Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[C:16]([OH:23])=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O>>[Cl:14][C:15]1[C:16]([OH:23])=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1cccc(Cl)c1O
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3cccc(Cl)c3O)CC2)nc[nH]1

Procedure:
6-[4-(3-Chloro-2-hydroxy-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3-chloro-2-hydroxybenzaldehyde (available from Aldrich). 1H NMR (400 MHz, DMSO-d6) δ 3.50-3.58 (m, 4H), 3.79 (s, 2H), 5.29 (s, 1H), 6.76-6.80 (m, 1H), 7.04-7.06 (m, 1H), 7.27-7.29 (m, 1H), 7.90 (s, 1H), 11.66 (br s, 1H). Mass spectrum (ES) MH+=321.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][NH2:33].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(C)=O.O>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([NH:33][O:32][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][O:26]3)=[O:25])=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1ccc(NC2CCN(Cc3ccccc3)CC2)nc1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc(NC2CCN(Cc3ccccc3)CC2)nc1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 15 h
Yield: 32.4 %

Procedure:
A mixture of (2E)-3-{6-[(1-benzyl-4-piperidyl)amino]-3-pyridyl)acrylic acid (430 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (157 mg), HOBt (181 mg) and EDCI (208 mg) in DMF (20 ml) was stirred at ambient temperature for 15 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (9:1-8:2). The eluted fractions containing the desired product were collected and evaporated in vacuo to give (2E)-3-(6-[(1-benzyl-4-piperidyl)amino]-3-pyridyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (180 mg).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH2:23])=[CH:17][CH:16]=1.[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:23][CH2:22][CH2:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CCN)cc1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CCNCc2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
0.39 ml of 4-tert-butylbenzaldehyde (2.25 mmol) and 0.230 ml 2-(4-methoxy-phenyl)-ethylamine (1.5 mmol) were dissolved in 4.5 ml methanol and after stirring for 30 min at rt, were refluxed for 2.5 h. After cooling down to rt, 85 mg (2.25 mmol) sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was then refluxed for 2.5 h. After cooling down to rt, the reaction mixture was treated with 4 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:1) to give 430 mg colorless viscous oil (96%). MS (ISP) 298.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[N:7]([Si](C(C)C)(C(C)C)C(C)C)[CH2:6][C:5]2([CH3:33])[CH3:32].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[NH:7][CH2:6][C:5]2([CH3:33])[CH3:32]
Reactant: COc1ccc(S(=O)(=O)c2cc3c(cc2F)C(C)(C)CN3[Si](C(C)C)(C(C)C)C(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COc1ccc(S(=O)(=O)c2cc3c(cc2F)C(C)(C)CN3)cc1
Yield: 64.3 %

Procedure:
5-Fluoro-6-(4-methoxy-benzenesulfonyl)-3,3-dimethyl-1-triisopropylsilanyl-2,3-dihydro-1H-indole (250 mg, 0.51 mmol) was treated with TBAF following similar methods to those described in Preparation 78 to give the title compound (110 mg) as a pale yellow oil. 1H NMR (CDCl3): 7.99-7.81 (2H, m), 7.21 (1H, d), 7.04-6.92 (2H, m), 6.73 (1H, d), 3.87 (3H, s), 3.35 (2H, s), 1.27 (6H, s).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[CH2:16]=O>CO>[N:10]1([CH2:16][NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: C=O
Reactant: NC(=O)c1ccccc1
Reactant: C1COCCN1
Solvent: CO
Product: O=C(NCN1CCOCC1)c1ccccc1
Reaction time: 0.08 h
Yield: 26.3 %

Procedure:
To a stirred solution of benzamide (0.30 g, 2.5 mmol) in MeOH (5 mL) was added morpholine (0.22 g, 2.5 mmol) and the resulting solution was cooled in an ice bath. Formaldehyde (0.215 mL, 2.5 mmol, 37% in water) was then added and the stirred solution was left on ice for 5 min and then it was allowed to stand at RT for another 10 min, and then it was placed in a 70° C. oil bath for 2 h. The solvents were evaporated and the isolated residue (a waxy solid) was chromatographed on a Chromatotron with dichloromethane/methanol mixture, 5:0.2 to 5:0.6 as eluent. The desired fractions were collected and the solvents were evaporated giving Mannich base 18 (0.145 g, 30%) as an oil which solidified in the freezer.
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:32]3[C:31](=[O:33])[NH:30][C:29]([C:34]([O:36]CC)=O)=[N:28][C:27]=3[S:26][CH:25]=2)=[CH:20][CH:19]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:82]2[CH:86]=[N:85][C:84]([O:87][CH2:88][CH2:89][O:90][C:91]3[CH:92]=[C:93]([CH2:97][NH2:98])[CH:94]=[CH:95][CH:96]=3)=[N:83]2)C=CC=CC=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:32]3[C:31](=[O:33])[NH:30][C:29]([C:34]([NH:98][CH2:97][C:93]4[CH:94]=[CH:95][CH:96]=[C:91]([O:90][CH2:89][CH2:88][O:87][C:84]5[N:85]=[CH:86][NH:82][N:83]=5)[CH:92]=4)=[O:36])=[N:28][C:27]=3[S:26][CH:25]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1nc2scc(-c3ccc(F)cc3)c2c(=O)[nH]1
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: O=C(NCc1cccc(OCCOc2nc[nH]n2)c1)c1nc2scc(-c3ccc(F)cc3)c2c(=O)[nH]1

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 5-(4-fluorophenyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 77 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (187.2 mg, 69%).
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[P:13](=O)([OH:16])([OH:15])[OH:14]>>[CH2:11]([OH:12])[C@H:9]([OH:10])[C@H:7]1[O:8][C:2](=[O:1])[C:3]([O:4][P:13]([OH:16])([OH:15])=[O:14])=[C:5]1[OH:6]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: O=P(O)(O)O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1OP(=O)(O)O

Procedure:
The solution E contained sodium salts of L-ascorbic acid, phosphoric acid and some L-ascorbyl 2-monophosphate, and can be recycled to the phosphorylation process for producing further ascorbyl monophosphate. The solution F contained only a small amount of the remaining L-ascorbic acid and can be recycled to the next batch for separation.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([Br:18])[C:3]=1[NH:19][C:20](=[O:32])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[C:22]=1[O:30][CH3:31].[H-].[Na+].I[CH3:36]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:15])([F:16])[F:14])[CH:5]=[C:4]([Br:18])[C:3]=1[N:19]([CH3:36])[C:20](=[O:32])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[C:22]=1[O:30][CH3:31]
Reactant: COc1c(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Br)cccc1[N+](=O)[O-]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C(=O)N(C)c2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Br)cccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of N-[2,6-dibromo-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]-2-methoxy-3-nitro-benzamide (obtained in a similar way as example I 4.1) (0.482 g, 0.806 mmole) in N,N-dimethylformamide (5 ml), magnetically stirred under argon atmosphere, at 25° C., in a round-bottomed flask, was added sodium hydride (60% suspension in oil, 0.039 g, 0.967 mmole). After the gas evolution had ceased, iodomethane (0.060 ml, 0.137 g, 0.967 mmole) was added and the mixture was stirred for 15 hours. The reaction mixture was quenched by addition of two drops of methanol, then concentrated under reduced pressure on a rotatory evaporator. The residue was placed on a silica gel column. Elution with a mixture of 15% ethyl acetate and 85% cyclohexane allowed the isolation of the title compound in quantitative yield (LC-MS analysis (method 6 described after the tables): retention time 1.22 min, observed M+H+ ion 611).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[O:15])[C:6](=[CH:9][C:10]=1[C:11](=[O:14])[CH2:12][CH3:13])[C:7]#N)[CH3:2].[OH2:16].S(=O)(=O)(O)[OH:18]>C(O)(=O)C>[CH2:1]([C:3]1[NH:4][C:5](=[O:15])[C:6](=[CH:9][C:10]=1[C:11](=[O:14])[CH2:12][CH3:13])[C:7]([OH:18])=[O:16])[CH3:2]
Reactant: O
Reactant: O=S(=O)(O)O
Reactant: CCC(=O)c1cc(C#N)c(=O)[nH]c1CC
Solvent: CC(=O)O
Product: CCC(=O)c1cc(C(=O)O)c(=O)[nH]c1CC

Procedure:
A mixture containing 40.8 g of 6-ethyl-1,2-dihydro-2-oxo-5-(n-propanoyl)nicotinonitrile, 50 ml of water, 75 ml of concentrated sulfuric acid and 200 ml of acetic acid was heated on a steam bath for 8 hours, cooled and concentrated on a rotary evaporator to remove the acetic acid and water. The remaining mixture was diluted with 300 ml of water and chilled for 1 hour in an ice bath. The white solid that separated was collected, washed with water and dried in a vacuum over at 80° C. and recrystallized from isopropyl alcohol-ether and dried in a vacuum oven at 90° C. to yield 34.6 g of 6-ethyl-1,2-dihydro-2-oxo-5-(n-propanoyl)nicotinic acid, m.p. 180°-182° C.
Reaction SMILES: O.[ClH:2].[C:3]([NH2:11])(=[NH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]([C:15]([CH3:17])=[O:16])([CH3:14])=[O:13].C(O)(C)C.O.C([O-])(=O)C.[Na+]>O>[ClH:2].[CH3:17][C:15]1([OH:16])[C:12]([CH3:14])([OH:13])[NH:11][C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:10]1
Reactant: N=C(N)c1ccccc1
Reactant: CC(=O)C(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC1(O)N=C(c2ccccc2)NC1(C)O
Reaction time: 4 h

Procedure:
To 56.4 g (0.323 mole) of benzamidine hydrochloride hydrate in 200 ml of warm water is added with vigorous stirring 40 ml of biacetyl. Within a few minutes a heavy precipitate forms and 150 ml of isopropyl alcohol is added followed by 5.0 g of sodium acetate hydrate dissolved in 15 ml of warm water. Stirring is continued for 4 hours after which time the product, 4,5-dimethyl-2-phenylimidazoline-4,5-diol hydrochloride, is filtered off and washed with isopropyl alcohol. Recrystallization from 95% ethanol gives the pure product, m.p. 162°-165° C (dec.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]1[C:21]3[C:16](=[CH:17][C:18](Br)=[CH:19][CH:20]=3)[CH:15]=[CH:14][C:13]=1[OH:23])=[C:7]([OH:24])[CH:6]=[CH:5]2.[CH3:25][C:26]1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH3:47][CH2:48]N(CC)CC.C=C>CN(C=O)C.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:25]([C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[C:12]([C:8]1[C:9]3[C:4](=[CH:3][C:2]([CH:47]=[CH2:48])=[CH:11][CH:10]=3)[CH:5]=[CH:6][C:7]=1[OH:24])=[C:13]([OH:23])[CH:14]=[CH:15]2)=[CH2:26]
Reactant: CCN(CC)CC
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Reactant: Oc1ccc2cc(Br)ccc2c1-c1c(O)ccc2cc(Br)ccc12
Agent: [Pd+2]
Agent: C=C
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1ccc2c(-c3c(O)ccc4cc(C=C)ccc34)c(O)ccc2c1
Yield: 54 %

Procedure:
A solution of 6,6′-dibromo-2,2′-dihydroxy-1,1′-binaphthyl (0.694 g, 1.56 mmol), Pd(OAc)2 (0.020 g, 5 mol %), P(o-tolyl)3 (0.080 g, 15 mol %) and Et3N (0.5 mL) in DMF (2 mL) was pressurized with ethylene (200 psi) at 750 C for 18 hrs. The resulting mixture was diluted in ethyl acetate (20 mL) and filtered through celite, followed by water (20 mL) and brine (20 mL) washes. The solution was dried over MgSO4 and evaporated to produce a tan solid, which was purified by column chromatography to yield the desired product in 54% yield (0.286 g).
Reaction SMILES: [CH3:1][C:2]1[O:17][C:7]2[CH:8]=[C:9]3[O:16][CH:15]=[CH:14][C:10]3=[C:11]([O:12]C)[C:6]=2[C:4](=[O:5])[CH:3]=1.B(Cl)(Cl)Cl.O>ClCCl>[OH:12][C:11]1[C:10]2[CH:14]=[CH:15][O:16][C:9]=2[CH:8]=[C:7]2[C:6]=1[C:4](=[O:5])[CH:3]=[C:2]([CH3:1])[O:17]2
Reactant: COc1c2ccoc2cc2oc(C)cc(=O)c12
Agent: ClB(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1cc(=O)c2c(O)c3ccoc3cc2o1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 82.1 %

Procedure:
To a suspension of visnagin (920 mg, 4.0 mmol) in dichloromethane (20 mL) at −78° C. was added a solution of boron trichloride (1.0 M, 4.0 mL, 4.0 mmol) and the reaction mixture was stirred at −78° C. for 15 min then rt for 16 h. The reaction mixture was cooled to 0° C. and water (25 mL) was added slowly at first. The organics were concentrated in vacuo and the resulting suspension was diluted with 5% citric acid (150 mL) and heated at 60° C. for 1 h. The suspension was filtered, washing with water (3×50 mL) and the resulting solid was dried in a vacuum oven to afford the title compound as a yellow solid (710 mg, 83%): 1H NMR (300 MHz, CDCl3): δ 2.38 (s, 3H), 6.06 (s, 1H), 6.97 (d, J=2.2 Hz, 1H), 6.99 (s, 1H), 7.55 (d, J=2.2 Hz, 1H), 13.52 (s, 1H). MS (ES+) m/z 217.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:31]1([S:37](Cl)(=[O:39])=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C1COCC1.O>[CH3:1][C:2]1[S:12][C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([NH:10][S:37]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)(=[O:39])=[O:38])=[C:4]2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1
Reactant: COc1cccc(-c2c(C)sc3nc(C)cc(N)c23)c1
Reactant: O=S(=O)(Cl)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)C4CCCCC4)c23)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 14.5 %

Procedure:
To a stirred solution of 2,6-dimethyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-amine (100 mg, 0.352 mmol) (Description 4) in THF (2 mL), cooled in an ice bath, was added LiHMDS (1M solution in THF) (0.774 mL, 0.774 mmol). The reaction mixture was stirred at RT for 45 min before the addition of cyclohexanesulfonyl chloride (0.161 g, 0.879 mmol). The reaction mixture was then stirred at RT for a further 12 h. The reaction mixture was then re-cooled in an ice bath before the addition of LiHMDS (1M solution in THF) (0.352 mL, 0.352 mmol). The reaction mixture was then stirred at RT for 45 min before the addition of cyclohexanesulfonyl chloride (0.064 g, 0.352 mmol). The reaction mixture was then stirred at RT for a further 12 h. The reaction mixture was then diluted with water (15 mL) and the aqueous layer extracted with DCM (3×30 mL) and the combined organic extracts dried over a phase separating column and concentrated. The residue was then purified by MDAP (basic conditions), to afford the title compound (22 mg). LCMS (A) m/z: 431 [M+1]+, Rt 1.16 min (basic).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH:6]([C:8]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[CH3:22])[C:12]2[N:23]=[C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[S:25][C:11]=2[C:10](=[O:32])[N:9]=1)[CH3:7]>CN(C)C=O.O>[N:1]([CH:6]([C:8]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[CH3:22])[C:12]2[N:23]=[C:24]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[S:25][C:11]=2[C:10](=[O:32])[N:9]=1)[CH3:7])=[N+:2]=[N-:3]
Reactant: Cc1c(Cl)cccc1Cn1c(C(C)Br)nc(=O)c2sc(N3CCOCC3)nc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Cl)cccc1Cn1c(C(C)N=[N+]=[N-])nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 65 °C
Yield: 52.2 %

Procedure:
To a solution of sodium azide (20.16 mg, 0.310 mmol) in N,N-Dimethylformamide (DMF) (1.5 mL) was added 5-(1-bromoethyl)-4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (100 mg, 0.207 mmol) in N,N-Dimethylformamide (DMF) (1.5 mL). The reaction was heated to 65° C. for 2 hr, and then the solution was cooled to room temperature. The reaction contents were diluted with water, producing a precipitate. The suspension was filtered using a fritted funnel, providing 5-(1-azidoethyl)-4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (48 mg, 0.108 mmol, 52.1% yield) as a crude brown solid that was used directly in the next reaction. LC/MS m/z MH+=446 (theoretical), found=446.1, 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.67 (d, J=6.82 Hz, 4H) 2.47 (s, 3H) 3.48-3.66 (m, 5H) 3.68-3.87 (m, 5H) 3.97 (q, J=6.57 Hz, 1H) 5.42 (d, J=17.18 Hz, 1H) 5.76 (d, J=17.18 Hz, 1H) 6.41 (d, J=7.58 Hz, 1H) 7.07 (t, J=7.83 Hz, 1H) 7.35 (d, J=8.08 Hz, 1H)
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][O:7][CH2:8][C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]1OCCC[O:19]1)=[CH:10][CH3:11].Cl.[BH4-].[Na+]>CC(C)=O.O>[F:1][C:2]([F:31])([F:32])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:26]=1)[CH2:6][O:7][CH2:8][C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][OH:19])=[CH:10][CH3:11]
Reactant: CC=C(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1C1OCCCO1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC=C(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1CO
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(2-(1-(3,5-bis(trifluoromethyl)benzyloxy)but-2-en-2-yl)phenyl)-1,3-dioxane (1.75 g, 3.8 mmol) in acetone (100 mL) and water (5 mL) at room temperature was added concentrated hydrochloric acid (0.4 mL). The resulting solution was stirred for 1.5 h. The reaction was quenched by the addition of saturated sodium bicarbonate, and poured into pentane. The organics were washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. The crude residue was dissolved in ethanol (20 mL), cooled to 0° C., and treated with sodium borohydride (0.14 g, 3.8 mmol). After 5 min, the ice bath was removed and stirring continued for 30 min. The mixture was recooled to 0° C., and quenched by addition of saturated ammonium chloride. The mixture was extracted with ether, washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (5%-->25% EtOAc/Hex) gave 1.22 g (79%) as colorless oil and as a mixture of E- and Z-isomers. 1H-NMR (mixture, CDCl3, 300 MHz) δ 7.76 (s, 1H), 7.62 (s, 1.5H), 7.59 (s, 0.4H), 7.20-7.50 (m, 3.3H), 7.13 (d, J=7.0 Hz, 0.2H), 7.05 (m, 0.8H), 5.96 (q, J=6.7 Hz, 0.8H), 5.72 (q, J=7.0 Hz, 0.2H), 4.05-4.80 (m, 6.2H), 2.65 (m, 1H), 1.85 (d, J=7.0 Hz, 0.6H), 1.66 (bs, 0.4H), 1.47 (d, J=6.7 Hz, 2.4H).
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.[CH2:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][NH:19]1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:20][CH2:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18]2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: c1ccc2c(c1)CCNC2
Solvent: COCCOC
Product: N#Cc1c(-c2ccco2)nc(N)nc1N1CCc2ccccc2C1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 1,2,3,4-tetrahydroisoquinoline in DME. ES-MS m/e (%): 318 (M+H+, 100).
Reaction SMILES: [CH2:1]([CH:3]([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:4][N:5]1[C:17]2[C:12](=[CH:13][C:14]([N+:22]([O-:24])=[O:23])=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33])=O)[CH:10]=2)[CH3:2].[Cl-].[OH:39][NH3+:40]>N1C=CC=CC=1>[CH2:1]([CH:3]([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:4][N:5]1[C:17]2[C:12](=[CH:13][C:14]([N+:22]([O-:24])=[O:23])=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33])=[N:40][OH:39])[CH:10]=2)[CH3:2]
Reactant: [NH3+]O
Reactant: CCCCC(CC)Cn1c2ccc(C(=O)c3ccccc3C)cc2c2cc([N+](=O)[O-])c3ccccc3c21
Agent: [Cl-]
Solvent: c1ccncc1
Product: CCCCC(CC)Cn1c2ccc(C(=NO)c3ccccc3C)cc2c2cc([N+](=O)[O-])c3ccccc3c21
Temperature: 0 °C
Reaction time: 16 h
Yield: 75.6 %

Procedure:
To [11-(2-ethyl-hexyl)-5-nitro-11H-benzo[a]carbazole-8-yl]-o-tolyl-methanone (0.36 g, 0.73 mmol) in pyridine (6 ml) is added hydroxylammonium chloride (0.10 g, 1.45 mmol) at 120° C. After stirring for 16 hours, the reaction mixture is poured into ice-water. The crude is extracted with AcOEt, and washed with water and brine. After drying over MgSO4 and concentration, the crude is purified by column chromatography on silica gel eluting with CH2Cl2 to obtain a yellow resin (0.28 g, 76%). The structure is confirmed by 1H-NMR spectrum (CDCl3). δ [ppm]: 0.79-0.90 (m), 1.13-1.48 (m), 2.21 (m), 2.29 (s), 4.69 (m), 7.25 (d), 7.37-7.47 (m), 7.55 (d), 7.67-7.75 (m), 7.90 (d), 8.04 (s), 8.60 (d), 8.89 (d), 8.92 (s).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.[NH2:33][NH2:34]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:33][NH:34]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: NN
Reactant: C[C@@H]1CC[C@H](C(=O)Nc2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Solvent: CCO
Product: C[C@@H]1CC[C@H](C(=O)Nc2ccccc2)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 100 °C
Yield: 29.2 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-N-phenyl-3-piperidinecarboxamide (10 g, 23.2 mmol) in EtOH (400 mL) was added hydrazine (22.8 mL, 465 mmol). The resulting mixture was heated in seal tube at 100° C. overnight, cooled down, and concentrated in vacuo. The crude solution was purified by the silica gel chromatography (200 g column) eluting from 100% CHCl3 to CHCl3/CH3OH/NH4OH (9:1:0.1). The pure fractions that contained the desired product were combined and concentrated in vacuo to afford the title compound (3 g). LC-MS (ES) m/z=443 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.18 (d, J=6.8 Hz, 3H), 1.75 (s, 2H), 1.83 (m, 1H), 1.92 (m, 1H), 5.37 (s, 2H), 6.10 (s, 2H), 6.64 (s, 1H), 7.03 (s, 1H), 7.32 (s, 2H), 7.29-7.34 (m, 2H), 7.64 (d, J=7.3 Hz, 4H), 7.96 (s, 1H), 8.32 (s, 1H), 10.06 (s, 1H), 11.49 (s, 1H). The rest of fractions that contained the desired product and a small amount of impurities were combined, concentrated in vacuo and crystallized from CH3OH (˜10 mL). The crystalline material was obtained (3.6 g).