Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[OH:18][CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[N:3]=1
Reactant: CN1CCC(O)CC1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CN1CCC(Oc2nc(N)nc(-c3ccco3)c2C#N)CC1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 4-hydroxy-1-methylpiperidine and DBU in DME. ES-MS m/e (%): 300 (M+H+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH2:29])[C:24]=1[N+:30]([O-:32])=[O:31]>CN(C=O)C.C(OCC)(=O)C>[NH2:29][C:25]1[C:24]([N+:30]([O-:32])=[O:31])=[C:23]([O:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[CH:6][CH:7]=2)[CH:28]=[CH:27][N:26]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Reactant: Nc1nccc(Cl)c1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2[N+](=O)[O-])cc1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
Tert-butyl 4-hydroxyphenylcarbamate (3.63 g, 17.4 mmol) was dissolved in dry DMF (150 mL). Potassium tert-butoxide (2.62 g, 23.4 mmol) was added and the stirring was continued for 30 minutes at room temperature. 4-Chloro-3-nitropyridin-2-amine (3.0 g, 17.3 mmol) was added as a solid in one portion and the reaction mixture was subsequently heated at 85° C. for 4 hours. The reaction mixture was cooled, diluted with ethyl acetate (800 ml) and washed with water (1×800 ml) and brine (2×800 ml). The organic layer was dried with magnesium sulphate and evaporated. The crude was chromatographed over silica (eluant ethyl acetate:cyclohexane 1:2) to yield 4.0 g (63% yield) of tert-butyl 4-(2-amino-3-nitropyridin-4-yloxy)phenylcarbamate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][CH2:37][CH:36]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:39][CH2:38][CH2:37][CH:36]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:45])([CH3:44])[CH3:46])[CH2:35]3)(=[O:32])=[O:33])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1CCCN(S(=O)(=O)c2ccccc2Br)C1
Product: CC(C)(C)OC(=O)NC1CCCN(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)C1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and racemic tert-butyl (1-((2-bromophenyl)sulfonyl)piperidin-3-yl)carbamate. MS (ESI): mass calcd. for C26H30FN5O4S, 527.20; m/z found, 528.3 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.34 (d, J=9.1, 2H), 8.10-8.07 (m, 1H), 8.00 (m, 1H), 7.73-7.68 (m, 1H), 7.64-7.59 (m, 1H), 7.44-7.40 (m, 1H), 7.35-7.29 (m, 2H), 3.30-3.20 (m, 2H), 3.15-3.06 (m, 1H), 2.51-2.40 (m, 1H), 2.30-2.21 (m, 1H), 1.79-1.70 (m, 1H), 1.65-1.56 (m, 1H), 1.39-1.28 (m, 10H), 1.26-1.14 (m, 1H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2=[O:24]>CCOCC.C1COCC1.II>[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2([OH:24])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: FC(F)(F)c1ccccc1Br
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1Nc2ccc(Cl)cc2C1(O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.6 %

Procedure:
A mixture of 2.3 g of magnesium and 0.01 g of iodine in 20 ml of ether is heated to reflux, a solution of 26 g of 1-bromo-2-trifluoromethylbenzene in 20 ml of ether is added dropwise and the resulting mixture is refluxed for 60 minutes. A solution of 9 g of 5-chloro-1H-indole-2,3-dione in 40 ml of THF is then added and refluxing is continued for 30 minutes. After cooling to RT, the reaction mixture is poured into an ice/concentrated HCl mixture and extracted with ether, the organic phase is washed with 1N NaOH solution and with water, and dried over Na2SO4, and the solvent is evaporated off under vacuum. 5.3 g of the expected product are obtained after crystallization from heptane, m.p.=205–208° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[C:25]([Br:29])=[C:26]([Br:28])[S:27][C:21]=2[N:20]=[C:19]1[CH:30]([NH:33][CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH2:31][CH3:32])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[C:25]([Br:29])=[C:26]([Br:28])[S:27][C:21]=2[N:20]=[C:19]1[CH:30]([N:33]([CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:31][CH3:32])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CCC(NCCN(C)C)c1nc2sc(Br)c(Br)c2c(=O)n1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(c1nc2sc(Br)c(Br)c2c(=O)n1Cc1ccccc1)N(CCN(C)C)C(=O)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
A solution of 4-bromobenzoyl chloride (19 mg, 0.085 mmol, 1 equiv) in dichloromethane (1 mL) was added to a solution of 3-benzyl-5,6-dibromo-2-(1-{[2-(dimethylamino)ethyl]amino}propyl)thieno[2,3-d]pyrimidin-4(3H)-one (2-7, 45 mg, 0.085 mmol, 1 equiv) and N,N-diisopropylethylamine (11 mg, 0.085 mmol, 1 equiv) in dichloromethane (5 mL), and the resulting reaction mixture was stirred under ambient conditions for 1 h. The reaction mixture was washed with saturated aqueous NaHCO3 solution, then brine, and dried (MgSO4) and concentrated. The residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present) to provide N-[1-(3-benzyl-5,6-dibromo-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)propyl]-4-bromo-N-[2-(dimethylamino)ethyl]benzamide (2-9) as a colorless foam. MS(M+1)=708.9
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH:14]([NH2:17])([CH3:16])[CH3:15]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:13][NH:17][CH:14]([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: C=C(C(=O)OC)c1ccc(Cl)cc1
Reactant: CC(C)N
Solvent: C1CCOC1
Product: COC(=O)C(CNC(C)C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-(4-chlorophenyl)acrylate (1.00 g, 5.09 mmol) was added as a solution in 2.5 mL of THF to a stirring solution of i-PrNH2 (650 uL, 7.63 mmol) in 10 mL of THF. The reaction was allowed to stir at room temperature overnight to completion by LCMS analysis. The solvent was removed under reduced pressure to give methyl 2-(4-chlorophenyl)-3-(isopropylamino)propanoate (LCMS (APCI+) [M−Boc+H]+ 256.1, Rt: 1.97 min), which was re-dissolved in 15 mL of DCM at room temperature. The Boc2O (1.29 mL, 5.59 mmol) was added to the stirring amine via pipette followed by a catalytic amount (1 mg) of DMAP. The reaction was allowed to stir overnight to completion by LCMS and TLC analysis of the mixture. The solution was concentrated in vacuo to afford methyl 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoate as an oily residue (LCMS (APCI+) [M−Boc+H]+ 256.1, Rt: 4.13 min) which was re-dissolved in 12.0 mL of THF and 4.0 mL of water. The solution was treated with LiOH—H2O (1.07 g, 25.4 mmol) and allowed to stir for 4 hours to completion by LCMS analysis. The solution was diluted with water and washed with diethyl ether (discarded). The aqueous was treated with 1M HCl solution until pH 2-3 and extracted with ethyl acetate several times. The organics were combined, washed with brine, separated, dried over MgSO4, filtered, and concentrated in vacuo to afford 3-(tert-butoxycarbonykisopropyl)amino)-2-(4-chlorophenyl)propanoic acid as a colorless oil (1.04 g, 60%). LCMS (APCI+) [M−Boc+H]+ 242.0.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]1=[O:20])[CH3:4].CC(C)=O>C(O)C>[CH2:3]([C:5]1[CH:6]([OH:20])[C:7]2[C:12]([CH:13]=1)=[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:10]=[CH:9][CH:8]=2)[CH3:4]
Reactant: CCC1Cc2c(cccc2-c2ccccc2)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: CCC1=Cc2c(-c3ccccc3)cccc2C1O
Reaction time: 3.5 h
Yield: 100.1 %

Procedure:
A 200-ml three-necked round flask equipped with a stirring bar, a Dimroth condenser, a dropping funnel and a thermometer was charged with 0.85 g (22.6 mmol) of sodium borohydride and 28 ml of ethanol. To the mixture was dropwise added a solution containing 10.6 g (45.1 mmol) of the above-obtained 2-ethyl-4-phenyl-1-indanone dissolved in 20 ml of ethanol at room temperature under a nitrogen atmosphere. After the addition was completed, the temperature of was elevated to 50° C., and the reaction mixture was stirred for 3.5 hours. After the reaction was completed, the unreacted sodium borohydride was decomposed by acetone. Then, the reaction mixture was concentrated under reduced pressure, and then dissolved in 50 ml of water and extracted with 50 ml of ether. After the organic phase was separated, the aqueous phase was extracted with 50 ml of ether two times. The combined organic phase was washed with 100 ml of a saturated aqueous solution of sodium chloride, followed by drying over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain 10.67 g of the desired product as a pasty pale yellow liquid (mixture of two kinds of isomers) (yield; 99%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:12][CH3:13])[C:10](=[O:14])[C:9]([F:16])([F:15])[CH2:8][N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:38]=[CH:37][C:27]([C:28]([NH:30][CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:29])=[CH:26][CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:17]1([N:7]2[CH2:8][C:9]([F:16])([F:15])[C:10](=[O:14])[N:11]([CH2:12][CH3:13])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([C:28]([NH:30][CH:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[O:29])=[CH:37][CH:38]=4)=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Nc1ccc(C(=O)NC2CCOCC2)cc1
Reactant: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCOCC4)cc3)ncc21
Yield: 46.6 %

Procedure:
A mixture of 0.05 g (0.15 mmole) of 2-chloro-9-cyclopentyl-5-ethyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-138), 0.04 g (0.18 mmole) of 4-amino-N-(tetrahydro-pyran-4-yl)-benzamide, 0.04 g (0.23 mmole) of p-toluenesulfonic acid monohydrate and 4.0 mL of 2-propanol was heated at 160 degrees for 2 hours in a microwave reactor. The cooled mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phases were extracted with dichloromethane, and the combined organic layers washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexanes-ethyl acetate (30:70), followed by recrystallization from ethyl acetate-hexanes-methanol to give 0.036 g of 4-(9-cyclopentyl-5-ethyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(tetrahydro-pyran-4-yl)-benzamide (I-143).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[CH:16]3[N:24]4[CH:19]([CH2:20][N:21](C([O-])=O)[CH2:22][CH2:23]4)[CH:18]4[C:28](=[O:33])[N:29]([CH3:32])[C:30](=[O:31])[CH:17]34)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[CH:16]3[N:24]4[CH:19]([CH2:20][NH:21][CH2:22][CH2:23]4)[CH:18]4[C:28](=[O:33])[N:29]([CH3:32])[C:30](=[O:31])[CH:17]34)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN1C(=O)C2C(C1=O)C1CN(C(=O)[O-])CCN1C2/C=C/c1ccc(-c2cccc(F)c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)C2C(C1=O)C1CNCCN1C2/C=C/c1ccc(-c2cccc(F)c2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
100 mg of tert-butyl (8-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyl-1,3-dioxodecahydro-2,5,7a-triazacyclopenta[a]indene-5-carboxylate (from Example 10) are dissolved in 9 ml of dichloromethane, and 3 ml of trifluoroacetic acid are added. The mixture is stirred at RT for 2 h, the solvent is then removed under reduced pressure and the crude product is purified by column chromatography (silica gel, MeOH:DCM).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1CCCCC1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:13][C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)CC(=O)O
Reactant: COc1ccc(C=O)cc1Br
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1ccc(C=CC(=O)O)cc1Br

Procedure:
3-Bromo-4-methoxybenzaldehyde (50 g, 232 mmol), malonic acid (36.3 g, 348 mmol) and 250 ml of anhydrous pyridine are introduced into a 500 ml round-bottomed flask. Piperidine (11.4 ml, 116 mmol) is added and the medium is brought to reflux for 3 h. The pyridine is removed under vacuum and the medium is run on to 500 ml of a 1M aqueous hydrochloric acid solution. The solid is filtered off, washed with water and dried over P2O5.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.[N+:11]([O-])([O-:13])=[O:12].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(F)ccc1C#N
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(F)c([N+](=O)[O-])cc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
4-Fluoro-2-methylbenzonitrile (10 mmol, 1.35 g) was dissolved in concentrated sulphuric acid (10 mL) under argon then treated with potassium nitrate (10 mmol, 1.01 g, 1 eq) at 0° C. portionwise to keep the temperature around 0° C. The mixture was allowed to stir for 2 h while warming up to room temperature. The mixture was then poured onto ice and extracted twice with ether. The organics were combined, dried and concentrated under reduced pressure to give the title compound as a solid (9.4 mmol, 1.7 g, 94% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[N:7]=1.[N+:20]([C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1)([O-:22])=[O:21].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([O:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([N+:20]([O-:22])=[O:21])[CH:24]=2)[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[N:7]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)nc(Cl)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(Oc3cccc([N+](=O)[O-])c3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.7 %

Procedure:
To a mixture of Compound 6-B (200 mg, 0.628 mmol) and 3-nitrophenol (96.2 g, 0.691 mmol) in dimethylformamide (2 mL) was added K2CO3 (173.7 mg, 1.26 mmol). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then filtered. The filtrate was diluted with water, then extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over Na2SO4. After filtration and removal of the volatiles in vacuo, the crude product was purified by flash column chromatography (PE/EA=20/1) affording Compound 6-C (200 mg, yield 75.6%, M+H+=421.92) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH:11]([NH2:13])=[O:12]>C(OCC)(=O)C.O>[C:5]1([C:3]2[N:13]=[CH:11][O:12][CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: NC=O
Solvent: CCOC(C)=O
Solvent: O
Product: c1ccc(-c2cocn2)cc1
Temperature: 130 °C
Yield: 39.1 %

Procedure:
Bromoacetophenone (595 mg, 2.99 mmol) and formamide (1781 μl, 44.8 mmol) were combined and heated at 130° C. for 90 min. The reaction was cooled then dilute with ethyl acetate and water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated. The concentrate was purified by chromatography on a Biotage 25M column using a 5-8% ethyl acetate in heptane gradiant to yield 4-phenyl-oxazole (170 mg, 1.17 mmol). TLC (5% ethyl acetate in heptane) of product: Rf=0.28.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.[Cl:23][SiH:24]([Cl:26])[Cl:25]>>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][Si:24]([Cl:26])([Cl:25])[Cl:23])=[CH:17][CH:16]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: ClCc1ccc(Cl)cc1
Agent: CCCCP(CCCC)CCCC
Product: Clc1ccc(C[Si](Cl)(Cl)Cl)cc1
Yield: 92.3 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.15 g (0.75 mmol) of tri-n-butylphosphine, 1.21 g (7.5 mmol) of 4-chlorobenzyl chloride, and 5.08 g (37.5 mmol) of trichlorosilane were reacted at 150° C. for 2 hrs. The resulting mixture was distilled to give 1.8 g of (4-Chlorobenzyl)trichlorosilane; H-NMR (CDCl3, ppm):2.93 (s, 2H, —CH2—), 7.29-7.38 (m, 4H, ArH).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=2[N+:16]([O-:18])=[O:17])=[CH:22][CH:21]=1
Reactant: Fc1ccc(S)cc1
Reactant: Cc1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Product: Cc1ccc(Sc2ccc(F)cc2)c([N+](=O)[O-])c1

Procedure:
The product from Example 6a (5.00 g, 17.53 mmol) was reacted with 4-fluorothiophenol (2.24 g, 17.53 mmol) in place of thiophenol following the procedure from Example 5H for 18 h giving 1-(4-Fluoro-phenylsulfanyl)-4-methyl-2-nitro-benzene which was purified by silica gel column chromatography eluting with 5% EtOAc/hexane providing a solid (3.39 g, 74%). 1-(4-Fluoro-phenylsulfanyl)-4-methyl-2-nitro-benzene was reduced with SnCl2 following the procedure from Example 5I giving 2-(4-Fluoro-phenylsulfanyl)-5-methyl-phenylamine.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[N:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[CH2:20][CH2:19]2)=[N:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:29]2[CH2:28][CH2:27][N:26]([C:24]([CH:21]3[CH2:22][CH2:23][N:18]([C:15]4[CH:16]=[CH:17][N:12]=[CH:13][N:14]=4)[CH2:19][CH2:20]3)=[O:25])[CH2:31][CH2:30]2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C(C1CCN(c2ccncn2)CC1)N1CCNCC1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)N2CCN(C(=O)C3CCN(c4ccncn4)CC3)CC2)cc1
Yield: 46.2 %

Procedure:
A solution of 4-cyanobenzoyl chloride (298 mg) in dichloromethane (10 ml) was added to a stirred mixture of 1-[1 (4-pyrimidinyl) piperidin-4-ylcarbonyl] piperazine (412.5 mg) and triethylamine (0.28 ml) in dichloromethane (15 ml) and the resultant mixture was stirred at ambient temperature for 2 hours. The mixture was partitioned between dichloromethane and water. The organic phase was washed with water, dried (Na2SO4) and evaporated. The residue was purified by column chromatography using 0.5 % methanol in dichloromethane. Recrystallisation from ethyl acetate/hexane gave, as a solid 1-(4-cyanobenzoyl)-4-[l-(4-pyrimidinyl)-4-piperidylcarbonyl]piperazine (280 mg), mp 192-193° C.;
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C@H:6]1[CH2:11][CH:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:9](=[O:19])[CH2:8][N:7]1[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[OH:19][CH:9]1[CH2:8][N:7]([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])[C@@H:6]([CH2:5][O:4][CH2:3][O:2][CH3:1])[CH2:11][CH:10]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: C=CCOC(=O)N1CC(=O)C(C(=O)OC(C)(C)C)C[C@@H]1COCOC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C=CCOC(=O)N1CC(O)C(C(=O)OC(C)(C)C)C[C@@H]1COCOC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-allyl 4-tert-butyl (2R)-2-[(methoxymethoxy)methyl]-5-oxo-1,4-piperidinedicarboxylate (1.21 g, 3.4 mmol) in methanol (40 ml) was added acetic acid (0.235 ml, 4.1 mmol) and sodium cyanoborohydride (0.255 g, 4.1 mmol) and the mixture were stirred at room temperature for 20 minutes. The solvent was removed in vacuo and it was confirmed whether a starting material run out by TLC. When the starting material remained, methanol (40 ml) was added thereto to dissolve the reaction mixture and then the solvent was again removed. Until the starting material run out, the procedure was repeated. After the starting material run out, the residue was purified by silica gel (30 g) chromatography to give 1-allyl 4-tert-butyl (2R)-5-hydroxy-2-[(methoxymethoxy)methyl]-1,4-piperidinedicarboxylate (1.22 g, quantitatively).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].C(N(CC)CC)C.[Br:15][C:16]([CH3:21])([CH3:20])[C:17](Br)=[O:18]>O1CCCC1>[Br:15][C:16]([CH3:21])([CH3:20])[C:17]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6])=[O:18]
Reactant: CC(C)(Br)C(=O)Br
Reactant: C=CCCCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCCCCOC(=O)C(C)(C)Br
Temperature: 4 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
5-Hexen-1-ol (42.6 g), triethylamine (45.8 g), and tetrahydrofuran (0.8 L) were mixed. After ice cooling, 2-bromoisobutyryl bromide (100 g) was dropped. The reaction liquid was stirred at 4° C. for 3 hours, and then at room temperature for 15 hours. The reaction liquid was then filtered, concentrated with an evaporator, and dissolved in diethyl ether (300 mL). The solution was washed with a 1N hydrochloric acid solution (2×300 mL), a saturated sodium bicarbonate solution (2×300 mL), and distilled water (2×300 mL), in this order. After that, the organic layer was dried over sodium sulfate, filtered, and concentrated with an evaporator. The product was then purified through a silica gel column (developing solvent: hexane/ethyl acetate=15/1), and concentrated to give 74.2 g of 5-hexenyl 2-bromo-2-methylpropanate of the following chemical formula (compound 1).