Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O.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:30][C:27]1[CH:28]=[CH:29][C:24]([C:11]2[CH:12]=[CH:13][C:8]([N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:9][CH:10]=2)=[CH:25][CH:26]=1
Reactant: Brc1ccc(I)cc1
Reactant: OB(O)c1ccc(N(c2ccccc2)c2ccccc2)cc1
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: C1CCOC1
Solvent: O
Product: Brc1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Yield: 87 %

Procedure:
A mixture of (4-(diphenylamino)phenyl)boronic acid (1.5 g, 5.19 mmol), 4-iodo-1-bromobenzene (1.33 g, 4.71 mmol), Na2CO3 (1.78 g, 16.8 mmol) and Pd(PPh3)4 (0.163 g, 0.141 mmol) in THF/H2O (28 mL/17 mL) was degassed and the resulting mixture was heated at reflux overnight under an argon atmosphere. After cooling, the mixture was poured into dichloromethane (150 mL), then washed with water (2×150 mL) and brine (100 mL). The organic phase was dried over Na2SO4, purified with flash column chromatography (silica gel, hexanes/ethyl acetate 50:1) then recrystallized in dichloromethane/methanol to afford a white solid (Compound 35)(1.64 g, in 87% yield).
Reaction SMILES: [C:1]1([CH:7]=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H].[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[C:1]1([CH:7]2[O:19][CH:12]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccccc1
Reactant: [H][H]
Reactant: [N-]=[N+]=Cc1ccccc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: c1ccc(C2OC2c2ccccc2)cc1
Yield: 58 %

Procedure:
Phenyl diazomethane (1 mmol in 6 ml of t-butylmethylether) was added to a stirred solution of a sulphide of formula (B) wherein R' is hydrogen (0.2 mmol), rhodium (II) acetate (4.0 mg, 0.01 mmol) and benzaldehyde (1 mmol) in dichloromethane (4 ml) at room temperature over a period of 24 hours. After the addition was complete the solvent was removed in vacuo and the residue was chromatographed over silica [eluent dichloromethane:petrol (2:3)] to give the titled compound in 58% yield and 11% ee.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=O.Cl.[NH2:14][CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[O:22]=[C:16]1[CH:15]([N:14]2[C:8](=[O:9])[C:3]3[C:4](=[CH:10][CH:11]=[CH:12][C:2]=3[CH3:1])[C:5]2=[O:7])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: NC1CCC(=O)NC1=O
Reactant: Cc1cccc2c1C(=O)OC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 82.3 %

Procedure:
A stirred solution of 3-methylphthalic anhydride (2.96 g, 18.2 mmol), 3-aminopiperidine-2,6-dione hydrogen chloride (3.00 g, 18.2 mmol) and sodium acetate (1.57 g, 19.1 mmol) in acetic acid (30 mL) was heated at reflux for 23 hours. The solvent was removed in vacuo to give a solid which was stirred with water (40 mL) for 1 hour, filtered, washed with water (30 mL), and then heated with decolorizing charcoal (1 g) in acetone (2 L) at reflux temperature for 30 min. The suspension was filtered through a pad of Celite to give a clear solution. The solvent of filtrate was removed in vacuo to give 2-(2,6-dioxopiperid-3-yl)-4-methylisoindoline-1,3-dione as a white solid (4.08 g, 82% yield)-mp 290.0-292.0° C.; 1H NMR (DMSO-d6); δ 2.03-2.09 (m, 1H, CHH), 2.50-2.60 (m, 2H, CH2), 2.63 (s, 3H, CH3), 2.83-2.95 (m, 1H, CHH), 5.13 (dd, J=5.4, 12.3 Hz, 1H, NCH), 7.65-7.79 (m, 3H, Ar), 11.13 (br s, 1H, NH); 13C NMR (DMSO-d6) δ 17.04, 21.99, 30.93, 48.76, 121.05, 127.89, 131.63, 134.37, 136.91, 137.61, 167.04, 167.83, 169.87, 172.74; Anal Calcd for C14H12N2O4: C, 61.76; H, 4.44; N, 10.29. Found: C, 61.68; H, 4.37; N, 10.17.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.N1(C2C=CN=CC=2)CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: OCc1ccccc1
Reactant: O=C(O)CCCCCCCBr
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: O=C(CCCCCCCBr)OCc1ccccc1
Yield: 100.2 %

Procedure:
This compound was prepared from 8-bromooctanoic acid (2.23 g; 10.0 mmol), benzyl alcohol (1.19 g; 11.0 mmol), N,N′-dicyclohexylcarbodiimide (DCC, 2.27 g; 11.0 mmol), and 4-pyrrolidinylpyridine (50 mg) in dry dichloromethane (50 mL) using Procedure A. 3.14 g (100%) product was obtained (clear oil that eventually solidified on standing).
Reaction SMILES: [F:1][CH:2]([F:16])[C:3]1[N:8]2[N:9]=[C:10]([C:12]([OH:14])=O)[N:11]=[C:7]2[N:6]=[C:5]([CH3:15])[CH:4]=1.[NH2:17][C:18]1[CH:19]=[C:20]([C:24]([C:26]2[C:34]3[CH:33]=[N:32][CH:31]=[N:30][C:29]=3[N:28]([CH:35]([CH3:37])[CH3:36])[CH:27]=2)=[O:25])[CH:21]=[N:22][CH:23]=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>[CH:35]([N:28]1[C:29]2[N:30]=[CH:31][N:32]=[CH:33][C:34]=2[C:26]([C:24]([C:20]2[CH:19]=[C:18]([NH:17][C:12]([C:10]3[N:11]=[C:7]4[N:6]=[C:5]([CH3:15])[CH:4]=[C:3]([CH:2]([F:1])[F:16])[N:8]4[N:9]=3)=[O:14])[CH:23]=[N:22][CH:21]=2)=[O:25])=[CH:27]1)([CH3:37])[CH3:36]
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Reactant: Cc1cc(C(F)F)n2nc(C(=O)O)nc2n1
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: Cc1cc(C(F)F)n2nc(C(=O)Nc3cncc(C(=O)c4cn(C(C)C)c5ncncc45)c3)nc2n1
Temperature: 50 °C
Reaction time: 16 h
Yield: 12 %

Procedure:
7-Difluoromethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylic acid (29.64 mg, 0.130 mmol) was added to (5-amino-pyridin-3-yl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (28.1 mg, 0.1 mmol), HATU (49.42 mg, 0.130 mmol) and DIPEA (22.4 uL, 0.13 mmol) in anhydrous DMF (1 mL). The mixture was stirred at 50° C. for 16 hours and then evaporated in vacuo and purified by prep-HPLC (method 5) to afford the title compound in 12% yield, 6.1 mg.
Reaction SMILES: I[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[CH3:15].[F:16][C:17]1[CH:18]=[CH:19][C:20](B2OC(C)(C)C(C)(C)O2)=[C:21]2[C:25]=1[C@H:24]([O:26][C:27]1[CH:40]=[CH:39][C:30]3[C@H:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:32][O:33][C:29]=3[CH:28]=1)[CH2:23][CH2:22]2.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:15][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[CH:6]=[C:7]([CH3:8])[C:2]=1[C:20]1[CH:19]=[CH:18][C:17]([F:16])=[C:25]2[C:21]=1[CH2:22][CH2:23][C@H:24]2[O:26][C:27]1[CH:40]=[CH:39][C:30]2[C@H:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:32][O:33][C:29]=2[CH:28]=1
Reactant: Cc1cc(-c2ccncn2)cc(C)c1I
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6ccncn6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from 4-(4-iodo-3,5-dimethylphenyl)pyrimidine and methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 15): tR=1.26 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][C:16]([CH3:18])=[C:15]([NH:19][C:20](=[O:24])[CH2:21][CH2:22]Br)[C:14]=1[CH3:25].[CH2:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:27].C(OCC)(=O)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][C:16]([CH3:18])=[C:15]([NH:19][C:20](=[O:24])[CH2:21][CH2:22][N:31]2[CH2:32][CH2:33][N:28]([CH2:26][CH3:27])[CH2:29][CH2:30]2)[C:14]=1[CH3:25]
Reactant: CCN1CCNCC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1NC(=O)CCBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN1CCN(CCC(=O)Nc2c(C)[nH]c(/C=C3\C(=O)Nc4ccc(F)cc43)c2C)CC1
Temperature: 25 °C
Yield: 32 %

Procedure:
N-{5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-3-bromo-propionamide (548 mg, 1.0 eq) was dissolved in 4 ml of DMF, stirred at room temperature to obtain a solution. To the solution was added 4-ethylpiperazine (850 mg, 4.0 eq). The reaction mixture was heated to 50° C. and reacted for 4 h. Once the reaction was completed as indicated by TLC, the reaction solution was added to 200 ml of ethyl acetate. Solid product was formed, collected by filtration, washed with ethyl acetate, dried, and purified by column chromatograph to obtain the target compound of 312 mg (yield 32%).
Reaction SMILES: [NH2:1][C@:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)([CH3:5])[CH2:3][OH:4].ClC1C=C(C[C:24](=[O:26])C)C=CC=1Cl.[C-]#[N:28].[K+].C(=O)([O-])[O-].[NH4+].[NH4+]>>[Cl:14][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[Cl:13])[CH2:6][C:2]1([CH3:5])[NH:1][C:24](=[O:26])[NH:28][C:3]1=[O:4]
Reactant: C[C@@](N)(CO)Cc1ccc(Cl)c(Cl)c1
Reactant: [C-]#N
Reactant: CC(=O)Cc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [NH4+]
Product: CC1(Cc2ccc(Cl)c(Cl)c2)NC(=O)NC1=O

Procedure:
Advantageously, compared to this preparation which comprises six steps in all, the preferred process for the purposes of the invention, which is faster and more economical, enables (S)-(-)-2-amino-2-(3,4-dichlorobenzyl)-1-propanol to be prepared in four synthesis steps from 3,4-dichlorophenylacetone. Essentially, the process consists in reacting the ketone by the Bucherer-Berg reaction with potassium cyanide and ammonium carbonate to obtain (+/-)-5-(3,4-dichlorobenzyl)-5-methylhydantoin, which is subjected in an alkaline aqueous-acetone medium to a stereospecific salification with (R)-(+)-α-methylbenzylamine so as to obtain the addition salt thereof with the (S)-(-) enantiomer of the hydantoin, which, being insoluble, is filtered off, and from which (S)-(-)-5-(3,4-dichlorobenzyl)-5-methylhydantoin is obtained in a state of optical purity greater than 98% by treatment in an acid solution.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[F:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21](F)[CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:21]3[CH:20]=[N:19][CH:18]=[C:17]([F:16])[CH:22]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cncc(F)c1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cncc(F)c1

Procedure:
The title compound, MS: m/e=312.1 (M+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 3,5-difluoro-pyridine.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.C(N(CC)CC)C.Cl.Cl.[CH:46]1([N:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)[CH2:48][CH2:47]1>ClCCl>[CH:46]1([N:49]2[CH2:54][CH2:53][N:52]([CH2:6][C:7]3[N:12]=[CH:11][C:10]4[N:13]=[CH:14][N:15]([C:16]5[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]6[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=6[C:30]([F:33])([F:31])[F:32])[CH3:23])[CH:20]=5)[C:9]=4[CH:8]=3)[CH2:51][CH2:50]2)[CH2:48][CH2:47]1
Reactant: C1CN(C2CC2)CCN1
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CN4CCN(C5CC5)CC4)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Temperature: 40 °C
Reaction time: 1 h

Procedure:
100 mg of [1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate and 205 mg triethylamine are dissolved in 2.5 ml dichloromethane. Under N2 atmosphere 1-cyclopropylpiperazine dihydrochloride (184 mg) is added. The reaction mixture is stirred at 40° C. for 1 hour and then concentrated to dryness under vacuum. The residue is purified by preparative HPLC (ammonium formate buffer/acetonitrile, elution gradient 97/3 to 0/100 (v/v)) to obtain the title product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Si:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH3:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.[C:23](=[S:25])=O.I[CH3:27].[NH4+].[Cl-]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([Si:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([CH3:15])[CH2:9][N:10]2[C:14]([C:23]([CH3:27])=[S:25])=[N:13][CH:12]=[N:11]2)=[CH:6][CH:7]=1
Reactant: C[Si](Cn1cncn1)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CI
Reactant: O=C=S
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=S)c1ncnn1C[Si](C)(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 72 h

Procedure:
To a -78° C. solution of 0.016 mol of lithio[bis(4-fluorophenyl)methyl(1H-1,2,4-triazol-1-ylmethyl)silane, prepared in 75 mL of THF as described in Example 1, was added 1 mL of liquid carbonyl sulfide. The solution was allowed to warm to 0° over 1 hour, and 1.0 mL (0.016 mol) of iodomethane was added. The reaction mixture was stored at 25° for 3 days, then poured into saturated aqueous NH4Cl. The aqueous layer was extracted twice with ether, and the combined organic layers were dried (MgSO4) and evaporated to give 5.2 g of the title compound as a yellow oil: nD 1.5694; ir (neat) 1710 (w), 1663; nmr (CDCl3) δ 0.7 (3H, s), 2.3 (3H, s), 4.6 (2H, s), 7.0 (4H, m), 7.4 (4H, m), 7.8 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([OH:10])[C:6]=2[CH:11]=1.Cl.Cl[CH2:14][C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([O:10][CH2:14][C:15]3[N:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:6]=2[CH:11]=1
Reactant: ClCc1ncccn1
Reactant: Oc1noc2ccc(Br)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1ccc2onc(OCc3ncccn3)c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 41.9 %

Procedure:
5-bromobenzo[d]isoxazol-3-ol (200 mg, 0.93 mmol), 2-(chloromethyl)pyrimidine hydrochloride (200 mg, 1.21 mmol) and cesium carbonate (1 g) were combined in 10 mL DMF and stirred at ambient temperature for two days. The reaction mixture was diluted with 60 mL ethyl acetate, washed with water and brine and evaporated under vacuum. Flash chromatographic purification on 12 g silica gel with 0-100% ethyl acetate in hexane gave O-alkylated product 5-bromo-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole (120 mg, 0.39 mmol).
Reaction SMILES: C(OC([C:6]1[NH:7][C:8]([CH3:18])=[C:9]([CH2:12][CH2:13][C:14]([O:16]C)=[O:15])[C:10]=1[CH3:11])=O)C.[OH-:19].[K+].Cl.[CH2:22]([OH:25])[CH2:23]O>O>[CH3:18][C:8]1[NH:7][CH:6]=[C:10]([CH3:11])[C:9]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15].[CH3:13][CH2:12][CH2:9][C:8]1[NH:7][CH:6]=[C:10]([CH3:11])[C:23]=1[C:22]([OH:25])=[O:19]
Reactant: [OH-]
Reactant: CCOC(=O)c1[nH]c(C)c(CCC(=O)OC)c1C
Reactant: OCCO
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCCc1[nH]cc(C)c1C(=O)O
Product: Cc1c[nH]c(C)c1CCC(=O)O
Temperature: 190 °C
Yield: 72 %

Procedure:
2-(2-thienyl)pyrrole was prepared according to Kruse C. G. et al, Heterocycles 26 (1985) 3141 and formylated yielding 2-formyl-5-(2-thienyl)pyrrole according to Bullock E. et al. J. Chem. Soc. (1963) 2326 2,4-dimethyl-3-carboxyethylpyrrole was prepared as follows: 2-ethoxycarbonyl-3,5-dimethyl-4-methoxycarbonylethylpyrrole (1.5 g, 5.9 mmol) and potassium hydroxide (6.6 g) were dissolved in ethyleneglycol (50 ml). The reaction mixture was refluxed (190° C.) for 3 h under nitrogen atmosphere. Water (10 ml) was added and the mixture was refluxed for an additional 2 h. The cooled reaction mixture was diluted with water (200 ml), acidified with concentrated hydrochloric acid and extracted with diethylether. The organic extracts were pooled, dried with sodium sulphate and evaporated to dryness. The product was purified with column chromatography using silica as a stationary phase and dichloromethane:methanol (10:1, v:v) as an eluent. Fractions containing the product were pooled and evaporated to dryness yielding 720 mg (72%) of 2,4-dimethyl-3-carboxy-ethylpyrrole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](Br)([F:7])[F:6])[CH3:2].I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([CH3:20])(=[O:19])=[O:18].CCOC(C)=O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:9])[C:5]([F:7])([F:6])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([CH3:20])(=[O:19])=[O:18])[CH3:2]
Reactant: CS(=O)(=O)c1ccccc1I
Reactant: CCOC(=O)C(F)(F)Br
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)c1ccccc1S(C)(=O)=O
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 2.7 %

Procedure:
To a stirred suspension of Cu(0) (496 mg, 78 mmol) in DMSO (2.5 mL) at room temperature under nitrogen atmosphere was added ethylbromodifluoroacetate (0.5 mL, 39 mmol). The reaction mixture was stirred at 35° C. for 30 min. Then the solution was brought to room temperature and 1-iodo-2-methanesulfonylbenzene (1.0 g, 35 mmol), as prepared in the preceding step, was added. The reaction mixture was stirred at 35° C. for 12 h. The reaction mixture was cooled to room temperature and passed through a bed of Celite using EtOAc to rinse. The filtrate was washed with saturated NH4Cl (50 mL) until the blue color dissipated. The organic phase was then washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo to afford 772 mg crude product. The residue was purified by flash column chromatography (20-40% ethyl acetate in hexanes) to yield the desired compound (264 mg, 27%). 1H-NMR (300 MHz, CDCl3) δ 8.18 (d, J=7.6 Hz, 1H), 7.94 (dd, J=7.7 Hz, 1.7 Hz, 1H), 7.76 (pd, J=7.6 Hz, 1.5 Hz, 2H), 4.31 (q, J=7.2 Hz, 2H), 3.15 (s, 3H), 1.29 (t, J=7.1 Hz, 3H). LC/MS (m/z) [M+1]+ 279.3 (calculated for C11H13F2O4S, 279.3).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[Cl-].[NH4+].[CH:10]1([OH:16])[CH2:15][CH2:14]CC=C1.[CH2:17]([O:19][CH2:20][CH3:21])[CH3:18]>>[CH2:17]([O:19][CH:20]([O:16][CH2:10][CH2:15][CH2:14][C:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1)[CH3:21])[CH3:18]
Reactant: OC1C=CCCC1
Reactant: CCOCC
Reactant: O=C1C=CCCC1
Agent: [Cl-]
Agent: [NH4+]
Product: CCOC(C)OCCCC1(O)C=CCCC1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
The organo-lithium intermediate compound formed in this above reaction mixture was transferred via a cannulus apparatus to a 250 ml oven dried, round bottom flask fitted with magnetic stir bar, septum, pressure equalizing additional funnel connected to a source of nitrogen and cooled to 0° C. in an ice/water bath. The addition funnel had been charged with 9.95 g (0.10 mol) of 2-cyclohexen-1-one and 100 ml of anhydrous ethyl ether. The cyclohexenone solution was added dropwise to the cold, stirred organolithium intermediate compound under nitrogen over a 1.5 hr period. The resultant mixture was stirred at 0° C. for one hr and then allowed to slowly warm to room temperature by stirring for 18 hr without replenishing the ice in the bath. The reaction mixture was poured into 250 ml of ice cold, 1/2 saturated ammonium chloride aqueous solution. The liquid phases were separated and the aqueous phase was extracted twice with 200 ml portions of diethyl ether. The combined ethereal liquid phases were washed with brine solution, dried over sodium sulfate and concentrated in vacuo to leave 21.4 g (93% yield) of the above named -cyclohex-2-ene-1-ol intermediate as a colorless oil which was used as such in the next step. The NMR of this intermediate was consistent with the above named intermediate compound.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([O:17][CH3:18])([C:15]#[N:16])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([Mg]Br)[CH3:20].C(O)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([CH:15]([NH2:16])[CH2:19][CH3:20])([O:17][CH3:18])[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[Mg]Br
Reactant: COC1(C#N)CCC(OCc2ccccc2)CC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCC(N)C1(OC)CCC(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under argon, 1.2 g of 39 were dissolved in 60 mL of absolute toluene. Then, 2.9 mL of ethylmagnesium bromide (3M in diethylether) were added dropwise. The mixture was allowed to warm to room temperature. After conversion was complete, the reaction mixture was cooled to 5° C. and 2 mL of dry ethanol were added. The mixture was filtered over celite and the filter cake was washed with tetrahydrofuran. Volatiles were removed in vacuo, the residue was dissolved in 20 mL of dry ethanol, 331 mg of sodium borohydride were added and the mixture was stirred for 2 h at 0° C. The mixture was evaporated, 20 mL of methyl tert.butyl ether and 20 mL of water were added and 1N aqueous hydrochloric acid was added dropwise until gas evolution ceased. The organic layer was separated, washed with brine, dried and evaporated to give 1 g of the desired product as a cis/trans mixture. Rt=0.96/0.99 min (Method M). Detected mass: 278.3 (M+H+).
Reaction SMILES: [CH:1]([N:4]1[CH:9]2[CH2:10][CH2:11][CH:5]1[CH2:6][C:7](=O)[CH2:8]2)([CH3:3])[CH3:2].N1C=CC=CC=1.Cl.[NH2:20][OH:21]>C(O)C>[CH:1]([N:4]1[CH:9]2[CH2:10][CH2:11][CH:5]1[CH2:6][C:7](=[N:20][OH:21])[CH2:8]2)([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)N1C2CCC1CC(=O)C2
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(C)N1C2CCC1CC(=NO)C2
Temperature: 23 °C

Procedure:
A mixture of 8-isopropyl-8-aza-bicyclo[3.2.1]octan-3-one (CAS no: 3423-28-7) (20.0 g, 120 mmol) in ethanol (500 mL) and pyridine (14.5 mL, 179 mmol) with hydroxylamine hydrochloride (8.81 g, 127 mmol) was refluxed for 16 h. Cooled to 23° C., the precipitate was filtered off, washed with diethyl ether leaving a solid, which was partitioned between dichloromethane and sodium carbonate solution, the organic layers dried over Na2SO4, filtered and the solvents evaporated to give the title compound as a white solid. (17.7 g, 82%); MS: m/e=183.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:7]([CH:8]=[O:9])=[CH:6][NH:5][N:4]=1.[H-].[Na+].Br[CH2:15][C:16]([NH:18][C:19]1[S:23][C:22]2[CH2:24][CH2:25][CH2:26][CH2:27][C:21]=2[C:20]=1[C:28]([NH2:30])=[O:29])=[O:17].O>CN(C=O)C>[CH:8]([C:7]1[C:3]([C:2]([F:1])([F:10])[F:11])=[N:4][N:5]([CH2:15][C:16]([NH:18][C:19]2[S:23][C:22]3[CH2:24][CH2:25][CH2:26][CH2:27][C:21]=3[C:20]=2[C:28]([NH2:30])=[O:29])=[O:17])[CH:6]=1)=[O:9]
Reactant: NC(=O)c1c(NC(=O)CBr)sc2c1CCCC2
Reactant: O=Cc1c[nH]nc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1c(NC(=O)Cn2cc(C=O)c(C(F)(F)F)n2)sc2c1CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
3-(trifluoromethyl)pyrazole-4-carbaldehyde (200 mg, 1.22 mmol) was dissolved in DMF (10 mL). NaH (60% [w/w] suspension in oil, 50 mg, 1.25 mmol) was added portionwise and the reaction mixture stirred at RT for 30 min. 2-(2-bromoacetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (386 mg, 1.22 mmol) was added and the reaction mixture heated at 65° C. for 2 h, then allowed to cool to RT. Water (10 mL) was added and the reaction mixture extracted with EtOAc (3×10 mL). The combined EtOAc layers were washed with water (5×10 mL), brine (10 mL), dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the desired product (470 mg, 1.17 mmol, 96%).