Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][NH2:11])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.C(N(CC)CC)C.C[O:20][C:21](=O)[N:22]=[C:23](SC)[C:24]([C:38]1[CH:43]=[C:42]([CH3:44])[N:41]=[C:40]([O:45][CH3:46])[CH:39]=1)=[N:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([CH3:37])[O:34][N:33]=2)=[CH:28][CH:27]=1>CN(C=O)C>[NH2:1][C:4]1[C:5]([N:10]2[C:21](=[O:20])[NH:22][C:23]([CH:24]([C:38]3[CH:43]=[C:42]([CH3:44])[N:41]=[C:40]([O:45][CH3:46])[CH:39]=3)[NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[N:36]=[C:35]([CH3:37])[O:34][N:33]=4)=[CH:28][CH:27]=3)=[N:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(C)nc(OC)c1
Reactant: NNc1ncccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccc3N)c(=O)[nH]2)cc(C)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30.2 %

Procedure:
After adding 32 mg of (3-nitropyridin-2-yl)hydrazine [CAS No. 15367-16-5] and 29 μl of triethylamine to a solution of 90 mg of {2-(2-methoxy-6-methylpyridin-4-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 3 ml of DMF, the mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 2 ml of a methanol:THF=1:1 mixed solvent. After adding 42 μl of acetic acid and 64 mg of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature for 4 hours. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give 2-(3-aminopyridin-2-yl)-5-{(2-methoxy-6-methylpyridin-4-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl amino]methyl}-2,4-dihydro-[1,2,4]triazol-3-one (30 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.F[C:17]1[C:22]([CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:21][CH:20]=[CH:19][N:18]=1>CS(C)=O.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][CH:12]([O:15][C:17]3[C:22]([CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: Fc1ncccc1C1CCOCC1
Reactant: Cc1ccc(NC2CCC(O)CC2)nc1
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(NC2CCC(Oc3ncccc3C3CCOCC3)CC2)nc1
Yield: 60 %

Procedure:
4-(5-methyl-pyridin-2-ylamino)-cyclohexanol (50 mg) was added to a solution of 2-fluoro-3-(tetrahydro-pyran-4-yl)-pyridine, as prepared in preparation 1a, (50 mg) in DMSO (15 mL) and the reaction mixture was stirred until TLC analysis confirmed the absence of starting materials. Then the mixture was diluted with water (10 mL), and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with water (5 mL) and brine (10 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography (EtOAc:Petrol ether=1:1) to provide (5-methyl-pyridin-2-yl)-{4-[3-(tetrahydro-pyran-4-yl)-pyridin-2-yloxy]-cyclohexyl}-amine (0.03 g, yield 60%) as a solid. [M+1] 368. IC50 (uM): 0.057.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH2:16]([C@@H:23]1[CH2:28][C@@H:27]([N:29]([CH2:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=[CH:39][CH:38]=2)[C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[CH2:26][CH2:25][NH:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>>[CH2:16]([C@@H:23]1[CH2:28][C@@H:27]([N:29]([CH2:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=[CH:39][CH:38]=2)[C:30](=[O:35])[C:31]([F:33])([F:34])[F:32])[CH2:26][CH2:25][N:24]1[C:5](=[O:7])[C:4]1[CH:8]=[C:9]([Br:11])[CH:10]=[C:2]([Br:1])[CH:3]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=C(c1cc(Br)cc(Br)c1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Yield: 52.1 %

Procedure:
197 mg (0.70 mmol) of 3,5-dibromobenzoic acid (prepared according to J. Organometallic Chem. 215, 281 (198 1)) are reacted in analogy to Example 2a first with 2 ml (27 mmol) of thionyl chloride and subsequently with 200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine and 130 μl (0.936 mmol) of triethylamine to give the title compound (168 mg, 52%). TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.60, FD-MS: M+ =687, 689, 691.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=3)=[CH:11][CH:10]=2)[C:5](=[O:23])[CH2:4][O:3]1.[CH3:24][NH2:25]>CO.O1CCCC1>[C:21]([C:17]1[CH:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][NH:6][C:2](=[O:1])[O:3][CH2:4][C:5]([NH:25][CH3:24])=[O:23])=[CH:14][CH:13]=2)[CH:20]=[CH:19][CH:18]=1)#[N:22]
Reactant: CN
Reactant: N#Cc1cccc(-c2ccc(CCN3C(=O)COC3=O)cc2)c1
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)NCCc1ccc(-c2cccc(C#N)c2)cc1
Yield: 48.6 %

Procedure:
2.0 g (6.53 mmol) of 4′-[2-(2,4-dioxo-1,3-oxazolidin-3-yl)ethyl]-3-biphenylcarbonitrile, prepared in step 11.2., are dissolved in a mixture of 13 ml of methanol and 9.8 ml of a 2N solution of methylamine (19.6 mmol) in tetrahydrofuran. The solution is left to react overnight and then evaporated to dryness and the residue is purified by chromatography on silica gel, eluting with a 96/4 then 95/5 mixture of dichloromethane and methanol. The product is recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 1.07 g of product in the form of a white powder.
Reaction SMILES: C[O:2][C:3]1[C:11]([O:12]C)=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].I>C(O)(=O)C.O>[OH:2][C:3]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1cccc(C(=O)O)c1OC
Agent: I
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cccc(O)c1O
Temperature: 25 °C
Yield: 99.3 %

Procedure:
2,3-Dimethoxybenzoic acid (2 g, 10.98 mmol) was dissolved in acetic acid (25 mL). Hydroiodic acid solution (25 mL, 47% in water) was added and the reaction stirred under reflux overnight. The reaction was allowed to cool to room temperature and the solvent removed in vacuo. The yellow solid obtained was dissolved in a minimum amount of water and extracted with EtOAc (4×50 mL). Organic layers were combined, washed with Na2S2O3 (10% solution, 2×50 mL), water (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to yield 1.68 g (99%) 2,3-dihydroxybenzoic acid as a white solid. 1H NMR (CD3OD): 7.34 (d, J =8.0 Hz, 1H), 6.99 (d, J=8.0 Hz, 1H), 6.72 (t, J=8.0 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH2:11][S:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:14](Cl)Cl.C[Si](C=[N+]=[N-])(C)C.CCCCCC>CO>[OH:1][C:2]1[CH:10]=[C:9]([CH2:11][S:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: CSCc1ccc(C(=O)O)c(O)c1
Reactant: ClCCl
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)c1ccc(CSC)cc1O
Reaction time: 0.17 h
Yield: 93 %

Procedure:
To a mixture of 2-hydroxy-4-(methylthiomethyl)benzoic acid (3.96 g, 20 mmol), CH2Cl2 (75 mL), and MeOH (15 mL) was added a solution of 2 M trimethylsilyldiazomethane (TMSCHN2) in hexane (10.5 mL, 21 mmol) over 30 min. After stirring for 10 min, the reaction was concentrated and vacuum dried. The residue was chromatographed (250 g SiO2, hexanes to 5% EtOAc/hexanes) to give the title compound as a colorless oil (3.96 g, 93%).
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([NH:19][CH2:20][C:21]([OH:23])=O)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([C:53]2[CH:58]=[CH:57][C:56]([Cl:59])=[CH:55][CH:54]=2)[N:32]2[CH2:35][C:34](=[CH:36][S:37]([CH2:40][C:41]3[CH:42]=[C:43]([N:47]4[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]4)[CH:44]=[CH:45][CH:46]=3)(=[O:39])=[O:38])[CH2:33]2)=[CH:27][CH:26]=1>ClCCl>[C:15]([O:14][C:12](=[O:13])[NH:19][CH2:20][C:21]([N:50]1[CH2:51][CH2:52][N:47]([C:43]2[CH:44]=[CH:45][CH:46]=[C:41]([CH2:40][S:37]([CH:36]=[C:34]3[CH2:33][N:32]([CH:31]([C:28]4[CH:27]=[CH:26][C:25]([Cl:24])=[CH:30][CH:29]=4)[C:53]4[CH:58]=[CH:57][C:56]([Cl:59])=[CH:55][CH:54]=4)[CH2:35]3)(=[O:38])=[O:39])[CH:42]=2)[CH2:48][CH2:49]1)=[O:23])([CH3:16])([CH3:17])[CH3:18]
Reactant: O=S(=O)(C=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)Cc1cccc(N2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)N1CCN(c2cccc(CS(=O)(=O)C=C3CN(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)C3)c2)CC1
Reaction time: 20 h
Yield: 102.2 %

Procedure:
1.02 g of supported EDCI (5 mM), 44 mg of N-Boc-glycine and then 10 cm3 of dichloromethane are successively added, at a temperature close to 20° C., to 108.5 mg of 1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine. After stirring for 20 hours at a temperature close to 20° C., the reaction mixture is filtered on sintered glass. The resin is rinsed with three times 5 cm3 of dichloromethane. The combined filtrates are washed with 20 cm3 of water, dried over magnesium sulfate, filtered on sintered glass and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40° C. 143 mg of (2-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)carbamic acid tert-butyl ester are thus obtained in the form of a cream-colored lacquer [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 1.40 (s, 9H), 2.93 (s, 3H), from 3.05 to 3.20 (mt, 4H), 3.57 (mt, 4H), 3.80 (mt, 2H), 3.84 (d, J=6 Hz, 2H), 4.19 (mt, 2H), 4.78 (s, 1H), 6.79 (t, J=6 Hz, 1H), 6.82 (d, J=8 Hz, 1H), 6.93 (broad s, 1H), 6.99 (dd, J=8 and 2.5 Hz, 1H), 7.27 (t, J=8 Hz, 1H), 7.36 (d, J=8 Hz, 4H), 7.46 (d, J=8 Hz, 4H)].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]2[CH2:22][C:18]3([CH2:21][CH2:20][CH2:19]3)[O:17][N:16]=2)[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Br-].[CH3:24][C:25]1[CH:26]=[CH:27][C:28]([Zn+])=[N:29][CH:30]=1>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:24][C:25]1[CH:26]=[CH:27][C:28]([C:2]2[CH:3]=[C:4]([CH:12]=[C:13]([C:15]3[CH2:22][C:18]4([CH2:21][CH2:20][CH2:19]4)[O:17][N:16]=3)[CH:14]=2)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[N:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(C2=NOC3(CCC3)C2)c1
Reactant: Cc1ccc([Zn+])nc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1COCCO1
Product: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(C3=NOC4(CCC4)C3)c2)nc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To a solution of tert-butyl 3-bromo-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)benzoate (1.42 g, 3.88 mmol) and bis(tri-tert-butylphosphine)palladium(0) (59.0 mg, 0.12 mmol) in dioxane (20 mL) was added 5-methyl-2-pyridylzinc bromide (0.5 M in THF; 15.5 mL, 7.75 mmol). The reaction mixture was heated to 70° C. After 1 h, the reaction was cooled to ambient temperature and the solvent was evaporated. Saturated aqueous sodium potassium tartrate was adde and the mixture was extracted with ethyl acetae (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→75% hexanes/ethyl acetate) gave the title compound (1.42 g). MS 379.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:20][C:21]4[NH:27][C:26](=[O:28])[CH2:25][CH2:24][NH:23][C:22]=4[N:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:39][CH2:40][CH2:41]I.O>CN(C=O)C>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:20][C:21]4[N:27]([CH2:41][CH2:40][F:39])[C:26](=[O:28])[CH2:25][CH2:24][NH:23][C:22]=4[N:29]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CCN4)cc2)CCC1
Reactant: FCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCF)C(=O)CCN4)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
To a solution of tert-butyl(1-(4-(2-oxo-8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-7-yl)phenyl)cyclobutyl)carbamate (101 mg, 0.21 mmol) in dry DMF (1 ml) was added sodium hydride (12 mg, 0.32 mmol) and 1-fluoro-2-iodoethane (27 μl, 0.32 mmol) under nitrogen. The resulting mixture was stirred for 1 hour at room temperature. Water was added and the mixture was extracted with EtOAc (3×10 ml). The combined organic phases were dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 100% EtOAc in cyclohexane) to give the title compound (52 mg, 47%). 1H NMR (500 MHz, CDCl3): 7.62 (1H, s), 7.31-7.22 (7H, m), 7.16-7.14 (2H, m), 5.01 (1H, s), 4.75 (1H, br s), 4.74 (2H, dt), 4.07 (2H, dt), 3.92-3.88 (2H, m), 2.73 (2H, t), 2.55-2.25 (4H, m), 2.10-2.03 (1H, m), 1.86-1.78 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([N:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH3:27])[CH2:22][CH2:21]3)[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:6][CH:5]=1)#[N:3].[OH-:28].[Na+]>S(=O)(=O)(O)O>[CH2:26]([N:23]1[CH2:22][CH2:21][N:20]([C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:19]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:2](=[O:28])[NH2:3])=[CH:9][CH:8]=3)[N:11]=2)[CH2:25][CH2:24]1)[CH3:27]
Reactant: CCN1CCN(c2nc(-c3ccc(C#N)cc3)cc3ccccc23)CC1
Reactant: [OH-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCN1CCN(c2nc(-c3ccc(C(N)=O)cc3)cc3ccccc23)CC1
Yield: 23.8 %

Procedure:
1-(4-Ethylpiperazin-1-yl)-3-(4-cyanophenyl)isoquinoline (1.0 g) obtained in Example 62 was reacted in concentrated sulfuric acid (40 ml) at 60° C. for 5 hr. The reaction solution was cooled and then poured over ice, and was then adjusted to pH 8 to 9 by a 8N aqueous solution of sodium hydroxide. The resulting white precipitates were collected by filtration, washed with water and dried, to give the title compound (0.25 g, yield; 23.8%).
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[C:5]([N+:11]([O-:13])=[O:12])[C:3]=1N.C(ON=O)(C)(C)C.[ClH:21]>C(#N)C>[Br:1][C:2]1[C:3]([Cl:21])=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=[C:7]([F:10])[C:8]=1[F:9]
Reactant: Nc1c([N+](=O)[O-])cc(F)c(F)c1Br
Reactant: Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: O=[N+]([O-])c1cc(F)c(F)c(Br)c1Cl
Reaction time: 0.13 h

Procedure:
To a mixture of anhydrous cupric chloride (3.1 g) and 2-bromo-3,4-difluoro-6-nitroaniline (4.6 g) in anhydrous acetonitrile (30 ml) was added t-butylnitrite (2.8 g) dropwise at 51° to 56° C. during 5 minutes. After stirring for 8 minutes at the same temperature, the reaction mixture was poured into chilled 10% diluted hydrochloric acid (30 ml) and extracted with benzene. The organic layer was washed with diluted hydrochloric acid and with water successively, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel chromatography eluting with dichloromethane-n-hexane (1:5) to give the title compound (4.0 g).
Reaction SMILES: CO.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:11])[CH3:10].[BH4-].[Na+]>O>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([OH:11])[CH3:10]
Reactant: CC(=O)c1ccccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(O)c1ccccn1
Reaction time: 4 h
Yield: 88.5 %

Procedure:
A methanol solution (100 mL) of 1-pyridin-2-ylethanone (10.0 g) was cooled to 0° C., sodium borohydride (6.2 g) was added thereto and stirred at that temperature for 4 hours. Then water was added to the reaction solution, and the organic solvent was evaporated off under reduced pressure. The resulting residue was extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated off under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=4/1 to 3/2) to obtain the entitled compound (9.0 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2Br)[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1B(O)O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(COC)OC>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:33]2[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:32]=2[O:31][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(C2=C(Br)CCC2)c1
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCOC(=O)c1cccc(C2=C(c3cc(Cl)ccc3OCc3ccccc3)CCC2)c1

Procedure:
3-(2-Bromocyclopent-1-enyl)-benzoic acid ethyl ester (0.148 g, 0.0005 mol), Pd(0)[PPh3]4 (30 mg), potassium carbonate (0.2 g) and (2-benzyloxy-5-chlorophenyl) boronic acid (150 mg, 0.0005 mol) in dimethoxyethane (5 mL) were refluxed for 17 h under nitrogen. The reaction mixture was then filtered through Kieselghur and evaporated down to an oil. Purification was carried out on a Water's separation pack (10 g) with dichloromethane/isohexane giving the product (85 mg).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]([OH:8])[C:4]([F:7])([F:6])[F:5].[OH-].[Na+].[P:13](OC1C=CC=CC=1)([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[P:13]([O:8][CH:3]([C:4]([F:7])([F:6])[F:5])[C:2]([F:10])([F:9])[F:1])([O:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[O:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Reactant: OC(C(F)(F)F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)C(OP(Oc1ccccc1)Oc1ccccc1)C(F)(F)F
Reaction time: 1 h
Yield: 18.5 %

Procedure:
An amount of 28.2 mmol of 1,1,1,3,3,3-hexafluoro-2-propanol together with 0.1 mmol of solid sodium hydroxide was added to 84.6 mmol of triphenyl phosphite at a temperature of 22° C. The mixture thus formed was stirred for one hour and then heated under reflux for another hour. Then the solvent was evaporated from the mixture, giving a residue which was distilled at sub-atmospheric pressure to isolate the title compound in a yield of 18.5%, calculated on starting 1,1,1,3,3,3-hexafluoro-2-propanol.
Reaction SMILES: Br[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=[O:4].[Cl-:20].[Ca+2].[Cl-]>C(#N)C.[Cl-].C[N+](C)(C)C>[Cl:20][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=[O:4]
Reactant: CCCCCCCCCCCCCCC(Br)C(=O)O
Reactant: [Cl-]
Agent: C[N+](C)(C)C
Agent: [Ca+2]
Solvent: CC#N
Product: CCCCCCCCCCCCCCC(Cl)C(=O)O
Yield: 92.2 %

Procedure:
To 2-bromohexadecanoic acid (1 g), after having been dissolved in acetonitrile (50 ml), were added calcium chloride (5 g) and tetramethylammonium chloride (1 g), and the mixture was heated under reflux for 6 hours. The reaction mixture was filtered, concentrated and distributed into chloroform and water, and the chloroform layer was dried over anhydrous sodium sulfate and concentrated to give 2-chlorohexadecanoic acid (0.80 g). 2-Chlorohexadecanoic acid (893 mg), para-nitrophenol (428 mg) and N,N'-dicyclohexylcarbodiimide (634 mg) were dissolved in N,N-dimethylformamide (DMF), and the mixture was stirred for 12 hours. Precipitates were removed by filtration, and DMF was removed by distillation to give the active ester of 2-chlorohexadecanoic acid. To the active ester, which was dissolved in DMF (500 mg), were added again 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (465 mg) and triethylamine (1.2 ml), and the mixture was stirred for 12 hours. The reaction mixture was concentrated, and the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK135 in the yield of 262 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH:10]3[CH:19]4[CH2:20][CH2:21][C:16]5([CH2:17][CH2:18]4)[C:11]3([CH2:12][CH2:13][N:14]([CH3:23])[C:15]5=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.B.CSC.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[C:8]2[O:9][CH:10]3[CH:19]4[CH2:20][CH2:21][C:16]5([CH2:17][CH2:18]4)[C:11]3([CH2:12][CH2:13][N:14]([CH3:23])[CH2:15]5)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1OC1C3CCC4(CC3)C(=O)N(C)CCC214
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Product: COc1cccc2c1OC1C3CCC4(CC3)CN(C)CCC214

Procedure:
The 9-methoxy-3-methyl-1,2,5,6,7,7a-hexahydro-4a,7-ethanobenzofuro[3,2-e]isoquinolin-4(3H)-one (V; R1 =Me, R2 =OMe, R3 =H) so obtained was heated under reflux with 0.7 mL of borane-methyl sulfide in tetrahydrofuran overnight. Conc. hydrochloric acid was added, the tetrahydrofuran was removed, and the residue was heated under reflux with 7 mL of acetic acid and 3 mL of conc. hydrochloric acid for two hours. The solvents were removed, water and toluene were added, and the aqueous layer was made basic and extracted with methylene chloride. Removal of the solvent and short-path distillation of the residue [150° bath, 0.5 μm (0.07 Pa)] gave 0.52 g of 9-methoxy-3-methyl-1,2,3,4,5,6,7,7a-octahydro-4a,7-ethanobenzofuro[3,2-e]isoquinoline as a viscous oil that slowly solidified. NMR spectrum (220 MHz in CDCl3): τ3.1 (d/d, J=6.5/2.5 Hz, 1); 3.5 (m, 2); 5.7 (narrow m, 1); 6.2 (s, 3); 8.0 (s, 3); and 7.5-9.3 (m, 15).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][NH2:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].[CH:22]1([N:28]=[C:29]=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][NH:21][C:29]([NH:28][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:30])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCN
Reactant: O=C=NC1CCCCC1
Product: CCCCc1nc2cnc3ccccc3c2n1CCCNC(=O)NC1CCCCC1
Yield: 90.8 %

Procedure:
Using the general method of Example 146 Part B, 3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylamine (2.00 g, 7.08 mmol) was reacted with cyclohexyl isocyanate (1.0 g, 7.98 mmol) to provide 2.62 g of N-[3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-cyclohexylurea.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(S)cc1
Reactant: Clc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc(Sc2ccccn2)cc1
Temperature: 75 °C
Yield: 91.8 %

Procedure:
Under nitrogen atmosphere, 127 g of 4-hydroxythiophenol, 112 g of chloropyridine, and 140 g of potassium carbonate were mixed. To the mixture was added 250 mL of dimethylformamide. The resultant was stirred, heated to 75° C. and further heated at 10° C. for 5 hours. At the time when the reaction completed substantially, the resultant was poured into 1.5 L of water. The precipitated crystals were collected by filtration, washed with water, and dried (yielded amount 184 g, and yield 91.8%).