Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[N:10][NH:11][C:12]2=[O:15])=[CH:7][CH:6]=1.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([NH:21][CH2:16][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[N:10][NH:11][C:12]2=[O:15])=[CH:7][CH:6]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)N
Reactant: O=c1[nH]ncc2ccc(OCC3CO3)cc12
Product: CC(C)(C)NCC(O)COc1ccc2cn[nH]c(=O)c2c1

Procedure:
7-(2,3-Epoxypropoxy)-1(2H)-phthalazinone was reacted with t-butylamine in a similar manner to that described in Example 1(iv) to give 7-(3-t-butylamino-2-hydroxypropoxy)-1(2H)-phthalazinone, the hydrochloride of which was recrystallised from ethanol and had m.p. 263°-264° (decomp).
Reaction SMILES: Cl.[O:2]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([CH:25]3[CH2:30][O:29]C(C4C=CC=CC=4)[O:27][CH2:26]3)[CH:16]=2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)CC>CO>[NH2:24][C:22]1[C:23]2[C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:2][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)=[CH:10][CH:11]=3)=[CH:16][N:17]([CH:25]([CH2:26][OH:27])[CH2:30][OH:29])[C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1COC(c2ccccc2)OC1
Agent: Cl
Solvent: CO
Solvent: CCCO
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C(CO)CO

Procedure:
Dilute hydrochloric acid (45 ml of 2M solution) was added to 5-(4-phenoxyphenyl)-7-(2-phenyl-1,3-dioxan-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (170 mg) and the mixture heated to boiling under reflux. Propan-1-ol (30 ml) was added and the mixture boiled under reflux for 6 hours and then the propanol was distilled off. The mixture was evaporated under reduced pressure to give a residue which was triturated with ethyl acetate and then filtered to give a solid which was dissolved in methanol, and purified by chromatography to give 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]propan-1,3-diol. The structure was confirmed by 1H nmr and mass spectra.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([CH2:10][CH2:11][CH2:12][N:13]3[C:17](=[O:18])[CH2:16][S:15][C:14]3=[O:19])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:20](=O)[CH2:21][CH2:22][CH3:23].N1CCCCC1>C(O)C>[CH:20](=[C:16]1[S:15][C:14](=[O:19])[N:13]([CH2:12][CH2:11][CH2:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:17]1=[O:18])[CH2:21][CH2:22][CH3:23]
Reactant: O=C1CSC(=O)N1CCCc1cccc2nccn12
Reactant: CCCC=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCCc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.51 g (5.5 mmol) of 3-[3-(imidazo[1,2-a]pyridin-5-yl)propyl]thiazolidine-2,4-dione and 0.50 ml (5.5 mmol) of n-butyraldehyde in 30 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, ethyl acetate→ethyl acetate/ethanol=10/1) to yield 1.22 g (67.3%, light yellow oily substance) of the desired product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:8]=[CH:7][S:6][CH:5]=1.[C:9]([O:15][CH3:16])(=[O:14])[CH2:10][C:11]([CH3:13])=O>C(OCC)C>[S:6]1[CH:7]=[CH:8][C:4]([CH2:3][CH2:2][NH:1]/[C:11](/[CH3:13])=[CH:10]\[C:9]([O:15][CH3:16])=[O:14])=[CH:5]1
Reactant: COC(=O)CC(C)=O
Reactant: NCCc1ccsc1
Solvent: CCOCC
Product: COC(=O)/C=C(/C)NCCc1ccsc1
Yield: 97.5 %

Procedure:
3.82 grams (30 millimoles) of 3-(2-aminoethyl)thiophene was added dropwise with stirring at room temperature to 3.6 grams (31 millimoles) of methyl acetoacetate and the stirring was continued over the weekend at ambient temperature. Thereafter, the mixture was diluted with 250 milliliters of diethyl ether and the resulting ether solution washed with 50 milliliters of brine and then dried over sodium sulfate. The ether solvent was then vaporized from the dried and filtered solution to obtain 6.59 grams of a methyl 3-(3-thienylethyl)aminocrotonate intermediate as a slightly yellowish oil.
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]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH2:18]1[C:22]2([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:21][CH2:20][N:19]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>>[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]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:25]1[CH2:26][CH2:27][C:22]2([CH2:18][N:19]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:20][CH2:21]2)[CH2:23][CH2:24]1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3c(C(=O)C4CC4)cnc4ccc(Br)cc34)CC2)C1
Yield: 72.9 %

Procedure:
Following general procedure B, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (200 mg, 0.640 mmol) was reacted with tert-butyl 2,8-diazaspiro[4,5]decane-2-carboxylate (169 mg, 0.704 mmol) to afford the desired product (240 mg, 73%) as a yellow foam: ESI MS m/z 514 [C26H32BrN3O3+H]+.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH3:7][P:8]([O-:14])[O:9][CH2:10][CH:11]([CH3:13])[CH3:12]>>[CH3:7][P:8]([CH2:1][CH:2]1[O:6][C:4](=[O:5])[CH2:3]1)(=[O:14])[O:9][CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: C=C1CC(=O)O1
Reactant: CC(C)COP(C)[O-]
Product: CC(C)COP(C)(=O)CC1CC(=O)O1

Procedure:
A mixture of 4.2 parts of diketene and 0.33 parts of bis-(t-butylcyclohexyl)perdicarbonate was added dropwise over 1 hour to 27.2 parts of vigorously stirred isobutyl methylphosphonite which was heated at 85° in a nitrogen atmosphere. After the addition the reaction mixture was passed down a wiped-wall still at a temperature of 50° C. and a pressure of 0.13 mb to remove the excess phosphonite. The residue was distilled on the wiped wall still at a temperature of 75° and a pressure of 0.13 mb. The product isobutyl methyl(2-oxo-4-oxetanylmethyl)phosphinate was obtained as a colourless oil with a characteristic infra-red band at 1820 cm-1.
Reaction SMILES: [F:1][C:2]1([F:28])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=O)[NH:4][C@:3]1([CH3:27])[C:12]1[CH:13]=[C:14]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)[CH:15]=[CH:16][C:17]=1[F:18].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>O1CCOCC1>[F:1][C:2]1([F:28])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=[S:38])[NH:4][C@:3]1([CH3:27])[C:12]1[CH:13]=[C:14]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(-c3cc(F)cc(F)c3)ccc2F)C1(F)F
Solvent: C1COCCO1
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(-c3cc(F)cc(F)c3)ccc2F)C1(F)F
Yield: 107.2 %

Procedure:
The reaction of (R)-6,6-difluoro-5,7,7-trimethyl-5-(4,3′,5′-trifluoro-biphenyl-3-yl)-[1,4]oxazepan-3-one (159 mg, 398 μmol) with Lawesson's reagent (131 mg, 319 μmol) in 1,4-dioxane (13 ml) yielded the (R)-6,6-difluoro-5,7,7-trimethyl-5-(4,3′,5′-trifluoro-biphenyl-3-yl)-[1,4]oxazepan-3-thione (142 mg, 86% yield) as a white foam. MS (ISP): m/z=416.2 [M+H]+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](N1C=CN=C1)=[O:11])[CH2:2]2.[CH:17]([OH:30])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH:17]([O:30][C:10](=[O:11])[O:9][C@@H:3]1[CH:4]2[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]2)[CH2:2]1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Product: O=C(OC(c1ccccc1)c1ccccc1)O[C@H]1CN2CCC1CC2

Procedure:
The desired product was prepared by reacting imidazole-1-carboxylic acid (R)-1-aza-bicyclo[2.2.2]oct-3-yl ester with benzhydrol.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:11])[CH:3]=1.[CH3:12][OH:13].C(N(CC)CC)C>>[CH3:12][O:13][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[F:11]
Reactant: CO
Reactant: O=C(Cl)c1ccc(Br)cc1F
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Bromo-2-fluorobenzoyl chloride (45.0 g, 0.190 mol) was slowly added to a solution of methanol (31 mL, 0.76 mol) and triethylamine (53 mL, 0.38 mol) at 0° C. and the mixture was stirred at room temperature overnight. The MeOH was removed under vacuum and the residue was dissolved in CH2Cl2 (500 mL). The organic layer was washed with water, dried (Na2SO4), and concentrated to give a white solid.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][O:5][CH3:6].O.[CH:8](=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:11]>CN(C)C=O>[CH3:6][O:5][CH2:4][O:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=1[CH:8]=[O:16]
Reactant: COCCl
Reactant: O=Cc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccccc1C=O
Reaction time: 0.17 h
Yield: 95.9 %

Procedure:
In N,N-dimethylformamide (20 mL) was dissolved 5.01 g (41.1 mmol) of commercially available salicylaldehyde, 1.80 g (45.0 mmol) of 60% sodium hydride was added to the solution in an ice bath, and after stirring the mixture in an ice bath for 10 minutes, 3.43 mL (45.2 mmol) of chloro(methoxy)methane was gradually added dropwise to the mixture and the resulting mixture was stirred in an ice bath for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 6.54 g (39.4 mmol, Yield: 95.9%) of 2-(methoxymethoxy)benzaldehyde.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)[CH3:11]>>[Br:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([O:12][CH2:10][CH3:11])[CH:18]=2)=[N:3][CH:4]=1
Reactant: CCOc1cccc(B(O)O)c1
Reactant: Cc1cc(Br)ncc1Br
Product: CCOc1cccc(-c2cc(C)c(Br)cn2)c1
Yield: 49 %

Procedure:
Obtained (1.14 g, yield 49%) following the procedure described in Intermediate 27, starting with 2,5-dibromo-4-methylpyridine (7.97 mmol, 2.0 g), 3-ethoxyphenylboronic acid (7.97 mmol, 1.32 gl).
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[N:14]=[C:13]([NH:15][C:16]([NH2:18])=[NH:17])[O:12][N:11]=1)#[N:2].[CH3:21][NH2:22]>C(O)C>[C:1]([N:3]=[C:4]([NH:22][CH3:21])[NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[N:14]=[C:13]([NH:15][C:16]([NH2:18])=[NH:17])[O:12][N:11]=1)#[N:2]
Reactant: CN
Reactant: CSC(=NC#N)NCCSCc1noc(NC(=N)N)n1
Solvent: CCO
Product: CNC(=NC#N)NCCSCc1noc(NC(=N)N)n1
Reaction time: 18 h

Procedure:
To a solution of 3-[2-(3-cyano-2-methyl-isothioureido)ethylthiomethyl]-5-guanidino-1,2,4-oxadiazole (0.7 g.) in ethanol (20 ml.) was added a 33% w/v solution of methylamine in ethanol (30 ml.) The solution was kept for 18 hours at 20°, evaporated in vacuo and the residue finally dried at 30°/0.05 mm. to give 3-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]-5-guanidino-1,2,4-oxadiazole as a white solid, m.p. 185°-188°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[N:24]2[CH2:29][CH:28]3[CH:26]([C:27]3([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:30]#[N:31])[CH2:25]2)=[CH:4][CH:3]=1.[OH:38]S(O)(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[N:24]2[CH2:25][CH:26]3[CH:28]([C:27]3([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:30]([NH2:31])=[O:38])[CH2:29]2)=[CH:6][CH:7]=1
Reactant: N#CC1(N2CCOCC2)C2CN(c3ncnc4c3nc(-c3ccccc3Cl)n4-c3ccc(Cl)cc3)CC21
Reactant: O=S(=O)(O)O
Product: NC(=O)C1(N2CCOCC2)C2CN(c3ncnc4c3nc(-c3ccccc3Cl)n4-c3ccc(Cl)cc3)CC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-[9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]-6-morpholin-4-yl-3-azabicyclo[3.1.0]hexane-6-carbonitrile 29A-8 (28 mg, 0.052 mmol) in concentrated H2SO4 (0.6 ml) was heated at 200° C. for two hours. After the reaction mixture was allowed to cool to room temperature and stir overnight, it was cooled in an ice bath and then carefully quenched with 5 M aqueous NaOH to pH 11. The mixture was extracted with ethyl acetate and then the combined organic layers were washed with brine, dried (MgSO4) and concentrated, in vacuo. The residue was purified on a Biotage™ Flash 12S column using 0–6% methanol in methylene chloride as eluant to give, after trituration from methylene chloride/hexanes, title compound 30A-1 (24 mg, 83%): +ESI MS (M+1) 550.4; 1H NMR (400 MHz, CD2Cl2) δ 8.27 (s, 1H), 7.52–7.49 (m, 1H), 7.44–7.32 (m, 5H), 7.20 (d, J=8.7 Hz, 2H), 5.54 (s, 1H), 5.47 (s, 1H), 5.03 (d, J=12.0 Hz, 1H), 4.37 (d, J=12.0 Hz, 1H), 3.97 (br d, J=9.1 Hz, 1H), 3.68–3.55 (m, 5H), 2.73–2.63 (m, 4H), 2.01 (br s, 1H), 1.96 (br s, 1H).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:3]1[C:13]([O:15][CH3:16])=[O:14].[CH2:17]([O:19][C:20](Cl)=[O:21])[CH3:18].O>C(Cl)Cl>[CH2:17]([O:19][C:20]([NH:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:3]1[C:13]([O:15][CH3:16])=[O:14])=[O:21])[CH3:18]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)c1c(-c2ccccc2)ccn1N
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)Nn1ccc(-c2ccccc2)c1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
Methyl 1-amino-3-phenyl-1H-pyrrole-2-carboxylate (0.200 g, 0.925 mmol) was dissolved in CH2Cl2 (20 mL) and then was added TEA (0.387 mL, 2.77 mmol), followed by ethylchloroformate (0.0890 mL, 0.925 mmol). The reaction mixture was stirred at room temperature for overnight. Water (50 mL) was added to reaction mixture and the aqueous mixture was extracted with CH2Cl2 (25×2 mL). The organic layer separated and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using CombiFlash (REDISEP®, silica gel, 24 g, 15% EtOAc/hexanes) to afford methyl 1-((ethoxycarbonyl)amino)-3-phenyl-1H-pyrrole-2-carboxylate (0.100 g, 37.5%). LCMS Condition B-39: retention time 2.14 min, [M+1]=289.0.
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6][C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=1)([CH3:10])[C:8]#[N:9]>CCO>[NH2:17][C:13]1[CH:12]=[C:11]([C:7]([CH3:10])([CH3:6])[C:8]#[N:9])[CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C#N)c1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C#N)c1cccc(N)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a suspension of tin (II) chloride bis hydrate (3.3 g, 13.1 mmol) in EtOH (25 mL) was added 2-methyl-2-(3-nitrophenyl)propanenitrile (800 mg, 4.2 mmol). The reaction mixture was stirred at 90° C. for 1 h. After cooling down to rt, the solvent was removed under reduced pressure and the residue taken in DCM, washed with water and a saturated solution of sodium hydrogen carbonate until pH=8. After combining, the organics were dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography (hexane/ethyl acetate 15%) to afford 2-(3-aminophenyl)-2-methylpropanenitrile (490 mg, 73%) as a colorless solid. 1H NMR (300 MHz, CDCl3) δ 1.69 (s, 6H), 3.75 (brs, 2H), 6.64 (d, J=9 Hz, 1H), 6.80-6.83 (m, 2H), 7.15-7.19 (m, 1H); LC-MS (ESI) m/z 161 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:22][O:23][CH3:24])([CH2:19][O:20][CH3:21])[O:4][C:5]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:6]=2[C:7]=1[C:8](=[S:11])[NH:9][CH3:10].O1CCCC1.[BH4-].[Na+]>CO>[OH:1][CH:2]1[CH:7]([C:8](=[S:11])[NH:9][CH3:10])[C:6]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:5]=2[O:4][C:3]1([CH2:22][O:23][CH3:24])[CH2:19][O:20][CH3:21]
Reactant: CNC(=S)C1=C(O)C(COC)(COC)Oc2ccc([N+](=O)[O-])cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=S)C1c2cc([N+](=O)[O-])ccc2OC(COC)(COC)C1O
Yield: 36.8 %

Procedure:
To a mixture of 2.7 g of 3-hydroxy-2,2-bis(methoxymethyl)-N-methyl-6-nitro-2H-1-benzopyran-4-carbothioamide, 12 ml of tetrahydrofuran and 46 ml of methanol was added 1.1 g of sodium borohydride (NaBH4) with stirring under ice-cooling and stirred under ice-cooling for 2 hours and subsequently further stirred at room temperature for 24 hours. The reaction solution was vacuum-distilled, water was added therein and the resultant mixture was extracted with methylene chloride. An organic layer was washed with water and dried. The solvent was distilled to obtain 1.0 g of 3,4-dihydro-3-hydroxy-2,2-bis(methoxymethyl)-N-methyl-6-nitro-2H-1-benzopyran-4-carbothioamide. Subsequently, to 700 mg of the obtained benzopyran derivative were added 0.75 g of p-toluenesulfonyl chloride and 11 ml of pyridine. The resultant mixture was refluxed with heating for 30 minutes and the solvent was distilled. Ice water was added to the residue and it was acidified to be hydrochloric acid and extracted with methylene chloride. An organic layer was washed with water and dried and the solvent was distilled. The resultant residue was purified according to silica gel column chromatography (developing solution, MeOH:CH2Cl2 =5:95) to obtain 500 mg of 2,2-bis(methoxymethyl)-N-methyl-6-nitro-2H-1-benzopyran-4-carboxamide with a melting point of 147°-149° C.
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[C:3]([C:14]([OH:16])=O)=[CH:2]1.C1C=CC2N(O)N=[N:23]C=2C=1.N.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]1[C:5]2[C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[C:3]([C:14]([NH2:23])=[O:16])=[CH:2]1
Reactant: O=C(O)c1c[nH]c2c1CCc1cnccc1-2
Reactant: On1nnc2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1c[nH]c2c1CCc1cnccc1-2
Yield: 30 %

Procedure:
A mixture of 4,5-dihydro-1H-pyrrolo[2,3-f]isoquinoline-3-carboxylic acid E6 (0.093 mmol), HOBT.NH3 (0.374 mmol), TBTU (0.186 mmol) and DIEA (0.374 mmol) in DMF (5 mL) was stirred 4 h at rt. The solvent was evaporated and the crude residue was purified by preparative HPLC (Phase A: 0.05% NH4OH pH10/AN 95/5, Phase B: AN; gradient phase B 0—50% 8 min, yield 30%). ESI (+) MS: m/z 214 (MH+). 1H NMR: 2.83 (t, J=7.93, 2H), 2.98 (t, J=8.05, 2H), 6.61-7.28 (m, 2H), 7.33 (d, J=5.00, 1H), 7.56 (d, J=2.80, 1H), 8.28-8.38 (m, 2H), 11.85 (bs, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].F[C:7]1[CH:12]=[CH:11][C:10]([N:13]=[N+:14]=[N-:15])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17].O.Cl>C(O)C>[N:13]([C:10]1[CH:11]=[CH:12][C:7]([NH:1][CH2:2][CH2:3][CH2:4][NH2:5])=[C:8]([N+:16]([O-:18])=[O:17])[CH:9]=1)=[N+:14]=[N-:15]
Reactant: NCCCN
Reactant: [N-]=[N+]=Nc1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=Nc1ccc(NCCCN)c([N+](=O)[O-])c1

Procedure:
2.5 ml (30 mM) 1,3-diaminopropane was dissolved in 25 ml ethanol. To this solution, was added a solution of 1.82 g (10 mM) 4-fluoro-3-nitrophenyl azide in 25 ml ethanol. The addition was performed dropwise with stirring. The mixture was stirred at room temperature for 16 hours. After this time, 150 ml of water were added and the pH adjusted to between 1 and 2 with concentrated HCl. This solution was filtered to remove the disubstituted amine, cooled on ice and the product was precipitated by the slow addition of concentrated aqueous ammonia with stirring. The product was collected by filtration of the cold mixture, washed with ice-cold water and dried in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])=[CH:11][CH:10]=1.B(O[O-])=[O:23].[Na+].O>B1C2CCCC1CCC2>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:23])=[CH:11][CH:10]=1
Reactant: O=BO[O-]
Reactant: C=CCCCC(=O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: O
Product: O=C(CCCCCO)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-(2′,4′-Dichloro-biphenyl-4-yl)-hex-5-en-1-one (1.1 g) was dissolved in 0.5 M 9-BBN (6.9 mL) and stirred at room temperature for 4 hours. Sodium perborate (1 g) was added and the mixture stirred at room temperature for 1 hour. Water (3 mL) was added and the mixture stirred at 50° C. for 2 hours, then overnight at room temperature. The mixture was extracted with ether, dried, and evaporated to give an oil. The oil was purified by column chromatography to give an oil which solidified to a white amorphous solid on standing, and which was recrystallised from ether/petrol to give the title compound as a white powder. 13C NMR (CDCl3): δ23.9, 25.5, 32.5, 38.6, 62.7, 127.4, 128.0, 129.7, 129.9, 131.9, 133.1, 134.5, 136.3, 138.0, 142.8 and 199.9. 1H NMR (CDCl3): δ 1.45 (2H, m), 1.60 (2H, m), 1.80 (2H, m), 3.01 (2H, t, J=6.5 Hz), 3.68 (2H, t, J=6.5 Hz), 7.28 (2H, d, J=8.2 Hz), 7.30 (1H, s), 7.50 (2H, m) and 8.01 (2H, d, J=8.2 Hz).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=4)[CH2:14][CH2:13]3)[N:11]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[C:10](=[O:33])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:34](Cl)(=[O:36])[CH3:35].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH:1]1([NH:7][C:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:20]=[C:21]([NH:25][C:34](=[O:36])[CH3:35])[CH:22]=[CH:23][CH:24]=4)[CH2:14][CH2:13]3)[N:11]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[C:10](=[O:33])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)Cl
Reactant: Nc1cccc(CN2CCC3(CC2)C(NC2CCCCC2)=NC(=O)N3c2cccc(F)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)Nc1cccc(CN2CCC3(CC2)C(NC2CCCCC2)=NC(=O)N3c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 2 mL CH2Cl2 suspension of 0.05 g (0.11 mmol) 4-(cyclohexylamino)-8-[3-aminobenzyl]-1-(3-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one, 0.1 mL (0.11 mmol) acetyl chloride and excess K2CO3 was allowed to stir at rt overnight. The reaction was filtered and concentrated then the remaining oil was dissolved in 1 mL CH2Cl2 and purified on an Isco automated system affixed with a Biotage Flash 25(S) cartridge eluted at 20 mL/min with 0-5% MeOH in CH2Cl2 over 15 min and hold at 5% MeOH for 30 min. The product eluted second, pure by HPLC/MS and NMR.
Reaction SMILES: [Br:1][C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:9]2[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1.Br[CH2:23][C:24]1[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=1>>[Br:1][C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:9]2[C:8](=[O:19])[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]#[N:31])[C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccccc1Cl
Reactant: N#Cc1ccccc1CBr
Product: Cn1c(=O)n(Cc2ccccc2C#N)c(=O)c2c1nc(Br)n2Cc1ccccc1Cl

Procedure:
8-Bromo-7-(2-chlorobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione (75A) and alpha-bromo-o-tolunitrile were reacted and purified as described in the General procedure G, Step B, to afford 75B as white crystals.