Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][Si:7]([CH3:10])([CH3:9])[CH3:8])=[O:3].C([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH:20]([O:31][CH2:32][C:33]2[CH:42]=[C:41]([O:43][CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=2)[CH2:19]1)C1C=CC=CC=1>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH:21]2[CH2:22][CH2:23][N:18]([C:2]([O:4][CH2:5][CH2:6][Si:7]([CH3:10])([CH3:9])[CH3:8])=[O:3])[CH2:19][CH:20]2[O:31][CH2:32][C:33]2[CH:42]=[C:41]([O:43][CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=2)=[CH:25][CH:26]=1
Reactant: C[Si](C)(C)CCOC(=O)Cl
Reactant: C[Si](C)(C)CCOCOc1cc(COC2CN(Cc3ccccc3)CCC2c2ccc(F)cc2)cc2ccccc12
Product: C[Si](C)(C)CCOCOc1cc(COC2CN(C(=O)OCC[Si](C)(C)C)CCC2c2ccc(F)cc2)cc2ccccc12

Procedure:
In an analogous manner to that described in Example 1(d) by cleavage of the benzyl group by means of β-trimethylsilylethyl chloroformate from (3RS,4RS)-1-benzyl-4-(4-fluoro-phenyl)-3-[4-(2-trimethylsilyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine there was obtained β-trimethylsilylethyl (3RS,4RS)-4-(4-fluorophenyl)-3-[4-(2-trimethylsilyl-ethoxymethoxy)-naphthalen-2-yl-methoxy]-piperidine-1-carboxylate as a light yellow oil; MS: 626 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][C:21]([F:24])([F:23])[F:22])[NH2:16]>>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:17]=[CH:18][C:19]([O:20][C:21]([F:22])([F:23])[F:24])=[C:13]([F:12])[CH:14]=1)=[O:9]
Reactant: Nc1ccc(OC(F)(F)F)c(F)c1
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(Cl)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 185.2 using 5-bromo-6-chloro-nicotinic acid and 3-fluoro-4-trifluoromethoxy-aniline to afford an off-white crystalline solid. HPLC (Condition 4) tR=6.43 min, UPLC-MS (Condition 3) tR=1.29 min, m/z=413 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2Cl.Cl.Cl.[CH3:17][N:18]([CH3:26])[C@H:19]1[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:25][C@H:22]1[CH2:23][CH2:24][C@H:19]([N:18]([CH3:26])[CH3:17])[CH2:20][CH2:21]1
Reactant: N#Cc1cnc2ccc(Br)cc2c1Cl
Reactant: CN(C)[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: CN(C)[C@H]1CC[C@H](Nc2c(C#N)cnc3ccc(Br)cc23)CC1

Procedure:
Following general procedure C, 6-bromo-4-chloroquinoline-3-carbonitrile (262 mg, 0.98 mmol) was reacted with trans-N1,N1-dimethylcyclohexane-1,4-diamine dihydrochloride (422 mg, 1.96 mmol) to afford the desired product (56 mg, 15%) as a yellow solid. ESI MS m/z 373 [C18H21BrN4+H]+
Reaction SMILES: [OH:1][C@:2]1([C@@H:17]2[CH2:21][S:20][C:19](=[O:22])[N:18]2[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH2:7][C@@H:6]([OH:8])[CH2:5][C@@H:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:3]1.O[C@:33]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@@H](O)C[C@@H](CCCC=C)O1>>[OH:8][C@H:6]1[CH2:5][C@@H:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:3][C@:2]([C@@H:17]2[CH2:21][S:20][C:19](=[O:22])[N:18]2[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)([O:1][CH3:33])[CH2:7]1
Reactant: C=CCCC[C@@H]1C[C@H](O)C[C@](O)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Reactant: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(O)C[C@@H](O)C[C@@H](CCc3ccccc3)O2)cc1
Product: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@@H](O)C[C@@H](CCc3ccccc3)O2)cc1

Procedure:
Application of the method shown in Example 13, with the modification that (R)-4-((2R,4S,6R)-2,4-dihydroxy-6-phenethyl-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one is substituted for (R)-4-((2R,4S,6R)-2,4-dihydroxy-6-(pent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, affords the title compound.
Reaction SMILES: [C:1]([CH:4]([C:10](=O)[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2].[CH3:13][Mg]Br.C(OC(=O)C)(=O)C>CCOCC>[C:10](=[C:4]([C:1]([CH3:2])=[O:3])[C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:11])[CH3:13]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: C[Mg]Br
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CCOC(=O)C(C(C)=O)=C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 63 %

Procedure:
To a solution of ethyl diacetyl-acetate maintained at 5°-10° [which can be prepared according to the method described in Helv. Chim. Acta, 35, 2280 (1952)] in 400 ml of anhydrous ether there were added 110 ml (0.33 mole) of a solution of 3 M methyl-magnesium bromide in ether. The reaction mixture was stirred for 24 hours at room temperature. After cooling, 50 ml of acetic acid anhydride were added and the whole was allowed to stand for 2 hours at room temperature, whereupon it was poured into ice-water. After separation, the organic phase was washed with a 5 % aqueous solution of NaOH, then with water, whereupon it was dried (Na2SO4) and concentrated. The subsequent distillation of the residue yielded 16.1 g (63 %) of ethyl α-isopropylidene-acetoacetate, b.p. 94°-98° /8 Torr. A pure sample was obtained by purification of the said product by chromatography on a colum (silica gel and benzene) followed by vapour phase chromatography.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[C:39]1(B(O)O)[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]=1>>[NH2:30][C:29]1[S:28][C:27]([CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH2:8])[CH2:11][CH2:12]1)=[O:24]
Reactant: OB(O)C1=CCCCC1
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Product: Cn1ncc(NC(=O)c2nc(C3CCCCC3)sc2N)c1N1CCC(CN)CC1
Yield: 51 %

Procedure:
Following the procedure for Example 281, Suzuki coupling of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and cyclohex-1-ene-1-boronic acid gave 282 (44 mg, 51% over three steps). 1H NMR (400 MHz, d4-MeOD) δ 7.45 (s, 1H), 3.71 (s, 3H), 3.21-3.08 (m, 4H), 2.85-2.76 (m, 1H), 2.64 (d, J=6.6 Hz, 2H), 2.09 (d, J=12.1 Hz, 2H), 1.90-1.81 (m, 4H), 1.76 (d, J=13.0 Hz, 1H), 1.59-1.25 (m, 8H). LCMS (ES+) m/z 418 (M+1)
Reaction SMILES: [ClH:1].[C:2]1([CH:8]([N:10]2[C:14]([CH2:15]O)=[CH:13][N:12]=[CH:11]2)[CH3:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>CC(O)C>[ClH:19].[Cl:1][CH2:15][C:14]1[N:10]([CH:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:9])[CH:11]=[N:12][CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: CC(c1ccccc1)n1cncc1CO
Agent: Cl
Solvent: CC(C)O
Product: CC(c1ccccc1)n1cncc1CCl

Procedure:
3 Parts of 1-(1-phenylethyl)-1H-imidazole-5-methanol monohydrochloride were added portionwise to 16 parts of thionyl chloride (exothermic reaction with evolution of SO2 /HCl). After the addition was complete, the whole was stirred and refluxed for 30 minutes. After cooling there were added 40 parts of 2-propanol, whereupon a solid was precipitated. It was filtered off and recrystallized from a mixture of 60 parts of 2-propanol and 60 parts of 2,2'-oxybispropane, yielding 1.5 parts of 5-(chloromethyl)-1-(1-phenylethyl)-1H-imidazole monohydrochloride; mp. 173.5-175° C. (dec.) (compound 8.49).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].C(=O)([O-])[O-].[Ca+2].[CH2:10]([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl.O>[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]([N:22]=[C:1]=[S:2])=[CH:23][CH:24]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClCCl
Product: S=C=Nc1ccc(OCc2ccccc2)cc1
Temperature: 15 °C
Reaction time: 4 h

Procedure:
Thiophosgene (12.63 g) was added at 0° C. to a stirred suspension of calcium carbonate (11.05 g) in a mixture of dichloromethane (100 ml) and water (100 ml). A solution of p-benzyloxyaniline (16.5 g) in dichloromethane (100 ml) was added dropwise at 0° C. over 30 minutes. The mixture was stirred for four hours at 15° C. The organic layer was separated, dried and the solvent removed by evaporation to give a residue which was extracted into boiling hexane to give 4-benzyloxyphenylisothiocyanate (m.p. 69° C.).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:19][C:20](=[O:46])[CH:21]([N:25]([C:27](=[O:45])[CH:28]([NH:37]C(OCCCC)=O)[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH3:26])[CH:22]([CH3:24])[CH3:23])[C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:19][C:20](=[O:46])[CH:21]([N:25]([C:27](=[O:45])[CH:28]([NH2:37])[CH2:29][C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[CH3:26])[CH:22]([CH3:24])[CH3:23])[C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCCOC(=O)NC(Cc1ccc(F)cc1)C(=O)N(C)C(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1nccs1)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1nccs1)N(C)C(=O)C(N)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34 %

Procedure:
To a solution of 2-((2-butoxycarbonylamino-3-(4-fluorophenyl)propionyl)-N-methylamino)-3-methylbutyric acid 2-(3-tert-butyl-4-hydroxyphenyl)-1-(thiazol-2-yl)ethylamide (A) (1.49 g, 2.28 mmol) in methylene chloride (20 ml), TFA (10 ml) was added and stirred at room temperature for 1.5 hours. The reaction mixture was evaporated to remove the solvent under reduced pressure; the thus obtained residue was mixed with methylene chloride, washed with a 2N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure. The thus obtained residue was subjected to silica gel column chromatography (developing solvent: methanol:aqueous ammonia:methylene chloride=3:0.1:100), giving the titled compound (430 mg).
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:9][CH3:10])[NH:5][CH2:6][CH2:7][SH:8])#[N:2].[H-].[Na+].Cl[CH2:14][C:15]1[O:19][C:18]([CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[CH:17][CH:16]=1>CN(C)C=O>[C:1]([N:3]=[C:4]([NH:9][CH3:10])[NH:5][CH2:6][CH2:7][S:8][CH2:14][C:15]1[O:19][C:18]([CH2:20][N:21]2[C:22](=[O:31])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]2=[O:30])=[CH:17][CH:16]=1)#[N:2]
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(CCl)o1
Reactant: CNC(=NC#N)NCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=NC#N)NCCSCc1ccc(CN2C(=O)c3ccccc3C2=O)o1
Reaction time: 2 h
Yield: 55.8 %

Procedure:
To a stirred solution of N"-cyano-N-(2-mercaptoethyl)- N'-methylguanidine (1.0 g) and sodium hydride (0.152 g ) in dry dimethylformamide (4 ml) at room temperature was added slowly a solution of 2-(5-chloromethyl-2-furanylmethyl)-1H- isoindole-1,3(2H)-dione (1.74 g) in dry dimethylformamide (8 ml). After stirring for 2 hr in the solution was evaporated to dryness and the oily residue suspended in an ethyl acetate (25 ml)-water (20 ml) mixture. The solid residue was filtered and crystallised from methanol to give the title compound (1.4 g) m.p. 179°-182°.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])OC(C)(C)C)[CH2:4][CH2:3]1.[C:16](OC(=O)C(C)C)(=O)[CH:17](C)[CH3:18].[ClH:27].O1CCOCC1>C(Cl)Cl>[ClH:27].[NH2:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9](=[O:15])[CH:17]([CH3:18])[CH3:16])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CC(C)C(=O)OC(=O)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)C(=O)N[C@H]1CC[C@@H](N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl cis-4-aminocyclohexylcarbamate (500 mg, 2.333 mmol) in DCM (20 mL) was added isobutyric anhydride (0.407 mL, 2.450 mmol). The solution was stirred overnight at RT. After 16 hours, 4 M HCl in dioxane (2.333 mL, 9.33 mmol) was added, and the reaction was stirred at RT overnight. The resulting white precipitate was collected by vacuum filtration and dried in vacuo to generate N-(cis-4-aminocyclohexyl)isobutyramide hydrochloride as an off-white powder (508 mg, 99% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8](Cl)[N:7]=1.[NH3:15].C(O)C>S([O-])([O-])(=O)=O.[Cu+2].CCOCC>[CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([NH2:15])[N:7]=1
Reactant: N
Reactant: Cc1cc(Cl)nc(NCCN(C)C)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCOCC
Solvent: CCO
Product: Cc1cc(N)nc(NCCN(C)C)c1

Procedure:
A mixture of 2-(2-dimethylaminoethylamino)-4-methyl-6-chloropyridine (from Example 77, Part A) (21.4 g., 0.1 mole), liquid ammonia (85 g) and copper sulfate catalyst (1.0 g) in 150 ml. ethanol is heated at 200° C. for 48 hours in a pressure vessel. The cooled reaction mixture is filtered and concentrated in vacuo. The residual oil is dissolved in 125 ml of chloroform, washed with excess sodium hydroxide and then with saturated sodium chloride solution, dried, filtered and concentrated in vacuo. The 16.0 g. of crude oil obtained is taken up in 100 ml of ether, filtered and extracted into dilute hydrochoric acid. The acidic extract is made basic and the product is extracted into ether. After drying and removing the ether in vacuo, the product (8.0 g.) is distilled. Purified material is collected at 125°-128° C. at 0.4 mm.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:6]=2[C:33]=1[Cl:34].[CH3:35][N:36]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[N:37]1>>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([S:20]([N:7]2[C:6]3[C:33]([Cl:34])=[C:2]([C:39]4[CH:38]=[N:37][N:36]([CH3:35])[CH:40]=4)[CH:3]=[CH:4][C:5]=3[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:9]=3[CH2:8]2)(=[O:22])=[O:21])=[CH:24][CH:25]=1)([CH3:31])([CH3:30])[CH3:32]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(Br)c(Cl)c32)cc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cn1cc(-c2ccc3c(c2Cl)N(S(=O)(=O)c2ccc(C(C)(C)C)cc2)Cc2ccc(C(F)(F)F)nc2N3)cn1

Procedure:
The title compound was prepared from 8-bromo-6-[(4-tert-butylphenyl)sulfonyl]-7-chloro-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (intermediate 64) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole according to the procedure of Example 495. Racemic mixture: LC/MS: m/e 576.1 (M+H)+; 1H NMR (500 MHz, CD3OD): δ 8.05 (1H, s), 7.80 (1H, s), 7.58 (1H, d), 7.41 (2H, d), 7.10 (3H, m), 7.05 (1H, d), 7.00-7.10 (2H, d), 5.19 (1H, d), 5.55 (1H, d), 3.96 (3H, s), 1.26 (9H, s). The racemic mixture was separated on a Chiracel OD-H column eluting with 20% EtOH in hexanes at 8.0 mL/min. The faster eluting enantiomer E1 had a retention time of 40 min. The slower eluting enantiomer E2 had a retention time of 50 min.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:4]1.[Cl:22][S:23](O)(=[O:25])=[O:24]>>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([S:23]([Cl:22])(=[O:25])=[O:24])=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]([C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])[CH2:4]1
Reactant: O=C(N1CC(CCl)c2c1ccc1ccccc21)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Product: O=C(N1CC(CCl)c2c1ccc1cc(S(=O)(=O)Cl)ccc21)C(F)(F)F
Temperature: 60 °C
Yield: 25.2 %

Procedure:
Solid 108 (1.6 g, 5.1 mmol) was gradually added to chlorosulfonic acid (6.0 mL, 90 mmol) with ice bath cooling. The mixture was then heated to 60° C. for 2 h, and the reaction was quenched by pouring slowly, with stirring, into ice-water. The precipitated solid was collected, washed with water, dried and chromatographed on silica gel. Elution with EtOAc/petroleum ether (from 1:4 to 1:1) gave 1-(chloromethyl)-3-(trifluoroacetyl)-1,2-dihydro-3H-benzo[e]indole-7-sulfonyl chloride (113) (0.53 g, 25%) as a pale yellow solid: mp (EtOAc/petroleum ether) 189-192° C.; 1H NMR (CDCl3) δ 8.70-8.64 (m, 2H), 8.13-8.08 (m, 2H), 8.00 (d, J=9.0 Hz, 1H), 4.72-4.68 (m, 1H), 4.55-4.48 (m, 1H), 4.33-4.25 (m, 1H), 3.98-3.93 (m, 1H), 3.68-3.61 (m, 1H), 13C NMR δ 154.9 (q, JC-F 38.4 Hz), 143.9, 140.7, 132.7, 131.8, 130.1, 130.0, 125.8, 124.8, 123.2, 119.6, 115.9 (q, JC-F 288 Hz), 52.8, 45.4, 42.4. Anal. (C15H10Cl2F3NO3S) C, H, N, Cl.
Reaction SMILES: [CH3:1][C:2]1[N: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>C(O)(=O)C.C(O)C.[Pt](=O)=O>[CH3:1][CH:2]1[NH:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cn1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCO
Product: CC1CCC(NC(=O)OC(C)(C)C)CN1
Temperature: 25 °C
Reaction time: 9 h
Yield: 86.7 %

Procedure:
To a solution of tert-butyl (6-methylpyridin-3-yl)carbamate (9.00 g) in a mixture of acetic acid-ethanol (1:1, 100 ml) was added platinum (IV) oxide (900 mg), and the mixture was stirred under hydrogen pressure (0.4 MPa) at room temperature for 9 hours. To the mixture was further added platinum (IV) oxide (2.0 g), and the mixture was stirred for 10 hours. The reaction mixture was filtered on celite, and thereto was added toluene. The mixture was concentrated under reduced pressure, and to the residue was added a 5% aqueous potassium carbonates solution. The mixture was extracted with chloroform, and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude product (8.03 g) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O-:2].[Na+].[NH:4]([C:11]1[N:16]=[C:15](Cl)[CH:14]=[C:13]([CH3:18])[N:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO.O>[NH:4]([C:11]1[N:12]=[C:13]([CH3:18])[CH:14]=[C:15]([O:2][CH3:1])[N:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1cc(Cl)nc(Nc2ccccc2)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(C)nc(Nc2ccccc2)n1
Temperature: 25 °C
Yield: 92 %

Procedure:
2.9 g of 28% methanolic solution of sodium methylate was dissolved in 40 ml of methanol, and thereto was added 3.3 g of 2-anilino-4-chloro-6-methylpyrimidine. After 2 hours of reaction with stirring at room temperature the reaction liquid was poured in water The solids deposited were filtered, dried, and recrystallized from n-hexane to afford 2 9 g of 2-anilino-4-methyl-6-methoxypyrimidine (yield 92 %). Melting point: 75°-76° C.
Reaction SMILES: [C:1]([N:8]([C:25]([O:27]C(C)(C)C)=O)[C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3[Cl:23])[CH:11]=[CH:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:32](OC(=O)NC(=O)CC)(C)(C)[CH3:33]>>[C:4]([O:3][C:1](=[O:2])[N:8]([C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3[Cl:23])[CH:11]=[CH:10]1)[C:25](=[O:27])[CH2:32][CH3:33])([CH3:5])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Reactant: CCC(=O)NC(=O)OC(C)(C)C
Product: CCC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1

Procedure:
The title compound is prepared analogously to di-Boc-[(1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl]-amine by replacing di-t-butyliminodicarboxylate with propionyl-carbamic acid tert-butyl ester.
Reaction SMILES: C[O:2][C:3]1[CH:23]=[CH:22][C:6]2[C:7]([CH:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)[C:11]#[N:12])=[N:8][O:9][C:5]=2[CH:4]=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:23]=[CH:22][C:6]2[C:7]([CH:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[C:11]#[N:12])=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc(CC(C#N)c2noc3cc(OC)ccc23)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: N#CC(Cc1ccc(O)cc1)c1noc2cc(O)ccc12
Yield: 61.9 %

Procedure:
To a solution of 2-(6-methoxy-1,2-benzisoxazol-3-yl)-3-(4-methoxyphenyl)propanenitrile (1.5 g, 4.9 mmoles) in CH2Cl2 (100 ml) under N2, was added BBr3 1M in CH2Cl2 (4 eq, 20 ml). The mixture was refluxed for 2 h, poured into water and extracted with EtOAc, dried over Na2SO4, filtered and concentrated under vacuum to give the crude product. Purification by flash chromatography (CH2Cl2/MeOH 98/2) and crystallisation from EtOH yielded the expected crystals (850 mg, 62%). mp 214° C.
Reaction SMILES: F[C:2]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:5].[CH3:21]C1C=C(C=CC=1[N+]([O-])=O)C(O)=O>>[CH3:21][C:17]1[CH:2]=[C:3]([CH:14]=[CH:15][C:16]=1[N+:18]([O-:20])=[O:19])[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:5]
Reactant: CN1CCC(NC(=O)c2ccc([N+](=O)[O-])cc2F)CC1
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Product: Cc1cc(C(=O)NC2CCN(C)CC2)ccc1[N+](=O)[O-]

Procedure:
3-methyl-N-(1-methyl-4-piperidyl)-4-nitro-benzamide was prepared in a manner analogous to Intermediate 62 utilising 3-Methyl-4-nitrobenzoic acid, available form Aldrich, as the starting Nitro acid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22]O)[CH:17]=2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:25]([N:27](CC)CC)C.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[C-]#N.[Na+]>CN(C=O)C.N1C=CC=CC=1>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:25]#[N:27])[CH:17]=2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(N)c2ncn(Cc3cccc(CO)c3)c2n1
Reactant: CCN(CC)CC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCCCOc1nc(N)c2ncn(Cc3cccc(CC#N)c3)c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.4 %

Procedure:
2-Butoxy-9-(3-hydroxymethylbenzyl)adenine (0.09 g, 0.27 mmol), triethylamine (0.20 g, 1.98 mmol), tosyl chloride (0.30 g, 1.57 mmol) and pyridine (0.4 ml) were added to DMF (10 ml), and the mixture was stirred at room temperature for 24 hours. To the reaction mixture was added sodium cyanide (0.40 g, 9.16 mmol), and the mixture was stirred at 80° C. for 18 hours. After removing the solvent, the residue was poured into water and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, concentrated and the residue was purified by column chromatography (SiO2 20 g, eluting solvent: CHCl3/MeOH=100/1) to give 2-butoxy-9-(3-cyanomethylbenzyl)adenine (0.04 g, 0.12 mmol, yield: 44%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH2:13]([N:15](CC)[CH2:16]C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CNC.O1CCCC1>C(#N)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([N:15]([CH3:16])[CH3:13])=[O:8]
Reactant: COc1ncc(Br)cc1C(=O)O
Reactant: CCN(CC)CC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1ncc(Br)cc1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 5-bromo-2-methoxynicotinic acid (80 mg, 0.34 mmol), triethylamine (192 μl, 1.38 mmol) and 2-(1 H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate in acetonitrile (1 mL) was added dimethylamine, 2 M in tetrahydrofuran (172 μl, 0.34 mmol). The reaction mixture was stirred at ambient temperature under an atmosphere of nitrogen for 3 h. The mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give a crude product which was purified by column chromatography using a gradient of ethyl acetate in heptane affording 54 mg (60%) of the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) ppm 8.36 (d, 1 H), 7.91 (d, 1 H), 3.88 (s, 3 H), 2.96 (s, 3 H), 2.78 (s, 3 H); MS (ESI) m/z 259, 261[M+H+].