Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH:22]3[CH2:23][C:9]4([CH2:13][N:12]([CH2:14][CH:15]5[CH2:19][CH2:18][CH2:17][CH2:16]5)[CH2:11][CH:10]4[C:20]4[CH:27]=[C:26]([N+:28]([O-])=O)[CH:25]=[CH:24][C:21]=43)[C:8]=2[CH:31]=1)([O-])=O>O1CCCC1.[Pt]=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[CH:22]3[CH2:23][C:9]4([CH2:13][N:12]([CH2:14][CH:15]5[CH2:16][CH2:17][CH2:18][CH2:19]5)[CH2:11][CH:10]4[C:20]4[CH:27]=[C:26]([NH2:28])[CH:25]=[CH:24][C:21]=43)[C:8]=2[CH:31]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)C1CN(CC3CCCC3)CC13CC2c1ccc([N+](=O)[O-])cc13
Agent: O=[Pt]
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)C1CN(CC3CCCC3)CC13CC2c1ccc(N)cc13
Yield: 123.7 %

Procedure:
A solution of 5.0 g of 5,11-dinitro-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole in tetrahydrofuran was hydrogenated at 50 lbs. pressure and room temperature with 0.2 g of platinum oxide catalyst to give 5.3 g of 5,11 -diamino-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole as an oil; nmr spectrum: δ 1.0-4.0 (m, 19); 3.4 (s, 4); 6.2-6.7 (m, 4); 6.8-7.0 (m, 2).
Reaction SMILES: [N+:1]([C:4]1[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[C:7]([O:8][C:9]2[CH:46]=[CH:45][C:12]([C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([CH3:44])([CH3:43])[C:23]4[CH:28]=[CH:27][C:26]([O:29][C:30]5[C:35]([C:36]([F:39])([F:38])[F:37])=[CH:34][C:33]([N+:40]([O-])=O)=[CH:32][CH:31]=5)=[CH:25][CH:24]=4)[CH:17]=3)([CH3:15])[CH3:14])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].COCCO>[NH2:40][C:33]1[CH:34]=[C:35]([C:36]([F:37])([F:38])[F:39])[C:30]([O:29][C:26]2[CH:27]=[CH:28][C:23]([C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([C:13]([CH3:14])([CH3:15])[C:12]4[CH:11]=[CH:10][C:9]([O:8][C:7]5[C:47]([C:49]([F:50])([F:51])[F:52])=[CH:48][C:4]([NH2:1])=[CH:5][CH:6]=5)=[CH:46][CH:45]=4)[CH:17]=3)([CH3:44])[CH3:43])=[CH:24][CH:25]=2)=[CH:31][CH:32]=1
Reactant: [H][H]
Reactant: CC(C)(c1ccc(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)cc1)c1cccc(C(C)(C)c2ccc(Oc3ccc([N+](=O)[O-])cc3C(F)(F)F)cc2)c1
Agent: [Pd]
Solvent: COCCO
Product: CC(C)(c1ccc(Oc2ccc(N)cc2C(F)(F)F)cc1)c1cccc(C(C)(C)c2ccc(Oc3ccc(N)cc3C(F)(F)F)cc2)c1
Yield: 89.1 %

Procedure:
Successively, to a reduction vessel equipped with a thermometer, reflux condenser and stirrer, 90 g (0.124 mol) of 1,3-bis[4-(4-nitro-6-trifluoromethylphenoxy)-α, α-dimethylbenzyl]benzene, 500 ml of methyl cellosolve and 5 g of 5%-Pd/c having a moisture content of 50% were charged and reacted at 70°~80° C. for 4 hours in a hydrogen atmosphere. After finishing the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to obtain 73.4 g (89% yield) of 1,3-bis[4-(4-amino-6-trifluoromethylphenoxy)-α, α-dimethylbenzyl]benzene as a light yellow crystal having a melting point of 118.5~119.2.
Reaction SMILES: [CH2:1]([O:8]C1C=C2C(=CC=1)NC=C2C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29](Cl)[CH:30]=2)[N:25]([CH2:33][C:34]([OH:36])=[O:35])[CH:24]=1)(=[O:22])[NH2:21]>>[CH2:1]([O:8][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH2:33][C:34]([OH:36])=[O:35])[CH:24]=[C:23]2[C:20](=[O:22])[NH2:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1cn(CC(=O)O)c2ccc(Cl)cc12
Reactant: O=Cc1c[nH]c2ccc(OCc3ccccc3)cc12
Product: NC(=O)c1cn(CC(=O)O)c2ccc(OCc3ccccc3)cc12

Procedure:
was prepared from 5-benzyloxy-1H-indole-3-carbaldehyde [6953-22-6] using similar protocols as described in Scheme A11 for the preparation of (3-carbamoyl-5-chloro-indol-1-yl)-acetic acid. White solid. MS (LC/MS): 325 [M+H]+, 649 [2M+H]+; tR (HPLC conditions b): 4.04 min.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:23])[N:4]2[C:8](=[C:9]([C:20]([OH:22])=O)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])[CH2:7][CH2:6][CH2:5]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[C:55]([O:59][CH2:60][CH2:61][O:62][NH2:63])([CH3:58])([CH3:57])[CH3:56]>CN(C=O)C>[C:55]([O:59][CH2:60][CH2:61][O:62][NH:63][C:20]([C:9]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[C:2]([F:1])[C:3](=[O:23])[N:4]2[C:8]=1[CH2:7][CH2:6][CH2:5]2)=[O:22])([CH3:58])([CH3:57])[CH3:56]
Reactant: CC(C)(C)OCCON
Reactant: O=C(O)c1c(Nc2ccc(I)cc2F)c(F)c(=O)n2c1CCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OCCONC(=O)c1c(Nc2ccc(I)cc2F)c(F)c(=O)n2c1CCC2
Temperature: 70 °C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
Example 1 (656 mg, 1.52 mmol), HATU (870 mg, 2.28 mmol) and N-Methylmorpholine (835 μL, 7.59 mmol) were stirred in DMF (7.6 mL) at r.t. for 10 min. O-(2-tert-Butoxy-ethyl)-hydroxylamine (303 mg, 2.28 mmol) was added, and the reaction stirred at 70° C. for 16 h. Purification by prep-HPLC gave 730 mg (73%) of compound 4a as a beige solid. MS (ES) [m+H] calc'd for C21H24F2IN3O4, 548. found 548.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[CH:16][N:15]=2)=[N:6]1.[F:26][C:27]([F:36])([F:35])[CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][C:30]1=O>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH:21][CH:31]3[CH2:32][CH2:33][N:29]([CH2:28][C:27]([F:36])([F:35])[F:26])[CH2:30]3)=[CH:16][N:15]=2)=[N:6]1
Reactant: O=C1CCCN1CC(F)(F)F
Reactant: Nc1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)ncc1NC1CCN(CC(F)(F)F)C1

Procedure:
400 mg (1.193 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5-diamine (synthesis described in US2004/67937; Example V) were reacted in analogy to the method in example 88A with 1-(2,2,2-trifluoroethyl)pyrrolidinone. After purification by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient), this gave 482 mg of the title compound (83% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:18])[CH2:17][CH2:16][CH2:15][CH:14]3[CH:10]2[CH2:11][CH2:12][NH:13]3)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:20][CH2:21][OH:22].C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)CC(O)=O.C(O)(=O)CC([O-])=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:18])[CH2:17][CH2:16][CH2:15][CH:14]3[CH:10]2[CH2:11][CH2:12][N:13]3[CH2:20][CH2:21][OH:22])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCBr
Reactant: OC1(c2ccc(Cl)c(Cl)c2)CCCC2NCCC21
Agent: O=C(O)CC(=O)O
Agent: O=C([O-])CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: OCCN1CCC2C1CCCC2(O)c1ccc(Cl)c(Cl)c1

Procedure:
3.8 g (3aRS,4SR,7aRS)-4-(3,4-dichlorophenyl)hexahydro-4-indolinol (see Example 3), 1.6 g 2-bromoethanol and 4 g sodium carbonate are heated for 4 hours at 100° in 50 ml dimethylformamide. The resulting mixture is evaporated to dryness, and the residue is partitioned between methylene chloride and 2N tartaric acid. The aqueous phase is made alkaline and repeatedly extracted with methylene chloride. The last-mentioned methylene chloride phase is dried over sodium sulphate, and evaporated to yield as an oily residue, the title compound in crude free base form, which is converted by addition of an equivalent amount of malonic acid, into the hydrogen malonate. M.Pt. 161°.
Reaction SMILES: [CH:1]1([C:4]2([F:26])[CH2:7][N:6]([C:8]3[N:13]=[C:12]([S:14]([CH3:17])(=O)=O)[N:11]=[C:10]([NH:18][C:19]4[NH:23][N:22]=[C:21]([CH3:24])[CH:20]=4)[C:9]=3[F:25])[CH2:5]2)[CH2:3][CH2:2]1.[F:27][C:28]([F:41])([F:40])[CH2:29][C:30]([NH:32][C:33]1[CH:38]=[CH:37]C(S)=[CH:35][CH:34]=1)=[O:31]>CN(C=O)C.C(OC(=O)C)C.C([O-])(O)=O.[Na+]>[CH3:24][C:21]1[CH:20]=[C:19]([NH:18][C:10]2[C:9]([F:25])=[C:8]([N:6]3[CH2:7][C:4]([CH:1]4[CH2:3][CH2:2]4)([F:26])[CH2:5]3)[N:13]=[C:12]([S:14][C:17]3[CH:35]=[CH:34][C:33]([NH:32][C:30](=[O:31])[CH2:29][C:28]([F:41])([F:27])[F:40])=[CH:38][CH:37]=3)[N:11]=2)[NH:23][N:22]=1
Reactant: O=C(CC(F)(F)F)Nc1ccc(S)cc1
Reactant: Cc1cc(Nc2nc(S(C)(=O)=O)nc(N3CC(F)(C4CC4)C3)c2F)[nH]n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Sc3ccc(NC(=O)CC(F)(F)F)cc3)nc(N3CC(F)(C4CC4)C3)c2F)[nH]n1
Reaction time: 6 h
Yield: 44.9 %

Procedure:
A solution of 6-(3-cyclopropyl-3-fluoroazetidin-1-yl)-5-fluoro-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylsulfonyl)pyrimidin-4-amine (64 mg, 0.17 mmol) and 3,3,3-trifluoro-N-(4-mercaptophenyl)propanamide (47 mg, 0.20 mmol) in DMF (3 ml) was heated to 80° C. and stirred for 6 hrs. The reaction was diluted with ethylacetate (20 ml) and Sat. NaHCO3 (20 ml) and the organic layer washed with brine (20 ml), dried (Na2SO4) and concentrated to give an oil. Compound was purified by mass directed preparative HPLC, eluted with acetonitrile/water/TFA to give the title compound as a white solid (TFA salt, 41.2 mg, 37%). 1H NMR (DMSO, 400 MHz) 0.46-0.50 (2H, m), 0.61-0.64 (2H, m), 1.38-1.45 (1H, m), 1.93 (3H, s), 3.55 (2H, q), 4.00-4.18 (4H, m), 5.27 (1H, s), 7.54 (2H, d), 7.71 (2H, d), 9.39 (1H, s), 10.57 (1H, s). ES+ 540.
Reaction SMILES: Cl.C(OC([NH:9][C:10]1[C:11]([F:38])=[CH:12][C:13]([F:37])=[C:14]([N:16]2[C:25]3[C:20](=[CH:21][C:22]([CH3:30])=[C:23]([F:29])[C:24]=3[N+:26]([O-:28])=[O:27])[C:19](=[O:31])[C:18]([C:32]([O:34]CC)=[O:33])=[CH:17]2)[CH:15]=1)=O)(C)(C)C>>[NH2:9][C:10]1[C:11]([F:38])=[CH:12][C:13]([F:37])=[C:14]([N:16]2[C:25]3[C:20](=[CH:21][C:22]([CH3:30])=[C:23]([F:29])[C:24]=3[N+:26]([O-:28])=[O:27])[C:19](=[O:31])[C:18]([C:32]([OH:34])=[O:33])=[CH:17]2)[CH:15]=1
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c([N+](=O)[O-])c(F)c(C)cc2c1=O
Agent: Cl
Product: Cc1cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c([N+](=O)[O-])c1F
Reaction time: 2 h
Yield: 68.8 %

Procedure:
12N Hydrochloric acid (2 ml) was added to ethyl 1-(5-tert-butoxycarbonylamino-2,4-difluorophenyl)-7-fluoro-6-methyl-8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylate (270 mg), and the mixture was stirred for 2 hours while heating under reflux. After the reaction mixture was allowed to cool, solids deposited were collected by filtration, washed successively with water and ethanol and dried to obtain the title compound (140 mg) as a pale yellow powder.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[Br:7].[CH3:8][S:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:7][C:3]1[CH2:4][CH2:5][CH2:6][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([S:9][CH3:8])=[CH:11][CH:12]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: BrC1=C(Br)CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CSc1ccc(C2=C(Br)CCC2)cc1
Yield: 32.6 %

Procedure:
Under nitrogen, 36.4 g (161 mmol) of 1,2-dibromocyclopentene (Aldrich) was reacted with 18.0 g (107 mmol) of 4-methylthiophenylboronic acid (Step 1) in 550 mL of toluene, 365 mL of ethanol, and 235 mL of 2M Na2CO3 in the presence of 6.0 g (5 mol %) of Pd(PPh3)4. The reaction was vigorously stirred at reflux overnight and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, dried (MgSO4), and reconcentrated. Purification by silica gel chromatography (Waters Prep-500) with hexane gave 9.39 g (22%) of 1-(2-bromocyclopenten-1-yl)-4-(methylthio)benzene (38 in Synthetic Scheme X when R5 =SCH3 and R1, R2, R3, R4, R6, and R7 =H) as a solid: mp 52°-54° C.; NMR (CDCl3) d 1.98-2.09 (m, 2H), 2.50 (s, 3H), 2.70-2.78 (m, 2H), 2.80-2.89 (m, 2H), 7.24 (d, J=8 Hz, 2H), 7.55 (d, J=8 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6](I)=[CH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18].O>CN(C)C=O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6](/[CH:18]=[CH:17]/[C:16]([O:20][CH3:21])=[O:19])=[CH:5][N:4]=1
Reactant: C=CC(=O)OC
Reactant: COc1ncc(I)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)/C=C/c1cnc(OC)nc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
2-Methoxy-5-iodopyrimidine (1.736 g, 7.36 mmol) was dissolved in 36 ml of N,N-dimethylformamide, and 99 mg of palladium acetate, 2.54 g (18.4 mmol) of potassium carbonate, 2.05 g (7.36 mmol) of tetrabutylammonium chloride and 3.168 g (36.8 mmol) of methyl acrylate were added thereto. The mixture was stirred in an argon atmosphere at 80° C. for 1 hour. Water was added to the reaction mixture, and the solution was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica-gel column chromatography (250 ml of silica gel, hexane:ethyl acetate=2:1 to 1:1) to give 1.26 g (6.49 mmol) of methyl (E)-3-(2-methoxy-5-pyrimidinyl)acrylate (yield: 88%).
Reaction SMILES: [CH:1]([SH:10])([C:7]([OH:9])=[O:8])[CH:2]([SH:6])[C:3]([OH:5])=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:23]([O:25][CH2:26][CH3:27])=[CH2:24].P([O-])([O-])([O-])=O>ClCCl.O1CCCC1.O.C(OCC)(=O)C>[CH2:23]([O:25][CH:26]([S:6][CH:2]([CH:1]([SH:10])[C:7]([OH:9])=[O:8])[C:3]([OH:5])=[O:4])[CH3:27])[CH3:24]
Reactant: O=C(O)C(S)C(S)C(=O)O
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(C)SC(C(=O)O)C(S)C(=O)O
Reaction time: 0.5 h

Procedure:
A solution of meso 2,3-dimercaptosuccinic acid (4.55 g, 25 mmol) in 50 mL dichloromethane or tetrahydrofuran or other similar aprotic solvents containing p-toluenesulfonic acid monohydrate (0.048 g, 0.252 mmol) is cooled to -18° to -25° C. with constant stirring. Ethyl vinyl ether (4.8 mL, 50 mmol) in 50 mL dichloromethane or other aprotic solvents is added dropwise to the cold solution over a period of 1.5 to 2 hours. The stirring is continued for an additional 30 minutes with the temperature maintained in the -18° to -25° C. range. Then 20 mL of pH 7 phosphate buffer is added, and the reaction mixture is allowed to warm with stirring for 10 to 15 minutes. The reaction mixture is then poured into a flask containing 100 mL of ethyl acetate and 25 mL of deionized water. The layers are separated and the aqueous portion is extracted three times, each time with 50 mL ethyl acetate. The organic layers are combined, washed with water and then brine. The washed ethyl acetate extract is then dried over anhydrous sodium sulfate. Removal of the solvent gives 2 to 3 g of bis S-(1-ethoxyethyl) 2,3-dimercaptosuccinic acid. The material is used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([OH:9])[N:3]=1.S(=O)(=O)(O)O.[N+:15]([O-])([O-:17])=[O:16].[K+]>C(OCC)C>[CH3:1][C:2]1[C:7]([N+:15]([O-:17])=[O:16])=[C:6]([CH3:8])[N:5]=[C:4]([OH:9])[N:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc(C)nc(O)n1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOCC
Product: Cc1nc(O)nc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.5 %

Procedure:
4,6-Dimethylpyrimidin-2-ol (10.0 g, 80.6 mmol) was added to sulfuric acid (80 mL) at 0° C. Then potassium nitrate (16.29 g, 161.1 mmol), was added to the reaction mixture at 0° C. The mixture was stirred at room temperature for 24 hr. The reaction mixture was poured slowly into diethyl ether (1000 mL) at 0° C. The precipitated solid was collected by filtration and washed with diethyl ether. A suspension of the solid in ethanol (50.0 mL) was neutralized with sodium hydrogen carbonate at room temperature. The solid was removed by filtration and the filter cake was washed with ethanol (ca. 3000 mL). The filtrate was concentrated in vacuo to give the title compound (13.15 g) as a pale yellow solid.
Reaction SMILES: O[CH2:2][C:3]1[N:13]=[C:6]2[NH:7][C:8]([CH3:12])=[CH:9][C:10](=[O:11])[N:5]2[N:4]=1.P(Br)(Br)[Br:15]>CN(C)C=O>[Br:15][CH2:2][C:3]1[N:13]=[C:6]2[N:7]=[C:8]([CH3:12])[CH:9]=[C:10]([OH:11])[N:5]2[N:4]=1
Reactant: Cc1cc(=O)n2nc(CO)nc2[nH]1
Reactant: BrP(Br)Br
Solvent: CN(C)C=O
Product: Cc1cc(O)n2nc(CBr)nc2n1
Reaction time: 0.5 h

Procedure:
2-(Hydroxymethyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7(4H)-one (U.S. Pat. No. 2,835,581) (1.8 g) is suspended in 5 ml of dimethylformamide, treated with 0.45 ml of phosphorus tribromide at 0° C. and stirred at this temperature for 1/2 hour. The dimethylformamide is evaporated in a high vacuum and the residue is digested with ice-cold water. The resulting precipitate is filtered off under suction and dried in a high vacuum (40° C.). There are obtained 1.97 g of 2-bromomethyl-5-methyl[1.2.4]triazolo[1,5-a]pyrimidin-7-ol as white crystals of melting point 217°-222° C.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].CN(C1C=CC=CN=1)C.[NH2:21][C:22]1[C:39]([OH:40])=[CH:38][C:25]2[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30][C:24]=2[CH:23]=1>C(Cl)Cl>[OH:40][C:39]1[C:22]([NH:21][S:8]([CH3:7])(=[O:10])=[O:9])=[CH:23][C:24]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])[CH2:27][CH2:26][C:25]=2[CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)c(O)cc2CC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCc2cc(O)c(NS(C)(=O)=O)cc2CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyridine (0.17 ml), methanesulfonyl chloride (0.16 ml) and dimethylaminopyridine (catalytic quantity) were added at 0° C. to a solution in DCM (10 ml) of 1,1-dimethylethyl 7-amino-8-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (0.5 g). The solution was stirred at room temperature overnight. Volatiles were evaporated under reduced pressure and the residue was partitioned between aqueous NaHCO3 and DCM. The organic layer was concentrated and submitted to column chromatography to provide the title compound (0.53 g) as a yellow oil. MS (m/z): 357 [MH]+.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH2:25][CH3:26].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCC=O
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCCC=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.61 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 0.431 g (5.0 mmol) of 1-pentanal in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=4/1) to yield 1.70 g (87.4%, yellow oily substance) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:13])[CH:3]=1.[N:14]1([CH2:19][C:20]2([CH2:23][NH2:24])[CH2:22][CH2:21]2)[CH2:18][CH2:17][CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([NH:24][CH2:23][C:20]2([CH2:19][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:21][CH2:22]2)=[O:8])=[C:4]([F:13])[CH:3]=1
Reactant: COc1cc(C(=O)O)c(F)cc1N
Reactant: NCC1(CN2CCCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCC2(CN3CCCC3)CC2)c(F)cc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
4-amino-2-fluoro-5-methoxy-benzoic acid (Intermediate 183; 500 mg, 2.70 mmol), [1-(pyrrolidin-1-ylmethyl)cyclopropyl]methanamine (Intermediate 33; 417 mg, 2.70 mmol), HATU (1.545 g, 4.05 mmol) and DIPEA (1.415 mL, 8.10 mmol) were dissolved in DMF (8 mL) and left to stir for 3 hours at room temperature. The reaction mixture was loaded onto an SCX-3 column pre-washed with methanol. The column was washed with methanol eluted with 2% 7N ammonia/methanol. Product containing fractions were combined and evaporated and the residue purified on a silica column (5-12% MeOH ammonia/DCM gradient elution) to yield the title compound as an orange-brown solid (200 mg, 23%).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH:39]4[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH:39]4[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(C4CCCCCC4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2c(C)cc(-c3cn(C4CCCCCC4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-cycloheptyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].[CH3:7][C:8]1([CH3:26])[C@@H:10](/[CH:11]=[CH:12]\[C:13](=O)[OH:14])[C@H:9]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>>[CH3:7][C:8]1([CH3:26])[C@@H:10](/[CH:11]=[CH:12]\[C:13](=[O:14])[O:6][CH2:1][C:2]([F:5])([F:4])[F:3])[C@H:9]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: CC1(C)[C@H](C(=O)OCc2ccccc2)[C@@H]1/C=C\C(=O)O
Reactant: OCC(F)(F)F
Product: CC1(C)[C@H](C(=O)OCc2ccccc2)[C@@H]1/C=C\C(=O)OCC(F)(F)F

Procedure:
Using the procedure of Example 53, trifluoroethanol and the product of Step B of Example 57 were reacted to obtain benzyl (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-(2,2,2-trifluoroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D° =+45° (c=0.6% in chloroform).