Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[N:13]=1.C(=O)(O)[O-].[Na+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:10][C:9](=[O:12])[NH:8][C:7]=2[N:13]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc2c(n1)NC(=O)CN2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc2c(n1)NC(=O)CN2C(=O)OCc1ccccc1
Reaction time: 0.75 h
Yield: 99.2 %

Procedure:
To 6-(methyloxy)-1,4-dihydropyrido[2,3-b]pyrazin-3(2H)-one (6.35 g, 35.4 mmol) in ethyl acetate (600 ml)/sodium bicarbonate (sat. solution) (200 ml) stirred vigorously was added at room temperature benzyl chloroformate (5.31 ml, 37.2 mmol). After 45 minutes the reaction was complete. The layers were separated and the organic layer was dried on magnesium sulphate, filtered and evaporated to afford the desired product as an off-white solid (11 g, 99%).
Reaction SMILES: ClC[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=1)[N:9]=[C:8]2[NH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](C(OC(C)(C)C)=O)[N:34]=[CH:33]2.[CH3:46][NH:47][CH3:48].[CH3:49]S(C)=O>>[CH3:46][N:47]([CH3:49])[CH2:48][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:18]=1)[N:9]=[C:8]2[NH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][N:34]=[CH:33]2
Reactant: CNC
Reactant: CS(C)=O
Reactant: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCCl
Product: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4[nH]ncc4c3)c2cc1OCCN(C)C
Temperature: 85 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
A solution of tert-butyl 5-(6-(2-chloroethoxy)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.25 g, 0.40 mmole) in DMSO (3 mL) was cooled to 0° C. To this was added dimethylamine gas (bubbled into solution for 15 minutes) and the reaction was slowly heated to 85° C. and stirred for 2 h. The mixture was poured onto ice-water and the crude product was filtered. The product was then dissolved in a mixture of CH2Cl2 and CH3OH and the solution was concentrated in vacuo. The residue was purified via preparative TLC (SiO2, 10% CH2Cl2/CH3OH). To the crude product was added TFA (5 mL) and the reaction was stirred at RT for 1 h. The solution was concentrated in vacuo and the residue was triturated with ether, filtered and dried under vacuum to give 6-(2-(dimethylamino)ethoxy)-N-(1H-indazol-5-yl)-7-methoxy-2-(3-(phenyl)phenyl)quinazolin-4-amine (0.096 g, 0.18 mmole, 45% over 2 steps). MS 531 (M+1). HPLC retention time 5.18 mins.
Reaction SMILES: NC(N)=[S:3].Cl[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].Cl[CH2:20][C:21]([O-:23])=O.[Na+].Cl>O>[C:7]1([CH:6]=[CH:20][C:21]([OH:23])=[S:3])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: NC(N)=S
Reactant: O=C([O-])CCl
Reactant: ClCc1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OC(=S)C=Cc1cccc2ccccc12
Yield: 95 %

Procedure:
A solution of 15.2 g (0.2 mol) of thiourea in 100 ml of water is introduced into a 1 liter three-necked flask equipped with a magnetic stirrer, a condenser and a dropping funnel, and 35.3 g (0.2 mol) of α-chloromethylnaphthalene are added all at once, at 50°-60° C. The mixture is heated until it reaches the refluxing temperature and is kept at the boil for quarter of an hour. The thiouronium salt precipitates. The mixture is then cooled and a solution of 32 g of sodium hydroxide (0.8 mol) in 50 ml of water is then added dropwise at about 60° C. The resulting mixture is heated under reflux until the solution becomes limpid and is then cooled, and a solution of about 0.28 mol of sodium chloroacetate (obtained by neutralising 26.36 g of chloroacetic acid with 23.52 g of sodium bicarbonate in 200 ml of water) is (then) added dropwise at 60°-70° C. The whole is then heated under reflux for half an hour after which it is cooled and acidified in the cold by adding 3 N HCl, thus precipitating α-naphthylmethylene-thiacetic acid, which is filtered off. 44.5 g of product are collected (yield: 95%). Instantaneous melting point=102°-103° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[C:18]([C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([S:28][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]3)=[CH:26][CH:27]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: O=c1ccc2cc(OCCCCBr)ccc2[nH]1
Reactant: CC(C)(C)c1ccc(S)cc1
Product: CC(C)(C)c1ccc(SCCCCOc2ccc3[nH]c(=O)ccc3c2)cc1

Procedure:
Prepared analogous to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p. 198°-199° C.) and 4-tert. butylthiophenol.
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:21][CH:22]1[CH2:29][CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=2[N:24]([CH2:34][C:35]([O:37]CC)=[O:36])[C:23]1=[O:40])[C:17]([O:19]C)=[O:18])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[OH-].[Na+].Cl>CO.O>[CH2:4]([O:3][C:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:21][CH:22]1[CH2:29][CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=2[N:24]([CH2:34][C:35]([OH:37])=[O:36])[C:23]1=[O:40])[C:17]([OH:19])=[O:18])=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)CN1C(=O)C(N[C@@H](CCCCNC(=O)OCc2ccccc2)C(=O)OC)CCCc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CN1C(=O)C(N[C@@H](CCCCNC(=O)OCc2ccccc2)C(=O)O)CCCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-[(5-carbobenzyloxyamino-1-(S)-methoxycarbonylpentyl)amino]-1-ethoxycarbonylmethyl-3,4,5,6-tetrahydro-1-benzazocin-2-(1H)-one (isomer B) (3.2 g) in methanol (20 ml) is added to a solution of sodium hydroxide (1.0 g) in water (3 ml). The reaction mixture is stirred at room temperature for 2 hours then acidified by the addition of 2N hydrochloric acid. The solution is evaporated under reduced pressure to give 3-[(5-benzyloxycarbonylamino-1-(S)-carboxypentyl)amino]-1-carboxymethyl-3,4,5,6-tetrahydro-1-benzazocin-2-(1H)-one (Isomer B).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[C:1]1([CH2:7][C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1)OCc1ccccc1
Yield: 83 %

Procedure:
A solution of phenyl acetic acid (27.2 g.), benzyl alcohol (21.6 g.) and p-toluenesulfonic acid (380 mg.) in 100 ml. of toluene was heated under reflux under a Dean-Stark trap until the theoretical (3.6 ml.) quantity of water had been collected. On cooling, the solution was washed with dilute NaHCO3 and saturated NaCl and solvent was removed in vacuo. The resulting oil was distilled at 125°-129° (0.4 torr)1 to give pure benzyl phenylacetate, 37.7 g. (83% yield). ##STR239##
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1.CO.C(Cl)Cl>C(O)C>[OH2:5].[Cl:2][CH2:1][CH:3]([OH:5])[CH2:4][N:24]1[CH2:23][CH2:22][N:21]([CH:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:10]2[CH:9]=[CH:8][C:7]([F:6])=[CH:12][CH:11]=2)[CH2:26][CH2:25]1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: ClCC1CO1
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: O
Product: OC(CCl)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 100783.6 %

Procedure:
To a mixture of epichiorohydrin (3.5 mL, 0.05 mmol) in ethanol (12 mL) at 0° C. (ice bath) and anhydrous NaH-CO3 (4.2 g, 0.05 mmol), [bis(4-fluorophenyl)methyl]piperazine (14.4 g, 0.05 mmol) in ethanol (200 mL) was added dropwise over 45 min under N2. The ice bath was removed and the mixture was allowed to come to room temperature. After 18 h the NaHCO3 was removed by filtration via a sintered glass funnel and the ethanol in the filtrate was removed in vacuo to give the crude product (21.3 g). Silica gel flash chromatography using 2.0% MeOH:CH2Cl2 gave pure product (10.05 g, 52.9%) as an amber oil. DCI/MS (M+1) 381.400 MHz 1H NMR (CDCl3)δ: 7.3 (m, 4H), 6.95 (m, 4H), 4.2 (s, 1H), 3.95 (m, 1H), 3.55 (m, 2H), 2.7 (m, 2H), 2.5 (m, 4H), 2.4 (m, 4H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Li]CCCC.[C:19]([S:23]([N:25]=[CH:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:24])([CH3:22])([CH3:21])[CH3:20].[NH4+].[Cl-]>C1COCC1.O.CCOCC>[C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:26]([NH:25][S:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:24])[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)CCC=NS(=O)C(C)(C)C
Reactant: Ic1ccccc1-c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCC(NS(=O)C(C)(C)C)c1ccccc1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A cooled (−78° C.) solution of commercially available 2-iodo-1,1′-biphenyl (1.916 g; 6.84 mmol) in anh. THF (62 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (4.27 ml; 6.84 mmol). The resulting solution was further stirred at −78° C. for 10 min. A solution of methyl 4-((tert-butylsulfinyl)imino)butanoate (1.500 g; 6.84 mmol) in anh. THF (8 ml) was added to the cooled reaction mixture, and stirring was continued from −78° C. to 0° C. over 1 h. The resulting reaction mixture was treated successively with aq. sat. NH4Cl (80 ml), Et2O (250 ml) and water (75 ml). The separated organic layer was then washed with brine (75 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) afforded methyl 4-([1,1′-biphenyl]-2-yl)-4-(1,1-dimethylethylsulfinamido)butanoate. LC-MS (conditions A): tR=0.85 min.; [M+H]+: 374.12 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[Li]C(C)(C)C.CN(C)CCN(C)C=N.[Li]CCCC.[I:28]I.C1[CH2:34][O:33]CC1>>[I:28][C:7]1[C:8]([CH:34]=[O:33])=[C:3]([O:2][CH3:1])[N:4]=[CH:5][CH:6]=1
Reactant: COc1ccccn1
Reactant: C1CCOC1
Reactant: II
Agent: CN(C)CCN(C)C=N
Agent: [Li]C(C)(C)C
Agent: [Li]CCCC
Product: COc1nccc(I)c1C=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
A −78° C. solution of 2-methoxypyridine (40 g, 0.37 mol) in THF (1 L) was treated with t-BuLi (163 mL, 0.41 mol), stirred at −78° C. for 0.5 h, treated with N-(2-dimethylaminoethyl)-N-methylformamidine (52.9 g, 0.41 mol) over 10 min, stirred at −78° C. for another 0.5 h, then warmed to −20° C. for 45 minutes. The mixture was cooled to −40° C., treated with n-BuLi (289 mL, 0.46 mol), stirred at −40° C. for 1.5 h, then cooled to −78° C. The cold mixture was added via syringe to a solution of I2 (187.8 g, 0.74 mol) in THF at −78° C., stirred at −78° C. for 0.5 h, then warmed to 0° C. The mixture was quenched with satd. NaS2O3, the organic layer washed with brine, dried over Na2SO4, concentrated under reduce pressure, and purified by chromatography. The resulting solid was washed with pet ether to afford 4-iodo-2-methoxynicotinaldehyde (22 g, 23%). 1H NMR (400 MHz, CDCl3): δ 10.20 (s, 1H), 7.84 (d, J=5.6 Hz, 1H), 7.53 (d, J=5.2 Hz, 1H), 3.99 (s, 3H).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:22]1([NH2:25])[CH2:24][CH2:23]1.[CH2:26]([O:28][C:29]([C:31]1[CH:32]=[C:33]2[CH:38]=[N:37][N:36]=[C:35]([NH:39][C:40]3[CH:45]=[C:44]([C:46](O)=[O:47])[CH:43]=[CH:42][C:41]=3[O:49][CH3:50])[N:34]2[C:51]=1[CH3:52])=[O:30])[CH3:27]>CN(C=O)C.O>[CH2:26]([O:28][C:29]([C:31]1[CH:32]=[C:33]2[CH:38]=[N:37][N:36]=[C:35]([NH:39][C:40]3[CH:45]=[C:44]([C:46](=[O:47])[NH:25][CH:22]4[CH2:24][CH2:23]4)[CH:43]=[CH:42][C:41]=3[O:49][CH3:50])[N:34]2[C:51]=1[CH3:52])=[O:30])[CH3:27]
Reactant: CCOC(=O)c1cc2cnnc(Nc3cc(C(=O)O)ccc3OC)n2c1C
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cnnc(Nc3cc(C(=O)NC4CC4)ccc3OC)n2c1C
Reaction time: 8 h

Procedure:
To a suspension of HOBt (30 mg, 0.20 mmol), EDCI (30 mg, 0.16 mmol), cyclopropyl amine (20 uL, 0.29 mmol) in DMF (0.5 mL) at RT was added 4-(5-carboxy-2-methoxy-phenylamino)-6-methyl-pyrrolo[1,2-d][1,2,4]triazine-7-carboxylic acid ethyl ester (13 mg, 0.035 mmol). The reaction was stirred overnight. Water (1 mL) was added and the precipitate collected. The product was purified by flash chromatography on silica gel (1-3% MeOH in CH2Cl2) giving the title compound, 7 mg, as a yellowish solid. HPLC (condition A) tR 4.37 min. MS m/z 410 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[C:9]([CH:10]=[O:11])[C:8]([OH:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:14]Br.CC(=O)OCC.CCCCCCC>C(O)(=O)C>[Br:14][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:12]=[C:9]([CH:10]=[O:11])[C:8]=1[OH:13]
Reactant: CC(C)(C)c1ccc(O)c(C=O)c1
Reactant: BrBr
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To a stirred solution of 5-tert-butylsalicylaldehyde (3.03 g, 16.97 mmol) in acetic acid (3.5 mL) was added a solution of bromine (0.90 mL, 17.56 mmol) in acetic acid (8.5 mL) dropwise within 15 min. The reaction mixture was stirred at room temperature for 3 h at 50° C. and was monitored by TLC (EA/heptane:1:4) and analytical HPLC analysis. Analytical HPLC analysis of the reaction mixture after 2.5 h shows the desired product ˜68% and the unreacted starting material ˜32%. A second batch of bromine (0.15 mL) in acetic acid (3 mL) was added and the reaction mixture was stirred at 50° C. for another 15 h. Analytical HPLC analysis of the reaction mixture after overnight stirring shows the desired product ˜96% and still shows the starting material ˜4%. The reaction mixture was diluted with dichloromethane (50 mL) and the organic layer was washed with 39% sodium bisulfite solution (1×10 mL), water, saturated NaHCO3 and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give the crude desired product as a pale yellow crystalline solid (4.6150 g). Purification of the crude product by Silica-gel flash chromatography on silica gel column and elution with 0-5% ethyl acetate in n-heptane afforded the desired product as a pale yellow crystalline solid (4.07 g, 93% yield). 1H NMR (400 MHz, CDCl3): δ 1.33 (s, 9H, t-Bu-), 7.49 (s, 1H, H-4), 7.81 (d, 1H, H-6), 9.85 (s, 1H, —CHO), 11.41 (s, 1H, —OH). 1H NMR of the isolated product was identical with that of a previously reported sample of the product (Girsch et al., 2008) LC-MS analysis of the product in negative mode shows the desired product's mass: m/z 255 (79BrM+−H) and m/z 257 (81BrM+−H). GC-MS analysis of the product in CI mode (Methane) shows the desired product's mass: m/z 256 (79BrM+) and m/z 258 (81BrM+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:16])[CH:13]=2)[O:8][CH2:7]1.[H-].[Na+].Cl[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][C:28]([Cl:34])=[CH:29][CH:30]=2)[N:25]=1.O>CN(C)C=O.C(OCC)(=O)C>[Cl:34][C:28]1[CH:27]=[C:26]2[C:31]([CH:32]=[CH:33][C:24]([CH2:23][O:16][C:12]3[CH:13]=[C:14]4[C:9](=[CH:10][CH:11]=3)[O:8][CH2:7][CH:6]([CH2:5][C:4]3[CH:3]=[C:2]([NH2:1])[CH:19]=[CH:18][CH:17]=3)[CH2:15]4)=[N:25]2)=[CH:30][CH:29]=1
Reactant: Nc1cccc(CC2COc3ccc(O)cc3C2)c1
Reactant: ClCc1ccc2ccc(Cl)cc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cccc(CC2COc3ccc(OCc4ccc5ccc(Cl)cc5n4)cc3C2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
To a stirred solution of 350 mg (1.37 mmole) of the product from Example 140 in 10 mL dimethylformamide at 0° C. was added 60 mg (1.51 mmole) sodium hydride. The mixture was stirred at 0° C. for 30 minutes, then 349 mg (1.64 mmole) 2-(chloromethyl)-7-chloroquinoline was added. The mixture was warmed to room temperature and stirred for 72 hours. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extract was washed with water and brine, dried (MgSO4) and concentrated to give an oil. Flash chromatography on silica gel eluting with 40% ethyl acetate in hexanes yielded 476 mg (81%) of the title product as a solid, mp 128°-130° C. Analysis calculated for C26H23N2O2Cl: C, 72.47; H, 5.38; N, 650. Found: C, 72.47; H, 5.12; N, 6.43.
Reaction SMILES: C([O-])(=O)C.[Na+].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH3:14])=[CH:9][CH:8]=1.C(O)C.Cl.[NH2:20][OH:21]>O>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[N:20][OH:21])[CH3:14])=[CH:9][CH:8]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=NO)c1ccc(O)cc1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
115.2 g (1.405 moles) of sodium acetate, 108.9 g (0.800 mole) of p-hydroxyacetophenone and 1000 ml of ethanol were added to a solution of 56.8 g (0.817 mole) of hydroxylamine hydrochloride in 1000 ml of water, and then the mixture was refluxed for 4 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure to a volume of about 500 ml, and the concentrate was allowed to cool at room temperature for 23 hours to precipitate crystals. The crystals were washed with 500 ml of water, and dried in air for 24 hours and in vacuo for a further 6 hours to give 102.1 g (84.5%) of p-hydroxyacetophenone oxime in the form of colorless needles melting at 145°-146°.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:12]=[C:13]([C:17]3[CH:21]=[C:20]([CH2:22][CH:23]([CH3:25])[CH3:24])[S:19][C:18]=3[S:26]([NH:29]C(C)(C)C)(=[O:28])=[O:27])[CH:14]=[CH:15][CH:16]=2)[CH:2]=1.B(Cl)(Cl)Cl.N1(C2C=CC=CN=2)CCCC1.Cl[C:50]([O:52][CH2:53][CH2:54][CH2:55][CH3:56])=[O:51].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:53]([O:52][C:50]([NH:29][S:26]([C:18]1[S:19][C:20]([CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:21][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][N:3]2[C:4]3=[N:5][CH:6]=[CH:7][CH:8]=[C:9]3[N:1]=[CH:2]2)[CH:12]=1)(=[O:28])=[O:27])=[O:51])[CH2:54][CH2:55][CH3:56]
Reactant: CC(C)Cc1cc(-c2cccc(Cn3cnc4cccnc43)c2)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: CCCCOC(=O)Cl
Agent: ClB(Cl)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1ccc(N2CCCC2)nc1
Solvent: ClCCl
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(Cn2cnc3cccnc32)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 3-(3-imidazo[4,5-b]pyridin-3-ylmethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (53.6 mg, 0.111 mmol; see Example 8(a)) in CH2Cl2 (2 mL) was added BCl3 (0.6 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. Water (5 mL) was added to the residue and this was then extracted with EtOAc. The combined organic phase was washed with water and brine, dried (over anhydrous MgSO4) and concentrated in vacuo. To the crude product dissolved in pyridine (1.5 mL) was added pyrrolidinopyridine (32.9 mg, 0.222 mmol) and butyl chloroformate (141.3 μL, 1.11 mmol) and the reaction mixture was stirred overnight. Citric acid (3 mL, 10% aq) was added to the reaction mixture, which was then extracted with EtOAc, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by LCMS (20-100% CH3CN in water) to give the title compound in 70% yield, over two steps, (41 mg, 0.078 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[NH:7][C:6](=[O:14])[CH2:5]2.[CH3:15]OC(N(C)C)OC.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>CN(C=O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:12])([CH3:13])[NH:7][C:6](=[O:14])[C:5]2=[CH:15][NH:36][C:33]1[CH:34]=[CH:35][C:30]([N:27]2[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]2)=[CH:31][CH:32]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CC1(C)NC(=O)Cc2cc(Br)ccc21
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(NC=C3C(=O)NC(C)(C)c4ccc(Br)cc43)cc2)CC1
Temperature: 25 °C
Yield: 31.7 %

Procedure:
6-Bromo-1,1-dimethyl-1,4-dihydro-2H-isoquinolin-3-one (210 mg, 0.83 mmol) and dimethoxymethyl-dimethyl-amine (250 mg, 2.1 mmol) in DMF (4 mL) is heated at 100° C. for 1 hour. After which the DMF is evaporated and toluene (6 mL) is added. This solution is then mixed with a solution of 4-(4-Methyl-piperazin-1-yl)-phenylamine (450 mg, 2.4 mmol) in toluene (4 mL) and the mixture is heated at reflux for 6 hours. The mixture is then allowed to cool to room temperature, upon cooling, precipitates formed. The precipitate is collected and further purified through chromatography to provide the title compound (120 mg, 31%). MS (ESI): 455.1, 457.1 (M+1)−1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][N:13]([O:16]C2CCCCO2)[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]([N:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2)[CH2:32][C:33]2[S:34][CH:35]=[CH:36][N:37]=2)[N:3]=1>O.C(O)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]([N:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2)[CH2:32][C:33]2[S:34][CH:35]=[CH:36][N:37]=2)[N:3]=1
Reactant: CN1CCN(N(Cc2nccs2)c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OC3CCCCO3)c2F)CC1
Solvent: CC(=O)O
Solvent: O
Product: CN1CCN(N(Cc2nccs2)c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(O)C=O)c2F)CC1
Reaction time: 8 h
Yield: 32.8 %

Procedure:
[(2R)-3-(2-{2-Chloro-5-fluoro-6-[(4-methyl-1-piperazinyl)(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (0.1688 g, 0.258 mmol) was taken up in water (2 mL) and acetic acid (8 mL). The reaction was left to stir overnight. Purification by RP-HPLC provided [(2R)-3-(2-{2-chloro-5-fluoro-6-[(4-methyl-1-piperazinyl)(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide as a beige solid (0.0483 g, 25%). LCMS: (M+H)+=571.2.
Reaction SMILES: C1(C[O:8][C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([O:19][C@H:20]3[CH2:24][CH2:23][O:22][CH2:21]3)[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])C=CC=CC=1.C1COCC1>[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:19][C@H:20]2[CH2:24][CH2:23][O:22][CH2:21]2)[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(O[C@H]2CCOC2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1cc(O)cc(O[C@H]2CCOC2)c1
Reaction time: 20 h
Yield: 96.6 %

Procedure:
10% Palladium on carbon (1.2 g) was added to a mixture of methyl 3-[(phenylmethyl)oxy]-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate (12 g, 36.54 mmol), in ethanol (80 mL) and THF (80 mL) in an argon filled flask. The flask was evacuated and the atmosphere replaced with hydrogen. The mixture was stirred for 20 hours, filtered through Celite® and the solvent removed in vacuo to give the desired compound as a white solid (8.41 g).