Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.C([O:22][C:23]1[C:24](=[O:39])[O:25][CH:26]([CH2:36][CH2:37]O)[C:27]=1[O:28]CC1C=CC=CC=1)C1C=CC=CC=1>>[CH:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]=2[CH:13]=[CH:14][C:2]=1[O:1][CH2:37][CH2:36][CH:26]1[O:25][C:24](=[O:39])[C:23]([OH:22])=[C:27]1[OH:28]
Reactant: Oc1ccc2oc3ccccc3c2c1
Reactant: O=C1OC(CCO)C(OCc2ccccc2)=C1OCc1ccccc1
Product: O=C1OC(CCOc2ccc3oc4ccccc4c3c2)C(O)=C1O
Yield: 12.3 %

Procedure:
Mitsunoble coupling of 0.22 g (1.2 mmol) of 2-hydroxydibenzofuran with 0.34 g (1.0 mmol) of 3,4-dibenzyloxy-5-(2-hydroxyethyl)-2(5H)-furanone and subsequent benzyl group deprotection by hydrogenation were performed in a similar manner as described in the synthesis of 3,4-dihydroxy-5-[2-(4-phenoxy)phenoxyethyl]-2(5H)-furanone to provide 40 mg (10% yield) of 5-[2-(dibenzofuran-2-oxy)ethyl]-3,4-dihydroxy-2(5H)-furanone a white solid.: mp 191-192° C. (ether/hexanes), 1H NMR (acetone-d6) δ 8.23-8.18 (m, 1H), 7.83-7.44 (m, 5H), 7.28-7.23 (m, 1H), 5.12 (dd, J=5.3, 8.7 Hz, 1H), 4.42 (dd, J=2.6, 4.7 Hz, 2H), 2.69-2.59 (m, 1H), 2.21-2.08 (m, 1H). 13C NMR (acetone-d6) δ 169.68, 157.31, 155.75, 153.70, 151.31, 127.76, 125.05, 124.83, 123.07, 121.34, 118.46, 116.42, 112.39, 111.90, 105.40, 72.72, 64.57, 32.64. Anal Calcd for C18H14O6 +0.25 H2O: C, 65.36; H, 4.57. Found: C, 65.52; H, 4.23.
Reaction SMILES: [Cl:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([NH2:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=O.C([BH3-])#N.[Na+]>CO.CC(O)=O>[Cl:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([NH:9][CH2:13][C:12]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Cl)c(I)cc1N
Reactant: CCOC(=O)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CNc1cc(I)c(Cl)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.8 %

Procedure:
To a solution of 4-chloro-5-iodo-2-methoxybenzenamine (6 g, 21.2 mmol) in MeOH (50 mL) at room temperature, AcOH (3 drops) and ethyl glyoxalate (5.6 g, 27.5 mmol, 50% in toluene) were added. The mixture was stirred at room temperature for 2 h and then sodium cyanoborohydride (5.32 g, 84.8 mmol) was added to the mixture. The resulting mixture was stirred at 50° C. for 16 h. The mixture was allowed to cool to room temperature, and partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford the crude product (8.6 g).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:14][C:15]1[C:16]([O:21][CH3:22])=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:14][C:15]1[C:16]([O:21][CH3:22])=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:11]
Reactant: CCOC(=O)[C@H](Cc1cccnc1OC)NC(=O)CNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1cccnc1OC)NC(=O)CN
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 100-mL round-bottomed flask was added ethyl N-(tert-butoxycarbonyl)glycyl-3-(2-methoxy-3-pyridinyl)alaninate (1.38 g, 3.62 mmol) and trifluoroacetic acid (5 mL, 67.3 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo to give the crude ethyl glycyl-3-(2-methoxy-3-pyridinyl)alaninate as a colorless oil, which was used without purification.
Reaction SMILES: C1C=CC=CC=1.[H-].[Na+].Br[CH2:10][CH2:11][CH2:12][C:13]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C:14]1=[O:22]>O>[CH2:26]([O:25][C:23]([C:13]12[CH2:12][CH2:11][CH2:10][CH:15]([C:16]3[C:21]1=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14]2=[O:22])=[O:24])[CH3:27]
Reactant: CCOC(=O)C1(CCCBr)C(=O)Cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C12CCCC(C1=O)c1ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of benzene (400 ml.) and sodium hydride (5.3 g. of a 57 percent suspension in nujol), which is free of nujol, is added dropwise, under dry nitrogen, 1-(3-bromopropyl)-1-ethoxycarbonyl-2-indanone (39.3 g.) in 100 ml. of benzene. The mixture is stirred at room temperature for 18 hours. Water is added and the organic layer is separated, washed with aqueous sodium chloride, dried, concentrated and distilled to give after a small forecut, 20.5 g. of the title product with b.p. 130°-145° at 0.5 mm.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@@H:24]1[CH2:28][C@@H:27]([C:29](=[O:33])[N:30]([CH3:32])[CH3:31])[CH2:26][C@@H:25]1[NH:34]C(=O)OC(C)(C)C)[N:17]=[CH:16]2.Cl>C(Cl)Cl.O1CCOCC1>[NH2:34][C@@H:25]1[C@H:24]([NH:23][C:18]2[N:17]=[CH:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:3]4[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[Cl:1])[CH:14]=3)[N:19]=2)[CH2:28][C@@H:27]([C:29]([N:30]([CH3:32])[CH3:31])=[O:33])[CH2:26]1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4C[C@@H](C(=O)N(C)C)C[C@@H]4NC(=O)OC(C)(C)C)ncc3c2)c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4C[C@@H](C(=O)N(C)C)C[C@@H]4N)ncc3c2)c1Cl
Reaction time: 3 h

Procedure:
Tert-butyl ((1S,2R,4R)-2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-4-(dimethylcarbamoyl)cyclopentyl)carbamate (0.086 g, 0.142 mmol) was taken up in DCM (2 ml) and treated with 4M HCl in dioxane (3 ml) and stirred for 3 hours. The solvent was removed to give crude (1S,3S,4R)-3-amino-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-N,N-dimethylcyclopentane-1-carboxamide, quantative yield. MS (ES+) C24H27Cl2N5O3 requires: 504, found: 505 [M+H]+.
Reaction SMILES: CCN(CC)CC.[CH:8](=[C:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])[CH2:9][CH2:10][CH2:11][CH3:12]>CO>[CH2:8]([CH:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCC=C1CCCC1=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCCC1CCCC1=O
Temperature: 50 °C
Reaction time: 110 h
Yield: 93.2 %

Procedure:
In a 100 ml-volume three-way-cocked eggplant type flask whose atmosphere had been displaced with nitrogen was charged 230 mg (0.14 mmole) of Ru2Cl4 ((+)-BINAP)2 (NEt3), and 5 g (32 mmole) of 2-pentylidenecyclopentanone and 50 ml of methanol were added thereto to form a solution. The solution was put in a 100 ml autoclave having been displaced with nitrogen and stirred at 50° C. under a hydrogen pressure of 90 kg/cm2 for 110 hours to conduct a hydrogenation reaction. The solvent was removed from the reaction mixture by distillation, and the residue was purified by silica gel column chromatography using a mixed solvent of diethyl ether and hexane (1:4 by volume) as an eluent to obtain 4.6 g (percent yield: 92%) of 2-pentylcyclopentanone.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:37])[C:19]([OH:36])([C:24]3[CH:25]=[CH:26][C:27]4[O:32][CH2:31][C:30](=[O:33])[N:29]([CH3:34])[C:28]=4[CH:35]=3)[C:20]([F:23])([F:22])[F:21])=[C:14]([Cl:38])[CH:13]=2)=[CH:7][N:6]=1)=[O:4].[OH-].[Na+].O.Cl>O1CCCC1>[Cl:38][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[CH:18]([CH3:37])[C:19]([OH:36])([C:24]1[CH:25]=[CH:26][C:27]2[O:32][CH2:31][C:30](=[O:33])[N:29]([CH3:34])[C:28]=2[CH:35]=1)[C:20]([F:21])([F:22])[F:23])[O:11][C:8]1[N:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(c1ccc(Oc2cnc(C(=O)O)cn2)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-{3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-propyl]-phenoxy}-pyrazine-2-carboxylic acid methyl ester (Example 227, 70 mg, 0.13 mmol) in tetrahydrofuran (0.5 ml) was added 1M aqueous NaOH solution (0.25 ml). The mixture was stirred 2 h at r.t. Water was added and the mixture was acidified using 1M aqueous HCl solution. The aqueous phase was extracted twice with AcOEt, dried (MgSO4) and concentrated. The solid residue was dried under high vacuum leading to the title compound (76 mg) as a white solid. MS (m/e, ISP neg. ion)=536.1 [M−H+].
Reaction SMILES: C([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]1[CH:22]=[C:21]([CH2:23][NH:24][C:25]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[N:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[O:20][N:19]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[OH: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]1[CH:22]=[C:21]([CH2:23][NH:24][C:25]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[N:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[O:20][N:19]=1
Reactant: CC(C)(C)OC(=O)N=C(NCc1cc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)no1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N=C(NCc1cc([C@@H]2CC[C@@H]3CN2C(=O)N3O)no1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.1 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-2-(5-((2,3-bis(tert-butoxycarbonyl)guanidino)methyl)isoxazol-3-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (240 mg, 0.42 mmol) in THF (20 mL) was added 10% Pd/C (120 mg). The mixture was stirred under H2 atmosphere at rt for 1.5 hrs. The reaction mixture was then filtered and concentrated to afford (2S,5R)-6-(hydroxy)-2-(5-((2,3-bis(tert-butoxycarbonyl)guanidino)methyl)isoxazol-3-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (200 mg, 99%) as white solid, which was directly used in the next step. ESI-MS (EI+, m/z): 481.2 [M+H]+.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].Cl.[OH-].[Na+].[CH2:12]1COC[CH2:13]1>CO.C(Cl)Cl>[O:3]=[C:1]1[CH2:2][CH2:13][CH2:12][N:4]1[CH2:5][C:6]([OH:8])=[O:7]
Reactant: CC(=O)NCC(=O)O
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: O=C(O)CN1CCCC1=O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
N-Acetylglycine (0.031 ml, 0.22 mmol) was dissolved in 1:1 10N NaOH/THF (2 ml) and was stirred at 50° C. for 1 h. The mixture was neutralized to pH 4 with 6N HCl, then concentrated. The yellowish solid was diluted with 1:1 MeOH/CH2Cl2 (25 ml), filtered to remove inorganic salts, and concentrated. The solid obtained was diluted again with 1:1 MeOH/CH2Cl2 and concentrated to give (2-oxo-pyrrolidin-1-yl)-acetic acid as a white solid. The crude product was used in the next reaction without purification.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].I[CH2:18][CH3:19].O>CN(C=O)C>[CH2:18]([O:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:19]
Reactant: O=Cc1cccc(O)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1c(O)cccc1C=O
Yield: 54.9 %

Procedure:
2,3-Dihydroxybenzaldehyde (1.12 g, 8.11 mmol), potassium carbonate (1.12 g, 8.11 mmol) and iodoethane (0.65 mL, 1.26 g. 8.11 mmol) in dry DMF (10 mL) were stirred at ambient temperature for 21 h. The reaction mixture was poured into water and extracted with diethyl ether. The ether layer was washed with water (2×), and extracted with 1N sodium hydroxide solution (3×). The basic extracts were combined and acidified by addition of 3N hydrochloric acid, then extracted with diethyl ether. The ether layer was washed with water (2×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 2-ethoxy-3-hydroxybenzaldehyde (0.74 g, 55%) as an orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9](#[N:12])[CH:10]=[CH2:11]>[Pd]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:11]=[CH:10][C:9]#[N:12])=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: C=CC#N
Agent: [Pd]
Product: N#CC=Cc1ccc(Br)cc1
Yield: 76 %

Procedure:
The procedure described in Example 47 is repeated, but using 7.07 g (25 mmols) of 4-bromoiodobenzene and 1.83 g (27.5 mmols) of acrylonitrile. After a reaction time of 8 hours at 130° C., 3.95 g (19.0 mmols) of 4-bromocinnamonitrile are obtained, corresponding to a yield of 76% of theory (conversion figure 7600; Pd content 0.01 mol %).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([F:20])[C:13]=1[F:21])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[NH3:23]>CCO>[NH2:23][CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([F:20])[C:13]=1[F:21])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Reactant: N
Solvent: CCO
Product: CCOC(=O)C(=CN)C(=O)c1cc(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
12.8 g of ethyl 3-ethoxy-2-(2,3,4,5-tetrafluoro-benzoyl)-acrylate are initially introduced into 16 ml of EtOH. A mixture of 3.3 ml of concentrated aqueous NH3 solution and 10 ml of EtOH is added dropwise with ice cooling. The mixture is subsequently stirred for 2 hours. Ice-water is then added, and the precipitated solid is filtered off under suction. Yield: 8.7 g, melting point: 118°-119° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C@@H:8]2[CH2:13][CH2:12][C@H:11]([N:14]3[C:18]4=[N:19][CH:20]=[N:21][C:22]([NH2:23])=[C:17]4[C:16]([C:24]4[CH:29]=[CH:28][C:27]([O:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[N+:37]([O-])=O)=[CH:26][CH:25]=4)=[N:15]3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.C(O)(=O)C>C(O)C.[Pd]>[NH2:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[O:30][C:27]1[CH:26]=[CH:25][C:24]([C:16]2[C:17]3[C:18](=[N:19][CH:20]=[N:21][C:22]=3[NH2:23])[N:14]([C@H:11]3[CH2:12][CH2:13][C@@H:8]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH2:9][CH2:10]3)[N:15]=2)=[CH:29][CH:28]=1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccccc5[N+](=O)[O-])cc4)c4c(N)ncnc43)CC2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccccc5N)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.6 %

Procedure:
A mixture of cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-[4-(2nitrophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.059 g, 0.091 mmol, 1 equiv), glacial acetic acid (0.03 mL, 0.5 mmol, 5 equiv), and 10% Pd-C (0.024 g, 0.4 wt/wt equiv) in ethanol (1 mL) was stirred at room temperature under a positive pressure of H2 for 16 h. Solids were removed by filtration with the aid of CH2Cl2 (10 mL) and the filtrate was concentrated to afford a yellow oil. The residue was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 10%-60% acetonitrile-0.1M ammonium acetate over 20 min, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to afford cis-3-[4-(2-aminophenoxy)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as an off-white solid (0.018 g, 0.036 mmol): 1H NMR (d6 DMSO, 400 MHz): δ H 8.22 (1H, s), 7.59 (2H, d, J=8.6 Hz), 7.05 (2H, d, J=8.7 Hz), 6.85-6.98 (3H, m), 6.58-6.61 (1H, m), 4.93 (2H, bs), 4.78-4.80 (1H, m), 2.20-2.50 (11H, m), 2.14 (3H, s), 2.05-2.09 (2H, m), 1.55-1.70 (4H, m); RP-HPLC (Delta Pak C18, 5 μm, 300 Å, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 12.00 min. MS: MH+ 499.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.[Br-:10].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.CO>[NH2:1][C:2]1[C:3]([Br:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1
Reactant: Nc1ccc(Cl)c(O)c1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: Nc1cc(O)c(Cl)cc1Br
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 17.8 %

Procedure:
To a solution of 5-amino-2-chloro-phenol (15.85 g, 110.4 mmol) in dichloromethane (300 ml) and MeOH (150 ml) was added tetrabutylammonium tribromide (58.6 g, 121.4 mmol). The mixture was stirred at room temperature for 20 minutes, and then was partitioned between saturated aqueous Na2SO3 and Et2O. The organic layer was separated, washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hex:EtOAc/7:3) gave 5-amino-4-bromo-2-chloro-phenol (4.38 g, 18%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([OH:20])[CH:18]=3)[N:13]([CH2:21][CH2:22][CH3:23])[C:12]=2[CH3:24])=[CH:5][CH:4]=1.[CH2:25]([O:27][C:28](=[O:33])[C:29](Br)([CH3:31])[CH3:30])[CH3:26]>>[CH2:25]([O:27][C:28](=[O:33])[C:29]([O:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:21][CH2:22][CH3:23])[C:12]([CH3:24])=[C:11]2[CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)([CH3:31])[CH3:30])[CH3:26]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCn1c(C)c(CCc2ccc(OC)cc2)c2cc(O)ccc21
Product: CCCn1c(C)c(CCc2ccc(OC)cc2)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
In accordance with a procedure analogous to that of Example 10, the above compound was prepared from 3-[2-(4-methoxy-phenyl)-ethyl]-2-methyl-1-propyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li][CH2:12]CCC.IC>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH3:12])[S:10][C:3]=12
Reactant: Clc1ccnc2ccsc12
Reactant: [Li]CCCC
Solvent: CI
Product: Cc1cc2nccc(Cl)c2s1
Yield: 81 %

Procedure:
This material was prepared from 7-chlorothieno[3,2-b]pyridine (1.69 g, 10 mmole) by treatment with n-BuLi and iodomethane (2 ml, 4.56 g, 32 mmole) in a manner as previously described for example 1b to give a pale yellow, low-melting solid (1.48 g, 81%). 1H NMR (DMSO-d6): δ 8.56 (1H, d, J=5.1 Hz), 7.48 (1H, d, J=5.1 Hz), 7.38 (1H, s), 2.65 (3H, s).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][C@@H:4]([NH2:19])[C:3]1=[O:20].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>O1CCCC1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:19][C@@H:4]2[N:5]=[C:6]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:2]([CH3:1])[C:3]2=[O:20])=[O:30])=[CH:24][CH:23]=1
Reactant: CN1C(=O)[C@H](N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CN1C(=O)[C@H](NC(=O)Nc2ccc(Cl)cc2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 1,3-dihydro-1-methyl-3(R)-amino-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([C:15]2[O:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH2:30][CH3:31])[CH3:14])=[CH:8][C:7]=1[CH3:32].[OH-].[Na+].C1COCC1>CO>[CH2:30]([C:16]1[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=2)[O:19][C:15]=1[CH:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:33])=[O:2])=[C:7]([CH3:32])[CH:8]=1)[CH3:14])[CH3:31]
Reactant: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1C(C)Oc1ccc(CCC(=O)OC)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1C(C)Oc1ccc(CCC(=O)O)c(C)c1

Procedure:
3-(4-{1-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionic acid methyl ester (0.095 g, 0.206 mmole) is treated with a mixture of NaOH(aq) (1 mL)/THF (3 mL)/MeOH (3 mL) at room temperature overnight. The organic solvents are removed on rota-vapor. The residue is diluted with water (10 mL), acidified to pH=2 with 6N HCl(aq). The precipitate is collected through filtration, washed with cold water (30 mL) and dried to provide the titled compound as a white solid. Mass [EI+] 448 (M++H), 446 (M+−H).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:24]=3[F:33])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].Cl.[NH2:35][OH:36].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20](=[NH:21])[NH:35][OH:36])=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:24]=3[F:33])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3F)c2C#N)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3F)c2C(=N)NO)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
4-[5-Cyano-6-(2-fluoro-4-Methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (0.5 g, 1.04 mmol) was dissolved in the mixture ethanol/water (30 mL/14 mL) and heated to 80° C. Hydroxylamine hydrochloride (7.22 g, 104 mmol) and potassium carbonate (14.5 g, 105 mmol) were slowly added and the mixture kept stirring at 80° C. for 1 h. The crude was filtered and the retrieved solid was thoroughly washed with acetonitrile. The filtrate was concentrated under reduced pressure, yielding a yellow solid residue, which was purified by HPLC to afford Compound A99 (0.51 g, 78%). Exact mass calculated for C21H27FN6O6S 510.17, found 511.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH3:24])=[CH:19][CH:18]=1.C([O-])(=O)C.[Na+]>>[Cl:1][C:2]1[N:11]=[C:10]([N:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[CH3:24])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: CNc1ccc(OC)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COc1ccc(N(C)c2nc(Cl)nc3ccc(OC)cc23)cc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 97.4 %

Procedure:
A mixture of 2,4-dichloro-6-methoxy-quinazoline (0.5g, 2.18 mmol), (4-methoxyphenyl)-methylamine (0.35 g, 2.61 mmol) and sodium acetate (0.21 g, 2.61 mmol) in 8 mL of solvent (THF:water=1:1) was stirred at 60-70° C. for 3 h. The reaction mixture was concentrated and the resulting solid was dissolved in ethyl acetate and transferred to the silica gel pad (30mg) and washed with 40% ethyl acetate/hexane as eluent. The filtrate was concentrated under reduced pressure to give 0.7 g of the clean product (98% yield). 1H NMR (DMSO): δ 7.6 (d, 1H), 7.36-7.31 (m, 3H), 7.08-7.05 (dd, 2H), 6.2 (d, 1H), 3.79 (s, 3H), 3.5 (s, 3H), 3.28(s, 3H). LC/MS: 330, (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.[Br:14]N1C(C)(C)C(=O)N(Br)C1=O.OS([O-])=O.[Na+].CCOC(C)=O>ClCCCl>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Br:14]
Reactant: COC(=O)c1cc(N)c(F)c(Cl)n1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)c1nc(Cl)c(F)c(N)c1Br
Temperature: 83 °C
Yield: 60.5 %

Procedure:
Methyl 4-amino-6-chloro-5-fluoropicolinate (1.0 g, 4.9 mmol) was combined with 1,3-dibromo-5,5-dimethylhydantoin (1.7 g, 5.9 mmol) in 1,2-dichloroethane (15 mL) and heated at reflux (83° C.) for 4 h. The cooled mixture was stirred with 10% NaHSO3 solution and EtOAc (30 mL). The organic phase was separated, washed with water (2×20 mL), brine (10 mL), dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (5-50% EtOAc-hexane) to give an orange solid (840 mg, 61%): mp 138-139° C.; EIMS m/z 282, 284; 1H NMR (400 MHz, CDCl3) δ 5.09 (s, 2H, NH2), 3.97 (s, 3H, Me); 19F NMR (376 MHz, CDCl3) δ −135.55 (s).