Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[O:9]C(=O)[C@H](C)[O:5][C:3]1=[O:4].C1OC(=O)COC1=O.C([O-])(=O)CCCCCCC.[Sn+4].C([O-])(=O)CCCCCCC.C([O-])(=O)CCCCCCC.C([O-])(=O)CCCCCCC.C(O)(=O)CO>C1(C)C=CC=CC=1>[C:3]([OH:5])(=[O:4])[CH2:2][OH:9].[C:3]([OH:5])(=[O:4])[CH:2]([CH3:1])[OH:9]
Reactant: C[C@@H]1OC(=O)[C@H](C)OC1=O
Agent: CCCCCCCC(=O)[O-]
Agent: O=C(O)CO
Agent: O=C1COC(=O)CO1
Solvent: Cc1ccccc1
Product: CC(O)C(=O)O
Temperature: 180 °C
Reaction time: 0.33 h

Procedure:
A PFA-made cylinder was charged with 35.72 g (0.248 mol) of recrystallized L-(-)-lactide and 162.4 g (1.4 mol) of glycolide, and 17.0 ml of bis-2-methoxyethyl phthalate, 0.20 ml of a toluene solution of tin octanoate at a molar concentration of 0.33 and 0.0626 g of glycolic acid were added. After toluene was removed under high vacuum of 0.1 mmHg, and purging with nitrogen was conducted twice, the contents were heated at 180° C. for 40 minutes with stirring. The heating was further continued for 4 hours and 20 minutes to conduct polymerization. The resultant polymer was ground into fine particles having a particle size of about 3 mm or smaller. The fine particles were dried at about 25° C. for 48 hours under reduced pressure of about 0.1 kPa, thereby obtaining a glycolic acid/lactic acid copolymer [Polymer (P-C2)]. The same process was conducted repeatedly to prepare a necessary amount of Polymer (P-C2).
Reaction SMILES: [C:1]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[CH3:24][C:25]([N:29]1[CH2:34][CH2:33][C:32]2[N:35]=[CH:36][S:37][C:31]=2[CH2:30]1)([CH3:28])[CH2:26][OH:27].O>CN(C)C=O.C(OCC)C>[Si:5]([O:27][CH2:26][C:25]([N:29]1[CH2:34][CH2:33][C:32]2[N:35]=[CH:36][S:37][C:31]=2[CH2:30]1)([CH3:24])[CH3:28])([C:1]([CH3:4])([CH3:3])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(CO)N1CCc2ncsc2C1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1CCc2ncsc2C1
Reaction time: 8 h
Yield: 93.5 %

Procedure:
tert-Butylchlorodiphenylsilane (1.93 g) and imidazole (994 mg) were added to a solution of 5-(1,1-dimethyl-2-hydroxyethyl)-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine (1.24 g) in N,N-dimethylformamide (5 ml) at room temperature, and the mixture was stirred overnight. Water and diethyl ether were added to the reaction mixture to separate an organic layer. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to obtain the title compound (2.46 g) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]([CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21]([O:23]C)=[O:22])[C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.O.[OH-].[Li+]>CO.O>[CH2:1]([N:8]([CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21]([OH:23])=[O:22])[C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(c1ccccc1)N(Cc1ccccc1)C(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(c1ccccc1)N(Cc1ccccc1)C(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h
Yield: 98.9 %

Procedure:
to a room temperature solution of methyl 2-(N-benzyl-4-nitrobenzamido)-2-phenylacetate (7.63 g, 18.9 mmol) dissolved in 40 mL methanol and 30 mL THF was added a solution of lithium hydroxide monohydrate (1.95 g, 46.5 mmol) dissolved in 15 mL water. The solution turned dark brown and gradually turned light orange over 15 minutes. After 30 minutes the solvent was removed under reduced pressure and the concentrate was diluted with 50 mL water and extracted with 2×50 mL dichloromethane. The organic extracts were combined and washed with 50 mL brine then stirred over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a colorless foamy solid (7.30 g, 99%). ESI− m/z=779.2 [2M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:19])/[CH:12]=[CH:13]/[C:14]([O:16]CC)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:20]1([Mg]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:19])/[CH:12]=[CH:13]/[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Br[Mg]c1ccccc1
Reactant: CCOC(=O)/C=C/C(=O)c1ccc(OC)c(OC)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)/C=C/C(=O)c2ccccc2)cc1OC
Temperature: 10 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Into a 200 ml four-neck flask were added 10 g (0.038 mol) of ethyl (E)-4-(3,4-dimethoxyphenyl)-4-oxo-2-butenoate obtained in Example 1 and 50 ml of tetrahydrofuran under a nitrogen atmosphere, and 22.5 ml (0.045 mol) of a tetrahydrofuran solution of 32% phenylmagnesium bromide was slowly added dropwise so as to maintain inner temperature at 10° C. or lower. Then, after 1 hour of stirring at room temperature, the whole was again cooled and 50 ml of a 5% ammonium chloride aqueous solution was added to effect hydrolysis. After liquid separation, the resulting organic layer after completion of the reaction was washed with 50 ml of a 10% sodium bicarbonate aqueous solution and then with 50 ml of water. After the solvent was removed by evaporation under reduced pressure, the residue was crystallized from 10 ml of ethanol to obtain 8.8 g (yield 78.0%) of the aimed compound. As a result of HPLC analysis, the purity was found to be 99.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[NH:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1.O.[N+:23]([O-])([OH:25])=[O:24]>S(=O)(=O)(O)O>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:7]=[C:2]([Cl:1])[C:3]=1[C:13]1[NH:14][C:15]([N+:23]([O-:25])=[O:24])=[C:16]([C:18]([F:21])([F:19])[F:20])[N:17]=1
Reactant: O=[N+]([O-])O
Reactant: FC(F)(F)c1cc(Cl)c(-c2nc(C(F)(F)F)c[nH]2)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1[nH]c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C(F)(F)F
Temperature: 120 °C

Procedure:
A mixture of 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylimidazole (1.0 g, 0.0027 mol) in fuming nitric acid (95%, 1 ml) and fuming sulphuric acid (30% free SO3, 1 ml) was stirred and heated at 120° C. for 3.5 hours. The mixture was poured into cold water (50 ml) and the solid was filtered off and washed with water. The resultant solid was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and n-hexane (1:5) to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-5-nitro 4-trifluoromethylimidazole (0.7 g) as an off-white solid, m.p. 244°-252° C.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](ON)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.20 g, 0.72 mmol) in dry DCM (20 mL) were added tert-butyl (3R)-3-(aminooxy)piperidine-1-carboxylate 11 (0.19 g, 0.86 mmol, J. Med. Chem. 2008, 51, 4601-4608), 1-hydroxybenzotriazole (0.14 g, 1.03 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.20 g, 1.03 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was purified by column chromatography to give tert-butyl (3R)-3-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidine-1-carboxylate 12 (0.28 g, 82%) as a white solid.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C@H:11]([NH:17][C@@H:18]1[C:24](=[O:25])[N:23]([CH2:26][C:27]([OH:29])=[O:28])[C:22]2[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=2[O:20][CH2:19]1)[C:12]([O:14]CC)=[O:13].C(O)(=O)C>[OH-].[Na+]>[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C@H:11]([NH:17][C@@H:18]1[C:24](=[O:25])[N:23]([CH2:26][C:27]([OH:29])=[O:28])[C:22]2[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=2[O:20][CH2:19]1)[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)[C@H](CCCCCCCN)N[C@H]1COc2ccccc2N(CC(=O)O)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: NCCCCCCC[C@H](N[C@H]1COc2ccccc2N(CC(=O)O)C1=O)C(=O)O
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
A solution of 3(S)-[8-amino-1(S)-ethoxycarbonyloctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid.dihydrochloride (0.3 g) in 1N sodium hydroxide solution (10 ml) is allowed to stand for 30 minutes at room temperature. After addition of acetic acid (2.5 ml), the mixture is subjected to Amberlite XAD-2 column chromatography eluting with methanol-water (1:2). The eluate is concentrated under reduced pressure and lyophilized to yield 3(S)-[8-amino-1(S)-carboxyoctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid (0.2 g) as colorless powder.
Reaction SMILES: O(CCSCC1C=CC(C2C=CC=C(C(O)=O)C=2)=CC=1)C1C=CC=CC=1.C([O:29][C:30]([C:32]1[C:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH2:44][S:45][CH2:46][CH2:47][O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:31])C.[OH-].[Li+]>C1COCC1.O1CCOCC1>[O:48]([CH2:47][CH2:46][S:45][CH2:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[C:33]1[C:32]([C:30]([OH:31])=[O:29])=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: CCOC(=O)c1ccccc1-c1ccccc1CSCCOc1ccccc1
Agent: O=C(O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1-c1ccccc1CSCCOc1ccccc1

Procedure:
2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid. 2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethyl ester (4.4 g, 11.21 mmol, 1 eq.) in 30% aqueous THF/dioxane was treated with lithium hydroxide (0.81 g, 33.63 mmol, 3 eq.). When complete, the reaction was worked up as described leaving a brown oil
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH3:31])[C:16](=[O:30])[C:17](Cl)=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([F:28])[CH:21]=3)[N:19]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[O:33]1[C:37]2[CH:38]=[CH:39][C:40](B(O)O)=[CH:41][C:36]=2[CH:35]=[CH:34]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:32])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH3:31])[C:16](=[O:30])[C:17]([C:40]3[CH:41]=[CH:36][C:35]4[C:39]=3[CH:38]=[CH:37][O:33][CH:34]=4)=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([F:28])[CH:21]=3)[N:19]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(-c2ccc(C#N)c(F)c2)c(Cl)c1=O
Reactant: OB(O)c1ccc2occc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(-c2ccc(C#N)c(F)c2)c(-c2ccc3coccc2-3)c1=O
Yield: 40.9 %

Procedure:
A mixture of {1-[5-chloro-4-(4-cyano-3-fluoro-phenyl)-1-methyl-6-oxo-1,6-dihydro-pyrimidin-2-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester (200 mg, 0.45 mmol), benzofuran-5-boronic acid (120 mg, 0.68 mmol), Pd(PPh3)4 (26 mg, 0.05 mmol) and 2M Na2CO3 (0.9 mL) in 1,4-dioxane (200 mL) was refluxed overnight under N2 atmosphere. The reaction mixture was diluted with water and extracted with EA (3×). The combined organics were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by silica chromatography to give 100 mg of the title product (42%). [M+H] Calc'd for C30H30FN5O4, 543. Found, 543.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Br-].C(CCCCCCCCC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(O)=O.[F:46][C:47]1[CH:54]=[C:53]([F:55])[CH:52]=[CH:51][C:48]=1C=O>>[F:46][C:47]1[CH:54]=[C:53]([F:55])[CH:52]=[CH:51][C:48]=1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:13])=[O:12]
Reactant: CCCCCCCCCCC(=O)O
Reactant: O=Cc1ccc(F)cc1F
Agent: O=C(O)CCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: O=C(O)CCCCCCCCCCc1ccc(F)cc1F

Procedure:
By the similar procedure of synthesis of B4, compound B2 (2.76 g, 5.38 mmol) and 2,4-difluorobenzaldehyde (588 mg, 4.14 mmole) were used as starting materials to afford compound B15 (431 mg, 1.45 mmol, 35%) as off-white solids. mp: 56° C. 1H-NMR (CDCl3, 400 MHz) δ 7.05-7.13 (m, 1H), 6.70-6.79 (m, 2H), 2.66 (t, J=7.6 Hz, 2H), 2.31 (t, J=7.4 Hz, 2H), 1.50-1.62 (m, 4H), 1.26 (m, 12H). 13C-NMR (CDCl3, 100 MHz) δ 180.00, 162.19, 159.80, 130.90, 125.31, 110.69, 103.44, 34.11, 30.15, 29.44, 29.36, 29.33, 29.19, 29.16, 29.03, 28.41, 24.69. HRMS (ESI) calculated for C17H24F2O2Na [M+Na]+: 321.1642, found: 321.1637.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1.[NH2:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C>O1CCOCC1>[CH2:25]([O:24][C:22]([CH2:21][C:17]1[CH:16]=[C:15]([NH:14][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=2)[CH:20]=[CH:19][CH:18]=1)=[O:23])[CH3:26]
Reactant: CCOC(=S)c1cnc(C)nc1Cl
Reactant: CCOC(=O)Cc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cccc(Nc2nc(C)ncc2C(=S)OCC)c1
Temperature: 60 °C
Yield: 95.8 %

Procedure:
A mixture of 5 g (21.5 mmol) of ethyl 4-chloro-2-methylthio-pyrimidine-5-carboxylate and 4 g (22.3 mmol) of ethyl 3-aminophenylacetate in 80 ml of 1,4-dioxan was treated with 6 ml (43 mmol) of triethylamine and then heated at 60° C. for 4 hours. The mixture was cooled and evaporated. The residue was partitioned between 120 ml of ethyl acetate and 100 ml of 2M hydrochloric acid. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 7.4 g (92%) of ethyl 4-[3-(ethoxycarbonylmethyl)phenyl]amino-2-methylthiopyrimidine-5-carboxylate as a pale orange colored oil which solidifies slowly to a white solid. [Mass spectrum (ESI) MH+ =376].
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:17])[CH:2]=[CH2:3]>[Pd].C(OCC)(=O)C>[O:10]([C:8]1[CH:7]=[CH:6][C:5]([OH:17])=[C:4]([CH2:1][CH2:2][CH3:3])[CH:9]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C=CCc1cc(Oc2ccccc2)ccc1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1cc(Oc2ccccc2)ccc1O

Procedure:
The phenol of Step B (141.4 g, 0.62 mole) was taken into 2 liters of ethyl acetate and the reaction vessel charged with 10% Pd/C catalyst (12 g). The reaction was stirred under H2 until the starting material was consumed. The reaction mixture was filtered through Celite and the cake washed with ethyl acetate (total volume ˜6 liters). The filtrate was concentrated to a dark oil which was taken into ether (1500 mL) and washed with 2N HCl (200 mL) sat'd. sodium bicarbonate and brine. The organic solution was dried over magnesium sulfate, filtered and concentrated to give a light brown oil. (125 g).
Reaction SMILES: Cl[C:2](=[CH2:5])[C:3]#[N:4].Cl.[C:7]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])(=[NH:9])[NH2:8].N12CCCCC1C=NCCC2>C(#N)C>[NH2:4][C:3]1[CH:2]=[CH:5][N:8]=[C:7]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[C:15](=[O:24])[C:16]3=[CH:23][CH:22]=[CH:21][CH:20]=[C:17]3[C:18]2=[O:19])[N:9]=1
Reactant: N=C(N)CCCCN1C(=O)c2ccccc2C1=O
Reactant: C=C(Cl)C#N
Agent: C1=NCCCN2CCCCC12
Agent: Cl
Solvent: CC#N
Product: Nc1ccnc(CCCCN2C(=O)c3ccccc3C2=O)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
A solution of 2-chloroacrylonitrile (1.75 g.) in acetonitrile (10 ml.) was added over 15 minutes to an ice-cooled mixture of 1-amidino-4-phthalimidobutane hydrochloride (5.64 g.), acetonitrile (50 ml.) and 1,5-diazabicyclo[5,4,0]undec-5-ene (6.08 g.). The mixture was stirred for a further two hours and then evaporated to dryness. The residue was treated with water (50 ml.) and the mixture extracted with ethyl acetate (2×50 ml.). The combined ethyl acetate extracts were extracted with N hydrochloric acid (3×30 ml.) and the combined aqueous extracts neutralised with sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate extracts were evaporated to dryness and the residue recrystallised from acetonitrile to give 4-amino-2-(4-phthalimidobutyl)pyrimidine (2.5 g.), m.p. 139°-140°.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[CH2:9](N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:9])[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8]
Reactant: CCN(CC)CC
Reactant: CC1C(=O)CCC1=O
Solvent: ClC(Cl)Cl
Product: CC1(C)C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of enone (1) (0.25 mM) and Thiol (0.25-0.275 mM) in dry chloroform (5 ml) was added catalytic amount of triethyl amine (20 μl) at room temperature and the reaction mixture was stirred at room temperature for 1-3 days under nitrogen atmosphere. The chloroform was removed under vacuum and residue was purified by flash column chromatography over silica using ethyl acetate in hexane as eluent to afford the title compound 2.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9]([CH2:12][C:13](OCC)=[O:14])(=O)[CH3:10].C(O)C>S(=O)(=O)(O)O>[CH3:10][C:9]1[C:8]2[C:1](=[CH:3][C:4]([OH:5])=[CH:6][CH:7]=2)[O:2][C:13](=[O:14])[CH:12]=1
Reactant: Oc1cccc(O)c1
Reactant: CCOC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cc1cc(=O)oc2cc(O)ccc12
Yield: 71 %

Procedure:
0.1 mole resorcinol and 0.1 mole ethyl acetylacetate in solution in 100 ml concentrated sulphuric acid are maintained at 5° C. for 3 hours. After recyrstallisation of the solid formed from ethanol, there are obtained 12.5 grams 4-methyl-7-hydroxy-coumarin, melting at 185° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:11]([O:14]C)=[N:12][CH:13]=2)=[C:6]([NH:28][C@H:29]([C:31]2[N:36]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:35](=[O:43])[C:34]3=[C:44]([CH3:47])[CH:45]=[CH:46][N:33]3[N:32]=2)[CH3:30])[N:5]=[CH:4][N:3]=1.B(Br)(Br)Br>>[NH2:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:11]([OH:14])=[N:12][CH:13]=2)=[C:6]([NH:28][C@H:29]([C:31]2[N:36]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:35](=[O:43])[C:34]3=[C:44]([CH3:47])[CH:45]=[CH:46][N:33]3[N:32]=2)[CH3:30])[N:5]=[CH:4][N:3]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(-c3c(N)ncnc3N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)cnc2OC)cc1
Agent: BrB(Br)Br
Product: COc1ccc(S(=O)(=O)Nc2cc(-c3c(N)ncnc3N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)cnc2O)cc1
Yield: 44.5 %

Procedure:
(S)—N-(5-(4-Amino-6-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidin-5-yl)-2-methoxypyridin-3-yl)-4-methoxybenzenesulfonamide (82 mg, 0.13 mmol) was treated with a solution of boron tribromide (1M in dichloromethane, 190 μl, 0.19 mmol) according to the method described in Example 23. The residue was purified using SP1® Purification System (0% to 100%, hexane-ethyl acetate) to give 37 mg (46% yield) of the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Br:9][C:10]1[CH:19]=[CH:18][C:13]([C:14](=O)[CH2:15]Br)=[CH:12][CH:11]=1>CC(C)=O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:15]=[C:14]([C:13]3[CH:18]=[CH:19][C:10]([Br:9])=[CH:11][CH:12]=3)[N:1]=2)[CH:4]=1
Reactant: Cc1ccc(N)nc1
Reactant: O=C(CBr)c1ccc(Br)cc1
Solvent: CC(C)=O
Product: Cc1ccc2nc(-c3ccc(Br)cc3)cn2c1

Procedure:
A mixture of 18.8 g of 2-amino-5-methylpyridine and 27.8 g of p-bromophenacyl-bromide in 200 ml of acetone was refluxed for 8 hrs. The precipitate was collected and dissolved in hot methanol and 2 ml of concentrated HBr was added. The methanol solution was then basified with ammonium hydroxide. The precipitated product was collected and recrystallized from ethanol; yield 18.5 g (68%); mp 215°-216° C.
Reaction SMILES: [C:1](Cl)(=[O:6])/[C:2](=[CH:4]/[CH3:5])/[CH3:3].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.Cl>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]2[C:11]=1[CH:4]([CH3:5])[CH:2]([CH3:3])[C:1]2=[O:6]
Reactant: COc1ccc(OC)cc1
Reactant: C/C=C(\C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(OC)c2c1C(=O)C(C)C2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.4 %

Procedure:
A1Cl3 (64 g, 0.48 mol) and CH2Cl2 (250 ml) (dried with magnesium sulfate) were placed under an argon atmosphere in a 500 ml three necked round bottomed flask fitted with a magnetic stirring apparatus, an addition funnel, an inner thermometer and a reflux condenser. A mixture of tigloyl chloride (33) (42 g, 0.35 mol) and 1,4-dimethoxybenzene (48.4 g, 0.35 mol, dissolved in CH2Cl2 (75 ml)) was added over a period of 1 h at −10° C. under vigorous stirring. After 2 h stirring at −2° C. to −5° C. the mixture was allowed to come to ambient temperature and was stirred overnight. The dark red mixture was then refluxed for 2 h, after cooling to ambient temperature the reaction mixture was poured carefully onto a mixture of concentrated HCl (300 ml) and ice (500 g). Then the resulting yellow mixture was transferred to a separation funnel, the lower CH2Cl2 layer was isolated and the aqueous layer extracted with diethyl ether (3×100 ml). The combined organic layers were dried over magnesium sulfate, filtered, and the solvents removed under reduced pressure to give a dark brown liquid. This residue was distilled using a 15 cm Vigreux column to obtain an orange-yellow light viscous liquid (110-115° C., 0.8 mbar). The liquid was purified via column chromatography [(SiO2, 25×9 cm) eluent: cyclohexane:ethylacetate (1:1)] to afford 2,3-dimethyl-4,7-dimethoxy-1-indanone (36) (9.53 g, 12%), Rf 0.35 (cyclohexane:ethylacetate (5:1)) as an orange liquid. The liquid was found to be a mixture of the two isomers of 4,7-dimethoxy-2,3-dimethyl-1-indanone (36a to 36b approximately 4:1).