Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)CO.[CH3:5][O:6][C:7]1[C:12]([O:13]C)=[C:11]([O:15][CH3:16])[CH:10]=[C:9](C=O)[CH:8]=1.C([O-])([O-])=O.[K+].[K+].O>C1(C)C=CC=CC=1>[CH3:16][O:15][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([O:6][CH3:5])[C:12]=1[OH:13]
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: OCCO
Product: COc1cccc(OC)c1O
Reaction time: 1 h
Yield: 65.5 %

Procedure:
By way of comparison, a test was carried out with a larger amount of ethylene glycol than that of Example 6. By heating under nitrogen with distillation 212 g (1 mole) of TMBA, 194 g (3 moles) of potash in pellets and 800 ml of ethylene glycol, reaction takes place. The temperature passes from 151° to 190° C. in 1 hour 20; it is held for 2 hours at 190° C. After cooling, dilution with water and neutralization to pH 6, there was obtained, by toluene extraction, 101 g of 2,6-dimethoxy phenol namely a yield of 65.6%. After recrystallization in a water/methanol mixture, with 10% of methanol, the product melted at 54°-55° C. By using a larger amount of ethylene glycol, demethylation and decarboxylation were hence produced.
Reaction SMILES: [NH:1]([C:8]1[N:17]=[CH:16][C:15]2[CH2:14][CH2:13][C:12]3[C:18]([C:22](OCC)=[O:23])=[N:19][N:20]([CH3:21])[C:11]=3[C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([CH2:29][NH2:30])[OH:28]>CO.CN(C)C=O>[NH:1]([C:8]1[N:17]=[CH:16][C:15]2[CH2:14][CH2:13][C:12]3[C:18]([C:22]([NH:30][CH2:29][CH2:27][OH:28])=[O:23])=[N:19][N:20]([CH3:21])[C:11]=3[C:10]=2[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccccc3)nc1-2
Reactant: NCCO
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1nc(C(=O)NCCO)c2c1-c1nc(Nc3ccccc3)ncc1CC2
Temperature: 65 °C
Yield: 60 %

Procedure:
To a suspension of 0.30 g (0.86 mmol) of ethyl 8-anilino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate in a mixture of 10 mL of methanol and 10 mL of dimethylformamide, 5 mL of ethanolamine were added. The mixture was heated in a close bottle under stirring at 65° C. After 5 hours the solvent was removed, the residue redissolved with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and evaporated. The residue was triturated with diethyl ether and the product collected by filtration (60% yield).
Reaction SMILES: [Cl:1][C:2]([O:4][CH2:5][CH3:6])=[O:3].N[C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[C:13]([SH:15])[S:14][C:10]=2[CH:9]=1.C([N:20](CC)CC)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[ClH:1].[CH2:5]([O:4][C:2]([NH:20][N:12]1[C:11]2[CH:16]=[CH:17][CH:8]=[CH:9][C:10]=2[S:14][CH:13]1[SH:15])=[O:3])[CH3:6]
Reactant: CCN(CC)CC
Reactant: Nc1ccc2nc(S)sc2c1
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)NN1c2ccccc2SC1S
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Ethyl chloroformate (23.88 g, 0.22 mole) was added dropwise to a solution of 6-amino-2-mercaptobenzothiazole (18.23 g, 0.1 mole), triethylamine (22.26 g, 0.22 mole), 4-dimethylaminopyridine (100 mg) in N,N-dimethylformamide (100 ml) with stirring at 0° C. over a 1/2 hour period. The mixture was brought to ambient temperature then stirred for 2 hours. The reaction mixture was added to dilute aqueous hydrochloric acid-ice to precipitate a solid product. Reprecipitation by dissolution in aqueous sodium hydroxide solution then acidification with 12N HCl gave 17.50 g of 6-(N-ethoxycarbonylamino-2-mercaptobenzothiazole, m.p. 310°-312° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[CH3:41][S:42]([C:45]1[CH:46]=[C:47]([S:51](Cl)(=[O:53])=[O:52])[CH:48]=[CH:49][CH:50]=1)(=[O:44])=[O:43]>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:51]([C:47]2[CH:48]=[CH:49][CH:50]=[C:45]([S:42]([CH3:41])(=[O:44])=[O:43])[CH:46]=2)(=[O:53])=[O:52])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2cccc(S(C)(=O)=O)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) were added dropwise a solution (3 mL) of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (323 mg) in tetrahydrofuran, 15-crown-5 (330 mg) and 3-(methylsulfonyl)benzenesulfonyl chloride (307 mg) under ice-cooling and the mixture was stirred for 1 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→1:1) to give the title compound as a pale-yellow oil (yield 504 mg, 96%).
Reaction SMILES: [CH:1]1([C:7]2[C:8]([OH:37])=[CH:9][C:10]([CH3:36])=[C:11]([CH:13]([C:22]3[CH:27]=[C:26]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[C:25]([OH:34])=[CH:24][C:23]=3[CH3:35])[C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([OH:21])[CH:15]=3)[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:38][S:39](Cl)(=[O:41])=[O:40].C(N(CC)CC)C>O1CCOCC1>[CH:28]1([C:26]2[C:25]([OH:34])=[CH:24][C:23]([CH3:35])=[C:22]([CH:13]([C:11]3[CH:12]=[C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[C:8]([OH:37])=[CH:9][C:10]=3[CH3:36])[C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([OH:21])[CH:15]=3)[CH:27]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[CH3:38][S:39]([OH:41])(=[O:20])=[O:40]
Reactant: CS(=O)(=O)Cl
Agent: Cc1cc(O)c(C2CCCCC2)cc1C(c1ccc(O)c(O)c1)c1cc(C2CCCCC2)c(O)cc1C
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O

Procedure:
Bis(5 -cyclohexyl-4-hydroxy-2-methylphenyl)-3,4-dihydroxyphenylmethane(1.0 mole), naphthoquinone-1,2-diazido-5-sulfonyl chloride (2.0 moles) and methanesulfonyl chloride(0.5 moles) were dissolved in dioxane (4,000 g). To the resulting solution, dioxane (1,500 g) having triethylamine (500 g) dissolved therein was added dropwise over 40 minutes at a controlled temperature not higher than 35° C. The precipitating salt was separated by filtration and the thus recovered reaction product was washed and dried to yield a mixed ester of bis(5-cyclohexyl-4-hydroxy-2-methylphenyl)-3,4-dihydroxyphenylmethane with naphthoquinone-1,2-diazido-5-sulfonic acid and methanesulfonic acid; the average degree of esterification was 50% for the quinonediazidosulfonate ester and 12% for the methanesulfonate ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[NH:6][C:5]2([CH2:17][NH:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:13]([F:16])([F:15])[F:14].[NH:28]1[C:32](B(O)O)=[CH:31][CH:30]=[N:29]1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]([NH:18][CH2:17][C:5]2([C:13]([F:14])([F:15])[F:16])[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:30]4[NH:29][N:28]=[CH:32][CH:31]=4)[CH:3]=3)[NH:8][C:7](=[O:12])[NH:6]2)=[O:27])=[CH:21][CH:22]=1
Reactant: O=C1Nc2ccc(Br)cc2C(CNC(=O)c2ccc(F)cc2)(C(F)(F)F)N1
Reactant: OB(O)c1ccn[nH]1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc(-c3ccn[nH]3)cc2C(CNC(=O)c2ccc(F)cc2)(C(F)(F)F)N1

Procedure:
N-{[6-bromo-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-4-yl]methyl}-4-fluorobenzamide (50 mg, 0.112 mmol), 1H-pyrazol-5-boronic acid (29 mg, 0.23 mmol), a palladium chloride-1,1-bis(diphenylphosphino)ferrocene complex (18.3 mg, 0.022 mmol) and potassium phosphate trihydrate (60 mg, 0.23 mmol) were suspended in DMF (0.5 mL) and water (0.05 mL), and the mixed solution was stirred at 120° C. for 30 minutes under microwave irradiation. After the reaction solution was left to cool, the solution was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed with water and saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The residue was purified by reverse-phase HPLC, whereby the objective compound (10 mg, 21%) was obtained as a pale yellow solid.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]3[CH:15]([C:16]([O:18]C)=[O:17])[CH2:14][CH2:13][CH2:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[Li].O>C1COCC1.CO.O>[C:1]1([C:7]2[S:8][C:9]3[CH:15]([C:16]([OH:18])=[O:17])[CH2:14][CH2:13][CH2:12][C:10]=3[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C1CCCc2nc(-c3ccccc3)sc21
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCCc2nc(-c3ccccc3)sc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of methyl 2-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazole-7-carboxylate (12.0 mg, 0.044 mmol) and LiOH.H2O (2.7 mg, 0.065 mmol) in THF/MeOH/H2O (1 mL, 3:1:1) was stirred at RT for 45 min. The mixture was acidified to pH=3 and extracted with DCM. The comb. org. layers were dried over MgSO4, and conc. in vacuo.
Reaction SMILES: [C:1]1([OH:15])[C:10]2[CH:9]3[CH2:11][CH2:12][CH2:13][CH:6]([CH:7]=[CH:8]3)[C:5]=2[C:4]([OH:14])=[CH:3][CH:2]=1.[H][H]>C(O)C.[Pd]>[C:4]1([OH:14])[C:5]2[CH:6]3[CH2:13][CH2:12][CH2:11][CH:9]([CH2:8][CH2:7]3)[C:10]=2[C:1]([OH:15])=[CH:2][CH:3]=1
Reactant: [H][H]
Reactant: Oc1ccc(O)c2c1C1C=CC2CCC1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(O)c2c1C1CCCC2CC1
Reaction time: 5 h

Procedure:
To a solution of the hydroquinone prepared in Step 1 in 100 mL ethanol was added Pd/C (250 mg) charged with hydrogen. The reaction was stirred under hydrogen for 5 h and the solid was removed through filtration. The solvent was removed and the residue was chromatographed to afford 5,6,7,8-tetrahydro-5,8-propano-naphthalene-1,4-diol as a light brown solid (3.9g). 1H-NMR (300 MHz, CDCl3) δ (ppm): 6.51 (s, 2H), 3.33 (bs, 2 H), 1.96-1.89 (m, 2 H), 1.70-1.57 9 (m, 6 H), 1.18 (m, 2 H);
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:34]=[CH:35][C:36]([CH3:40])=[C:37]([OH:39])[CH:38]=1>C1COCC1>[OH:39][C:37]1[CH:38]=[C:33]([NH:32][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:31])[CH:34]=[CH:35][C:36]=1[CH3:40]
Reactant: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Reactant: Cc1ccc(N)cc1O
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(C)c(O)c2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 65.8 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 69, 100 mg, 0.240 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methylphenol (36.76 mg, 0.264 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was dissolved in EtOAc. The resulting solution was diluted with Hexanes to initiate the precipitation of the product. The solid precipitate that formed was filtered then washed with ˜1 mL of i-prOH yielding 66% (85 g, 0.158 mmol) of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7](Br)=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH2:12]([NH2:14])[CH3:13].C1COCC1>C(Cl)Cl.O>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:14][CH2:12][CH3:13])[C:5]2=[N:4][CH:3]=1
Reactant: CCN
Reactant: Brc1cncc2ncc(Br)n12
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CCNc1nccn2c(Br)cnc12
Temperature: 70 °C
Yield: 53 %

Procedure:
3,5-Dibromo-imidazo[1,2-a]pyrazine (D) (200 mg, 0.722 mol) was added to 2M ethylamine in THF (10.8 ml, 30 eq.). The mixture was heated at 70° C. in sealed tube for 8 hr. The mixture was then cooled to rt, and diluted with DCM (100 ml) and water (50 ml). The organic layer was washed with brine, dried and concentrated. The residue was purified on a silica gel column to give 92.2 mg (yield 53%) of (3-bromo-imidazo[1,2-a]pyrazin-8-yl)-ethyl-amine as a crystalline solid.
Reaction SMILES: O.[OH-].[Li+].[C:4]([O:8][C:9]([NH:11][C@@H:12]([CH:29]([CH3:31])[CH3:30])[C:13]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][C@H:16]1[C:24]([O:26]CC)=[O:25])=[O:14])=[O:10])([CH3:7])([CH3:6])[CH3:5]>O.C1COCC1.CO>[C:4]([O:8][C:9]([NH:11][C@@H:12]([CH:29]([CH3:31])[CH3:30])[C:13]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][C@H:16]1[C:24]([OH:26])=[O:25])=[O:14])=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCOC(=O)[C@@H]1Cc2ccccc2N1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccccc2C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.7 %

Procedure:
Lithium hydroxide monohydrate (187 mg, 4.46 mmol, Eq: 3) in water (4.5 mL) was added to an ice-bath cooled solution of (S)-ethyl 1-((S)-2-(tert-butoxycarbonylamino)-3-methylbutanoyl)indoline-2-carboxylate (0.58 g, 1.49 mmol, Eq: 1.00) in THF (13.5 mL) and MeOH (4.5 mL). The cooling bath was removed and the reaction was stirred at rt for 1 h. 0.1 M Aqueous KHSO4 (50 mL) was added to the reaction mixture and the resulting mixture was extracted with DCM (2×50 mL). The aqueous layer was further acidified with 1 M aqueous HCl (˜5 mL) and extracted again with DCM (2×50 mL). The organic layers were combined, dried over Na2SO4 and concentrated in vacuo. The residue was azeotroped with hexanes to give (S)-1-((S)-2-(tert-butoxycarbonylamino)-3-methylbutanoyl)indoline-2-carboxylic acid (0.56 g), m/z=363 (M+H).
Reaction SMILES: Br.[N:2]1([C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH2:10][CH2:11][C:12](=[O:18])[NH:13]3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])O.[Na+].N1(C2C=CC=C3C=2CCC(=O)N3)CCNCC1.[Cl:41][C:42]1[CH:43]=[C:44]([CH:48]=[C:49]([Cl:51])[CH:50]=1)[C:45](Cl)=[O:46]>CN(C=O)C.C(N(CC)CC)C>[Cl:41][C:42]1[CH:43]=[C:44]([CH:48]=[C:49]([Cl:51])[CH:50]=1)[C:45]([N:5]1[CH2:6][CH2:7][N:2]([C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH2:10][CH2:11][C:12](=[O:18])[NH:13]3)[CH2:3][CH2:4]1)=[O:46]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: O=C1CCc2c(cccc2N2CCNCC2)N1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCc2c(cccc2N2CCN(C(=O)c3cc(Cl)cc(Cl)c3)CC2)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
5-(1-Piperazinyl)-3,4-dihydrocarbostyril monohydrobromide (3.5 g) was suspended in 40 ml DMF. After adding 960 mg of sodium hydrogencarbonate, the suspension was stirred at room temperature for 30 minutes to convert the starting compound to 5-(1-piperazinyl)-3,4-dihydrocarbostyril. Then, to the mixture was added 2.34 ml of triethylamine and the mixture was stirred at room temperature while slowly adding dropwise 10 ml of DMF solution containing 3.0 g of 3,5-dichlorobenzoyl chloride. After completion of addition the reaction mixture was stirred for 40 minutes. The reaction mixture was poured into a large amount of saturated saline solution and extracted with chloroform. The extract was washed with saturated sodium hydrogencarbonate solution and subsequently with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and residual crystals were recrystallized from methanol-chloroform to give 1.8 g of 5-[4-(3,5-dichlorobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 255°-257° C., colorless needles.
Reaction SMILES: O=S(Cl)[Cl:3].[CH3:5][O:6][C:7]1[CH:12]=[C:11]([CH2:13]O)[CH:10]=[CH:9][N:8]=1>C(Cl)(Cl)Cl>[CH3:5][O:6][C:7]1[CH:12]=[C:11]([CH2:13][Cl:3])[CH:10]=[CH:9][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)ccn1
Solvent: ClC(Cl)Cl
Product: COc1cc(CCl)ccn1
Reaction time: 16 h

Procedure:
1.57 ml (21.6 mmol) of SOCl2 are added dropwise, whilst cooling with ice and under a N2 atmosphere, to a solution of 1.5 g (10.8 mmol) of 2-methoxy-4-(hydroxymethyl)-pyridine [for preparation see J. Org. Chem. 54 (1989), 5580] in 13 ml of chloroform. After 16 h at RT, the mixture is concentrated by evaporation, water and 2N sodium hydroxide solution are added to the residue, and extraction immediately takes place 3 times with chloroform. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated by evaporation to form 2-methoxy-pyridin-4-yl-methylchloride; 1H NMR (CDCl3) δ 8.15 (d, 1H), 6.90 (d, 1H), 6.76 (s, 1H), 4.49 (s, 2H), 3.94 (s, H3C).
Reaction SMILES: Br[C:2]1[C:3]([C:20]2[S:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[CH:41][CH:40]=[C:39]3[C:35]=2[CH:36]=[CH:37][N:38]3[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])O1>>[Cl:25][C:22]1[S:21][C:20]([C:3]2[C:2]([C:34]3[CH:42]=[CH:41][CH:40]=[C:39]4[C:35]=3[CH:36]=[CH:37][N:38]4[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[CH:7][N:6]=[C:5]([NH:8][CH2:9][CH2:10][N:11]3[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]3=[O:19])[N:4]=2)=[CH:24][CH:23]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2ccc(Cl)s2)n1
Reactant: CC(C)(C)OC(=O)n1ccc2c(B3OC(C)(C)C(C)(C)O3)cccc21
Product: CC(C)(C)OC(=O)n1ccc2c(-c3cnc(NCCN4C(=O)NC(=O)C4(C)C)nc3-c3ccc(Cl)s3)cccc21

Procedure:
The title compounds were prepared from 1-{2-[5-bromo-4-(5-chlorothiophen-2-yl)pyrimidin-2-ylamino]ethyl}-5,5-dimethylimidazolidine-2,4-dione and tert-butyl 4-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate in a manner analogous to Example 269, then purified and separated by C-8 prep HPLC to give tert-butyl 4-{4-(5-chlorothiophen-2-yl)-2-[2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)ethylamino]pyrimidin-5-yl}-1H-indole-1-carboxylate: MS (M+H)+ 581; and 1-{2-[4-(5-chlorothiophen-2-yl)-5-(1H-indol-4-yl)pyrimidin-2-ylamino]ethyl}-5,5-dimethylimidazolidine-2,4-dione: MS (M+H)+ 481.
Reaction SMILES: [N:1]([CH:4]([CH3:14])[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH:4]([CH3:14])[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:11])([CH3:10])[CH3:12]
Reactant: CC(CNC(=O)OC(C)(C)C)N=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CC(N)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 813.1 %

Procedure:
A mixture of afford tert-butyl 2-azidopropylcarbamate (7.0 g, 3.6 mmol) and Pd/C (0.7 g) in MeOH (250 mL) was stirred under a H2 (1 atm) atmosphere (RT, 16 h). The mixture was filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, eluting with saturated NH3 in MeOH-DCM (0-10%) to afford tert-butyl 2-aminopropylcarbamate (5.1 g, 83.7%) as a light yellow oil. 1HNMR (CDCl3): δ 4.9 (bs, 1H, NH), 3.15 (m, 1H, CH), 3.0 (m, 1H, CH2), 2.8 (m, 1H, CH2), 1.7 (bs, 2H, NH2), 1.5 (s, 9H, CH3), 1.0 (d, 3H, CH3).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]2C2CCCCO2)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4].[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>CO>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[NH:12]2)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Temperature: 25 °C

Procedure:
To a solution of 2-(butoxy)-8-(methoxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (7.34 g) in methanol (100 mL) was added trifluoroacetic acid (10 mL). The mixture was stirred at ambient temperature over the weekend to give a suspension.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.[F:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[S:24](Cl)(=[O:26])=[O:25]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:24]([C:17]2[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=2[F:15])(=[O:25])=[O:26])[CH:5]=[N:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)Cl)c(F)c1
Reactant: Nc1cncc(Br)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2cncc(Br)c2)c(F)c1
Yield: 75.9 %

Procedure:
5-Bromopyridin-3-amine (500 mg, 2.89 mmol) was dissolved in dichloromethane (14 ml) and pyridine (4 ml) was added. To this mixture 2-fluoro-4-methoxybenzene-1-sulfonyl chloride (1 g, 4.45 mmol) was added dropwise and the mixture stirred at reflux for 5 h. Once at room temperature, the reaction mixture was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by flash chromatography (0% to 50% DCM/AcOEt) to give 792 mg (76% yield) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1.[CH:15]([NH:18][C:19]1[CH:23]=[CH:22][NH:21][N:20]=1)([CH3:17])[CH3:16]>ClCCl>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=[C:2]([N:21]2[CH:22]=[CH:23][C:19]([NH:18][CH:15]([CH3:17])[CH3:16])=[N:20]2)[CH:11]=1
Reactant: CC(C)Nc1cc[nH]n1
Reactant: COc1ccc2c(Cl)cc(Cl)nc2c1
Solvent: ClCCl
Product: COc1ccc2c(Cl)cc(-n3ccc(NC(C)C)n3)nc2c1
Temperature: 115 °C
Yield: 82.1 %

Procedure:
A mixture of 2,4-dichloro-7-methoxy-quinoline (1.34 g, 5.88 mmol) and isopropyl-(1H-pyrazol-3-yl)-amine (1.10 g, 8.80 mmol) was heated at 115° C. for 3 h while stirring in a sealed tube. After ˜20 min. of heating, the pressure built up in the tube was released by using a needle. The mixture was then dissolved in dichloromethane and loaded onto a silica gel column. Elution with dichloromethane and methanol afforded [1-(4-chloro-7-methoxy-quinolin-2-yl)-1H-pyrazol-3-yl]-isopropyl-amine (1.53 g, 82%). LC/MS=317.2 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[O:16][CH3:17].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[N:26]=[C:27]=[O:28].CCN(CC)CC>C1COCC1>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[NH:26][C:27](=[O:28])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1N
Reactant: O=C=Nc1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1c(Cl)cccc1Cl
Reaction time: 18 h
Yield: 59 %

Procedure:
To a mixture of tert-butyl 4-amino-3-methoxyphenylacetate (2.15 g, 9.04 mmol), 2,6-dichlorophenyl isocyanate (1.70 g, 9.04 mmol) in THF (40 ml) was added Et3N (0.25 ml, 9.04 mmol) at room temperature. After 18 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane, to give tert-butyl 4-[N′-(2,6-dichlorophenyl)ureido]-3-methoxyphenylacetate (2.27 g, 59%) as a colorless powder. mp 177-181° C. (dec.); 1H-NMR (CDCl3) δ1.43 (s, 9H), 3.74 (s, 2H), 3.83 (s, 3H), 6.34 (s, 1H), 6.81 (s, 1H), 6.84 (d, J=8.3 Hz, 1H), 7.06 (br, 1H, 7.27 (t, J=8.1 Hz, 1H), 7.39 (d, J=8.1 Hz, 2H), 8.04 (d, J=8.3 Hz, 1H).