C)C3)nc1

Procedure:
The title compound was prepared in a similar manner as described for Example 144, from 4-(4-dimethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (143a) (60 mg, 0.16 mmol) and 2-amino-5-methylpyridine (34.8 mg, 0.321 mmol) to give a brown solid (25 mg, 34% yield). 1H NMR (400 MHz, CDCl3) δ 8.98 (br. s., 1 H) 8.19 (d, J=8.34 Hz, 1 H) 8.11 (s, 1 H) 7.66 (dd, J=8.46, 1.89 Hz, 1 H) 7.31-7.43 (m, 1 H) 7.12 (s, 1 H) 7.07 (d, J=1.26 Hz, 1 H) 6.80 (dd, J=8.59, 2.27 Hz, 1 H) 6.69 (dd, J=10.61, 2.27 Hz, 1 H) 3.14 (s, 3 H) 2.98 (s, 3 H) 2.91 (s, 2 H) 2.35 (s, 3 H) 1.50 (s, 6 H); LCMS for C26H26FN3O4 m/z 464.20 (M+H+); Anal. Calcd. for C26H26FN3O4.0.27 TFA.1.0 H2O: C, 62.22; H, 5.56; N, 8.20; Found: C, 61.87; H, 5.36; N, 8.56.