Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([CH3:25])=[CH:22][CH:23]=2)[N:18]=[C:17]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[OH:32])[N:16]=1.C(N(CC)CC)C>C(Cl)Cl>[OH:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:17]1[N:16]=[C:15]([N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)[C:24]2[C:19](=[CH:20][C:21]([CH3:25])=[CH:22][CH:23]=2)[N:18]=1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CC[C@H](NC(=O)OC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
tert-Butyl(S)-pyrrolidin-3-ylcarbamate (245 mg, 1.31 mmol) was dissolved in 1.8 mL of anhydrous CH2Cl2 and cooled to 0° C. 2-(4-Chloro-7-methylquinazolin-2-yl)phenol (300 mg, 1.1 mmol) dissolved in 1.8 mL of anhydrous CH2Cl2 was added dropwise to the mixture followed by triethylamine (134 mg, 184 μL, 1.32 mmol). The reaction was allowed to warm to room temperature and was stirred overnight. Purification via silica gel chromatography using 10-100% ethyl acetate/hexanes gave tert-butyl(S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate. LC/MS: m/z 421.0 (M+H)+ at 2.84 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[CH2:14][C:15](O)=[O:16].C(Cl)Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[F:3][C:4]1[C:5]([CH2:14][CH2:15][OH:16])=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=C(O)Cc1c([N+](=O)[O-])ccc(F)c1F
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)c(F)c1CCO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 108.8 %

Procedure:
19.8 g of the sodium borohydride was added to 60 ml of tetrahydrofuran, and, while the mixed solution was cooled on ice below 10° C., a solution obtained by dissolving 60 g (276 mmol) of 2,3-difluoro-6-nitrophenylacetic acid in 20 ml of tetrahydrofuran was dropped to the mixed solution through I hour. Then, 120 ml of tetrahydrofuran solution dissolving 90 ml of boron trifluoride ethyl ether complex was dropped to the reaction solution through 1 hour below 10° C. The solution was stirred for 15 minutes under cooled on ice and for 20 minutes at room temperature. To 1.5 1 of methylene chloride, 1.2 1 of ice/water, 84 g of sodium hydrogen carbonate was added, and, while well stirring this solution, the reaction solution was slowly added to this solution. The obtained solution was stirred overnight. The organic layer was separated from the solution, and after drying over magnesium sulfate, solvent was removed by distillation to obtain 61 g of oily 3,4-difluoro-2-(2-hydroxyethyl)nitrobenzene. To this oily material, 58 ml (414 mmol) of triethylamine and 500 ml of methylene chloride were added, and while cooling on ice, 100 ml of methylene chloride solution containing 19 ml (331 mmol) of acetyl chloride was dropped to the solution. After stirring for 1 hour and 30 minutes, 5 ml of acetyl chloride was further added to the mixture, and after 30 minutes, the mixture was washed with 200 ml of water twice. After drying over magnesium sulfate, the solvent was removed by distillation to obtain 76.5 g of 2-(2-acetoxyethyl)-3,4-difluoronitrobenzene.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9]C=O)=[C:4]([Cl:12])[N:3]=1.C(O)C>Cl>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[C:4]([Cl:12])[N:3]=1
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Agent: Cl
Solvent: CCO
Product: Nc1nc(Cl)c(N)c(Cl)n1
Yield: 64.6 %

Procedure:
N-(2-Amino-4,6-dichloro-5-pyrimidinyl)formamide (Example 3, 500 mg, 2.42 mmol) was dissolved in 0.1N hydrochloric acid (5 ml, 2.5 mequiv) and ethanol (7 mL) at reflux. The solution was refluxed for 5 hours. Volatiles were removed in vacuo. The residue was partitioned between water (30 mL) adjusted to pH 8 with dilute ammonium hydroxide and ethyl acetate (75 mL). The ethyl acetate layer was dried (sodium sulfate). Evaporation of the ethyl acetate left pink solid (0.40 g). Recrystallization of the solid from 95% ethanol gave the title compound (IV) as light pink needles (280 mg, 65%); darkens and shrinks to black solid above 185° C., does not become fluid below 300° C.; 1H-N (DMSO-d6) and mass spectra identical to those described in Example 4.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=1)=[O:9])([CH3:4])[CH3:3].[H][H]>C(O)C.C1COCC1.[Pd]>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1)=[O:9])([CH3:1])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(C(=O)NCc2cccc([N+](=O)[O-])c2)cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)NCc2cccc(N)c2)cc(C(C)(C)C)c1O
Yield: 42.8 %

Procedure:
In a 250 ml Parr flask, 2.40 g (6.2 mmoles) of 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(3-nitrophenyl)methyl]-benzamide is dissolved in 45 ml of an absolute ethanol/THF mixture (1/2) in the presence of 10% Pd/C. The mixture is agitated under 20 PSI of hydrogen, at 30° C., for three hours. After filtration on celite, the filtrate is concentrated to dryness and the residue is purified on a silica column (eluant: heptane/ethyl acetate: 60/40). The pure fractions are collected and concentrated under reduced pressure to produce 0.94 g (45%) of a white powder. Melting point: 171-172° C.
Reaction SMILES: [CH2:1]([C:3]1([CH2:15][CH3:16])[O:8][C:7](=[O:9])[NH:6][C:5]2[CH:10]=[CH:11][C:12](I)=[CH:13][C:4]1=2)[CH3:2].[N+:17]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18]>O>[CH2:1]([C:3]1([CH2:15][CH3:16])[O:8][C:7](=[O:9])[NH:6][C:5]2[CH:10]=[CH:11][C:12]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:17]([O-:19])=[O:18])[CH:25]=3)=[CH:13][C:4]1=2)[CH3:2]
Reactant: CCC1(CC)OC(=O)Nc2ccc(I)cc21
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Solvent: O
Product: CCC1(CC)OC(=O)Nc2ccc(-c3cccc([N+](=O)[O-])c3)cc21

Procedure:
Prepared from 4,4-diethyl-6-iodo-1,4-dihydrobenzo[d][1,3]oxazin-2-one and 3-nitrophenyl boronic acid according to Procedure A. Off-white solid: mp 193-194° C. 1H-NMR (CDCl3) δ 9.19 (s, 1H, D2O exchangeable), 8.38 (t, 1H, J=1.9 Hz), 8.20 (m, 1H), 7.83 (m, 1H), 7.61 (t, 1H, J=8.0 Hz), 7.50 (dd, 1H, J=8.2, 2.0 Hz), 7.23 (d, 1H, J=1.7 Hz), 6.99 (d, 1H, J=8.3 Hz), 2.09 (q, 4H, J=7.4 Hz), 0.96 (t, 6H, J=8.3 Hz); MS (EI) m/z 325 ([M−H]−, 100%). Anal. Calc. For C18H18N2O4.0.3 H2O: C, 65.17; H, 5.65; N, 8.44. Found: C, 65.31; H, 5.60; N, 8.10.
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]([C:9]1[N:14]=[C:13]([NH:15]C=O)[CH:12]=[CH:11][N:10]=1)=[N:6][O:7][CH3:8])C.[OH-].[K+].Cl>C(O)C>[NH2:15][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([C:5](=[N:6][O:7][CH3:8])[C:4]([OH:18])=[O:3])[N:14]=1
Reactant: CCOC(=O)C(=NOC)c1nccc(NC=O)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CON=C(C(=O)O)c1nccc(N)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 1.7 %

Procedure:
To a solution of ethyl 2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (30.8 g) in ethanol (308 ml) was added 1N alcoholic solution (550 ml) of potassium hydroxide and the mixture was stirred for 3.5 hours at ambient temperature. The reaction mixture was cooled in an ice bath and adjusted to pH 3 with concentrated hydrochloric acid (53 ml). The resultant solid was filtered and washed with ethanol (60 ml), water (100 ml), acetone (100 ml) to give a crude product (28.8 g). This product (1 g) was recrystallized from water (10 ml) to give a purified product of 2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid (dihydrate, syn isomer) (0.4 g), mp. 178°-183° C. (dec.). The following compound was obtained according to the similar manner to that of Preparation 21-(1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=1.C(N(CC)CC)C.Cl.[CH:39]12[CH2:44][CH:43]1[CH2:42][NH:41][CH2:40]2.Cl>C1COCC1.CO>[ClH:1].[CH:39]12[CH2:44][CH:43]1[CH2:42][N:41]([C:9]1[N:8]=[C:7]([NH:6][CH2:5][C:4]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:13]([NH:15][CH2:16][C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[O:14])=[CH:11][N:10]=1)[CH2:40]2
Reactant: C1NCC2CC12
Reactant: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)NCc2ncccn2)cc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NCc2ncccn2)cc1Cl
Yield: 72.4 %

Procedure:
In absolute anhydrous THF (10 mL) was dissolved 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylsulfinyl)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide (100 mg, 0.22 mmol). Triethylamine (0.22 g, 2.2 mmol) was added dropwisely, and 3-azabicyclo[3.1.0]hexan hydrochloride salt (42 mg, 0.35 mmol) was added. The reaction mixture was heated to reflux overnight. The solvent was removed by rotary evaporation, and water was added, followed by extraction with DCM. The organic phase was dried over sodium sulfate and purified by silica gel column chromatography (DCM/methanol=20/1 to 10/1) to give a solid. The solid was dissolved in methanol (0.05 mL), and hydrochloric acid (1 mol/L) was added. The solvent was removed to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide hydrochloride (40 mg, 39% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]2[C:8](=[O:15])[O:9][C:10]([O:12][CH2:13][CH3:14])=[N:11][C:6]=2[CH:5]=1)([O-])=O.C1CCCCC=1>C1C=CC=CC=1.[Pd]>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]2[C:8](=[O:15])[O:9][C:10]([O:12][CH2:13][CH3:14])=[N:11][C:6]=2[CH:5]=1
Reactant: CCOc1nc2cc([N+](=O)[O-])ccc2c(=O)o1
Agent: [Pd]
Solvent: c1ccccc1
Solvent: C1=CCCCC1
Product: CCOc1nc2cc(N)ccc2c(=O)o1
Yield: 47 %

Procedure:
7-Nitro-2-ethoxy-4H-3,1-benzoxazin-4-one (1 gm, 4.2 m mol.), 10% Pd-C (1 gm), and cyclohexene (2.5 ml) were refluxed in dry benzene (50 ml) under anhydrous conditions for 3 hours. The hot reaction mixture was filtered immediately through celite and the catalyst on celite was washed with hot benzene (25 ml). The combined filtrate was evaporated to dryness under reduced pressure. The residue was stirred in anhydrous ether (30 ml) to give 410 mg (47%) of the title compound, 7-amino-2-ethoxy-4H-3,1-benzoxazin-4-one, as a pale yellow powder, after filtration. The product can be further purified by chromatography on silica gel column, if necessary (silica gel 60; EtOAc:pet. ether=1:2); m.p. 185°-187° C.; IR (KBr): νmax 3425, 3330 cm-1 (NH2), 1740 cm-1 (C=O), 1640 cm-1 (C=N); N'NMR (CDCl3): δ 1.43 ppm (t, J=7.1 Hz, 3H, OCH2CH3), 4.30 ppm (b, 2H, NH2), 4.75 ppm (q, J=7.1 Hz, 2H, OCH2CH3), 6.5-7.98 ppm (m, 3H, aromatic protons).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]([CH2:20][OH:21])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1.O>CN(C)C=O>[N+:31]([C:28]1[CH:29]=[CH:30][C:25]([O:21][CH2:20][CH:9]2[CH2:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11][N:10]2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:26][CH:27]=1)([O-:33])=[O:32]
Reactant: OCC1CN(c2ccccc2)CCN1Cc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCC2CN(c3ccccc3)CCN2Cc2ccccc2)cc1
Reaction time: 20 h

Procedure:
Suspend 4-phenyl-1-(phenylmethyl)-2-piperazinemethanol (7.8 g, 27.6 mmol) in dimethylformamide under nitrogen and add 60% sodium hydride (1.22 g, 30.4 mmol). Stir for 20 h as solid slowly dissolves. Add 1-fluoro-4-nitrobenzene (4.29 g, 30.4 mmol) and stir at room temperature. Monitor the progress of the reaction by thin-layer chromatography. Upon completion of the reaction, add water (100 mL) to the reaction mixture and extract with methylene chloride (2×100 mL). Remove the solvent in vacuo and recrystallize the residue from ethyl acetate/hexanes (1/1) (80 mL) to provide the title compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:4](=[CH:5][C:6](=[O:29])[C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:3]1.N1C(C)=CC=CC=1C.N#N.FC(F)(F)S(O[Si:46]([CH:53]([CH3:55])[CH3:54])([CH:50]([CH3:52])[CH3:51])[CH:47]([CH3:49])[CH3:48])(=O)=O>C(Cl)Cl>[O:29]=[C:6]1[CH:5]=[C:4]2[C@:24]([CH3:27])([CH2:25][CH2:26][C@H:2]([O:1][Si:46]([CH:53]([CH3:55])[CH3:54])([CH:50]([CH3:52])[CH3:51])[CH:47]([CH3:49])[CH3:48])[CH2:3]2)[C@@H:23]2[C@@H:7]1[C@H:8]1[C@:20]([CH3:28])([CH2:21][CH2:22]2)[C@@H:11]([C@H:12]([CH3:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:9]1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: N#N
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C=C4C[C@@H](O[Si](C(C)C)(C(C)C)C(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
To a solution of methyl 3β-hydroxy-7-oxochol-5-en-24-oate (2) (5.02 g, 12.5 mmoles) and 2,6-lutidine (3.32 ml, 28.5 mmoles) in CH2Cl2 (23 ml) cooled in an ice bath in a N2 atmosphere was added dropwise with magnetic stirring triisopropylsilyl trifluoromethanesulfonate (4.56 g, 17 mmoles). After 2 hrs, the reaction was diluted with CH2Cl2 (150 ml). It was then washed with cold 2N HCI, washed twice with H2O and then with saturated brine before drying with MgSO4. Evaporation in vacuo and purification of the residue by flash chromatography on silica gel with hexane-EtOAc (10:1) gave 5.88 g of 3 as a colorless syrup. NMR (CDCl3): δ 0.67 (s, 3H, 18-Me); 0.93 (d, 3H, 20-Me); 1.06 (s, 18H, TIPS Me); 1.19 (s, 3H, 19-Me); 3.66 (s, 3H, CO2Me); 3.68 (m, 1H, 3-H); 5.66 (s, 1H, 6-H).
Reaction SMILES: [IH:1].[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5](Cl)[N:4]=1>O>[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5]([I:1])[N:4]=1
Reactant: I
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Solvent: O
Product: Nc1nc(I)c2[nH]cnc2n1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Charge 57% Hydriodic acid (10.90 kg) into a suitable vessel under nitrogen and then the solution was cooled to 0 to 10° C. Then 2-amino-6-chloropurine (0.8 kg) was charged into the solution at about 15° C. After 2 h for the completion, water (8 kg) was slowly charged to the reaction mixture at r.t. and stirred for about 0.5 h. The yellow precipitate was filtered and washed with water. The wet cake was transferred to a suitable vessel, and water (2.0 kg) and 20% NaOH aqueous solution (0.4 kg) were slowly charged to dissolve the solids at r.t. Then THF (2.14 kg) was charged into the solution and 10% HOAc (4.8 kg) was slowly charged into the solution at about 35° C. to observe slurry mixture. The resultant slurry was stirred filtered and washed with acetone (3.8). The wet cake was dried under vacuum at 70° C. to afford SPT1255C1 (1.14 kg). Yield: 90-98%. 1H NMR (400 MHz, DMSO-d6) 6.65 (s, 2H, NH2), 8.04 (s, 1H, H8)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12](=O)[NH:11][C@H:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][CH:21]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(Cc2ccccc2)C(=O)[C@@H](Cc2ccc(Br)cc2)N1
Solvent: C1CCOC1
Product: Brc1ccc(C[C@@H]2CN(Cc3ccccc3)CCN2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To (R)-1-benzyl-3-(4-bromo-benzyl)-piperazine-2,5-dione (0.5 g, 1.34 mmol) in THF (10 mL) was added 2M BH3SMe2 (2.68 mL, 5.36 mmol). The mixture was stirred in RT under argon for 4 days; more 2M BH3SMe2 (2.68 mL, 5.36 mmol) was added and stirred for 3 days. Reaction mixture was quenched with EtOH (3 mL) and removed the solvent in rotavap, added EtOH (5 mL) and stirred at 70° C. for 2 hr and concentrated to give colorless oil as a crude product. MS (ESI) 345 (M+H).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)CCCOc1ccc2c(c1)CCN(C1CCC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCOc1ccc2c(c1)CCN(C1CCC1)CC2
Temperature: 25 °C

Procedure:
Ethyl 4-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]butanoate (E167a) (2.2 g, 6.6 mmol) was dissolved in methanol (40 ml) and treated with 2N sodium hydroxide (10.0 ml). After stirring at reflux for 1 hour, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude mixture was applied to a SCX ion exchange cartridge (Varian bond-elute) and washed with water and then methanol. The organic fractions were reduced in vacuo to afford the title compound (E283); MS (ES+) m/e 304 [M+H]+.
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=[O:8])=[O:2].O>S(=O)(=O)(O)O.CO>[CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:2]
Reactant: COC(=O)CCCCC=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: O=CCCCCC(=O)O
Yield: 56.9 %

Procedure:
36 g of methyl 5-formylvalerate, 90 g of water and 0.5 g of sulfuric acid were refluxed for 3.5 hours, the methanol formed being distilled off constantly. Fractional distillation under reduced pressure gave 18.5 g (yield 57% of theory) of 5-formylvaleric acid of boiling point 106°-112° C./1 mbar. 13C NMR spectrum in D-chloroform: chemical shifts relative to tetramethyl silane as internal standard=21, 24, 34 and 44 ppm (4 methylene groups), 178 ppm (formyl group) and 203 ppm (carboxyl group).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7](=[O:11])[O:8][C:9](=O)[C:2]=12.[BH4-].[Na+].C(O)(=O)C>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7](=[O:11])[O:8][CH2:9][C:2]=12
Reactant: O=C1OC(=O)c2ncccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C1OCc2ncccc21
Temperature: 15 °C
Reaction time: 4 h
Yield: 13.3 %

Procedure:
A solution of furo[3,4-b]pyridine-5,7-dione (3.0 g, 20 mmol) in THF (20 mL) is treated with sodium borohydride (0.75 g, 20 mmol). The reaction mixture is placed under an argon atmosphere and the temperature is maintained at 15° C. with a water bath. Acetic acid (2.4 g, 39 mmol) is added dropwise at 15° C. The reaction mixture is stirred for 4 h and is then concentrated on a rotary evaporator. The crude residue is then treated with acetic acid (8 mL) and acetic anhydride (8.0 mL) and heated at 100° C. overnight. The reaction mixture is cooled and concentrated. The residue is purified by chromatography (silica gel, gradient elution 30% EtOAc/hexane to 50% EtOAc/hexane). The product containing fractions are concentrated to give the title compound as a white solid (360 mg, 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[CH:17]([OH:19])[CH3:18].Cl[C:21]1[CH:22]=[CH:23][C:24]2[N:25]([C:27]([CH2:30][NH:31][C:32]3[C:41]4[C:36](=[CH:37][C:38]([O:42][CH3:43])=[CH:39][N:40]=4)[N:35]=[CH:34][CH:33]=3)=[N:28][N:29]=2)[N:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[Cl:1][C:2]1[CH:7]=[C:6]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([CH2:30][NH:31][C:32]4[C:41]5[C:36](=[CH:37][C:38]([O:42][CH3:43])=[CH:39][N:40]=5)[N:35]=[CH:34][CH:33]=4)=[N:28][N:29]=3)[N:26]=2)[CH:5]=[CH:4][C:3]=1[CH:17]([OH:19])[CH3:18]
Reactant: CC(O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Reactant: COc1cnc2c(NCc3nnc4ccc(Cl)nn34)ccnc2c1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cnc2c(NCc3nnc4ccc(-c5ccc(C(C)O)c(Cl)c5)nn34)ccnc2c1
Temperature: 100 °C

Procedure:
A suspension of 1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanol (228 mg, 807 μmol), N-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine (197 mg, 576 μmol), dichloro[1,1′bis(diphenylphoshino)ferrocene]palladium(ii) dichloromethane adduct (127 mg, 173 μmol), cesium carbonate (751 mg, 2306 μmol) in dioxane (3 mL) and water (0.6 mL) was sparged with argon for 5 min then heated to 100° C. for 6 h. Reaction cooled then partitioned between 9:1 CHCl3/IPA (20 mL) and 1M NaOH (15 mL). Aqueous further extracted with 9:1 CHCl3/IPA (2×10 mL). The combined organics dried over MgSO4. concentrated, then purified on 40 g silica eluting with an isocratic 7% 2M NH3 in MeOH/DCM. Product further purified prep HPLC eluting with water/ACN (0.1% TFA). After collected fractions were reduced to a clear the residue was dissolved in 1:1 ACN/water and pH adjusted to 9 with 1M NaOH (3-4 drops). Resulting solid collected by filteration and solid washed with water (2 mL). MS (ESI pos. ion) m/z: 462 (MH+). Calc'd exact mass for C23H20ClN7O2: 461.
Reaction SMILES: S(=O)(=O)=O.[BrH:5].Br.[CH3:7][C:8]1[C:9]([CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])=[N:10][CH:11]=[CH:12][CH:13]=1.Br>FC(Cl)(F)C(Cl)(Cl)F.ClCCl>[Br:5][C:12]1[CH:13]=[C:8]([CH3:7])[C:9]([CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])=[N:10][CH:11]=1
Reactant: Br
Reactant: Cc1cccnc1CCCCN
Agent: O=S(=O)=O
Solvent: ClCCl
Solvent: FC(F)(Cl)C(F)(Cl)Cl
Product: Cc1cc(Br)cnc1CCCCN
Yield: 51.5 %

Procedure:
A solution of sulphur trioxide (150 ml) in 1,1,2-trifluorotrichloroethane (350 ml) was added over ca 30 min. to a suspension of 4-(3-methyl-2-pyridyl)butylamine dihydrobromide (17 g) [prepared by passing hydrogen bromide gas through a solution of the amine in dichloromethane] in 1,1,2-trifluorotrichloroethane (100 ml) and the mixture was heated under reflux for ca 16 hr. The solvent was removed by distillation and unbrominated starting material was removed by acetylation as described in Example 1(b) to yield 4-(5-bromo-3-methyl-2-pyridyl)-butylamine (6.53 g) as an oil.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][CH2:2][C:3]([C:10]1[CH:11]=[CH:12][C:7]([F:6])=[CH:8][C:9]=1[F:13])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Fc1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCl)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.5 %

Procedure:
Chloroacetyl chloride (113 g, 1.0 mole) was added dropwise to a stirred mixture of 1,3-difluorobenzene (114 g, 1.0 mole) and anhydrous aluminum chloride (146.6 g, 1.1 mole) at room temperature (20° C.). The mixture was stirred for a further five hours at 50°-55° C. Methylene chloride (48.5 ml) was added slowly as the mixture was allowed to cool to room temperature. The methylene chloride layer was separated, washed with water (2×320 ml) and the solvent removed by distillation at reduced pressure leaving a pale yellow solid (180 g).