Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[N:16]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:19]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1.C(Cl)Cl>[ClH:26].[ClH:1].[ClH:26].[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]2[N:19]=[C:15]([CH:12]3[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]3)[N:16]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH:17]=2)=[CH:21][CH:22]=1
Reactant: CN(C)CCn1cc(-c2ccc(Cl)cc2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(C)CCn1cc(-c2ccc(Cl)cc2)nc1C1CCNCC1
Yield: 74.07 %

Procedure:
Add 4M HCl in 1,4-dioxane (2 mL) to 4-[4-(4-chloro-phenyl)-1-(2-dimethylamino-ethyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.8 g; 0.0018 mol; 1.0 equiv), in DCM and stir at RT for 6 h. Concentrate the reaction, crystallize from diethyl ether and filter to get the title compound (0.6 g; 74.07%). MS (ES+): m/z=333 (M+H)
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][C:29](OC)=[O:30])=[CH:21][CH:20]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])=[CH:23][CH:24]=1
Reactant: COC(=O)CCCCc1ccc(OCc2nc(-c3ccc4ccccc4c3)oc2C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(CCCCCO)cc1

Procedure:
According to the method described for Reference Example 45, 4-chloromethyl-5-methyl-3-(2-naphthyl)oxazole was allowed to react with methyl 5-(4-hydroxyphenyl)valerate to give methyl 5-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]phenyl]valerate. Then, according to the method described for Reference Example 42, methyl 5-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]phenyl]valerate was subjected to reduction with lithium aluminum hydride to give 5-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]phenyl]pentan-1-ol. Recrystallization from ethyl acetate--ether gave colorless needles, m.p.128°-129° C.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:30]([OH:36])(=[O:35])[CH2:31][C:32]([OH:34])=[O:33]>CO.ClCCl>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:30]([O-:36])(=[O:35])[CH2:31][C:32]([O-:34])=[O:33]
Reactant: O=C(O)CC(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: ClCCl
Solvent: CO
Product: O=C([O-])CC(=O)[O-]
Temperature: 27.5 °C
Reaction time: 15 h

Procedure:
Sunitinib (2.0 g) was suspended in 10% methanol in dichloromethane (30 mL) at 25° C., followed by addition of malonic acid (0.29 g) .The reaction mass was maintained under stirring at 25-30° C. for 15 hrs. The solids obtained were filtered, suck dried and dried under vacuum for a period of 10 hrs at 60° C. to obtain sunitinib malonate. (2.0 g; yield: 80%)
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([Cl:10])[CH:5]=[CH:4][N:3]=1.[C:11]([Si:15]([CH3:18])([CH3:17])Cl)([CH3:14])([CH3:13])[CH3:12].N1C=CN=C1.C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[C:7]([CH2:8][O:9][Si:15]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:18])[CH3:17])=[C:6]([Cl:10])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1c(Cl)ccnc1Br
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1c(Cl)ccnc1Br
Temperature: 15 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
A mixture of 160b (20 g, 90.0 mmol), tert-butyldimethylchlorosilane (17.6 g, 117 mmol) and imidazole (12.2 g, 180 mmol) in N,N-dimethylformamide (300 mL) was stirred at 15° C. for 12 h. See FIG. 5. TLC (petroleum ether:ethyl acetate=3:1) showed that the starting material was completely consumed. The mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL×2). The organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with petroleum ether:ethyl acetate=20:1) to afford 2-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-chloropyridine 160c (30 g, 99%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][C:17]#[N:18]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:16][C:17]#[N:18]
Reactant: Oc1cccc(F)c1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCOc1cccc(F)c1
Temperature: 50 °C
Yield: 94.2 %

Procedure:
To a solution of 3-fluorophenol (560 mg, 5.0 mmol) in DMF (10 mL) is added potassium carbonate (828 mg, 6.0 mmol) followed by chloroacetonitrile (0.315 mL, 50.0 mmol). The reaction mixture is stirred and heated at 50° C. for 14 h. The reaction mixture is cooled to RT, diluted with EtOAc, and washed with water, brine, then dried (MgSO4), and filtered. The filtrate is evaporated, and the residue purified by chromatography on silica gel; elution with dichloromethane gives 712 mg of the product 386.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH:5]=O.[CH3:14][NH:15][CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][N:15]([CH3:16])[CH3:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: CNC
Reactant: O=Cc1cc(Br)cc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)Cc1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)benzaldehyde (30 g, 118.6 mmol) in methylene chloride (150 mL) was added dimethylamine (2.0 M in THF, 118 mL) and the reaction was stirred at room temperature for 15 min. The reaction was cooled to 0° C. and sodium triacetoxyborohydride (37.7 g, 178 mmol) was added. The resulting mixture was warmed to room temperature and stirred for 3 h. The solvents were removed under reduced pressure and saturated sodium bicarbonate solution was added. The resulting mixture was extracted three times with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Silica gel chromatography (90/10 to 60/40 ethyl acetate/hexanes gradient) provided 1-[3-bromo-5-(trifluoromethyl)phenyl]-N,N-dimethylmethanamine as a colorless oil (Int-8, 24.9 g, 74% yield). LC-MS: (FA) ES+ 282; 1H NMR (300 MHz, CDCl3) δ ppm 7.68 (s, 1H), 7.65 (s, 1H), 7.52 (s, 1H), 3.44 (s, 2H), 2.25 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2Br)[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:29])[C:18](=[O:28])[NH:19][N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30](B(O)O)([CH3:32])=[CH2:31].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:30]([CH3:32])=[CH2:31])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:29])[C:18](=[O:28])[NH:19][N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)B(O)O
Reactant: CC1C(=O)NN=C2COc3cc(Br)c(OC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: C=C(C)c1cc2c(cc1OC1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)C1C)CO2
Temperature: 25 °C
Yield: 328.2 %

Procedure:
A mixture of 3-(7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester (Example #65, Step G, 0.030 g, 0.064 mmol), isopropenyl boronic acid (0.032 g, 0.193 mmol), K2CO3 (0.018 g, 0.13 mmol) and Pd(dppf)Cl2.CH2Cl2 (0.011 g, 0.013 mmol) in dioxane (3 mL) and H2O (0.5 mL) was stirred at 80° C. for 15 h. The mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was purified by preparative TLC (eluting with 20% EtOAc in petroleum ether) to give 3-(7-isopropenyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester as a white solid (0.09 g, 33%). LC/MS (Table 1, Method 2) Rt=1.241 min.; MS m/z: 429 [M+H]+.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(N(CC)CC)C.[CH:19]([O:22][CH2:23][C:24](Cl)=[O:25])([CH3:21])[CH3:20]>ClCCl>[CH:19]([O:22][CH2:23][C:24]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])=[O:25])([CH3:21])[CH3:20]
Reactant: COC(=O)c1ccccc1N
Reactant: CC(C)OCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccccc1NC(=O)COC(C)C
Temperature: 25 °C
Yield: 67.4 %

Procedure:
To a solution of 4.90 g (33 mmol) of methyl anthranilate and 6.1 ml of triethylamine in 50 ml of dichloromethane was dropwise added a solution of 4.43 g (33 mmol) of isopropoxyacetylchloride in 20 ml of dichloromethane under chilling with ice for a period of 15 min. The resulting mixture was stirred over night at room temperature. The reaction mixture was washed sequentially with 5 % aqueous sodium carbonate, 3 N hydrochloric acid and 5% aqueous sodium carbonate, and then was dried over anhydrous sodium sulfate. The solvent was distilled off to leave 5.59 g of the desired compound as a residual pale brown oil. (Yield: 68.6 %)
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[CH3:17][C:18]1[O:19][C:20]([C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:23]([C:21]3[N:22]=[C:18]([CH3:17])[O:19][C:20]=3[C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)=[O:24])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Reactant: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Product: Cc1cccc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3nc(C(C)(F)F)cs3)n2)c1

Procedure:
Following general procedure A, starting from 2-[4-(1,1-Difluoro-ethyl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid.
Reaction SMILES: C1(O[C:8](=[O:42])[O:9][CH2:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][N:29]([C:32]5[C:40]6[CH:39]=[CH:38][S:37][C:36]=6[CH:35]=[CH:34][CH:33]=5)[CH2:28][CH2:27]4)[CH:19]=3)[CH2:14][CH2:13][C:12]2=[O:41])C=CC=CC=1.[NH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1.N12CCCN=C1CCCCC2.O>C1COCC1>[S:37]1[CH:38]=[CH:39][C:40]2[C:32]([N:29]3[CH2:28][CH2:27][N:26]([CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:18]4[CH:19]=[C:20]5[C:15]([CH2:14][CH2:13][C:12](=[O:41])[N:11]5[CH2:10][O:9][C:8]([N:43]5[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]5)=[O:42])=[CH:16][CH:17]=4)[CH2:31][CH2:30]3)=[CH:33][CH:34]=[CH:35][C:36]1=2
Reactant: C1CCNCC1
Reactant: O=C(OCN1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21)Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCN1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21)N1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
To a solution (3 ml) of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester phenyl ester (0.29 g) synthesized in the same manner as in Example 5 in THF were added piperidine (0.5 ml) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.05 ml), and the mixture was stirred at room temperature for 16 hr. Water was added and the reaction mixture was extracted with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by moderate-pressure basic silica gel column chromatography (hexane:ethyl acetate=1:0 to 1:1) to remove phenol, and concentrated under reduced pressure. The residue was purified by moderate-pressure silica gel column chromatography (hexane:ethyl acetate=1:0 to 0:1) to give the title compound (yield 0.21 g, 74%) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)#[N:2].[O:16]([CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C.O>[O:16]([CH2:23][CH2:24][CH2:25][N:26]1[CH2:27][CH2:28][N:29]([CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:3]2([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:1]#[N:2])[CH2:30][CH2:31]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Reactant: c1ccc(OCCCN2CCNCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: N#CC1(c2ccccc2)CCCCC1N1CCN(CCCOc2ccccc2)CC1
Temperature: 25 °C
Yield: 50 %

Procedure:
5.0 g (0.025 mol) of 4-cyano-4-phenylcyclohexanone and 5.5 g (0.025 mol) of 3-phenoxypropylpiperazine were dissolved with 3.0 g of acetic acid in 70 ml of ethanol and then, while stirring at room temperature, a solution of 1.7 g (0.027 mol) of sodium cyanoborohydride was slowly added dropwise. The mixture was stirred overnight and then diluted with water and extracted with dichloromethane. The organic phase was subsequently washed with dilute acid (pH 4), dilute sodium hydroxide solution and water and finally dried and evaporated. The residue was converted into the hydrochloride with isopropanolic hydrochloric acid, and the product was recrystallized from isopropanol/water. Yield: 50%, C26H33N3O×2 HCl dihydrochloride, melting point >250° C.
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:7][CH2:6][C:5]([C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)([C:8]#[N:9])[CH2:4][CH2:3]1.O.C(O)([C:20](F)([F:22])[F:21])=O.C(OO)(C)(C)C>FC(C1C=CC=CC=1)(F)F>[F:21][CH:20]([F:22])[C:13]1[N:12]=[CH:11][C:10]([C:5]2([C:8]#[N:9])[CH2:4][CH2:3][C:2]([F:1])([F:16])[CH2:7][CH2:6]2)=[CH:15][N:14]=1
Reactant: O=C(O)C(F)(F)F
Reactant: N#CC1(c2cncnc2)CCC(F)(F)CC1
Agent: CC(C)(C)OO
Solvent: O
Solvent: FC(F)(F)c1ccccc1
Product: N#CC1(c2cnc(C(F)F)nc2)CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To a solution of compound 4,4-difluoro-1-(pyrimidin-5-yl)-cyclohexanecarbonitrile (1.5 g, 6.72 mmol) and DFMS (6.0 g, 0.02 mol) in trifluoromethylbenzene (53 mL) and H2O (21 mL) at room temperature was added TFA (766 mg, 6.72 mmol) followed by slow addition of t-BuOOH (5.2 g, 70% solution in H2O) with vigorous stirring. The reaction mixture was stirred at room temperature overnight. TLC indicates about 50% starting material remained, a second addition of DFMS (6.0 g, 0.02 mol) and t-BuOOH(5.2 g, 70% solution in H2O) were added to the reaction mixture. Upon consumption of starting material, the reaction mixture was portioned between DCM (20 mL) and saturated NaHCO3 solution (20 mL), the organic layer was separated and the aqueous layer was extracted with DCM (3×20 ml). The organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (Petroleum ether:EtOAc=3:1) to give 1-(2-(difluoromethyl)pyrimidin-5-yl)-4,4-difluorocyclohexanecarbonitrile (800 mg, Yield: 44.4%). 1H NMR (CDCl3 400 MHz): δ9.03 (s, 2H), 6.71 (t, J=54.4 Hz, 1H), 2.40-2.27 (m, 6H).
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[CH2:14]([CH2:16][NH2:17])[OH:15]>>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([NH:17][CH2:16][CH2:14][OH:15])[NH:7][C:6]=2[CH:8]=1
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Reactant: NCCO
Product: O=S1(=O)N=C(NCCO)Nc2cc(Cl)sc21
Temperature: 0 °C
Yield: 60 %

Procedure:
A solution of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (206 mg, 0.8 mmol) in ethanolamine (1.0 ml) was stirred for 18 h at 100° C. in a sealed flask. The cooled solution was concentrated in vacuo and the residue was stirred with water (5 ml) at 0° C. followed by adjustment to pH 2 with 4M hydrochloric acid. The product was isolated by filtration, washed with water, and recrystallised from ethanol/water to give 135 mg (60%) of the pure title compound; mp 260-261° C. dec.; 1H-NMR (DMSO-d6): δ3.26 (distorted q, 2H), 3.50 (t, 2H), 4.85 (br s, 1H), 7.07 (s, 1H), 7.20 (br s, 1H), 10.9 (br s, 1H); MS: m/e 281/283 (M+); (C7H8N3Cl1O3S2) calc C, 29.84; H, 2.86; N, 14.91; found C, 30.13; H, 2.84; N, 14.79.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[C:8]([I:14])[CH:7]=1>ClCCl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([I:14])[CH:7]=1
Reactant: COc1ccc(Cl)cc1I
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(Cl)cc1I
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.6 %

Procedure:
109.4 g (0.436 mol) of boron tribromide were added over 10 minutes to a stirred solution of 90 g (0.335 mol) of 4-chloro-2-iodoanisole in dichloromethane (900 ml) at −78° C. under nitrogen. Cooling was removed and allowed to warm to room temperature and stirred for 5 hours. Poured onto ice and diluted with a further 800 ml of water. The organic phase was separated, the aqueous extracted with dichloromethane and the combined organics washed with saturated sodium bicarbonate, dried and evaporated to give 84.87 g of off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[C:19]3[CH2:20][CH2:21][CH2:22][C:23](=[O:24])[C:18]=3[O:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[F:25][C:26]1[CH:27]=[C:28]([Mg]Br)[CH:29]=[C:30]([F:32])[CH:31]=1>C1COCC1>[F:25][C:26]1[CH:27]=[C:28]([C:23]2([OH:24])[C:18]3[O:17][N:16]=[C:15]([C:5]4[CH:6]=[CH:7][C:8]([N:9]5[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]5)=[C:3]([O:2][CH3:1])[CH:4]=4)[C:19]=3[CH2:20][CH2:21][CH2:22]2)[CH:29]=[C:30]([F:32])[CH:31]=1
Reactant: Fc1cc(F)cc([Mg]Br)c1
Reactant: COc1cc(-c2noc3c2CCCC3=O)ccc1-n1cnc(C)c1
Solvent: C1CCOC1
Product: COc1cc(-c2noc3c2CCCC3(O)c2cc(F)cc(F)c2)ccc1-n1cnc(C)c1
Reaction time: 3 h
Yield: 69.6 %

Procedure:
To a mixture of 3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5,6-dihydrobenzo[d]isoxazol-7(4H)-one (880 mg, 2.72 mmol) in THF (15 ml) at 0° C., was added slowly (3,5-difluorophenyl)magnesium bromide (6.54 mL of 0.5 M solution in THF, 3.27 mmol) and the reaction was stirred for 3 hr. Additional amount of (3,5-difluorophenyl)magnesium bromide (6.0 mL of 0.5 M solution in THF, 3.0 mmol) was added and stirring was continued at 0° C. for 2 hr. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic phase was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography using 0-6% MeOH in DCM as solvent to afford the 828 mg of the title product.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:7]=[C:8]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][S:12][C:10]=2[N:11]=1)C.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[C:15]1([C:14]2[C:9]3[C:8]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[N:7][C:6]([CH2:5][CH2:4][OH:3])=[N:11][C:10]=3[S:12][CH:13]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)Cc1nc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: OCCc1nc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
A stirred solution of {5-phenyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3-d]pyrimidin-2-yl}acetic acid ethyl ester (0.10 g, 0.248 mmol) in anhydrous tetrahydrofuran (1 ml) was cooled in an ice-bath and treated, under a nitrogen atmosphere, with diisobutylaluminium hydride (1M solution in hexane, 1.04 ml, 1.04 mmol) over about 15 minutes. The reaction mixture was allowed to warm up and left to stir at ambient temperature for 3 hours. The resultant mixture was then cooled in an ice-bath and quenched by the slow addition of methanol (0.5 ml) followed by water (1 ml). The mixture was then diluted with 2M sodium hydroxide solution (10 ml) and extracted with ethyl acetate (3×20 ml). The combined organic extracts were dried (MgSO4) and the solvent removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with ethyl acetate and 40°-60° petroleum ether (4:1) gave 2-{5-phenyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3-d]pyrimidin-2-yl}ethanol as an off-white solid (0.05 g), m.p. 90°-92° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:18]=2[NH:19][C:20]2[C:21]([CH3:30])=[C:22]3[C:26](=[C:27]([Cl:29])[CH:28]=2)[NH:25][CH:24]=[CH:23]3)[C:16]#[N:17])=[CH:7][CH:6]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>COCCOC>[Cl:29][C:27]1[CH:28]=[C:20]([NH:19][C:18]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[CH:12][C:11]=2[C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)=[CH:10][CH:9]=2)[C:21]([CH3:30])=[C:22]2[C:26]=1[NH:25][CH:24]=[CH:23]2
Reactant: CN1CCNCC1
Reactant: Cc1c(Nc2c(C#N)cncc2-c2ccc(OCCCl)cc2)cc(Cl)c2[nH]ccc12
Solvent: COCCOC
Product: Cc1c(Nc2c(C#N)cncc2-c2ccc(OCCN3CCN(C)CC3)cc2)cc(Cl)c2[nH]ccc12
Yield: 93.1 %

Procedure:
A solution of 5-[4-(2-chloroethoxy)phenyl]-4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]nicotinonitrile (144 mg, 0.3 mmol) and 1-methylpiperazine (330 mg, 3.3 mmol) in DME (3 mL) was stirred at 110° C. for 48 h. After the solution was concentrated, 1 N HCl was added and the aqueous phase was extracted with ethyl acetate, adjusted to pH of 10 by adding sodium carbonate, and extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over magnesium sulfate, and concentrated to give 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-{4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}nicotinonitrile as a yellow solid (140 mg, 84% yield). HPLC retention time: 5.1 min.(g); MS: 501.3 (M+H); and HRMS: 501.2159.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH2:9])=[CH:3][CH:2]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:11](=[O:13])[CH3:12])=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(CCN)cc1
Product: CC(=O)NCCc1ccc(C)cc1

Procedure:
In close analogy to the procedure described above, 2-p-tolyl-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: Br.C[O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]([OH:17])=[O:16])=[N:13][CH:14]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>>[OH:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]([OH:17])=[O:16])=[N:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc(Cc2ccc(C(=O)O)nc2)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(Cc2ccc(O)cc2)cn1
Yield: 70.7 %

Procedure:
Five milliliters of 47% hydrobromic acid were added to 1.5 g of 5-(4-methoxybenzyl)picolinic acid. The mixture was heated under reflux for three hours. After allowing to cool, the reaction mixture was adjusted to around pH 2 with 10% aqueous NaOH solution to form crystals. The crystals were collected by filtration and then recrystallized from methanol to obtain 1.0 g of 5-(4-hydroxybenzyl)-picolinic acid as crystals of a melting point of 213°~215° C.