Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:17][C@@H:18]1[CH2:23][NH:22][CH2:21][CH2:20][NH:19]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.O(C(C)(C)C)[Na]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:17][C@H:18]1[NH:19][CH2:20][CH2:21][N:22]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]3[S:16][N:15]=[CH:14][N:13]=3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH2:23]1
Reactant: O=S(=O)(Nc1ncns1)c1ccc(Br)cc1
Reactant: C[C@@H]1CNCCN1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2ccc(S(=O)(=O)Nc3ncns3)cc2)CCN1
Yield: 18.8 %

Procedure:
Synthesized according to general procedure 8. The reaction was set up with 4-bromo-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (4.7 mmol), (R)-2-methylpiperazine (4.7 mmol), Pd2(dba)3 (0.12 mmol), 2-(di-t-butylphosphino)biphenyl (0.50 mmol), NaO-tBu (10 mmol), and toluene (12 mL). For the purification, 10% MeOH in CH2Cl2 with the addition of 1% triethylamine was used as a solvent system to obtain the desired amine as a white solid (300 mg, 19% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=340.2; tR=1.56 min.
Reaction SMILES: O=P(Cl)(Cl)Cl.[C:6]1([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN([CH:26]=[O:27])C.[OH-].[Na+]>O>[CH:26]([C:14]1[S:13][C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=1)=[O:27]
Reactant: CN(C)C=O
Reactant: c1ccc(-c2ccsc2-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cc(-c2ccccc2)c(-c2ccccc2)s1
Temperature: 25 °C

Procedure:
POCl3 (80 mmol, 7.32 mL) was added at 0° C. to a solution of 2,3-diphenylthiophene (18 g, 76 mmol) in DMF (18 mL, 0.23 mol). At the end of the addition, the reaction mixture was allowed to warm to room temperature and refluxed for 3 h. Then it was cooled to room temperature and poured into a mixture of ice and a 10% solution of sodium hydroxide in water. The oily precipitate obtained was filtered and washed with cold methanol and hexane. The residue was crystallized. Yield 15 g (75%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([NH:15][C:16]2[C:17](=[O:35])[N:18]([C:22]3[CH:23]=[C:24]([CH:31]=[CH:32][C:33]=3[CH3:34])[C:25]([NH:27][CH:28]3[CH2:30][CH2:29]3)=[O:26])[CH:19]=[CH:20][N:21]=2)[CH2:14][CH2:13][CH2:12]1.[CH2:36]([CH2:38][NH2:39])[OH:37]>>[CH:28]1([NH:27][C:25](=[O:26])[C:24]2[CH:31]=[CH:32][C:33]([CH3:34])=[C:22]([N:18]3[CH:19]=[CH:20][N:21]=[C:16]([NH:15][C:11]4([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[O:4][CH2:3][CH2:2][NH:39][CH2:38][CH2:36][OH:37])[CH2:14][CH2:13][CH2:12]4)[C:17]3=[O:35])[CH:23]=2)[CH2:30][CH2:29]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CCC2)c1=O
Reactant: NCCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCNCCO)CCC2)c1=O

Procedure:
The title product was prepared from 3-(3-(1-(2-(2-chloroethoxy)phenyl)cyclobutylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide (Example 268 g) and ethanolamine using a similar method to that described for example 167f.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@H:15]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH3:16])[NH:13][C:12]1=[O:27])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].[OH-].[Na+]>C(Cl)Cl.[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O.C(OCC)C>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@H:15]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH3:16])[N:13]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:12]1=[O:27])[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)OCc1ccccc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(CC(=O)OC(C)(C)C)[C@@H]1[C@@H](C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3S,4S)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-[(1R)-1-benzyloxycarbonylethyl]azetidin-2-one (755 mg) in methylene chloride (10 ml), there were added successively t-butyl bromoacetate (1.88 g), 50% sodium hydroxide (620 mg) and triethylbenzylammonium chloride (220 mg), followed by stirring at room temperature for 2 hours. The reaction mixture was diluted with water and diethyl ether. The aqueous layer was separated from the organic layer and extracted two times with diethyl ether. The extracts were combined with the organic layer, washed with water two times and brine three times, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography to give (3S,4S)-3-[(1R)-1-t-butyl-dimethylsilyloxyethyl]-4-[(1R)-1-benzyloxycarbonylethyl]-1-(t-butyloxycarbonylmethyl)azetidin-2-one.
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[CH3:16][O:17][CH2:18][C:19]#[C:20][C:21]([OH:23])=O.[NH2:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[CH:30][C:29]([C:35]#[N:36])=[C:28]2[NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([Br:44])[CH:39]=1>O1CCCC1.N1C=CC=CC=1>[Br:44][C:40]1[CH:39]=[C:38]([NH:37][C:28]2[C:27]3[C:32](=[CH:33][CH:34]=[C:25]([NH:24][C:21](=[O:23])[C:20]#[C:19][CH2:18][O:17][CH3:16])[CH:26]=3)[N:31]=[CH:30][C:29]=2[C:35]#[N:36])[CH:43]=[CH:42][CH:41]=1
Reactant: COCC#CC(=O)O
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Product: COCC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.2 %

Procedure:
Isobutyl chloroformate(0.410 g, 3.0 mmol) and N-methylmorpholine(0.910 g, 9.0 mmol) were added to an ice cold solution of 0.680 g (6.0 mmol) of 4-methoxy-2-butynoic acid in 20 mL of tetrahydrofuran under N2. After stirring for 30 min, a solution of 0.500 g (01.47 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 10 mL of pyridine was added and the mixture was stirred at 0° C. for 2 h. The reaction was quenched with ice water, and then poured into saturated sodium bicarbonate and brine. The product was collected, washed with ethyl acetate, and dried in vacuo to give 0.200 g (35%) of yellow solid; ESMS m/z 435.1 (M+H+); mp 198-202° C.(dec).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[N:6]=[C:5]2[NH:24][CH2:25][C:26]([F:29])([F:28])[F:27].[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:18][CH:19]=2)[N:6]=[C:5]3[NH:24][CH2:25][C:26]([F:27])([F:28])[F:29])=[CH:33][CH:32]=1
Reactant: NS(=O)(=O)c1ccc(CNc2nc(NCC(F)(F)F)c3cc(Br)ccc3n2)cc1
Reactant: OB(O)c1ccc(F)cc1
Product: NS(=O)(=O)c1ccc(CNc2nc(NCC(F)(F)F)c3cc(-c4ccc(F)cc4)ccc3n2)cc1

Procedure:
The title compound was synthesized by analogy to Example 51 using 4-{[6-bromo-4-(2,2,2-trifluoro-ethylamino)-quinazolin-2-ylamino]-methyl}-benzenesulfonamide and 4-fluorobenzene boronic acid. The resulting product was characterized as follows: MS (m/z): 506 ([M+H]+, 100); HPLC Rt=2.85 minutes (Method A).
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([Cl:14])=[CH:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11])(=O)C.B(F)(F)F.CCOCC>CO>[NH2:4][C:5]1[S:6][C:7]([Cl:14])=[CH:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc(Cl)sc1NC(C)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1cc(Cl)sc1N

Procedure:
A mixture of 14.2 parts of methyl 2-acetamido-5-chlorothiophene-3-carboxylate, 360 parts by volume of methanol and 30 parts by volume of boron trifluoride-etherate is refluxed for 4 hours. After evaporation of the solvent the residue is treated in a manner similar to that used in Reference Example 19, whereby methyl 2-amino-5-chlorothiophene-3-carboxylate is obtained as crystals melting at 100°-102.5° C. This product is identical with that obtained in Reference Example 19.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:28]=[C:27]([S:29][CH3:30])[CH:26]=[CH:25][C:14]=1[C:15]([C:17]1[CH:18]=[N:19][O:20][C:21]=1[CH:22]1[CH2:24][CH2:23]1)=[O:16].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>ClCCl>[Cl:12][C:13]1[CH:28]=[C:27]([S:29]([CH3:30])=[O:9])[CH:26]=[CH:25][C:14]=1[C:15]([C:17]1[CH:18]=[N:19][O:20][C:21]=1[CH:22]1[CH2:24][CH2:23]1)=[O:16]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(C(=O)c2cnoc2C2CC2)c(Cl)c1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1ccc(C(=O)c2cnoc2C2CC2)c(Cl)c1
Temperature: -15 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
3-Chloroperbenzoic acid (1.3 g) was added to a solution of 4-[2-chloro-4-(methylsulphenyl)benzoyl]-5-cyclopropylisoxazole (2.0 g) in dichloromethane whilst maintaining the temperature below -15° C. The mixture was stirred at -15° C. for 2 hours and allowed to warm to room temperature. The mixture was stirred for 2 hours and then recooled to -15° C. 3-Chloroperbenzoic acid (0.7 g) was added and the mixture was stirred at -15° C. for 1 hour and at room temperature for 1 hour. A solution of sodium metabisulphite was added. The organic layer was washed with water, dried (magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was purified by column chromatography on silica eluted with ethyl acetate and hexane (3:2) to give 4-[2-chloro-4-(methylsulphinyl)benzoyl]-5-cyclopropylisoxazole (1.3 g) as a white solid, m.p.117° C.
Reaction SMILES: [CH3:1][C:2]12[CH2:12][C:6]3([CH2:13][N:14]4[C:18]([CH3:19])=[CH:17][CH:16]=[N:15]4)[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([O:20][CH2:21][CH2:22][OH:23])([CH2:5]3)[CH2:3]1)[CH2:9]2.[I:24]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]12[CH2:3][C:4]3([O:20][CH2:21][CH2:22][OH:23])[CH2:10][C:8]([CH3:11])([CH2:7][C:6]([CH2:13][N:14]4[C:18]([CH3:19])=[C:17]([I:24])[CH:16]=[N:15]4)([CH2:5]3)[CH2:12]1)[CH2:9]2
Reactant: Cc1ccnn1CC12CC3(C)CC(C)(C1)CC(OCCO)(C3)C2
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(I)cnn1CC12CC3(C)CC(C)(C1)CC(OCCO)(C3)C2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the 2-({3,5-dimethyl-7-[(5-methyl-1H-pyrazol-1-yl)methyl]tricyclo[3.3.1.13,7]dec-1-yl}oxy)ethanol (3.5 g, 11 mmol) in N,N-dimethylformamide (30 ml) was added N-iodosuccinimide (3.2 g, 14.22 mmol). The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was then diluted with ethyl acetate and washed with aqueous sodium thiosulfate, water and brine. After drying over anhydrous sodium sulfate, the mixture was filtered and concentrated. The residue was purified by normal phase chromatography to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:6]1[C:14]2[NH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)([CH3:5])[CH3:4].ClCCl.[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>C(N(CC)CC)C>[CH:27]([C:26]([NH:1][CH2:2][C:3]([C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[NH:11][C:10]=2[CH:14]=1)([CH3:4])[CH3:5])=[O:30])([CH3:29])[CH3:28]
Reactant: CC(C)C(=O)Cl
Reactant: COc1ccc(-c2nc3cccc(C(C)(C)CN)c3[nH]2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2nc3ccc(C(C)(C)CNC(=O)C(C)C)cc3[nH]2)cc1
Reaction time: 10 h

Procedure:
1.9 g. 4-(2-Aminomethylpropan-2-yl)-2-(4-methoxyphenyl)-benzimidazole (obtained in Example 6) in 200 ml. dichloromethane are reacted with 2.5 ml. triethylamine and 0.82 g. isobutyric acid chloride at ambient temperature. After 10 hours, the solvent is removed in a vacuum and the residue is digested with water and 2N aqueous ammonia solution. The reaction mixture is extracted 4 times with dichloromethane and the organic phase is dried over anhydrous sodium sulphate, filtered and evaporated. Ethyl acetate is added thereto, a part thereof is distilled off with the dichloromethane and left to crystallise and the product is filtered with suction. The product is recrystallised from ethyl acetate to give 0.6 g. of the title compound; m.p. 218°-220° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([CH:8]([OH:17])[C:9]([F:16])([F:15])[C:10](OCC)=[O:11])[CH:7]=1.[BH4-].[Na+]>CO.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([CH:8]([OH:17])[C:9]([F:16])([F:15])[CH2:10][OH:11])[CH:7]=1
Reactant: CCOC(=O)C(F)(F)C(O)c1cc(Br)ccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: OCC(F)(F)C(O)c1cc(Br)ccc1F
Reaction time: 1 h

Procedure:
To a solution of ethyl 3-(5-bromo-2-fluorophenyl)-2,2-difluoro-3-hydroxypropanoate (20.0 g, 61.3 mmol) in MeOH (160 mL), NaBH4 (7.0 g, 184.2 mmol) was added portion wise over a period of 30 min. at 0° C. Stirring was continued for 1 h at 0° C. and reaction was monitored by TLC. Upon complete consumption of the starting material, reaction mass was concentrated under reduced pressure and treated with saturated ammonium chloride solution. The crude reaction mass was dissolved in ethyl acetate and organic layer was washed with brine (15 mL) followed by drying over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure to furnish title compound with sufficient purity. Yield=17 g (97%). TLC (50% ethyl acetate in Hexane): Rf=0.32),
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]([F:46])([F:45])[C:11]1[CH:12]=[C:13]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:14][N:15]([C:32]1[N:33]=[N:34][N:35]([CH3:37])[N:36]=1)[C@H:16]1[CH2:22][CH2:21][CH2:20][NH:19][C:18]2[CH:23]=[C:24]([C:28]([F:31])([F:30])[F:29])[C:25]([CH3:27])=[CH:26][C:17]1=2>C(O)(=O)C>[F:46][C:10]([F:45])([F:9])[C:11]1[CH:12]=[C:13]([CH:38]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:40]=1)[CH2:14][N:15]([C@H:16]1[CH2:22][CH2:21][CH2:20][NH:19][C:18]2[C:23]([Br:1])=[C:24]([C:28]([F:29])([F:30])[F:31])[C:25]([CH3:27])=[CH:26][C:17]1=2)[C:32]1[N:33]=[N:34][N:35]([CH3:37])[N:36]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Solvent: CC(=O)O
Product: Cc1cc2c(c(Br)c1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reaction time: 2 h
Yield: 91.8 %

Procedure:
Add N-bromosuccinimide (1.10 g, 6.19 mmol) in one portion to a solution of (S)-(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine (2.85 g, 5.16 mmol) (Example 3, Step 18) in acetic acid (25 mL) at room temperature. Stir for 2 hours. Evaporate the solvent under reduced pressure. Partition the residue between ethyl acetate (250 mL) and aqueous Na2CO3 (250 mL). Separate the layers, dry over Na2SO4, filter and concentrate. Purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (0-30%), to provide the title compound as an off-white solid (2.99 g, 92%). MS (ES+): 631, 633 (M+H).
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[CH2:9]1)C1C=CC=CC=1.[CH3:19][NH:20][CH3:21]>>[CH3:19][N:20]([CH3:21])[C:13]1[CH:12]=[CH:11][C:10]2[CH2:9][NH:8][CH2:17][CH2:16][C:15]=2[N:14]=1
Reactant: Clc1ccc2c(n1)CCN(Cc1ccccc1)C2
Reactant: CNC
Product: CN(C)c1ccc2c(n1)CCNC2

Procedure:
N,N-Dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine was prepared via reaction of 6-benzyl-2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine with dimethylamine, followed by hydrogenation to remove the protecting group.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N+:12]([O-])([OH:14])=[O:13]>CC(O)=O>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([OH:11])=[C:6]([N+:12]([O-:14])=[O:13])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(O)cc1OC
Solvent: CC(=O)O
Product: COc1cc(O)c([N+](=O)[O-])cc1OC

Procedure:
In SCHEME 9 3,4-dimethoxyphenol (36) is selectively nitrated with 70% HNO3 in AcOH to give 4,5-dimethoxy-2-nitrophenol (37) which is further converted to the corresponding triflate (38) with trifluoromethylsulfonic anhydride (Tf2O) and pyridine in dichloromethane. Triflate (38) is reacted under inert conditions with a boronic acid of general type (31) under Suzuki-type basic conditions (Pd(PPh3)4 and aqueous potassium phosphate in toluene) to a biaryl of type (39). Biaryl (39) is further hydrolized with aqueous lithium hydroxide in THF and MeOH or MeCN to give the corresponding carboxylic acid (40) which is converted to a building block of type (41) by reaction with oxalyl chloride in anhydrous dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][CH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][N:23]([CH2:25][CH2:26][OH:27])[CH3:24])[CH2:18][CH2:17]1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:28].[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:17][CH2:18][C@H:19]([CH2:22][N:23]([CH2:25][CH2:26][OH:27])[CH3:24])[CH2:20][CH2:21]2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1NC1CCC(CN(C)CCO)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](CN(C)CCO)CC1

Procedure:
Following general procedure II, 1-[6-chloro-4-(4-{[(2-hydroxyethyl)(methyl)-amino]methyl}cyclohexylamino)-1,5-naphthyridin-3-yl]ethanone (70 mg, 0.18 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (76 mg, 0.27 mmol) followed by formation of the dihydrochloride salt to afford the desired product (68 mg, 64%) as a light yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.15 (s, 1H), 8.46 (d, J=9.0 Hz, 1H), 8.34 (d, J=9.0 Hz, 1H), 8.12 (s, 2H), 5.74-5.71 (m, 1H), 3.90 (t, J=5.0 Hz, 2H), 3.39-3.37 (m, 1H), 3.28-3.26 (m, 2H), 3.06-3.02 (m, 1H), 2.97 (s, 3H), 2.76 (m, 3H), 2.46-2.43 (m, 2H), 2.13-2.03 (m, 3H), 1.69-1.66 (m, 2H), 1.44-1.42 (m, 2H); ESI MS m/z 517 [M+H]+; HPLC>99% (AUC), tR=9.74 min.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][OH:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Br:23]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][OH:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:23])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrBr
Reactant: Nc1nc(OCCCO)nc2c1ncn2Cc1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Nc1nc(OCCCO)nc2c1nc(Br)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54 %

Procedure:
6-Amino-9-benzyl-2-(3-hydroxypropoxy)purine (210 mg, 0.7 mmol) and bromine (0.5 ml) were dissolved in methylene chloride (200 ml). The solution was stirred at room temperature for 4 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on magnesium sulfate and concentrated in vacuo to dryness. The residue was purified with silica gel chromatography (5% methanol/chloroform) to give the subject compound (143 mg, yield 54%).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)N.Cl.N([O-])=O.[Na+].[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>O.[Cu]>[CH:19]1[CH:20]=[CH:21][C:16]([S:22][C:3]2[C:2]([C:1]([OH:10])=[O:9])=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:17][CH:18]=1
Reactant: Sc1ccccc1
Reactant: Nc1ccccc1C(=O)O
Agent: [Cu]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: O=C(O)c1ccccc1Sc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Anthranilic acid (41.0 g, 300 mmol) is dissolved in 200 mL of water, then 64 mL of HCl is added. The solution is cooled to 0° C. and diazotized with a solution of NaNO2 (22 g, 319 mmol) in 45 mL of water. The diazonium salt solution is stirred at 0° C. for 30 min. and then is kept at 0° C. while it is added dropwise during the course of 2.5 hours to a rapidly stirring, 0° C. solution of thiophenol (34.0 g, 309 mmol) in 300 mL of water containing 60 g (1500 mmol) of NaOH and 3 g of copper powder. Caution is exercised during the addition because of the explosive nature of diazo sulfide which can accumulate during addition. The mixture is stirred at 0° C. for 1 hour, allowed to warm to 25° C. overnight and then heated in a steam bath for 1 hour. The mixture is cooled and the solid is removed by filtration and washed with 200 mL of cold water. The combined filtrates are acidified with concentrated HCl, and the brown precipitate is collected and recrystallized successively with ethanol, ethanol-water (3:2) and benzene-hexane to give 2-carboxydiphenyl sulfide. 2-Carboxydiphenyl sulfide is dissolved in 100 mL of methanol and chilled to 0° C., then poured into a 100 mL of aqueous 0.51 M sodium metaperiodate at 0° C. The mixture is stirred overnight, then the solvent is evaporated. The solid residue is washed with water and recrystallized from ethanol-water to give 2-carboxydiphenyl sulfoxide. Other examples of the synthesis of 2-carboxydiphenyl sulfoxide can be found in the following references: Mayer, F., Chem. Ber. (1909), 42:3047; Weedon, et al., Am. Chem. J. (1905), 33:392-402; Brannigan, et al., J Med. Chem. (1976), 19:798; Livant, Martin, J. Am. Chem. Soc. (1977), 99:5761; Brown, et al., J. Chem. Soc. Perkin Trans. I(1972), 2842; Dhareshwar, Hosangadi, Indian J. Chem. Sec. B (1978), 16:143.