Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH:5]([C:7]1[C:16]([C:17]([NH:19][C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[O:18])=[C:15]([OH:25])[C:14]2[C:9](=[C:10]([C:26]([F:29])([F:28])[F:27])[CH:11]=[CH:12][CH:13]=2)[N:8]=1)[CH3:6])(=O)C.Cl>C(O)C>[OH:25][C:15]1[C:14]2[C:9](=[C:10]([C:26]([F:27])([F:29])[F:28])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([CH:5]([OH:4])[CH3:6])[C:16]=1[C:17]([NH:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1)=[O:18]
Reactant: CC(=O)OC(C)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Agent: Cl
Solvent: CCO
Product: CC(O)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Reaction time: 1 h
Yield: 63.2 %

Procedure:
A mixture of 4.3 g of the product of Example 1, 50 ml of ethanol of 25 ml of concentrated hydrochloric acid was refluxed with stirring for one hour and was then cooled and iced and vacuum filtered. The product was washed and dried under reduced pressure at 60° C. The said product was added to 300 ml of water and the mixture was extracted with ethyl acetate. The organic phase was washed with water, dried and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was crystallized from ethyl acetate. The mixture was iced and vacuum filtered and the recovered product was washed and dried under reduced pressure at 60° C. to obtain 2.45 g of 4-hydroxy-2-(1-hydroxyethyl)-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamide melting at 205° C. and then at 235° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[N-:13]=[N+:14]=[N-].[Na+]>Cl.O>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(N)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(N=[N+]=[N-])cc1
Reaction time: 0.33 h

Procedure:
p-Toluidine (9.3 mM) was dissolved in hydrochloric acid (5M; 10 ml), and the mixture cooled to <0° C. Sodium nitrite (10.28 mM) was dissolved in a minimum amount of water, and this solution was added dropwise to the reaction over 30 minutes. The solution was stirred for 20 minutes, then the presence of the oxidising agent was tested for using starch/iodide paper. Sodium azide (37.38 mM) was then added slowly to the reaction mixture over a period of 1 hour (due to vigorous effervescing). The reaction was quenched, once all the sodium azide had been added, in water (50 ml), and quantitatively transferred to a conical flask with water (50 ml). The mixture was neutralised with sodium carbonate, until pH=6. The organics were extracted into dichloromethane (3×30 ml), washed with water (2×20 ml), dried over magnesium sulphate, and excess solvent removed under vacuum. The p-azidotoluene thus obtained was an oil and was isolated via chromatography (100% petroleum/ether 40-60). 1H NMR: d6DMSO: δ: 2.37 (s; 3H; CH3); 7.0 (d;2H; H3 ;H5); 7.3 (d; 2H; H2 ; H6)
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[N:25]=[C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[S:27][CH:28]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9]([N:32]2[CH2:33][CH2:34][N:29]([C:26]3[S:27][CH:28]=[C:24]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[F:17])[N:25]=3)[CH2:30][CH2:31]2)=[O:16])[O:4][N:3]=1
Reactant: Fc1ccccc1-c1csc(N2CCNCC2)n1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4ccccc4F)cs3)CC2)c1C
Temperature: 70 °C
Reaction time: 14 h
Yield: 37.7 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (240 mg, 0.834 mmol), 1-[4-(2-fluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.760 mmol) and diisopropylethylamine (0.265 ml, 1.52 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 14 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the desired product (115 mg, 37.8%) as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8]Br)=[CH:5][CH:4]=1)#[N:2].[OH2:13]>CS(C)=O>[C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([CH:8]=[O:13])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: O
Solvent: CS(C)=O
Product: N#Cc1ccc(C(=O)C=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.1 %

Procedure:
A solution of 4-cyanophenacyl bromide (11.20 g, 49.99 mmol) in dimethylsulfoxide (83 mL) was treated with water (0.90 mL, 49.99 mmol). After stirring for 24 h at room temperature, it was poured into ice-water, and extracted with ether. The organic layer was washed with water and then brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by a silica gel column chromatography eluting 20-50% ethyl acetate in hexane to afford 4-cyanophenylglyoxal (5.10 g, 64.1%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH:22]([CH3:24])[CH3:23])[C:17]([O:19]CC)=[O:18])[C:10](=[O:25])[CH:9]=2)[CH:7]=1.[OH-].[Li+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH:22]([CH3:23])[CH3:24])[C:17]([OH:19])=[O:18])[C:10](=[O:25])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)C(C(C)C)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Agent: [Li+]
Agent: [OH-]
Product: COc1cn(C(C(=O)O)C(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
3.70 g (9.52 mmol) of ethyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-methylbutanoate (racemate) were hydrolysed with lithium hydroxide according to General Method 6B. Yield: 2.80 g (82% of theory)
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([C:16](=O)[CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:12][CH:11]=2)[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[CH:2]1.O.[NH2:24][NH2:25]>C(O)C>[N:1]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:17][CH2:18][C:19](=[O:21])[NH:24][N:25]=3)=[CH:12][CH:11]=2)[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)CCC(=O)c1ccc(-n2cnc3c2CCCC3)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=C1CCC(c2ccc(-n3cnc4c3CCCC4)cc2)=NN1
Yield: 50.7 %

Procedure:
A mixture of 9 g of 4-(4,5,6,7-tetrahydro-1H-benzimidazol-1-yl)-γ-oxobenzenebutanoic acid and 3.5 g of hydrazine hydrate in 80 ml of ethanol is heated under reflux for six hours. The reaction mixture is allowed to cool and filtered. The crude product is finally crystallized from 2-methoxyethanol to yield 4.5 g of the product 4,5-dihydro-6-[4-(4,5,6,7-tetrahydro-1H-benzimidazol-1-yl)phenyl]-3(2H)-pyridazinone, mp 296°-297° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9](O[Si](C(C)(C)C)(C)C)[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[N:27]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[NH2:32][C:28]1[N:27]=[C:26]2[C:31]([C:9]([C:10]3[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=3)=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:25]2)=[CH:30][CH:29]=1
Reactant: Nc1cccc(N)n1
Reactant: CC(C)(C)[Si](C)(C)OC(C(=O)c1ccc(F)cc1)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Temperature: 135 °C
Reaction time: 1 h

Procedure:
1-(4-Fluorophenyl)-2-t-butyldimethylsiloxy-2-(4-pyridyl)ethanone (16) (3.45 g, 10.0 mmol), 2,6-diaminopyridine (1.09 g, 10.0 mmol), p-toluenesulfonic acid monohydrate (13.3 g, 70.0 mmol), and xylene (140 mL) were warmed to 60° C. under argon (note: all condensation reactions of this type were conducted behind an explosion shield). After 1 h at 60° C., the reaction was warmed to 135° C. for 3 h. After allowing the reaction to cool to 23° C., the top layer of xylene and p-toluenesulfonic acid was decanted from the bottom layer of gummy product residue. The lower product layer was partitioned between saturated bicarbonate (100 mL), and ethyl acetate (250 mL). The ethyl acetate layer was washed with brine (1×100 mL), and dried (Na2SO4). After concentration in vacuo, the residue was purified by applying flash chromatography (2 liters of ethyl acetate:hexane 7:3 followed by 100% ethyl acetate) to afford the cleanly separated regioisomer (17): Mass Spectrum (CI) 305 (MH+).
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]CCCCCCC.[SH:21]C(O)CCCCCCCCCC.C(O)C>C(Cl)(Cl)Cl>[SH:21][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:20]
Reactant: CCCCCCCCCCC(O)S
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: OCCCCCCCCCCCS

Procedure:
Five (5) mg of the oleic acid-stabilized CdSe quantum dots and 50 mg of 1-mercapto-1-undecanol were mixed with 5 ml of chloroform and 5 ml of ethanol. The mixture was then sonicated for 3 hours. Then, 40 ml of chloroform was added to the mixture to obtain a precipitate of 11-mercapto-1-undecanol capped CdSe quantum dots. The precipitate was dissolved in ethanol and dimethyl sulfoxide (“DMSO”).
Reaction SMILES: [CH2:1]([N:7]1[CH:11]=[C:10]([CH2:12][CH2:13][CH3:14])[N:9]=[N:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[I:15][CH3:16]>>[I-:15].[CH2:1]([N:7]1[CH:11]=[C:10]([CH2:12][CH2:13][CH3:14])[N+:9]([CH3:16])=[N:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCn1cc(CCC)nn1
Reactant: CI
Product: CCCCCCn1cc(CCC)[n+](C)n1
Product: [I-]
Temperature: 40 °C

Procedure:
1-hexyl-4-propyl-1H-1,2,3-triazole and excess iodomethane were added to a 20 mL vial. The reaction was heated at 40° C. for 3 days. The iodomethane was allowed to evaporate in the hood. The following structure of 1-hexyl-3-methyl-4-propyl-1H-1,2,3-triazol-3-ium iodide was confirmed:
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[CH2:11][C:12]([CH3:16])(C)[CH2:13]I.[OH-].[K+].[CH3:19]S(C)=O>>[CH3:11][C:12]1([CH3:16])[CH2:13][CH2:19][C:7]1([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]#[N:9]
Reactant: CC(C)(CI)CI
Reactant: N#CCc1ccccc1
Reactant: CS(C)=O
Agent: [K+]
Agent: [OH-]
Product: CC1(C)CCC1(C#N)c1ccccc1
Reaction time: 8 h

Procedure:
A mixture of phenylacetonitrile (47.4 g) and 1,3-diiodo-2,2-dimethylpropane (131.2 g) was added dropwise over 2 hours at 25° C. to a stirred solution of powdered potassium hydroxide (90.7 g) in dry dimethylsulphoxide (600 ml) under a nitrogen atmosphere. The mixture was stirred overnight then poured onto water and extracted with ether (1000 ml). The extracts were decolourised with charcoal, filtered and concentrated in vacuo to yield an orange-brown oil which was distilled under vacuum to give 2,2-dimethyl-1-phenylcyclobutane carbonitrile, (b.p. 101°-106° C./0.6mbar) as a pale yellow oil.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]([N:8]2[CH2:13][CH2:12][N:11]3[C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][C:24]([NH:27][C@@H:28]([CH2:37][S:38][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[CH2:29][CH2:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[C:23]([S:45]([C:48]([F:51])([F:50])[F:49])(=[O:47])=[O:46])[CH:22]=4)(=[O:20])=[O:19])=[N:15][N:16]=[C:10]3[CH2:9]2)[CH2:3][CH2:2]1.[Cl:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[C:60]([CH:65]=O)=[CH:61][CH:62]=[CH:63][CH:64]=2)=[CH:55][CH:54]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:52][C:53]1[CH:54]=[CH:55][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[CH2:65][N:1]2[CH2:7][CH2:6][CH2:5][CH:4]([N:8]3[CH2:13][CH2:12][N:11]4[C:14]([NH:17][S:18]([C:21]5[CH:26]=[CH:25][C:24]([NH:27][C@@H:28]([CH2:37][S:38][C:39]6[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=6)[CH2:29][CH2:30][N:31]6[CH2:32][CH2:33][O:34][CH2:35][CH2:36]6)=[C:23]([S:45]([C:48]([F:49])([F:50])[F:51])(=[O:47])=[O:46])[CH:22]=5)(=[O:19])=[O:20])=[N:15][N:16]=[C:10]4[CH2:9]3)[CH2:3][CH2:2]2)=[CH:57][CH:58]=1
Reactant: O=Cc1ccccc1-c1ccc(Cl)cc1
Reactant: O=S(=O)(Nc1nnc2n1CCN(C1CCCNCC1)C2)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=S(=O)(Nc1nnc2n1CCN(C1CCCN(Cc3ccccc3-c3ccc(Cl)cc3)CC1)C2)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.2 %

Procedure:
To a vial containing N-(7-azepan-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-4-((R)-3-morpholin-4-yl-1-phenylsulfanylmethyl-propylamino)-3-trifluoromethanesulfonyl-benzenesulfonamide (62 mg, 0.080 mmol) and 4′-chloro-biphenyl-2-carbaldehyde (52.1 mg, 0.241 mmol) was added methanol (2.5 mL) under nitrogen. The reaction was stirred in an ice bath for 10 minutes and then acetic acid (5.51 μL, 0.096 mmol) was added. After stirring in the ice bath for an additional 15 minutes, sodium cyanoborohydride (40.3 mg, 0.642 mmol) was added. The reaction was then allowed to warm to ambient temperature and stir for 72 hours. The reaction mixture was concentrated, filtered and purified via flash chromatography on silica gel (10-50% methanol in CH2Cl2) to afford the title compound (50 mg, 64% yield).
Reaction SMILES: [Si]([O:8][C:9]1[C:17]([CH2:18]/[CH:19]=[C:20](\[CH3:32])/[CH:21]([CH2:28][CH2:29][CH2:30][Br:31])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]([O:33][CH3:34])[C:15]([CH3:35])=[C:14]2[C:10]=1[C:11](=[O:36])[O:12][CH2:13]2)(C(C)(C)C)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOCC>[OH:8][C:9]1[C:17]([CH2:18]/[CH:19]=[C:20](\[CH3:32])/[CH:21]([CH2:28][CH2:29][CH2:30][Br:31])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]([O:33][CH3:34])[C:15]([CH3:35])=[C:14]2[C:10]=1[C:11](=[O:36])[O:12][CH2:13]2
Reactant: CCOC(=O)CC(CCCBr)/C(C)=C/Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CC(CCCBr)/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.2 %

Procedure:
A solution of of ethyl (E) 6-(4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-3-(3-bromopropyl)-4-methylhex-4-enoate (1.62 g) was dissolved in THF (25 ml), cooled to 0° C., and a solution of tetrabutylammonium fluoride trihydrate (919 mg) in THF (5 ml) was added. The reaction was stirred for 15 min, diluted with ether, washed water (2X), brine, and dried. The solvent was evaporated, and the resulting oil chromatographed on silica gel (15%-20% ethyl acetate in hexanes) to give ethyl (E) 6-(1,3-dihydro-4-hydroxy-6-methoxy7-methyl-3-oxoisobenzofuran-5-yl)-3-(3-bromopropyl)-4-methylhex-4-enoate (810 mg).
Reaction SMILES: [Cl:1]Cl.BrBr.[CH2:5]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:12][N:11]=1)[CH2:6][CH2:7][CH2:8][CH3:9]>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:18]1[S:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[N:11][CH:12]=2)=[CH:20][CH:19]=1
Reactant: ClCl
Reactant: CCCCCc1ccc(-c2cccs2)cn1
Agent: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCc1ccc(-c2ccc(Cl)s2)cn1
Reaction time: 1 h

Procedure:
7.3 g of chlorine are passed in, or 17 g of bromine are added dropwise, with stirring, to a solution of 23.1 g of 2-(2-pentyl-5-pyridyl)-thiophene in 40 ml of CCl4 at 20°. After the mixture has been left to stand for 1 hour, it is warned at 50° for 2 hours, washed with dilute sodium hydroxide solution and worked up in the customary manner to give 5-chloro-2-(2-pentyl-5-pyridyl)-thiophene, m.p. 32°, c.p. 18° (or 5-bromo-2-(2-pentyl-5-pyridyl)-thiophene).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1.C(N(C(C)C)CC)(C)C>ClC(Cl)C>[C:20]([O:19][C:17]([N:13]1[CH2:14][CH2:15][CH2:16][C@H:11]([NH:10][C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=2)[CH2:12]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC[C@H](Nc2nc(Cl)ncc2Br)C1

Procedure:
A solution 5-bromo-2,4-dichloro-pyrimidine 4 g, 17.6 mmol), (S)-tert-butyl 3-aminopiperidine-1-carboxylate (3.6 g, 17.6 mmol) and diisopropylethylamine (3.1 ml, 18 mmol) in dichloroethane (200 ml) was warmed to 40-50° C. for 16 hours. The reaction was cooled and washed with water, dried (MgSO4), and filtered. The oil was purified by silica gel chromatography (10-25% ethyl acetate/hexane) to give (S)-3-(5-bromo-2-chloro-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester as an oil that was taken to the next step. The oil was diluted with dichloromethane (100 ml) cooled to 5° C. and treated with trifluoroacetic acid (40 ml). After stirring at room temperature for 5 hours, all solvent was evaporated. The residue was dissolved in chloroform (150 ml) and washed with cold dilute aqueous sodium carbonate. The organics were dried (MgSO4) and evaporated to give an oil that solidified on standing in ether/hexane to give 3.5 g (68%) of (5-bromo-2-chloro-pyrimidin-4-yl)-(S)-piperidin-3-yl-amine as a solid. 1H NMR (300 MHz), dmso-d) δ ppm, 8.23 (s, 1H), 7.17 (s, 1H), 3.99 (m, 1H).
Reaction SMILES: [Li]CCCC.[Br:6][C:7]1[CH:12]=[C:11]([CH:13]([O:16][CH3:17])[O:14][CH3:15])[CH:10]=[C:9](Br)[CH:8]=1.B(OC)(OC)[O:20]C>C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]([OH:20])[CH:10]=[C:11]([CH:13]([O:16][CH3:17])[O:14][CH3:15])[CH:12]=1
Reactant: COC(OC)c1cc(Br)cc(Br)c1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(OC)c1cc(O)cc(Br)c1
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 45.4 %

Procedure:
To a stirring solution of 23 mL of n-BuLi (1.6 M in hexanes) in 20 mL of THF at −78° C. was added 5.31 g of 1,3-dibromo-5-(dimethoxymethyl)benzene in 80 mL of THF dropwise over a period of about 55 min. After 50 min., 3.2 mL (28.7 mmol) of B(OMe)3 was added, and the solution was stirred at −78° C. for 20 min. The cold bath was removed and stirring continued with gradual warming to r.t. After 1 h, 1 N HCl (45 mL) was added, and the aqueous layer was extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, filtered, and concentrated. To a stirring mixture of crude product in 70 mL of 1N NaOH at 0° C. was added 14.5 mL of H2O2 (30 wt % in H2O) dropwise. After 25 min., 5 N HCl was added to a pH=1, and EtOAc and H2O were added. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (15% EtOAc/hexanes) provided 1.92 g of 3-bromo-5-(dimethoxymethyl)phenol as a pale yellow solid with some impurity.
Reaction SMILES: O.[NH2:2]N.[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=O)[CH:12]=[CH:13][N:14](C)C>C(O)C>[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][NH:14][N:2]=1
Reactant: NN
Reactant: CN(C)C=CC(=O)c1ccccc1Cl
Solvent: O
Solvent: CCO
Product: Clc1ccccc1-c1cc[nH]n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.2 %

Procedure:
7 g (0.0540 mol) of hydrazine hydrate are added, slowly and at room temperature, to a solution of 10.5 g (0.050 mol) of 1-(2-chlorophenyl)-3-dimethylamino-2-propen-1-one, prepared in Example 1, in 60 ml of ethanol. The reaction mixture is stirred for 5 hours at room temperature then left standing for 12 hours before being concentrated to dryness. The residue is recrystallised from a heptane/ethyl acetate mixture. 6.9 g (0.0386 mol) of 3-(2'-chlorophenyl)-1H-pyrazole are obtained, which melts at 93° C. (yield 77%) (compound 60).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:24])=[C:7]([C:15]([C:17]2[CH:18]=[N:19][N:20]([CH3:23])[C:21]=2[OH:22])=[O:16])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])=[O:4].C(N(CC)CC)C.[CH3:32][CH2:33][S:34][C:35](Cl)=[O:36]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:24])=[C:7]([C:15]([C:17]2[CH:18]=[N:19][N:20]([CH3:23])[C:21]=2[O:22][C:35]([S:34][CH2:33][CH3:32])=[O:36])=[O:16])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])=[O:4]
Reactant: CCSC(=O)Cl
Reactant: COC(=O)c1c(S(C)(=O)=O)ccc(C(=O)c2cnn(C)c2O)c1C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCSC(=O)Oc1c(C(=O)c2ccc(S(C)(=O)=O)c(C(=O)OC)c2C)cnn1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.1 %

Procedure:
5-Hydroxy-1-methylpyrazol-4-yl 3-(methoxycarbonyl)-2-methyl-4-(methylsulfonyl)phenyl ketone (290 mg, 0.82 mmol) was dissolved in dry tetrahydrofuran (15 mL), and triethylamine (166 mg, 1.64 mmol) was added thereto. A solution (4 mL) of 96% S-ethyl chlorothiolformate (107 mg) dissolved in dry tetrahydrofuran was added thereto little by little under cooling with ice water. The reaction mixture was stirred for 90 minutes while the reaction temperature was allowed to warm to room temperature. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:4) to obtain the desired product as an amorphous solid (202 mg, 0.46 mmol) (yield: 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[NH2:20][C:21]1[N:30]=[C:29]([NH:31][C@H:32]2[CH2:37][CH2:36][CH2:35][CH2:34][C@H:33]2[NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:46][CH3:47])[CH:27]=2)[N:22]=1.O>C(Cl)Cl>[C:42]([O:41][C:39]([NH:38][C@@H:33]1[CH2:34][CH2:35][CH2:36][CH2:37][C@@H:32]1[NH:31][C:29]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:46][CH3:47])[CH:27]=2)[N:22]=[C:21]([NH:20][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:30]=1)=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: COc1ccc2nc(N)nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c2c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2nc(NC(=O)c3ccc(Cl)cc3)nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 58.9 %

Procedure:
A solution of 68 mg of 4-chlorobenzoyl chloride and 200 mg of diisopropylethylamine in 8 mL of methylene chloride was combined with 150 mg of cis-2-(2-amino-6-methoxyquinazolin-4-yl)amino-N-tert-butoxycarbonylcyclohexylamine, and stirred at room temperature for 15 hours. The reaction solution was combined with water, extracted with chloroform, and dried. After the solvent was distilled off, the residue was purified by column chromatography on silica gel (chloroform:methanol=30:1) to obtain 120 mg of the desirable compound.
Reaction SMILES: CO[C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:22][C:3]([C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9][CH:8]=[CH:7][N:6]=2)=[O:4])[CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1nccnc1Nc1ccccc1
Reactant: Nc1cccc(Cl)c1
Product: O=C(Nc1cccc(Cl)c1)c1nccnc1Nc1ccccc1

Procedure:
The title compound, MS: m/e=325.1 (M+H+), was prepared in accordance with the general method of example 1, step 2 from 3-phenylamino-pyrazine-2-carboxylic acid methyl ester and 3-chloroaniline.